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Horses

Lymphoma

Lymphoma is the general term denoting malignant transformation of lymphoid cells, but it is often used in equine medicine in place of the term lymphosarcoma, which is specifically the malignant transformation of lymphoid cells into solid (or sarcomatous) tumors. Lymphoid leukemia (or “true” leukemia) denotes the malignant transformation of lymphoid cells within the bone marrow. Both forms of lymphoid neoplasia may be accompanied by circulating neoplastic cells.

Lymphoma is one of the most common internal neoplasms of the horse, but the prevalence of lymphoma in horse populations is relatively low — ranging from 0.002% to 0.05%, based on United States abattoir surveys and from 0.2% to 3.0%, based on necropsy surveys. No established risk factors for equine lymphoma exist, and the etiology is unknown. A breed or sex predilection does not appear to be a factor, and the majority of patients are between 4 and 10 years of age. However, individual cases of lymphoma in a fetus and in horses younger than 1 year or older than 20 years of age have been reported.

Clinical Signs of Lymphoma

A diverse spectrum of clinical signs has been associated with lymphoma. The signs and progression of disease relate to the sites of tumor involvement and are not specific to lymphoma. The most common clinical signs are decreased appetite, depression, weight loss, fever, lymphadenopathy, and dependent edema. In a study of 20 cases of lymphoma confirmed by histology, the clinical findings included — in descending order of frequency — weight loss, fever, peripheral lymphadenopathy, abdominal mass, upper or lower respiratory signs, ocular signs, colic, and diarrhea.

Numerous lymphoma tumor locations have been reported and include peripheral and internal lymph nodes, spleen, liver, kidney, intestine, heart, lung, nasopharynx, eye and adnexa, skeletal muscle, skin, reproductive organs, and central and peripheral nervous system. Four anatomic forms of lymphoma are well described: multi-centric — 50%; alimentary — 19%; mediastinal — 6%; and extranodal — 25%. Combinations of these four classic forms of lymphoma occur in approximately 50% of cases.

Multicentric, or generalized, lymphoma is the most commonly reported form and involves multiple peripheral and internal lymph nodes and other organs. The most commonly involved peripheral lymph nodes are the mandibular, caudal cervical, retropharyngeal, and superficial inguinal. The most commonly involved abdominal lymph nodes are the mesenteric, colonic, and deep iliac. Splenomegaly occurs in 25% of the cases, and hepatomegaly or perirenal masses are found infrequently. The multiple sites of involvement probably represent metastasis via the blood and lymphatic circulatory systems. Notably, this is the most common form to be associated with circulating neoplastic lymphocytes, referred to as the “leukemic phase” of lymphoma. Clinical signs reflect dysfunction of affected organs, and the course of the disease is typically rapid once signs become evident.

The alimentary type is the most acute form of lymphoma. It causes rapid deterioration and involves the small intestine and associated mesenteric lymph nodes. Distant metastasis appears slow to develop. Alimentary lymphoma is commonly detected in horses from 2 to 5 years of age. Signs are considered nonspecific and include weight loss, decreased appetite, fever, dependent edema, and diarrhea or abdominal pain of varying severity and duration. Affected horses may have a blunted oral glucose tolerance response and reduced serum albumin concentration, which suggests intestinal malabsorption. Immune-mediated hemolytic anemia and hyperglobulinemia have also been reported to accompany this condition.

Lymphoma of the mediastinal lymph nodes typically occurs in adult horses. The most common clinical signs are referable to compression of intrathoracic structures and include pleural effusion, tachypnea, dyspnea, and dependent edema. Less common findings include a persistent cough, tachycardia, jugular vein distention, and forelimb lameness. Neoplastic cells may be observed in the pleural fluid and the paraneoplastic syndrome of hypercalcemia has been associated with this form of lymphoma.

The most common extranodal sites of tumor development are — in descending order — the skin, upper respiratory tract, eyes or adnexa, and central nervous system. Lymphoma of the skin — the cutaneous form — is the least common form of lymphoma in horses, although it represented the most common form in one report. Tumors are readily identified as nonpainful, dermal, or subdermal masses that are firm and well circumscribed and may be haired, nonhaired, or ulcerated. Horses may have a solitary mass or multiple masses that range in size from a few millimeters up to several centimeters in diameter. The most commonly affected regions include the shoulder, perineum, axilla, and trunk. Clinical signs are referable to internal metastasis and may not be present during the initial examination. Tumors may develop rapidly or slowly and may spontaneously regress and reappear. However, cutaneous lymphoma generally manifests as a slowly progressive extension of an internal malignancy and involves multiple or single, nonulcerated dermal or subdermal masses of neoplastic lymphocytes (i.e., a sarcomatous form). The most rare form of cutaneous lymphoma is termed mycosis fungoides, which differs from the sarcomatous form in that it represents a diffuse infiltration with neoplastic lymphocytes of the dermis or subdermis. This rare form of cutaneous lymphoma is also chronic and progressive and, without appropriate histologic examination of the skin, may be easily mistaken for other diffuse non-neoplastic dermatoses.

Extranodal lymphoma of the eye or adnexa most commonly involves the palpebral conjunctiva and eyelids and may be associated with exophthalmus, exposure keratitis, uveitis, chemosis, and conjunctivitis. Lymphoma has been occasionally reported to involve the upper respiratory tract, thus causing signs of upper airway obstruction with and without nasal discharge. A single recent report involved tumor infiltration of the tongue. Reports of peripheral nerve sheath and epidural infiltration also exist and may be considered rare differentials for lameness and ataxia, respectively. Metastatic periarticular involvement that causes lameness has also recently been reported.

Diagnosis of Lymphoma

Diagnosis of lymphoma can be difficult, and ante mortem confirmation occurs in less than 60% of cases. The key to ante mortem diagnosis is a persistent diagnostician. Neoplasia must always be considered in an adult horse with recurrent inflammatory and febrile episodes that are unresponsive to antimicrobial therapy. The physical examination should include transrectal abdominal palpation and careful thoracic auscultation and percussion. However, the definitive diagnosis of lymphoma requires the observation of neoplastic cells in aspirates or biopsy specimens of lymph nodes and other masses or in centesis samples of body cavity fluids, bone marrow aspirates, or peripheral blood.

Cytologic observations consistent with neoplastic transformation of lymphoid cells include mitotic figures, prominent nucleoli, and binucleation, but evaluation of tissue architecture is equally important in the detection of neoplastic transformation and can only be obtained with biopsy. The observation of neoplastic lymphocytes in the peripheral blood is uncommon and may be a late manifestation of lymphoma in the horse, thus indicating dissemination and bone marrow involvement. When neoplastic cells are observed in the peripheral blood, the leukemia is characterized as subleukemic or leukemic if the total white blood cell count is normal or increased, respectively. Lymphoma is aleukemic when neoplastic cells are not present in peripheral blood. Furthermore, the leukemia may be characterized by the appearance of the transformed cells: acute or lymphoblastic leukemia if immature; chronic or lymphocytic leukemia if mature.

Since publication of the last edition of this text, significant strides have been made in classifying lymphomas using antibodies to cell surface antigens (). Probably the greatest anticipated utility of immunophenotyping equine lymphomas is in the prognostication and choice of anti-neoplastic agent(s), as has been realized in human and small animal veterinary medicine. In addition, immunophenotyping should aid in determining the cell lineage of more poorly differentiated equine tumors, in the correct classification as T cell versus B cell lymphomas, in recognizing phenotypic-specific distri-bution patterns, and in determining the apparent proliferation rates of lymphoid tumors. For example, immunophenotyping has lead to the discovery of a previously unrecognized form of equine lymphoma — the T cell-rich, B cell lymphoma, a form that appears to be prone to subcutaneous tumors. This phe-notype may be a major form of lymphoma in horses and represents 11 out of 24 (or 46%) B cell lymphoma cases and about 33% of all lymphomas.

Paraneoplastic syndromes are the indirect systemic effects of cancer and may have profound consequences on disease expression. The cause of these syndromes is often unknown but generally thought to be mediated by soluble substances released from the neoplastic cells. A few of the paraneoplastic syndromes that may be relevant to horse cancer patients include cachexia, hypercalcemia, hypoglycemia, hypertrophic osteopathy, anemia, disseminated intravascular coagulation, leukocytosis, hyperproteinemia, fever, and various neurologic abnormalities. Adjunct therapy aimed at diminishing paraneoplastic syndromes may have a profound effect on patient comfort and clinical course ().

Anemia is a common finding and occurs in 30% to 50% of horses with lymphoma. Typically, the anemia is mild, normochromic, and normocytic and reflects bone marrow suppression. Immune-mediated hemolytic anemia may be suspected based on a positive direct Coombs’ test. Thrombocytopenia can be profound and has resulted in bleeding diathesis. The number of leukocytes and lymphocytes in the peripheral blood is often within normal limits. With leukocytosis, mature neutrophilia and increased serum fibrinogen activity are most commonly observed and indicate the presence of inflammation. Leukopenia and pancytopenia are uncommon findings.

Common alterations of plasma proteins include increased fibrinogen, total protein, and globulin concentrations. Gammopathy may reflect chronic inflammation but may also reflect neoplastic clonal expansion of B cell lymphocytes (see later section on plasma cell myeloma). Hypoalbuminemia may occur in response to a profound gammopathy or from gastrointestinal loss and rarely from end-stage liver failure as a consequence of hepatic involvement. Both selective (immunoglobulin M [IgM]) and generalized immunoglobulin deficiencies have been occasionally associated with lymphoid neoplasia in horses. Biochemical alterations that may be seen include hypercalcemia, increased liver enzyme activity, and azotemia.

Prognosis and Treatment of Lymphoma

In the majority of patients, rapid deterioration follows the onset of clinical signs associated with internal disease. Horses with lymphoma limited to cutaneous involvement, however, have survived for several years with and without chemotherapeutic intervention. Immunosuppressive glucocorticoid therapy (0.02-0.2 mg/kg dexamethasone [Azium] IV, IM, or PO q24h) may be palliative for steroid-responsive malignancies and may also suppress immune-mediated sequelae, including hemolytic anemia and thrombocytopenia. Cutaneous lesions may regress in 2 to 6 weeks, at which time the dose may be gradually reduced. If glucocorticoid administration is tapered too quickly or is discontinued, more aggressive lymphoid tumors may reappear. Signs of acute laminitis have been observed during glucocorticoid therapy in equine cancer patients and were the grounds for discontinuing therapy.

Few reports discuss use of a specific antineoplastic agent in the treatment of equine lymphoma. The expense and possible toxicity of chemotherapy in the horse are the most common reasons cited for nontreatment. However, the use of a multiple-agent induction protocol in horses with lymphoma has been reported () and is summarized here. Cytosine arabinoside (Cytosar-U; 200-300 mg/m2 SQ or IM) is given once every 1 or 2 weeks. Chlorambucil (Leukeran; 20 mg/m2 PO) is given once every 2 weeks. Prednisone (Deltasone; 1.1-2.2 mg/kg PO) is given every other day throughout the treatment period. Alternatively, cyclophosphamide (Cytoxan; 200 mg/m2 IV given once every 2-3 weeks) is substituted for chlorambucil. Antineoplastic agents are given on alternating weeks but have been given on the same day without apparent consequence. Response to induction therapy should occur within 2 to 4 weeks, but if a response is not observed, adding vincristine (Oncovin; 0.5 mg/m2 IV once a week) to the induction protocol has been recommended.

With remission, the induction protocol is used for a total of 2 to 3 months and then is switched to a maintenance protocol. The first cycle of maintenance therapy increases the treatment interval for each antineoplastic agent by one week; prednisone, however, is given for the duration of therapy and is gradually reduced in dose. After 2 to 3 months on the first cycle, if the horse is still in remission, the second cycle is begun, adding one more week to the treatment intervals of each agent. Several cycles of maintenance therapy can be given; however, most horses in remission are treated for a total of 6 to 8 months.

Other reported protocols include single-agent use of l-asparaginase (Elspar; 10,000-40,000 IU/m2 IM once every 2-3 weeks) or cyclophosphamide (as described previously) and combinations of either cytosine arabinoside or cyclophosphamide with prednisone.

Unfortunately, the likelihood that remission rates and survival times for specific chemotherapeutic protocols and well characterized lymphoid neoplasms in horses (based on a suitably large number of cases) will soon be available is not high. Nevertheless, anecdotal reports suggest remission is possible in some cases of equine lymphoma.

Categories
Horses

Treatment of Thrombocytopenia

No treatment for primary bone marrow megakaryocyte hypoplasia exists. (Treatment for DIC is discussed in: “Hemostatic Disorders.”) Treatment for IMTP is similar to immune-mediated hemolytic anemia. Medication withdrawal should be implemented with adjustment of antibiotic or drug therapy to a molecularly dissimilar agent. Attempts should be made to identify and treat potential underlying diseases. In life-threatening cases, whole blood or platelet rich plasma transfusion is indicated. Dexamethasone (0.05-0.1 mg/kg IV q24h) is generally indicated to decrease Fc binding, phagocytic removal, and antibody production. When the platelet count is greater than 100,000/μl, the dose of steroid should be reduced 0.01 mg/kg/day with close monitoring for disease recurrence. Prednisolone (1 mg/kg IM ql2h) may be attempted, but not all horses respond favorably to this protocol. Steroids should not be discontinued until the platelet count has been within normal limits for at least 5 days. If steroid therapy has been implemented for greater than 2 weeks, every-other-day administration should be implemented in the tapering dose protocol. Splenectomy has been reported in humans and dogs, but long-term outcome has not been reported in the horse. The vinca alkaloid, vincristine at a dose of 0.01 to 0.025 mg/kg IV weekly, has been used with steroid therapy to increase the peripheral platelet count with some success. Because vincristine has immunosuppressive activities, neutropenia may develop; this is an indication for drug discontinuation. Although anecdotal evidence suggests some improvement of thrombocytopenia with the use of azothiaprine (3-5 mg/kg PO q24h) and cyclophosphamide (300 mg/m2 body surface area), no data are currently available to support their routine use. Complications associated with immunosuppressive therapies may include laminitis and profound immunosuppression that lead to secondary sepsis. Concentrated immunoglobulin therapy has been used for human patients with profound IMTP. The mechanism is multifaceted; however, blocked Fc receptor binding, steric hinderance of immune complex adherence, enhanced T lymphocyte suppressor activity, and reduced B lymphocyte function are proposed actions of excessive Ig administration. The recommended dose is 200 to 1000 mg IgG/kg per day for 2 to 5 days or approximately 6 L plasma per dose for a 450-kg horse. Although equine plasma transfusion carries a reduced risk of adverse effects when compared with glucocorticoids, the cost associated with treatment may be prohibitive. A less expensive alternative to equine plasma is lyophilized equine IgG (Lyphomune, Diagnon Corporation; Rockville, Md.); however, its use in IMTP has been limited in horses.

Whole blood transfusion or platelet-rich plasma can be used to treat thrombocytopenic patients that have persistent hemorrhage. Platelet-rich plasma is harvested by centrifuging fresh blood for a short time at a slow speed (3 to 5 minutes at 250 g). Blood or plasma should be collected into plastic bags because glass activates platelets, and either product should be used immediately. Platelet transfusion is a transient life-saving procedure, and the ultimate outcome depends on the individual case.

Cases of secondary IMTP that result from drug administration often resolve rapidly after drug withdrawal, except in cases associated with chrysotherapy (gold salts), which may require months to years to resolve. Many cases of equine IMTP recover in approximately 3 to 4 weeks. Cases that are secondary to EIA or neoplasia carry a poor to grave prognosis. Reports exist in which chronic recurrent thrombocytopenia has continued for an extended period of time and required intermittent steroid administration.

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Horses

Treatment of Cutaneous Lymphosarcoma

Glucocorticoids remain the mainstay of treatment of cutaneous T cell-rich, B cell lymphoma. Tumor regression is typically noted following the systemic administration of dexamethasone (0.02-0.2 mg/kg IV, IM or PO q24h) or prednisolone (1-2 mg/kg PO q24h). In these authors’ experience, dexamethasone proves more effective than prednisolone in treating lymphosarcoma. Once cutaneous lesions have regressed in size and number, the glucocorticosteroid dose can be gradually tapered. However, a rapid decrease or discontinuation of glucocorticosteroid administration may result in recurrence of cutaneous lesions. Relapses are anecdotally reported to be sometimes more refractory to treatment. Long-term maintenance therapy may be required in these cases. These authors prefer to use a dose of 0.04 mg/kg of dexamethasone (approximately 20 mg for an average-size horse) once daily until significant regression of tumors has occurred; the dose then is reduced to 0.02 mg/kg daily and then to every 48 hours. Intralesional injections of betamethasone or triamcinolone can also be performed with success; this may be impractical when presented with a large number of cutaneous lesions. Topical application of corticosteroid preparations may result in clinical improvement in cases with ulceration; however, results of its use have not been reported. In addition to im-munosuppression, laminitis is a potential side effect of corticosteroid administration.

Exogenous progestins may demonstrate an antiproliferative effect on lymphosarcoma tumors. The exact mechanism of action has not been determined; however, it is believed to be due to the presence of progesterone receptors, which have been demonstrated on both neoplastic and normal equine lymphoid tissues. Progestogens also have glucocorticoid-like activity, which may also account for the response observed in some cases of lymphosarcoma. In one study, progesterone receptors were identified on 67% of the subcutaneous lymphosarcoma tumors that were evaluated (primarily representing T cell-rich, B cell tumors). In the mare diagnosed with simultaneous cutaneous histiolymphocytic lymphosarcoma and a granulosatheca cell ovarian tumor, partial regression of the skin lesions occurred following a ten-day course of the synthetic progestin, altrenogest (0.044 mg/kg q24h PO). A temporary response was also observed after unilateral ovariectomy. The ovarian tumor stained positive for estradiol and led the authors to believe it was estrogen-secreting. The authors speculated that the steroid hormones secreted by the ovarian tumor may have influenced growth of the T cell-rich, B cell tumors by leading to low progesterone concentrations. Anecdotal reports of tumor regression during pregnancy also exist. In one mare with cutaneous T cell lymphosarcoma, regression of nodules was noted after surgical excision, a single intralesional injection of betamethasone (0.04 mg/kg), and an 8-day course of the oral progestogen, megestrol acetate (0.2 mg/kg q24h). Surgical excision may be efficacious in cases in which a single or a small number of cutaneous nodules exists.

The administration of autologous tumor cell vaccines may benefit horses with cutaneous lymphosarcoma. In one report, tumor regression was achieved by using a combination of low-dose cyclophosphamide and autologous tumor cells infected with vaccinia virus. Cyclophosphamide is thought to potentiate the immune response by decreasing suppressor T cell activity. Infection of tumor cells with the vaccinia virus was performed to augment the host antitumor immune response. The treatment protocol included intravenous administration of cyclophosphamide (300 mg/m2) via a jugular catheter over a period of 2 to 3 minutes on days 1 and 36. Immunization with tumor-cell vaccine was performed on days 4 and 21. Response to immunostimulation was confirmed by development of a delayed-type hypersensitivity response to autologous tumor cells injected intradermally in the horse. Potential side effects of cyclophosphamide administration in other species include immunosuppression, enterocolitis, myelosuppression, and hemorrhagic cystitis. No side effects were noted in the horse in this report.

Treatment of epitheliotropic (cutaneous T cell lymphosarcoma) in horses remains speculative because of a paucity of reported cases. Surgical excision of small lesions may be curative. Retinoids and vitamin A analogs inhibit malignant lymphocyte proliferation in human and canine patients with epitheliotropic lymphosarcoma. No reports of the use of retinoids in horses have been published. However, these authors noted no gross or histologic improvement in treating one case of equine epitheliotropic lymphosarcoma with retinoid cream. Side effects included local erythema and signs of irritation after repeated applications.

Investigations as to the effectiveness of radiation therapy and systemic chemotherapy in the management of equine cutaneous lymphosarcoma are needed. Local therapy that consists of intralesional injection of cutaneous nodules with cisplatin has been used successfully in horses with a small number of lesions. Combination chemotherapy that consists of cytosine arabinoside, chlorambucil or cyclophosphamide, prednisone, and vincristine has been reported for use in horses with multicentric lymphosarcoma, as has L-asparaginase.

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Diseases

Neoplasia

Cause of Neoplasia

In dogs, tumors of the large intestine are more common than tumors of the stomach and small intestine. The mean age of dogs affected with colonic neoplasia is variably reported between 7 and 11 years of age. Most colonic tumors of dogs are malignant and include the adenocarcinomas, lymphosarcomas, and gastrointestinal stromal tumors (leiomyosarcoma, neurofibrosarcoma, fibrosarcoma, and ganglioneuroma). Leiomyosarcomas are the most common (91 %) of the gastrointestinal stromal tumors. Most colonic neoplasia develop in the descending colon and rectum, although leiomyosarcomas more frequently develop in the cecum. Local tumor invasion apparently occurs at a slower rate with canine colonic neoplasia, and metastasis to distant sites is relatively uncommon. Benign colonic neoplasia (e. g., adenomas, adenomatous polyps, leiomy-oma’s) also occur, although they are less common than malignant tumors. Malignant transformation of adenomatous polyps to carcinoma in situ and invasive adenocarcinoma has been demonstrated in the dog just as it has in humans. Mb Extramedullary plasmacytomas are an uncommon tumor of the gastrointestinal tract but occur in the large intestine and rectum. All of the aforementioned tumors are associated with signs of inflammation and obstruction (i. e., hematochezia, tenesmus, dyschezia). Carcinoids (rare 5-hydroxytryptamine (5-HT]-secreting tumors) are occasionally associated with diarrhea because of the effects of 5-HT on secretion and motility.

In cats, adenocarcinoma (46%) is the most common tumor of the large intestine, followed by lymphosarcoma (41%) and mast cell tumors (9%). The mean age of cats affected with colonic neoplasia is 12.5 years. The descending colon (39%) and the ileocolic sphincter (28%) are the most common sites of colonic neoplasia in the cat. Unlike colonic tumors in the dog, feline colonic tumors have a high rate (63%) of metastasis and, of course, metastasis is associated with decreased survival time. Metastatic sites include colonic lymph nodes, mesenteric lymph nodes, liver, spleen, bladder, urethra, omentum, meso-colon, lungs, duodenum, and peritoneum.

Neoplasia: Pathophysiology

Mechanical obstruction is the most common pathophysiologic consequence of locally invasive colonic tumors. Other non-neoplastic processes such as intussusception, FIP granuloma, fibrosing stricture, linear and nonlinear foreign bodies, hematoma, and phycomycosis lesions also cause intraluminal obstruction. Prolonged obstruction induces smooth muscle hypertrophy proximal to the site of the obstruction. Other pathophysiologic consequences of intestinal obstruction are pronounced fluid secretion and malabsorption of water and solutes; fluid, electrolyte, and acid-base disturbances; proliferation and translocation of luminal bacteria; and inflammation, devitalization, and perhaps even perforation of the colon. Secretory diarrheas have been reported with carcinoids of the rectum, colon, and intestine.

Clinical Examination

Most affected dogs have signs of hematochezia, mucoid feces, tenesmus, and dyschezia of varying severity. Importantly, the clinical signs observed with colorectal neoplasia are often indistinguishable from other causes of obstruction or chronic colitis. Hematochezia is infrequently reported with leiomyosarcomas or leiomyomas, presumably because these tumors do not typically involve the mucosa. Other clinical signs depend on the tumor type and location. Vomiting, malabsorption, and cachexia may be observed, for example, when multifocal or diffuse tumors (e. g., lymphosarcoma) involve the proximal portions of the gastrointestinal tract. Gastrointestinal stromal tumors, particularly the leiomyomas, have been associated with hypoglycemia and the resulting clinical signs of muscular weakness and seizure activity. Functional plasmacytomas secrete a single class of immunoglobulin and affected animals may go on to develop hyperviscosity syndrome (e. g., retinal bleeding, epistaxis). If colonic perforation has occurred, animals may be presented moribund with fever, lethargy, anorexia, vomiting, abdominal pain, and collapse.

Vomiting (65%), diarrhea (52%), and weight loss (46%) are common clinical signs in cats with colonic neoplasia. Most cats with colonic (and alimentary) lymphosarcoma are FeLV-negative. These lymphomas are thought to be caused by FeLV, with integrated virus causing neoplastic transformation in the absence of viral replication. Although most lymphomas in cats appear to be comprised of malignant T lymphocytes, most colonic (and alimentary) lymphomas are of B cell origin. Alimentary and colonic lymphomas originate primarily from submucosal lymphocytes, mucosal lymphoid follicles, or both, although one recent study reported an epitheliotropic form of T cell intestinal lymphomas. Epitheliotropic T cell lymphomas have not yet been reported in the feline colon.

Diagnosis of Neoplasia

Canine rectal adenocarcinomas are palpable in 60% to 80% of clinical cases, but colonic and cecal lesions are not as readily apparent on physical examination. More than 50% of cats with colonic masses have a palpable abdominal mass.

Survey and contrast radiographic and ultrasonographic studies have been used with varying levels of success in the diagnosis of canine and feline colonic neoplasia. Annular stenotic lesions associated with adenocarcinoma of the colon may manifest as proximal colonic dilation on survey radiographs.

Radiographic contrast material more precisely outlines the narrowing of the lumen at the site of the tumor. Although still of some clinical utility, contrast studies have been largely superceded by ultrasonography and other imaging modalities. Ultrasonography is presently considered to be the most effective means of diagnosing colonic tumors in dogs and cats and appears to be useful in evaluating mural lesions and associated abdominal changes such as lymphadenopathy. Ultrasonography was reported to be useful 84% of the time in localizing feline colonic neoplasia in one study. Ultrasonographic features of colonic tumors include transmural wall thickening with complete loss of the normal wall layering, fluid accumulation proximal to the lesion, and reduced regional motility. Transabdominal fine needle aspiration, peritoneal fluid cytology, and endoscopic exfoliative cytology may be useful in the diagnosis of lymphoma, but histopathology is generally required for a definitive diagnosis of other colonic neoplasia. CT and magnetic resonance imaging (MRI) scanning have not been sufficiently evaluated at this time for reasonable comparisons to be made with ultrasonography.

Flexible colonoscopy with mucosal biopsy is the preferred method of diagnosis for colonic neoplasia. Endoscopic abnormalities may include mass effect, mucosal bleeding, increased mucosal friability, erosions and ulcers, and circumferential luminal narrowing with submucosal infiltrative lesions. Multiple biopsy specimens should always be taken from diseased tissue, adjacent healthy tissue, and the transition zone between healthy and diseased tissue. With tumor necrosis, the pathologist will have a much better chance of diagnosing and staging the disease by evaluating non-necrotic tissue.

Treatment of Neoplasia

The treatment of colonic neoplasia will depend upon tumor type, anatomic location, and presence and extent of metastases. Complete surgical excision is the recommended therapy for focal adenocarcinomas, cecal leiomyosarcomas, and obstructive lymphomas. Multiagent chemotherapy (prednisone, vincristine, cyclophosphamide) has been used to treat colonic lymphoma, but it does not appear to alter survival time in affected cats. Cyclo-oxygenase II (COX II) up-regulation may contribute to the growth characteristics of some canine colonic neoplasia. Selective COX II inhibitors (e. g., piroxicam, meloxicam) may therefore be useful in the treatment of some canine colonic neoplasia. Plasmacytomas may be managed with adjuvant chemotherapy (e. g., prednisone, melphalan) after surgical excision. Radiation therapy has been used to palliate recurrent adenocarcinomas with varying results and complications; however, postradiation peritonitis and perforation have been reported in some cases.

Prognosis of Neoplasia

The prognosis for adenomatous polyps, leiomy-omas, and fibromas is generally favorable. Adenocarcinomas, lymphosarcomas, and plasmacytomas tend to recur, metasta-size, or both to distant sites. Dogs with annular colorectal adenocarcinomas have a particularly poor prognosis with a median survival time (MST) of only 1.6 months. The prognosis for most malignant tumors is generally guarded. Surgical resection alone results in 22 month (dogs) and 15 month (cats) average survival times in dogs and cats. It should be noted that cats undergoing subtotal colectomy for colonic adenocarcinoma had a longer survival time than those receiving mass resection only (MST of 138 days versus 68 days). Not surprisingly, cats with metastatic lesions had much shorter survival times, 49 days versus 259 days.

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Veterinary Medicine

Anemia, Thrombocytopenia, And Hypoproteinemia

1. Are transfusions essential in an emergency situation?

Absolutely. Transfusions are frequently needed for veterinary patients as a result of various emergency situations, including blood loss, disseminated intravascular coagulation (DIC), clinical syndromes associated with the hypocoagulable state of malignancy and other diseases, and other hematologic abnormalities. In general, transfusions and specific blood components should be given only when specifically indicated. Other emergency support procedures, such as fluid therapy, should be used concurrently. The recent availability of blood components commercially makes this form of therapy practical for general practitioners. Finally, bovine hemoglobin is a viable option in an emergency situation when blood is not available.

2. When should blood component therapy be used? How long can blood components be stored?

Blood components should be administered when clinically indicated to either dogs or cats, especially in an emergency setting. Because blood component therapy takes time to prepare and to administer, forethought is essential. Blood component therapy should be initiated early in the management of critical patients but only when indicated. Whole blood or packed red blood cells may be administered immediately or stored for at least 21 days. Fresh frozen plasma has adequate levels of clotting factors for up to 1 year. Frozen plasma stored for longer than 1 year may have a diminished amount of clotting factors V and VII and von Willebrand’s factor. Dog blood can be drawn into human unit bags, holding approximately 450 ml of blood and 50 ml of anticoagulant. The plasma can be decanted to make packed cells. In cats a unit is frequently defined as 50 ml, which is the maximal amount that can be drawn safely from average adult cats.

3. What type of blood should be used to transfuse dogs or cats with acute blood loss?

Although there is a theoretical advantage to transfusing fresh whole blood, packed red blood cells may be administered with excellent results. Red blood cells stored for more than 2 weeks may have a depletion of 2,3 DPG (diphosphoglycerate), which may diminish red blood cell oxygen-carrying capacity. Transfusion should be performed to keep the hematocrit above 15% in dogs and above 10% in cats, when possible. In each case, the patient’s response to transfusion should be just as important a determinant as the hematocrit or amount to be transfused. Dogs and cats with acute blood loss are less tolerant of low hematocrit values, whereas those with a gradual reduction in red blood cell numbers are able to adapt to extremely low red blood cell numbers, especially cats.

4. What is bovine hemoglobin (Oxyglobin)? When should it be used in an emergency situation instead of blood?

Oxyglobin is the brand name of one product derived from bovine hemoglobin that acts to increase hemoglobin and arterial oxygen. Emergency treatment of the following conditions generally results in clinical improvement in up to 95% of the patients.

• Immune-mediated hemolysis

• Blood loss (rodenticide, trauma, surgery, gastrointestinal bleeding)

• Ineffective erythropoiesis (red cell aplasia, ehrlichiosis)

Treatment success was defined as dogs in which no further oxygen support (e.g., transfusion), was necessary 24 hours after Oxyglobin treatment. The success rate in the treatment goup was 95% vs. 32% in controls.

5. What are the indications to transfuse a dog with immune-mediated hemolytic anemia?

Immune-mediated hemolytic anemia may require the administration of red blood cells, even if it results in lysis in some of the transfused blood. An immune-mediated hemolytic event may result in acute or gradual onset of a low hematocrit. Therefore, the patient may present like an animal with either acute or chronic blood loss. Adjunctive therapy with glucocorticoids, azathioprine, and cyclosporine is often essential to treat the underlying disease. Dogs and cats with hemolytic anemia cannot be cross-matched adequately because of the presence of antibodies. Frequent evaluation of packed cell volume is essential.

6. What are the indications to transfuse a dog with nonregenerative anemia?

Generally nonregenerative anemia is relatively mild and often does not require transfusion. However, in some cases nonregenerative anemia is quite severe and requires either fresh whole blood or packed red blood cells. Some dogs and cats with nonregenerative anemia do quite well clinically until they are stressed for any reason. Stresses include but are not limited to unexpected confinement or kenneling, disease of any kind, or presentation to the veterinarian for routine evaluation. In addition, the administration of erythropoietin may be of value; however, antibodies directed to the erythropoietin are possible.

7. How should oxyglobin be administered?

Oxyglobin is given to dogs at 30 mL/kg IV at a rate of up to 10 ml/kg/hr. The product can be wanned to 37°C before administration. The half-life is between 30 and 40 hours.

8. What adverse effects are associated with the administration of Oxyglobin?

• Anaphylactic reactions

• Circulatory overload in cases of overdose, (>10 ml/kg/hr), or in patients with preexisting cardiac disease. Monitor central venous pressure and clinical signs for circulatory overload

• Discoloration of skin (yellow-orange), feces (red to dark green), and urine (brown-black)

• Vomiting

• Diarrhea and decreased skin elasticity (may occur within 48 hours of transfusion)

9. What are the indications to treat a patient with thrombocytopenia?

Platelet counts greater than 30,000-40,000 are rarely associated with bleeding disorders. Indeed, a gradual reduction in platelet counts may result in healthy-appearing patients with only 2000-3000 platelets. Recently released platelets have much greater function than older platelets. Platelet transfusion should be used only in dogs or cats that exhibit clinical signs. Platelet-rich plasma may be considered in such patients; however, the half-life of platelets may last for only days or weeks or less, especially in the presence of immune-mediated conditions. One unit per 20 kg body weight of platelet-rich plasma or fresh whole blood should be administered and repeated every hour until an adequate platelet count is reached.

10. What drug can be used to increase platelet numbers, assuming adequate megakaryocytes are present?

Vincristine (0.5 mg/m2 IV every 1-3 weeks) may be administered to induce premature release of platelets from the bone marrow at other sites during this time. The platelet count usually increases 3-5 days after vincristine is administered.

11. What is disseminated intravascular coagulation (DIC)?

Disseminated intravascular coagulation is a syndrome with severe bleeding and consumption of clotting factors and platelets.

12. How is disseminated intravascular coagulation treated?

Approximately one unit of fresh frozen plasma can be used and repeated as needed to maintain prothrombin and partial thromboplastin time at 1-1.5 times the normal bleeding time. Use of heparin is controversial; however, if used in conjunction with platelets, it may have beneficial results. When all cell lines (red blood cells and platelets) are decreased, fresh whole blood also can be used.

13. When are plasma transfusions used to treat dogs with hypoproteinemia?

Plasma transfusions may be of value in patients with decreased albumin levels. Administration of protein may cause a slow increase in plasma proteins because only 40% of the body albumin is in the intravascular space, whereas 60% resides within the interstitial space. Therefore, the administration of fresh frozen plasma must increase the albumin not only within the circulating space but also within the interstitial spaces, which may require repeated administration of proteins. Obviously, the administration of fresh frozen plasma from various donors may result in the development of antibodies. Colloidal solutions such as dextrans or hetastarch also may be useful despite the fact that their half-life may be quite short.

14. How do you determine how much blood or blood components to administer?

Animals with significant acute blood loss should be treated first for shock with crystalloid solutions. Hypertonic saline is also a reasonable choice in select patients. Packed red blood cells may be given with crystalloid fluids or whole blood. As a general rule, one unit of packed red blood cells is administered per 20 kg body weight with close adjustments to maintain the hematocrit above 15%. Dogs that require whole blood for either acute or chronic anemias should be transfused using the general guidelines below:

General rule: amount to transfuse

ml donor blood = [(2.2 X wtkg) x (40dog or 30cat) x PCVdesired – PCVrecipient])PCVdonor

where PCV = packed cell volume; 2.2 ml of blood/kg raises PCV by 1 % when transfused blood has a PCV of 40.

General rule: rate of transfusion

Dogs: 0.25 ml/kg/30 min or faster (22 ml/kg/day) with close patient monitoring

Cats: 40 ml/30 min with close patient monitoring

Whenever plasma transfusions are considered, it should be remembered that 60% of the blood volume is plasma. In addition, only 40% of the albumin in an animal is in the plasma. Therefore, it takes half a dozen units of plasma to raise the albumin of a 66-pound dog from 1.8 gm/dl to 3 gm/dl.

15. What are the possible complications after transfusion?

Hemolysis is probably the most serious adverse effect; however, it is relatively rare. An acute hemolytic reaction may result in elevated temperature, heart rate, and respiration rate; tremors; vomiting; and collapse. When this occurs, blood component transfusion should be stopped, and the patient’s plasma should be checked for hemoglobinemia. Crystalloid fluids should be initiated, and urine output should be monitored. Delayed hemolysis is also possible in some patients.

Fever that develops during transfusion may indicate bacterial contamination of the blood, or the fever may be related to leukocyte antigens that cause an elevation of endogenous pyrogens. Elevation in body temperature is more commonly seen in cats than in dogs.

Allergic reactions may manifest as urticaria and angioneurotic edema. If such signs are noted, the transfusion should be discontinued, and glucocorticoids should be administered.

When large volumes of blood are administered, volume overload should be monitored and treated appropriately.

Citrate toxicity, another possible complication of stored blood transfusion, may cause an acute decrease in serum ionized calcium. Citrate toxicity may induce muscle tremors, facial twitches, and seizures as a result of hypocalcemia. Intravenous calcium gluconate and cessation of transfusion are the treatments of choice.

Rarely, blood ammonia levels may rise and cause associated clinical signs, such as mental dullness or seizures. This is usually seen in blood that is stored over a prolonged period and is usually associated with packed red blood cells. Treatment should be the same as for hepatoencephalopathy.

Categories
Veterinary Medicine

Extravasation of Hemotherapeutic Drugs

1. What chemotherapy agents may cause a perivascular reaction or slough and is this truly an oncologic emergency?

Many chemotherapeutic agents are known to induce significant tissue injury after extravasation. Some are severe, irreversible vesicants; others are irritants. Immediate treatment of this condition can result in reduction of dramatic morbidity and in some cases, mortality. The agents commonly used in veterinary medicine include the following:

Actinomycin D Etoposide Vincristine
Daunorubicin Mithramycin Mitoxantrone
Doxorubicin Vinblastine Cisplatin
Epirubicin

Management of extravasation in human and veterinary medicine is anecdotal and extremely controversial. Despite this controversy, guidelines have been established for clinical use (see question 4).

2. How can perivascular reactions or slough be prevented?

As expected, accurate and secure first-stick catheter placement is absolutely essential in administering drugs that can cause tissue damage if extravasated perivascularly. Generally, only small (22-23 gauge) indwelling intravenous catheters should be used when treatment volumes exceed 1 ml; 23-25-gauge butterfly needles are used for administering small volumes of drugs such as vincristine. All persons involved in patient care should note when and where blood samples are taken by venipuncture and where catheters have been placed previously. This practice prevents administration of chemotherapeutic agents through veins that may leak because of previous procedures. Only recently placed catheters should be used for administration of chemotherapeutic agents. Extreme care should be taken in administering drugs to animals with fragile veins (e.g., diabetics and some aged animals). The catheter should be checked for patency with a large injection of saline (e.g., 12-15 ml) before and after administration of the drug. In addition, the catheter must be checked for patency during infusion, and the injection site must be checked during treatment.

3. What is the best method to diagnose a chemotherapy-induced extravasation?

Usually there is no doubt whether an extravasation has occurred. It should be noted, however, that some drugs will go perivascularly without any reaction from the patient. Some agents are highly caustic if given perivascularly; animals may vocalize or physically react to pain at the injection site. Treatment for extravasation must begin immediately. Evidence of tissue necrosis generally does not appear for 1-10 days after injection and may progress for 3-4 weeks. Lesions may start as mild erythema and progress to an open, draining wound that will not heal without extensive debridement and plastic surgery weeks to months after the perivascular slough begins when all damage is evident. The lesions occur early with vinca alkaloids and late with anthracycline antibiotics such as doxorubicin.

4. What is the treatment of choice for perivascular injection of a chemotherapeutic agent?

Every person involved with the administration of chemotherapeutic agents should be aware of procedures for treatment of extravasation. The procedures should be posted in a common area, and all materials needed to treat extravasation should be readily accessible. Because of extensive use in veterinary practice, doxorubicin and vinca alkaloids are the most common cause of perivascular sloughs. Unfortunately, no method effectively eliminates tissue necrosis. The following procedure is currently believed to be helpful:

• Once extravasation is noted, stop the infusion or injection.

• Do not remove the catheter.

• Aspirate back as much fluid and blood as possible from the perivascular space.

• For doxorubicin, apply ice packs continually for 3-4 hours to reduce spread of the drug into adjacent tissue. Treatments that have not been consistently helpful include sodium bicarbonate, corticosteroids, dimethyl sulfide (DMSO), alpha tocopherol, N-acetylcysteine, glutathione, lidocaine, diphenhydramine, cimetidine, propranolol, and isoproterenol.

• For vincristine and vinblastine, apply hot compresses for at least 3-4 hours and inject saline subcutaneously to disperse the drug from the local site.

• Once tissue damage is identified, an Elizabethan collar and bandages with a nonstick pad are essential to allow the area to heal without self-trauma. The bandage should be changed daily as long as the area is draining or has the potential for infection. If a bacterial infection is noted, culture and sensitivity testing and appropriate use of antimicrobials are essential. Frequent cleansing and debridement may be necessary. In some cases, reconstructive surgical repair is essential.

Categories
Veterinary Herbal Medicine

Herbs for Cancer

Cancer biology is yet to be fully understood. Cellular mutation may occur as a result of free radical damage (with activation of oncogenes or suppression of tumor suppressor genes) and genetic susceptibility and toxicity (e.g., hepatopathogenic toxins). In traditional herbal medicine, cancer is nearly always viewed as a sign of systemic toxicity. However, immune dysregulation has to be considered, and can occur with stress, toxin, heavy metal and pesticide exposure, dysbiosis, hormonal imbalance, nutrient imbalance, infection, inflammation, and radiation. Chemotherapy is also a major cause of immune dysregulation; for example, vincristine is weakly myelosuppressive, and cyclophosphamide and glucocorticoids are strongly myelopsuppressive.

Many chemotherapeutic drugs currently in use in medicine were first identified in plants, including taxol, vinblastine and vincristine, and etoposide and teniposide. Herbs offer a rational potential in the treatment of cancer in animals; however, it is important to note that herbs may be used for purposes other than direct antitumor activity. On the other hand, just about any selection of herbs prescribed to treat a patient will more than likely have some anticancer activity because of the presence of widely occurring anticancer constituents like flavonoids.

Although little research has been conducted in cats and dogs specifically, a plethora of research pertains to rats, mice, hamsters, and guinea pigs. At least pocket pets are amply catered to if they are diagnosed with cancer! Herbs can be used to help manage the effects of chemotherapy; to assist in recuperation after chemotherapy, radiation, or surgery; to complement conventional cancer treatment; to provide an alternative to conventional treatment in some cases; to assist in cancer prevention; and to support various systems that are affected by cancer. One of the approaches used by veterinary herbalists is to treat cancer as a chronic disease, with emphasis on improving the health of the whole body, regardless of the presence of cancer. Anecdotal evidence from veterinary herbalists indicates that herbs offer improved quality of life and may support remission in some cases.

The rational use of herbal medicine for the treatment of patients with cancer depends on a growing understanding of the biological mechanisms by which cancer cells proliferate, maintain life, and die. These include differentiation (the maturation process of cells), angiogenesis (the growth of new blood vessels into tumors), apoptosis (programmed cell death), invasion (the spread of the tumor mass into adjacent tissue), metastasis (the spread of tumor cells to distant locations), mitosis (the proliferation of cells), and evasion of the immune system. As these mechanisms have become elucidated, their weak points have been identified and have become the targets of research that is both conventional and complementary. The selection of several herbs that have different mechanisms of action provides a broad spectrum of anticancer activity. A holistic strategy that incorporates all elements discussed here is proposed under “Review of Strategies for Cancer Prescriptions” at the end of this post.

Targets Unique to Neoplastic Cells for Cancer Therapy
• Genetic instability
• Abnormal transcription factor activity
• Abnormal signal transduction
• Abnormal cell-to-cell communication
• Abnormal angiogenesis
• Invasion and metastasis
• Abnormal immune function

Mechanisms of Interest

Antineoplastic/cytotoxic actions

It is logical to select herbs is on the basis of cancer biology. An extremely comprehensive review of anticancer plants and natural compounds is provided in John Boik’s book, Natural Compounds in Cancer Therapy (2001). This book explains in great detail the mechanisms of action of many plants and their constituents. It is important to note that most herbs have many actions, and this list is merely indicative of the wide range of such mechanisms that have been documented. (Search Medline for more information; use the herb name and cancer or activity as search terms.)

Boik highlights the importance of synergism as a strategy by which lower doses can be used without reduced efficacy; he also discusses the use of herbs with different antineoplastic mechanisms for targeting events that take place in the progression of cancer. Choosing compounds that have direct-acting, indirect-acting, and immune-stimulating activities is likely to inhibit procancer events. Constituents like flavonoids can target multiple aspects of tumor biology.

Anticancer Mechanism of Selected Herbs and Constituents

Apoptosis Inducers Inhibitors of Local Invasion
• Greater celandine (Chelidonium majus) (Note: This is a very strong herb that is usually administered topically.) These are herbs or constituents that inhibit hyaluronidase and its assistant enzymes or elastase, or that affect collagen or cell migration.
• Baical skullcap (Scutellaria baicalensis)
• Bupleurum (Bupleurum falcatum) • Gotu kola (Centella asiatica)
• Boswellia (Boswellia serrata) • Horse chestnut (Aesculus hippocastanum)
• Turmeric (Curcuma longa) • Butcher’s broom (Ruscus aculeatus)
• Saint John’s Wort (Hypericum perforatum) • Turmeric (Curcuma longa)
• Garlic (Allium sativum) • Panax (Panax ginseng)
• Flavonoids (apigenin, luteolin, genistein, quercetin, reversatrol) • Hawthorn (Crataegus spp)
• Bilberry (Vaccinium myrtillus)
Differentiation Inducers • Dong quai (Angelica sinensis)
• Burdock (Articum lappa) • Flavonoids (proanthocyanidins, anthocyanidins, apigenin, reversatrol, genistein, luteolin, quercetin)
• Boswellia (Boswellia serrata)
• Berberine • Mushroom polys ace ha rides
• Flavonoids (reversatrol, apigenin, luteolin, genistein, quercetin) • Emodin
• Boswellic acids
• Emodin Inhibitors of Metastasis
Cytotoxic Agents These are herbs or constituents that have anticoagulant activity.
• Mistletoe (Viscum album)
• Limonene • Aloe succus (Aloe vera)
• Emodium • Green tea (Camellia sinensis)
Inhibitors of Angiogenesis • Cordyceps (Cordyceps sinensis)
• Reishi mushrooms (Canoderma lucidum)
These include herbs and constituents that inhibit increased vascular permeability, or that beneficially affect prostanoid and leukotriene systhesis, or that inhibit mast cell degranulation. Garlic (Allium sativum)
• Panax (Panax ginseng)
• Astragalus (Astragalus membranaceus)
• Dong quai (Angelica sinensis)
• Butcher’s broom (Ruscus aculeatus) • Feverfew (Tanacetum parthenium)
• Gotu kola (Centella asiatica) • Dan shen (Salvia miltiorrhiza)
• Horse chestnut (Aesculus hippocastanum) • Turmeric (Curcuma longa)
• Garlic (Allium sativum) • Flavonoids (including reversatrol, anthocyanidins, genistein, apigenin, luteolin, quercetin)
• Turmeric (Curcuma longa)
• Siberian ginseng (Eleutherococcus senticosis) • Emodium
• Ginkgo (Cinkgo biloba)
• Picrorrhiza (Picrorrhiza kurroa)
• Flavonoids (including proanthocyanidins, anthocyani-dins, reversatrol, genistein, apigenin, luteolin, quercetin)
• Emodium

 

Adaptogens

This strategy recognizes that a patient can live with cancer as opposed to having to die of cancer. Many of our elderly animal patients, in particular, have never been in better health than when they are on herbal and nutritional treatment, even though they have cancer, because the prescriptions that they are given promote overall health. Herbs should be used to strengthen body resistance, and vitality is enhanced through the use of adaptogens. Most adaptogens also have anticancer activity.

Astragalus (Astragalus membranaceus): Astragalus induces cell differentiation and cell death in vitro and exerts anticarcinogenic effects through activation of cytotoxic activity and the production of cytokines in mice.

Ashwagandha (Wlthania Somnitera): The anti-tumor and radiosensitizing effects of Withania have been studied. Growth of carcinoma in mice was inhibited and survival increased with Withania treatment, especially when it was combined with radiation. When given before irradiation, it synergistically increased survival, even in mice with advanced tumors. Complete regression of sarcoma in mice caused by Withania root extract was observed.

Eleuthero (Eleutherococcus Senticosis): This herb was able to inhibit tumor growth and prolong survival time in tumor-bearing mice; these effects were significantly related to enhanced immune response. Siberian ginseng appeared to reduce the quantity of conventional antimetabolites that were needed to attain antiproliferative effects on tumor cells in vitro.

Asian Ginseng (Panax Ginseng): This herb induces cell differentiation, reduces the effects of chemical carcinogens, mitigates inflammatory carcinogenesis, induces apoptosis, inhibits proliferation, and has proved beneficial in the treatment of a number of cancers in humans.

Herbs for Cancer: Immune Modulators

Alteratives

In traditional herbal medicine, alteratives represent a key strategy for the treatment of cancer. Alteratives act through the lymphatic, blood, and eliminatory systems to facilitate and enhance the breakdown and removal of metabolic wastes. They are also used to improve the absorption and assimilation of nutrients. Alteratives are thus considered to be “blood purifiers” or “detoxifiers”, believed to circulate and improve blood flow, while removing waste from blood and lymph. The function of these herbs is to optimize the body’s eliminative functions performed via the liver, kidneys, lungs, and gastrointestinal system.

Ideally, these herbs are chosen according to their other actions and affinities for particular organs or systems, so as to maximize their benefit. For example, poke root and cleavers are specific for the lymphatic system. Many of these herbs contain alkaloids and flavonoids and have documented anticancer activity; many others have not been studied. Modifying prescriptions every 2 to 3 months reduces the risk of potential toxicity associated with some of these herbs.

Alteratives include the herbs listed here:

Burdock (Articum Lappa): Differentiation-inducing activities have been demonstrated against mouse myeloid leukemia cells. The most active derivative induced more than half of leukemia cells to become phagocytic cells.

Dandelion root (Taraxacum officinale): in vitro antitumor activity has been documented for an aqueous extract of dandelion. The mechanism of action was thought to be similar to that of tumor polysaccharides such as lentinan.

Sheep Sorrel (Rumex Acetosella): One study found that Rumex acetosella polysaccharide displayed antitumor activity in mice that were implanted with sarcoma (180 solid tumors).

Oregon Grape (Mahonia Aquifolium): Berberine has anticancer activity and exhibits the ability to induce apoptosis in leukemia cells. In addition, some protoberberines are highly effective as cytotoxic agents against several carcinoma lines; berberine consistently showed the highest cytotoxicity among the alkaloids tested.

Other herbs

• Barberry (Berberis vulgaris)

• Echinacea (Echinacea pupurea)

• Stillingia (Stillingia sylvatica)

• Yellow dock (Rumex crispus)

• Poke root (Phytolacca decandra)

• Cleavers (Gallium aparine)

• Red clover (Trifolium pratense)

Herbs for Cancer: Antioxidants

Analgesics

Cancer patients suffering pain may be administered anti-inflammatory, antispasmodic, and analgesic herbs as necessary. A review of these herbs can be found in the section on neurology, pain, and behavior.

Platelet-Activating Factor Inhibitors

Platelet-activating factor (PAF) is an ether-linked phospholipid that has been postulated to be a stimulator of malignant tumor growth; it may be significant in the early stages of tumor development.

Ginkgo (Ginkgo Biloba): Ginkgolides have been reported to competitively inhibit the binding of PAF to its membrane receptor.

Anticachectic Activity

Coptis (Coptis Chinensis): This herb was investigated in mice bearing colon carcinoma cells that cause IL-6-related cachexia after cell injection. Coptis significantly attenuated weight loss in tumor-bearing mice compared with controls, without changing food intake or tumor growth. It was therefore shown to exert an anticachectic effect associated with tumor IL-6 production, and it was suggested that this effect might be due to berberine.

Anticancer Action by Organ/System

Popular “Anticancer” Herbal Remedies

Review of Strategies for Cancer Prescriptions

Categories
Complementary Medicine

Granulamatous Meningoencephalitis

GME – Granulamatous Meningoencephalitis
/ Peripheral Neuropathies

Definition and cause

Peripheral neuropathies may represent numerous specific diagnoses. Many are inherited and have no successful treatment. When diagnosing such conditions it is helpful to divide them into categories of disease, including degenerative, genetic, idiopathic, inflammatory-noninfectious, inflammatory-infectious, metabolic, neoplasia, trauma, and vascular. Each particular case has a pathophysiology responsible for neurological dysfunction, and this identification may be immensely helpful in selecting proper biological therapy.

Often, the pathophysiology of many of these cases is never fully elucidated and clinicians may be forced to select therapy without a full understanding of the true condition. Common causes are immune-mediated, infectious, secondary to degenerative diseases such as diabetes or cancer, or secondary to a toxic reaction to chemotherapeutics or chemical toxins.

Establishing a complete diagnosis is well worth the effort. It may be very helpful to cooperate with internists and neurologists to determine successful treatment plans for patients suffering from neuropathies. Clients need to be counseled early on that these conditions may not respond and may even continue to deteriorate, even if the correct causation is determined.

Medical therapy rationale, drug(s) of choice, and nutritional recommendations

Medical therapy depends upon the underlying cause. If properly diagnosed and treated, the hope is that the neuropathy will resolve. Immune-mediated neoplasia most often require ongoing immunosuppressing therapies such as corticosteroids and chemotherapeutics.

Anticipated prognosis

The prognosis depends upon determining the underlying cause. Generally, a response is seen 1 to 3 months after initiating the therapy. The prognosis is poor to guarded if there is no response to the initial medical therapy.

Integrated veterinary medicine

The underlying process is inflammation of the central nervous system. While the specific cause is not reported, inflammation and immune-mediated processes most often necessitate the selection of corticosteroids as the primary therapy. The integrative approach, therefore, is to use nutrients, nutraceuticals, medicinal herbs, and combination homeopathics that have anti-inflammatory properties and can help to balance the immune system and reduce an exaggerated response. Clinicians should use any appropriate therapy in these cases; integrative therapy using conventional medicine, nutrition, and biological agents may speed recovery and improve patient comfort.

Nutrition

General considerations / rationale

While medical therapy is focused locally upon inflammation, the nutritional approach adds glandular support for the organs of the immune system as well as nutrients to help improve brain and nerve function.

Note: Because granulamatous meningoencephalitis and its symptoms can range from local to systemic, it is recommended that blood be analyzed both medically and physiologically to determine concurrent disease. This helps clinicians to formulate therapeutic nutritional protocols that address the central nervous system as well as other organ systems (see site, Nutritional Blood Testing, for additional information).

Appropriate nutrients

Nutritional / gland therapy: Glandular brain, nerve, adrenal, and thymus supply the intrinsic nutrients that help to reduce cellular inflammation and improve nerve and immune function. This helps to spare the brain and nerve from ongoing immune attack and helps slow degeneration and loss of function (see Gland Therapy in site for a more detailed explanation).

Phospholipids found in glandular brain are a source of unsaturated omega-3 fatty acids, which are now thought to play a vital role in the development and maintenance of the central nervous system. High concentrations of phosphatidyl choline and serine are found in brain tissue. Horrocks (1986) reported on the potential clinical use of these nutrients in chronic neurological conditions.

Phosphatidyl serine: Phosphatidyl serine is a phospholipid that is essential for the integrity of cell membranes, particularly those of nerve and brain cells. It has been studied extensively in people with impaired mental functioning and degeneration with positive results.

Lecithin / phosphatidyl choline: Phosphatidyl choline is a phospholipid that is integral to cellular membranes, particularly those of nerve and brain cells. It helps to move fats into the cells and is involved in acetylcholine uptake, neurotransmission, and cellular integrity. As part of the cell membranes, lecithin is an essential nutrient required by all of the body’s cells for general health and wellness.

Magnesium: Physiologically, magnesium activates adenosine triphosphatase, which is required for the proper functioning of the nerve cell membranes and fuels the sodium potassium pump. Magnesium is associated with neuromuscular function and conditions such as muscle cramping, weakness, and neuromuscular dysfunction. Magnesium is recommended for therapy for epilepsy and weakening muscle function.

Sterols: Plant-derived sterols such as betasitosterol show anti-inflammatory properties that appear to be similar to corticosteroids. A cortisone-like effect without the associated immune suppressing effects is beneficial in any inflammatory process in the central nervous system. Bouic reports on the immune enhancing and balancing effect of plant sterols that are also beneficial to animals with immune-mediated diseases.

Essential fatty acids: Research also confirms the benefits of essential fatty acids’ calming effect on the central nervous system.

Chinese herbal medicine / acupuncture

General considerations / rationale

Granulamatous meningoencephalitis is a combination of External Wind, Heat, and Toxin invading the Ying and Blood, which affects Wei and Qi at the same time. This leads to Heart and Pericardium disturbances.

Peripheral neuropathy may be a result of trauma or it may be due to Cold and Wind invasion, leading to Qi and Blood stagnation in the Meridians.

In granulamatous meningoencephalitis, the Wind blows the pathogenic influence into the body. Heat and Toxins then invade the Ying and Blood layers of the body. The Heat refers to fever and inflammation. Toxins are the substances that cause the inflammation. Wei is the immune system, so there is a disruption of immunoregulation, which is in agreement with the Western understanding of an immune basis to this disease. Neurological signs appear when the Ying level is affected. At the Xue level, the Heart and Pericardium, which house and protect the mind, are disturbed. When this occurs, the patient does not react properly to the environment. This can explain the seizures with the attendant loss of consciousness.

Treatment is aimed at decreasing the inflammation, fever, and pain, and normalizing the neurological function.

In peripheral neuropathy the ancient Chinese physicians were well aware of the ability of trauma to damage nerves. When they could not point to trauma as a cause, they theorized that Wind blew Cold into the body. Cold was able to slow the transit of Blood and Qi in the Meridians. Without a normal flow of Blood and Qi, the limbs could not function properly. Treatment is aimed at normalizing limb function.

Appropriate Chinese herbs for granulamatous meningoencephalitis

Achyranthes (Niu xi): Has shown analgesic effects. In mice it was shown to decrease pain reactions to body torsion and hot plates. It also demonstrated anti-inflammatory effects.

Arctium Niu bang zi: Has anti-inflammatory and antipyretic effects.

Buffalo horn shaving (Niu jiao): A strong pain reliever that also decreases edema.

Coix (Yi yi ren): Can help control pain and inflammation. It helps prevent carrageenin-induced foot swelling and dimethylbenzene-induced ear swelling in mice. A study involving 26 women with severe dysmenorrhea found that coix significantly decreased pain by more than 90%.

Forsythia (Lian qiao): Has anti-inflammatory, analgesic, and anti-pyretic effects and can prevent edema.

Gastrodia (Tian ma): Can help decrease pain. It decreases the level of dopamine in the brain, and this may be responsible for the analgesic effect (Huang 1993). It was shown to decrease agar-induced swelling in mice and carrageenin- and 5-HT-induced swelling in the feet of rats. This anti-inflammatory action may be useful in treating granulamatous meningoencephalitis.

Grass-leaf sweet-flag root (Shi chang pu): Contains alpha-asarone, which demonstrated an efficacy of approximately 85% in treating seizures in a group of 90 people. It may help decrease seizures in patients with granulamatous meningoencephalitis.

Honeysuckle (Jin yin hua): An anti-inflammatory and antipyretic herb.

Isatis (Da qing ye): Has anti-inflammatory effects.

Licorice (Gan cao): Contains glycyrrhizin and glycyrrhetinic acid, which have anti-inflammatory effects. They have approximately 10% of the corticosteroid activity of cortisone. They decrease edema and decrease the formulation of granulomas.

Lophatherum (Dan zhu ye): An antipyretic herb.

Mint (Bo he): Decreases fever and inflammation.

Platycodon (Jie geng): Contains platycodin, which has antipyretic effects. It also has anti-inflammatory effects via its ability to increase corticosterone secretion.

Pueraria (Ge gen): Reduces fevers (Modern traditional Chinese medicine Pharmacology 1997).

Schizonepeta (Jing jie): Has analgesic properties.

Scutellaria (Huang qin): Contains baicalin and biacalein, which have been shown to suppress inflammation in mice. It also can lower fever.

Silkworm (Jiang can): Has been shown to be effective in stopping experimentally induced seizures in mice. In one trial, 77% of humans with epilepsy who were treated with Jiang responded well. This suggests that it may help reduce seizure activity in patients with granulamatous meningoencephalitis.

Uncaria (Gou teng): Has been proven to prevent seizures in animals.

Acupuncture for granulamatous meningoencephalitis

The World Health Organization recognizes the efficacy of acupuncture for the treatment of headache (World Health Organization 2006). In addition, acupuncture has been shown to be better than phenobarbital at stopping fever-induced seizures in children. This may have a dual effect of addressing both the seizure and fever aspects of granulamatous meningoencephalitis.

Appropriate Chinese herbs for forelimb neuropathies

Angelica root (Dang gui): Increases phagocytic activity of macrophages, which may help patients with infectious peripheral neuropathies. It also decreases inflammation, which may make it beneficial in inflammatory etiologies.

Astragalus (Huang qi): Can improve humoral and cellular immune functions, which may help in the case of bacterial or viral neuropathies.

Centipede (Wu gong): Has antibiotic properties. It inhibits cancer cells in vitro, which indicates that it may be useful for neuropathies secondary to these causes.

Cinnamon twig (Gui zhi): Inhibits some bacteria and viruses.

Earthworm (Di long): Has anti-neoplastic effects. The mechanism is not yet elucidated, but it may be due to enhanced immunity and scavenging of free radicals. This may help in some forms of neoplastic neuropathy.

Jujube fruit (Da zao): Can inhibit dimethylbenzene-induced ear swelling in mice, and egg white-induced toe swelling in rats. It may also ameliorate inflammatory neuritis.

Licorice (Gan cao): Inhibits bacteria and viruses. It may be efficacious in viral and bacteria-mediated neuropathies.

Milettia (Ji xue teng): Has antiviral effects. It has been shown to inhibit herpes virus I (simplex), a virus known to be neurotropic. In addition, it has demonstrated activity against cancers via increased NK activity in mice.

Rehmannia / cooked (Shu di huang): May help improve the conditions of nerves. One trial examined the results of an herbal supplement containing rehmannia with Rou cong rong, Lu han cao, Gu sui bu, Yin yang huo, Ji xue teng, and Lai fu zi in 1,100 patients with myelitis. 73% had significant improvement, and another 13% had moderate improvement in clinical signs.

Tumeric (Jiang huang): May decrease neuronal inflammation. It inhibits MIP-2 (macrophage inflammatory protein-2) production. This chemical has been implicated in traumatic brain injury, which strongly suggests applicability in patients with neuropathy.

White peony (Bai shao): Contains paeoniflorin, which is a strong anti-inflammatory. In addition, it seems to have a neurotropic effect. It contains gallotannin, which prevents neuron damage in mice with cobalt-induced seizures (Sunaga 2004). This may make it a powerful herb for decreasing neuronal inflammation.

Wild ginger (Xi xin): Inhibits carrageenin-induced foot swelling. It may prevent inflammation in the nervous system, thereby treating inflammatory neuropathies.

Appropriate Chinese herbs for hindlimb neuropathies

Achyranthes (Niu xi): Decreases egg-white-induced foot swelling in rats. It may help decrease inflammation in the nervous system.

Alpinia (Yi zhi ren): Has demonstrated some anti-neoplastic activity.

Antler powder (Lu jiao jiao): Enhances the phagocytic function of macrophages and can be used as an adjuvant in cancer treatment.

Astragalus (Huang qi): See forelimb paralysis, above.

Cornus (Shan zhu yu): Can inhibit carrageenin-induced toe swelling in rats and mice. This suggests that it may be useful in cases of inflammatory etiologies.

Dioscorea (Shan yao): Stimulates both the humoral and cellular immune system. It may help with infectious causes of neuropathy.

Eucommia (Du zhong): Contains chlorogenic acid, which has antibacterial effects. It stimulates cellular immunity, which may make it useful when the neuropathy is due to infectious etiologies.

Ophiopogon (Mai men dong): Effective against Staphylococcus albus, Bacillus subtilis, E. coli, and Salmonella typhi.

Papaya (Mu gua): Has inhibitory effects on tumors.

Poria (Fu ling): Has antibiotic effects. It also stimulates cellular immunity. Finally, it has demonstrated anti-neoplastic activity.

Rehmannia / cooked (Shu di huang): See forelimb paralysis, above.

White atractylodes (Bai zhu): Has demonstrated anti-neoplastic efficacy.

Appropriate Chinese herbs for facial neuropathies

Angelica root (Dang gui): See forelimb neuropathies, above.

Centipede (Wu gong): See forelimb neuropathies, above.

Cnidium (Chuang xiong): Increases the phagocytic function of macrophages. It may be helpful in infectious neuropathies.

Gastrodia (Tian ma): Decreases nerve pain from toxins and vascular causes.

Ginseng (Ren shen): Prevents the decrease in plasma T3 and T4 levels as laboratory animals age. It may be useful in hypothyroid-induced neuropathies.

Siler (Fang feng): Has antibiotic properties. It is also anti-neoplastic.

Silkworm (Jiang can): Can inhibit some bacteria.

White aconite (Bai fu zi): May help with facial nerve disorders. In one study, 90% of 418 people with facial numbness recovered completely when an herbal formula containing typhonium (Bai fu zi), angelica root (Dang gui), scorpion (Quan xie), sick silkworm (Jiang can), and centipede(Wu gong) was injected into acupoints.

Homotoxicology

General considerations / rationale

Granulamatous meningoencephalitis is an intracranial proliferative inflammatory process involving mesenchymal cells, which may present in a generalized inflammatory form or a mass form. The cause is unknown. Lymphocytes and macrophages are the primary inflammatory cells that are present (Bagley 2005).

There is no published material on this condition in any homotoxicology references, which makes the material that follows an academic discussion. Goldstein (2006) has successfully used the protocol below in combination with other integrative modalities discussed in this section.

Because connective tissue elements function in an abnormal and deleterious manner, this condition represents a disease to the right of the Biological Divide, most likely the Impregnation and Degeneration phases. There may be Dedifferentiation Phase factors involved. Examination of such cases for chemical or viral agents may prove interesting in researching the cause. Antihomotoxic agents discussed in the encephalitis / meningitis section are applicable. Phase remedies and deep detoxification with support of energy-producing enzyme systems represent a logical clinical approach to this condition. The expected prognosis is guarded. The use of drugs such as corticosteroids and immunosuppressants are warranted to preserve patient comfort and ability. As with all neurological problems, use of a qualified neurologist may be helpful in establishing the correct diagnosis and most current treatment options.

Selecting symptom remedies and detoxification protocols is extremely important in neurology cases. Many homeopathic and herbal agents have affinity for neural tissue in specific body regions (neck, face, lumbar spine, extremities), and the integrative clinician should always be sure to consider the anatomical region is designing proper treatment programs. In traumatic cases, the use of simple single antihomotoxic formulas such as Traumeel S may give immediate improvement. Most cases of peripheral neuropathies presented to veterinarians represent deeper homotoxicoses and require combinations of therapy and careful monitoring of progress. Always remember that the goal of therapy is regressive vicariation and that signs of inflammation and discharge may well represent the beginning of healing in a patient. Inherited conditions generally carry a guarded prognosis, but may improve or stabilize with biological therapies integrated with conventional medical handlings, and it is beneficial to have a basic understanding of these approaches when faced with a nonresponsive or difficult case.

The development of acutely painful conditions similar to shingles in humans may represent the movement of homotoxins from chronic Impregnation and Degeneration phases to the Inflammation Phase, and should be welcomed as a potentially good sign. Other neurological signs may occur during these regressive vicariations (i.e., altered awareness, personality changes, tics, and seizures) and may require experienced handling as the patient moves from right to left of the Six-Phase Table of Homotoxicology.

Appropriate homotoxicology formulas

Aesculus compositum: Useful in improving circulation following stroke or reduced cerebral circulation (Aesculus hippocastanum and Secale cornutum). Areteria suis supports the arteries. Solanum nigrum further supports cerebral function, particularly in cases with confusion, epileptic seizures, or disorientation. Several other agents support homotoxin removal and improve vessel stability.

Apis homaccord: Generally useful in edema, but also in cerebral sensitivity. May assist cardiac-induced cerebral weakness through Scilla, Apisinum, and Apis mellifica. The main symptoms of Apis may be summed up as follows for quick reference: sensitivity to touch and jarring; irritation of the meninges, especially from suppressed eruptions; diseases of the serosa, joints, and meninges; infiltration of the cellular tissues; and serous meningitis. Apis is also found in Aesculus compositum, Cerebrum compositum, Blacenta compositum, and Tonsilla compositum.

Arsuraneel: Used for patients not responding to initial therapy; this formula may move them into a recovery phase through stimulation of the general defenses. Useful in cases with seizures, anxiety, feeling worse at night, paresis, and muscular disability.

Belladonna homaccord: Belladonna, which has an affinity for the central nervous system, is useful in patients manifesting seizures and who scream out at night. Violent delirium is characteristic of Belladonna, above all in fever. Belladonna’s typical action on the eyes is also well-known, with cramps in the muscles of the eyes and eyelids, enlargement of the pupils and, in particular, an inflammatory or irritative condition of the conjunctiva with marked photophobia, lachrymation, and pain. Belladonna is indicated in incipient boils, tonsillitis, and surface inflammations such as erysipelas, conjunctivitis, scarlet fever, otitis, cholangitis, meningitis, and other inflammatory affections. A delirious state occurs with a violent rise in temperature with considerably raised sensitivity of all the senses and a disproportionate sensitivity to touch, noises, light, cold air — especially draughts and jarring — as can be the case in meningitis. Along with nasal catarrhs, there may be catarrhs of the larynx and trachea, with slight mucus, accompanied a typical cough, which is dry, rough, and barking, with hoarseness. In the digestive organs, Belladonna affects acute gastric catarrhs. Belladonna is also common to Traumeel, Spigelon, Viburcol, BHI-Inflammation, BHI-Neuralgia, and BHI-Recovery formulas.

BHI-Inflammation: Contains Rhus toxicodendron for cases of weakness and paresis. Cases may be aggravated after lying in wet grass. Patients that benefit may have pustular, pruritic skin conditions; joint pain; myelitis; vertigo / dizziness; intercostal pain; and other types of neuralgia. Commonly used in combination with other antihomotoxic agents.

Bryaconeel: Used for neuralgia, serous membrane inflammation such as meningitis (Bryonia cretica), acute feverish conditions, and influenza-like signs. Contains Phosphorus to support parenchymatous organs such as the lung and liver. Moderates severe or overaggressive vicariations. Used in meningitis in cases not responsive to primary therapy.

Cerebrum compositum: Supports cerebral tissue, stem cells, and vessels (Cerebrum suis, Placenta suis, Arnica montana). Treats memory loss and forgetfulness and improving memory (Selenium, Thuja occidentalis, Acidum phosphoricum, Manganum phospohoricum, Semecarpus anacardium, Ambra grisea, Conium maculatum, Medorrhinum-Nosode). Supports cerebral function and vascular structures (Kalium phophoricum). Treats vertigo, stupor, headache, and weakness (Gelsemium sempervirens, Kalium bichromicum, Ruta graveolens) anxiety (Aconitum napellus), and exhaustion (China, Amarita cocculus). Supports capillary and other circulation, as well as lymph (Aesculus hippocastanum) and enzyme systems and difficulty sleeping (Hyoscyamus niger).

Coenzytne compositum: Supports energy production through enzyme induction and repair, and is useful in repairing damage to enzyme systems of metabolism and following administration of drugs injurious to metabolism. Sulfhydral groups in Cysteinum assist in repairing therapeutic damage and in cases of forelimb weakness. Phase remedy in Degeneration and Dedifferentiation phases.

Cruroheel: Has strong connective tissue effects and is useful in difficult cases or those with strong vicariations.

Discus compositum: Clears the deep matrix and supports connective tissue repair, and treats irritation originating in the spinal column. Contain a number of useful remedies that particularly benefit musculoskeletal function, including Funiculus umbicalis suis (also contained in Cutis compositum, Blacenta compositum, Tbyroidea compositum, Tonsilla compositum, and Zeel) for debility. Treats arteriosclerosis, cervical spondylosis, collagen diseases, scleroderma, fibromas, vascular pathology, geriatric indications of all kinds, dystonia of the autonomic nervous system, autoimmune diseases, damage from antibiotics and other drugs, general iatrogenic damage, multiple sclerosis, and muscular atrophy. Also contains Niconitamidum, which is used to activate the energy metabolism in insufficiencies of the respiratory chain. The substance, which occurs naturally in the body, is an important component of NAD and NADP. Treats deficiencies of Nicotinamidum that lead to mental and neurological disturbances. It is common to the remedies Coenzytne compositum, Discus compositum, Ginseng compositum, Ubichinon compositum, Zeel, and BHI-Enzyme.

Echinacea compositum: Contains Aconitum, which is indicated for catarrhs, neuralgic symptoms with paresthesia, hyperthermia, and encephalitis with very high temperatures (e.g. post-vaccinial encephalitis or meningo-encephalitis, which may be activated by the implantation of living cells). Low potencies are normally given in pyrexia and organic complaints. The component Aconitum is common to several useful remedies, including Barijodeel, Bryanconeel, Cerebrum compositum, Gripp-Heel, and Traumeel. Baptisia is included for meningitis and encephalitis, serious feverish infections, general blood poisoning, and states of confusion. Aesculus compositum, Arnica-Heel, and other complexes are also included.

Engystol N: Has antiviral effects through immunostimulation.

Galium-Heel: Phase remedy in the matrix and cellular phases. Provides powerful support of the immune system (Echinacea augustifolia). Assists in drainage of cell and matrix, supports renal tubular function, and decreases swelling and edema (Apis mellifica, Galium aparine, and Galium mollugo). It is a critical component in the deep detoxification formula. Doses should be administered with regard to clinical condition and response, with the dose reduced if strong reactions are noted.

Gelsemium homaccord: Treats neuralgia and nerve pain, headache, and posterior weakness. Commonly required in aging large-breed dogs. This is a major antihomotoxic agent used in many neuropathy cases. Think of this agent in trembling pets because Gelsemium is known as the “trembling” remedy.

Ginseng compositum: Treats eyelid weakness and exhaustion.

Glyoxal compositum: Provides mitochondrial repair of damaged enzyme systems in Degeneration and Dedifferentiation phase disorders.

Listeriosis nosode: This remedy is not available in any of the homotoxicology combinations, but could be useful as a single remedy. The zoonotic organism Listeria monocytogenes causes a disease characterized by granulomatous meningoencephalitis in small animals.

Lymphomyosot: Used after cortisone therapy and for mesenchymal purging in chronic disease states.

Neuralgo-Rheum-Injeel: The components Causticum Hahnemanni and Rhus toxicodenron are powerful neurological remedies that cover a wide variety of chronic rheumatic-arthritic complaints, skin conditions, and intercostalsciatic neuralgias.

Placenta compositum: Supports hypophysis after cortisone therapy. Contains sulfur to support enzyme and metabolic repair. Regenerative of hypophyseal-adrenal axis, and repairs vascular structures. Used intermittently in endocrine disorders.

Psorinonheel: Useful in deep, constitutional / genetic homotoxicoses. Consider in experimental application in inherited conditions. This remedy contains Cicuta, which is indicated for meningitis with hypersensitivity. It is a complementary remedy in tuberculous meningitis.

Solidago compositum: Deposition Phase remedy needed to remove debris from the matrix after regressive vicariation begins. In Traditional Chinese Medicine, the Kidney Chi governs the Brain, and as such, neurological issues may benefit from support of the Kidney and related tissues. Part of the deep detoxification formula. An interesting indication in this remedy is for Coxsackie virus nosode, which is used for abacterial meningitis and encephalitis.

Spigelon: Helpful for symptoms of headache, cerebral conditions with inflammation, and weakness of connective tissues.

Thyroidea compositum: Used for matrix drainage and autoregulation repair. Contains low levels of thyroid, pineal, spleen, bone marrow, umbilical cord, and liver to support glandular function and repair. Galium aparine drains the matrix and cellular components. Cortisonum aceticum in low potency assists in repairing damage from excess levels of cortisone. Precursors and Krebs cycle constituents promote energy metabolism through the Michae-lis-Menten law of enzyme activity. Pulsatilla and Sulfur assist in regulation rigidity-type situations. Part of the deep detoxification formula.

Tonsilla compositum: Main antihomotoxic drug for chronic diseases involving endocrine disorders. Supports a wide number of tissues including tonsil, lymph node, bone marrow, umbilical cord (stem cell precursors), spleen, hypothalamus, liver, embryo, and adrenal cortex. Contains Cortisonum aceticum and thyroid hormone in nanodilutions. Also contains Psorinum for deep constitutional, lack of reaction cases. Degeneration Phase agent.

Ubichinon compositum: Provides mitochondrial repair of energy production mechanisms. Used in chronic diseases and iatrogenic injury to mitochondria from antibiotic therapy, and is part of the deep detoxification formula. Parabenzochinon, a critical component in this regard, is indicated for autoimmune issues, and has been recommended for a state of paresis occurring after poliomyelitis, encephalitis or vaccinations, disturbance in neuromuscular coordination, conditions such as multiple sclerosis and tumors in the spinal area with pains and paresis, and brain tumors. In many cases of meningeal irritation, parabenzoquinone deals with the terrible pains better than an opiate.

Authors’ suggested protocols

Nutrition

Brain / nerve and immune support formulas: 1 tablet for each 25 pounds of body weight BID.

Phosphatidyl serine: 25 mgs for each 25 pounds of body weight BID.

Lecithin / phosphatidyl choline: One-fourth teaspoon for each 25 pounds of body weight BID.

Betathyme: 1 capsule for each 35 pounds of body weight BID (maximum, 2 capsules BID).

Essential fats: One-half teaspoon for every 35 pounds of body weight with food.

Magnesium: 10 mgs for every 10 pounds of body weight SID.

Chinese herbal medicine / acupuncture

For granulamatous meningoencephalitis, the patent formula is Yin Qiao San. It contains arctium (Niu bang zi), forsythia (Lian qiao), honeysuckle (Jin yin hua), licorice (Can cao), lophatherum (Dan zhu ye), mint (Bo he), phragmites root (Lu gen), platycodon (Jie geng), schizonepeta (Jing jie), and soybean (Dan dou chi). It is dosed according to the manufacturer’s recommendation. Yin Qiao San has been shown experimentally to decrease inflammation. It inhibited dimethlybenzine-induced increase in skin capillary permeability. It also has antipyretic effects similar to aspirin. In addition it has been shown to have antibacterial and antiviral efficacy (Shanghai Health and Epidemic Prevention Station 1960). Finally, it has analgesic properties as demonstrated using hot plate and acetic torsion experiments in mice. It was used to treat encephalitis B in 37 people with good response. In another study on people with encephalitis (nonspecified origin), 74 of 81 people recovered completely, 2 did not respond completely and 5 people died.

An alternative herbal supplement is H25 granulamatous meningoencephalitis Disorder at a dose of 1 capsule per 10 to 20 pounds twice daily. In addition to the herbs in Yin Qiao San, H25 granulamatous meningoencephalitis also contains achyranthes (Niu xi), buffalo horn shavings (Niu jiao), chrysanthemum (ju hua), coix (Yi yi ren), gastrodia (Tian ma), grass-leaf sweet-flag root (Shi chang pu), hoelen spirit (Fu shen), isatis leaf (Da qing ye), isatis root (Ban Ian gen), papaya (Mu gua), phellodendron (Huang bai), pueraria (Ge gen), scutellaria (Huang qin), silkworm (Jiang can), and uncaria (Gou teng).

These formulas can be combined with conventional drugs, but often are only needed for a short period of time.

The author uses the following acupuncture points for granulamatous meningoencephalitis: ST36, GV14, CV17 and GB20.

For forelimb neuropathies, the authors recommend H41 Forelimb Paralysis at a dose of 1 capsule per 10 to 20 pounds twice daily. In addition to the herbs discussed above, H41 Forelimb Paralysis contains codonopsis (Dang shen) and scorpion (Quan xie), which increase the efficacy of the formula.

The author recommends the following acupuncture points: LIU, SI9, TH6, LI10, ST36, and Bai Hui.

For hindlimb neuropathies the authors recommend H 72 Hindlimb Paralysis / Incontinence at a dose of 1 capsule per 10 to 20 pounds twice daily. In addition to the herbs mentioned above, H72 Hindlimb Paralysis / Incontinence contains American ginseng (Xi yang shen), ciborium (Gou ji), cynomorium (Suo yang), fossil bones / raw (Long gu), lindera (Wu yao), mantis egg case (Sang piao xiao), polygonatum (Yu zhu), and tortoise plastron (Gui ban). These herbs enhance the function of the herbal supplement.

The author uses the following acupuncture points: ST36, UB60, BL30, and Bai Hui.

For facial neuropathies the authors use H 73 Facial Nerve Paralysis at a dose of 1 capsule per 10 to 20 pounds twice daily. In addition to the herbs listed above, H 73 Facial Nerve Paralysis contains scorpion (Quan xie) to improve the efficacy of the formula.

The author recommends the following acupuncture points: ST4, ST6,ST7, and SI9.

Homotoxicology

Deep detoxification may assist noninherited conditions, and support of energy metabolism through the use of catalysts should be considered. Use of antihomotoxic agents that match the patient’s symptoms may be helpful. Treatment must be individualized to the specific patient’s needs. Any clinician successfully treating either inherited or acquired polyneuropathies should report their findings for publication.

GME (granulamatous meningoencephalitis)

Symptom formula: Two protocols exist.

1. Administer Echinacea compositum IV and Solidago compositum and Galium-Heel as an autosanguis, and dispense anoral cocktail consisting of Traumeel, Psorinoheel, and Aesculus compositum BID to TID. Use Ubichinon compositum orally BID. Administer Spigelon for pain and inflammation associated with the illness, and consider Listeria nosode, obtained from a single remedy company, or Heel-Germany.

2. Administer Gelsemium homaccord, BHI-Inflammation, Spigelon, and Traumeel S mixed together and given PO BID for 3 weeks, then alternate with Pulsatilla compositum in an attempt to shift regulation rigidity. Give Cerebrum compositum 1 to 3 times weekly. Consider autosanguis therapy.

Deep detoxification formula: Galium-Heel, Lymphomyosot, Hepar compositum, Solidago compositum, Thyroidea compositum (alternated with Tonsilla compositum in inflammatory conditions), Coenzyme compositum, and Ubichinon compositum combined and given orally twice weekly. Consider giving these and the above symptom formula agents as autosanguis therapy.

Acquired peripheral neuropathies

In nearly all cases it would be appropriate to administer Neuralgo-Rheum and Discus compositum 2 to 3 times weekly by injection.

Deep detoxification formula: Galium-Heel, Lymphomyosot, Hepar compositum, Solidago compositum, Thyroidea compositum (alternated with Tonsilla compositum in inflammatory conditions), Coenzyme compositum, and Ubichinon compositum combined and given orally twice weekly. Consider giving these agents as autosanguis therapy.

Diabetic polyneuropathy

Lymphomyosot, Syzygium compositum, and Mucosa compositum given orally in conjunction with alpha-lipoic acid. (See also Diabetes mellitus protocol).

Hypothyroid polyneuropathy

Administer in addition to proper thyroid hormone replacement therapy. Thyroidea compositum given twice weekly alone or as part of the deep detoxification formula if the condition is stable.

Iatrogenic pharmaceutical injury (vincristine, vinblastine, and colchicines)

Deep detoxification formula, IV fluid support, and avoidance of the offending drug until it can be cleared.

Idiopathic

Deep detoxification formula, and also consider BHI-Body Pure for 1 to 3 months.

Immune-mediated (autoimmune such as systemic lupis erythmatosis)

See autoimmune protocols.

Infectious (Neospora caninum and FeLV)

Use clindimycin for Neospora. See the FeLV protocol section. Tonsilla compositum given twice weekly and Echinacea compositum daily by injection during acute involvement. Engystol may improve immune function given daily. Traumeel S if acute inflammation or swelling is involved.

Toxic injury (metals, solvents such ascarbon tetracycline, organophosphate, insecticides)

Deep detoxification formula in conjunction with appropriate antidote, plus supportive and chelation therapy.

Product sources

Nutrition

Brain / nerve and immune support formulas: Animal Nutrition Technologies. Alternatives: Immune System Support — Standard Process Veterinary Formulas; Immuno Support — Rx Vitamins for Pets; Immugen — Thorne Veterinary Products.

Phosphatidyl serine: Integrative Therapuetics.

Lecithin / phosphatidyl choline: Designs for Health.

Betathyme: Best for Your Pet. Alternative: Moducare Thorne Veterinary Products.

Beyond essential fats: Natura Health Products. Alternatives: Flax oil — Barlean’s Organic Oils; Hemp oil — Nature’s Perfect Oil; Ultra EFA — Rx Vitamins; Omega- 3,6,9 — Vetri Science.

Magnesium: Over the counter.

Chinese herbal medicine

Yin Qiao San: Mayway Corp.

Formulas H25 granulamatous meningoencephalitis, H41 Forelimb Paralysis, H72 Hindlimb Paralysis / Incontinence, and H73 Facial Nerve

Paralysis: Natural Solutions, Inc.

Homotoxicology

BHI / Heel Corporation

Categories
Veterinary Drugs

Cytarabine

Chemistry

A synthetic pyrimidine nucleoside antimetabolite, cytarabine occurs as an odorless, white to off-white, crystalline powder with a pKa of 4.35. It is freely soluble in water and slightly soluble in alcohol. Cytarabine is also commonly known as ARA-C or Cytosine Arabinoside. It may also be known as 1-beta-D-Arabinofuranosylcytosine or Arabinosylcytosine.

Storage – Stability – Compatibility

Cytarabine sterile powder for injection should be stored at room temperature (15-30°C). After reconstituting with bacteriostatic water for injection, solutions are stable for at least 48 hours when stored at room temperature. One study however, demonstrated that the reconstituted solution retains 90% of its potency for up to 17 days when stored at room temperature. If the solution develops a slight haze, the drug should be discarded.

Cytarabine is reportedly compatible with the following intravenous solutions and drugs: amino acids 4.25%/dextrose 25%, dextrose containing solutions, dextrose-saline combinations, dextrose-lactated Ringer’s injection combinations, Ringer’s injection, lactated Ringer’s injection, sodium chloride 0.9%, sodium lactate 1/6 M, corticotropin, lincomycin HCl, methotrexate sodium, metoclopramide HCl, potassium chloride, prednisolone sodium phosphate, sodium bicarbonate, and vincristine sulfate.

Cytarabine compatibility information conflicts or is dependent on diluent or concentration factors with the following drugs or solutions: cephalothin sodium, gentamicin sulfate, hydrocortisone sodium succinate, and methylprednisolone sodium succinate. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel).

Cytarabine is reportedly incompatible with the following solutions or drugs: carbenicillin disodium, fluorouracil, regular insulin, nafcillin sodium, oxacillin sodium, and penicillin G sodium.

Pharmacology

Cytarabine is converted intracellularly into cytarabine triphosphate which apparently competes with deoxycytidine triphosphate, thereby inhibiting DNA polymerase with resulting inhibition of DNA synthesis. Cytarabine is cell phase specific, and acts principally during the S-phase (DNA synthesis). It may also, under certain conditions, block cells from the G1 phase to the S phase.

Uses – Indications

In veterinary medicine, cytarabine is used primarily in small animals as an antineoplastic agent for lymphoreticular neoplasms, myeloproliferative disease and CNS lymphoma. Refer to the Dosages below or the Protocols (at the end of this section), for more information.

Pharmacokinetics

Cytarabine has very poor systemic availability after oral administration and is only used parenterally. Following IM or SQ injections, the drug peaks in the plasma within 20-60 minutes, but levels attained are much lower than with an equivalent IV dose.

Cytarabine is distributed widely throughout the body, but crosses into the CNS in only a limited manner. If given via continuous IV infusion, CSF levels are higher than with IV bolus injection and can reach 40-60% of those levels found in the plasma. In humans, cytarabine is only about 13% bound to plasma proteins. The drug apparently crosses the placenta, but it is not known if it enters milk.

Circulating cytarabine is rapidly metabolized by the enzyme cytidine deaminase, principally in the liver, but also in the kidneys, intestinal mucosa, and granulocytes, to the inactive metabolite ara-U (uracil arabinoside). About 80% of a dose is excreted in the urine within 24 hours as both ara-U (~90%) and unchanged cytarabine (~10%).

Contraindications – Precautions – Reproductive Safety

Cytarabine is contraindicated in patients hypersensitive to it. Because of the potential for development of serious adverse reactions, cytarabine should only be used in patients who can be adequately and regularly monitored.

The person preparing or administering cytarabine for injection, need not observe any special handling precautions other than wearing gloves. However, should any contamination occur, thoroughly wash off the drug from skin or mucous membranes.

Cytarabine’s safe use in pregnancy has not been established and it is potentially teratogenic and embryotoxic.

Adverse Effects – Warnings

The principal adverse effects of cytarabine is myelosuppression (with leukopenia being most prevalent), but anemia and thrombocytopenia can also be seen. Myelosuppressive effects are more pronounced with IV administration and reach a nadir at 5-7 days, and generally recover at 7-14 days.

Gi disturbances (anorexia, nausea, vomiting, diarrhea), conjunctivitis, oral ulceration, hepatotoxicity and fever may also be noted with cytarabine therapy. Anaphylaxis has been reported, but is believed to occur very rarely.

Cytarabine is a mutagenic and potentially carcinogenic agent.

Overdosage – Acute Toxicity

Cytarabine efficacy and toxicity (see Adverse Effects) are dependent not only on the dose, but also the rate the drug is given. In dogs, the IV LD50 is 384 mg/kg when given over 12 hours and 48 mg/kg when infused IV over 120 hours. Should an inadvertent overdose occur, supportive therapy should be instituted.

Drug Interactions

Presumably due to causing alterations in the intestinal mucosa, cytarabine may decrease the amount of digoxin (tablets only) that is absorbed after oral dosing. This effect may persist for several days after cytarabine has been discontinued.

Limited studies have indicated that cytarabine may antagonize the anti-infective activity of gentamicin or flucytosine. Animals receiving either of these drugs with cytarabine should be closely monitored for decreased anti-infective efficacy. Drug/Laboratory Interactions

None reported.

Doses

For more information, refer to the protocol references found in the appendix or other protocols found in numerous references, including: Handbook of Small Animal Practice; Handbook of Small Animal Therapeutics; and Textbook of Veterinary Internal Medicine, 3rd Edition.

Doses for dogs:

For susceptible neoplastic diseases:

a) 100 mg/m2 IV or SQ once daily for 2-4 days; repeat prn 20 mg/m2 intrathecally for 1-5 days.

b) 100 mg/m2 IV (slowly), IM, or SQ once daily for 4 days, if no toxicity develops may increase dose by 50%.

Doses for cats:

For susceptible neoplastic diseases:

a) 100 mg/m2 IV or SQ once daily for 2-4 days; repeat prn 20 mg/m2 intrathecally for 1-5 days.

b) 100 mg/m2 once daily for 2 days; 10 mg/m2 once daily for 2 weeks.

Monitoring Parameters

1) Efficacy; see the Protocol section or refer to the references from the Dosage section above for more information.

2) Toxicity; see Adverse Effects above. Regular hemograms are mandatory. Periodic liver and kidney function tests are suggested.

Client Information

Clients must be briefed on the possibilities of severe toxicity developing from this drug, including drug-related mortality. Clients should contact the veterinarian should the patient exhibit any symptoms of profound depression, abnormal bleeding and/or bruising.

Dosage Forms – Preparations – FDA Approval Status – Withholding Times

Veterinary-Approved Products:

None

Human-Approved Products:

Cytarabine Powder for Injection 100 mg, 500 mg, 1 g & 2 g in vials; Cytosar-U® (Upjohn) (Rx); generic (Rx)

Cytarabine Injection 20 mg/ml in 5 ml vials and 50 ml bulk vials; Tarabine PRS® (Adria) (Rx)

Categories
Veterinary Drugs

Cyclophosphamide

Chemistry

A nitrogen-mustard derivative, cyclophosphamide occurs as a white, crystalline powder that is soluble in water and alcohol. The commercially available injection has pH of 3 to 7.5. Cyclophosphamide may also be known as CPM, CTX or CYT.

Storage – Stability – Compatibility

Cyclophosphamide tablets and powder for injection should be stored at temperatures less than 25°C. They may be exposed to temperatures up to 30°C for brief periods, but should not be exposed to temperatures above 30°C. Tablets should be stored in tight containers. The commercially available tablets (Cytoxan®) are manufactured in bi-level manner with a white tablet containing the cyclophosphamide found within a surrounding flecked outer tablet. Therefore, the person administering the drug need not protect their hands from cyclophosphamide exposure unless the tablets are split or crushed.

Cyclophosphamide injection may be dissolved in aromatic elixir to be used as an oral solution. When refrigerated, it is stable for 14 days.

After reconstituting the powder for injection with either sterile water for injection or bacteriostatic water for injection the product should be used within 24 hours if stored at room temperature and within 6 days if refrigerated.

Cyclophosphamide is reportedly compatible with the following intravenous solutions and drugs: Amino acids 4.25%/dextrose 25%, D5 in normal saline, D5W, sodium chloride 0.9%. It is also compatible in syringes or at Y-sites for brief periods with the following: bleomycin sulfate, cisplatin, doxorubicin HCl, droperidol, flurouracil, furosemide, heparin sodium, leucovorin calcium, methotrexate sodium, metoclopramide HCl, mitomycin, vinblastine sulfate, and vincristine sulfate. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel).

Pharmacology

While commonly categorized as an alkylating agent, the parent compound (cyclophosphamide) is not, but cyclophosphamide’s metabolites such as phosphoramide mustard do act as alkylating agents interfering with DNA replication, RNA transcription and replication, and ultimately disrupting nucleic acid function. The cytotoxic properties of cyclophosphamide are also enhanced by phosphorylating activity the drug possesses.

Cyclophosphamide has marked immunosuppressive activity and both white cells and antibody production are decreased, but the exact mechanisms for this activity have not been fully elucidated.

Uses – Indications

In veterinary medicine, cyclophosphamide is used primarily in small animals, both as an antineoplastic agent and an immunosuppressant. Refer to the Dosages section below or the Protocols (at the end of this section), for more information. Cyclophosphamide has also been used as a chemical shearing agent in sheep.

Pharmacokinetics

While the pharmacokinetics of cyclophosphamide have not been detailed in dogs or cats, it is presumed that the drug is handled in a manner similar to humans. The drug is well absorbed after oral administration with peak levels occurring about 1 hour after dosing. Cyclophosphamide and its metabolites are distributed throughout the body, including the CSF (albeit in subtherapeutic levels). The drug is only minimally protein bound and is distributed into milk and presumed to cross the placenta.

Cyclophosphamide is metabolized in the liver to several metabolites. Which metabolites account for which portion of the cytotoxic properties of the drug are a source of controversy. After IV injection, the serum half-life of cyclophosphamide is approximately 4-65 hours, but drug/metabolites can be detected up to 72 hours after administration. The majority of the drug is excreted as metabolites and unchanged drug in the urine.

Contraindications – Precautions – Reproductive Safety

There are no absolute contraindications to the use of cyclophosphamide, but it must be used with caution in patients with leukopenia, thrombocytopenia, previous radiotherapy, impaired hepatic or renal function, or in those for whom immunosuppression may be dangerous (e.g., infected patients).

Because of the potential for development of serious adverse effects, cyclophosphamide should only be used in patients who can be adequately and regularly monitored.

Cyclophosphamide’s safe use in pregnancy has not been established and it is potentially teratogenic and embryotoxic. Cyclophosphamide may induce sterility (may be temporary) in male animals.

Adverse Effects – Warnings

Primary adverse effects in animals associated with cyclophosphamide are myelosuppression, gastroenterocolitis (nausea, vomiting, diarrhea), alopecia (especially in breeds where haircoat continually grows, e.g., Poodles, Old English Sheepdogs), and hemorrhagic cystitis.

Cyclophosphamide’s myelosuppressant effects primarily impact the white cells lines, but may also effect red cell and platelet production. The nadir for leukocytes occurs generally between 7-14 days after dosing and may require up to 4 weeks for recovery.

Sterile hemorrhagic cystitis induced by cyclophosphamide is thought to be caused by the metabolite acrolein. Up to 30% of dogs receiving long-term (>2 months) cyclophosphamide can develop this problem. In cats, cyclophosphamide-induced-cystitis (CIC) is rare. Initial symptoms may present as hematuria and dysuria. Because bacterial cystitis is not uncommon in immune-suppressed patients, it must be ruled out by taking urine cultures. Diagnosis of CIC is made by a negative urine culture and inflammatory urine sediment found during urinalysis. Because bladder fibrosis and/or transitional cell carcinoma of the bladder is also associated with cyclophosphamide use, these may need to be ruled out by contrast radiography. It is believed that the incidence of cyclophosphamide-induced-cystitis may be minimized by increasing urine production and frequent voiding. The drug should be given in the morning and animals should be encouraged to drink/urinate whenever possible. Recommendations for treatment of CIC include discontinuation of the cyclophosphamide, furosemide, and corticosteroids. Refractory cases have been treated by surgical debridement, 1% formalin or 25% DMSO instillation in the bladder.

Other adverse effects that may be noted with CTX therapy include pulmonary infiltrates and fibrosis, depression, immune-suppression with hyponatremia, and leukemia.

In recovering dogs with immune-mediated hemolytic anemia, taper the withdrawal of the drug slowly over several months and monitor for early signs of relapse. Rapid withdrawal can lead to a rebound hyperimmune response.

Overdosage – Acute Toxicity

There is only limited information on acute overdoses of this drug. The lethal dose in the dogs has been reported as 40 mg/kg IV. If an oral overdose occurs, the animal should be hospitalized for supportive care.

Cyclophosphamide: Drug Interactions

Phenobarbital (or other barbiturates) given chronically may increase the rate of metabolism of cyclophosphamide via microsomal enzyme induction and increase the likelihood of toxicity development.

Allopurinol and thiazide diuretics may increase the myelosuppression caused by cyclophosphamide.

The absorption of orally administered digoxin tablets and elixir may be decreased when cyclophosphamide is also being given. This effect may even occur several days after the cyclophosphamide was administered.

Succinylcholine metabolism may be slowed with resulting prolongation of effects, as cyclophosphamide may decrease the levels of circulating pseudocholinesterases.

Use caution when using cyclophosphamide with other cardiotoxic agents (e.g., doxorubicin) as potentiation of cardiotoxicity may occur.

Drug/Laboratory Interactions

Uric acid levels (blood and urine) may be increased after cyclophosphamide use. The immunosuppressant properties of cyclophosphamide may cause false negative skin test results to a variety of antigens, including tuberculin, Candida, and Trichophyton.

Cyclophosphamide: Doses

For more information, refer to the protocol references found in the appendix or other protocols found in numerous references, including: Handbook of Small Animal Practice; Handbook of Small Animal Therapeutics; Current Veterinary Therapy X: Small Animal Practice; and Textbook of Veterinary Internal Medicine, 3rd Edition.

Doses for dogs:

For susceptible neoplastic diseases:

a) 50 mg/m2 PO or IV 4 days/week.

b) 50 mg/m2 PO or IV 4 days/week or 200 mg/m2 IV weekly.

c) For multiple myeloma in patients refractory to melphalan: 1 mg/kg PO once daily.

For macroglobulinemia in patients refractory to chlorambucil: 1 mg/kg PO once daily.

As an immunosuppressant:

a) For adjunctive therapy for immune-mediated hemolytic anemia (probably should be reserved for dogs w/fulminant intravascular hemolysis, autoagglutination or those that require repeated transfusion or have persistant reticulocytopenia): Initially at 2 mg/kg/day IV or PO for 4 days; no treatment for 3 days and then repeat cycle.

b) For immune-mediated hemolytic anemia: 50 mg/m2 for 4 consecutive days per week. May be overtreatment; efficacy not proven.

c) For immune-mediated hemolytic anemia if glucocorticoids unsuccessful: Add cyclophosphamide at 2.2 mg/kg (50 mg/m2) PO or IV once daily for 4 consecutive days of each week. Discontinue CTX when PC V increases significantly and attempt to slowly reduce steroids dose and D/C eventually, if possible.

c) For immune-mediated hemolytic anemia: Usually steroids used initially, but cyclophosphamide (&/or azathioprine) may be indicated early in therapy for cases with severe hemolysis and agglutination. Cyclophosphamide 2 mg/kg PO once daily for 4 days, stop for 3 days, then repeat. Animals should receive steroids, CTX, and azathioprine if they exhibit massive agglutination and intravascular hemolysis (poor prognosis).

d) For immune-mediated thrombocytopenia: If corticosteroids ineffective, may use either vincristine, azathioprine or cyclophosphamide. CTX dose: 50 mg/m2 PO once daily for 3-4 days/week. May give initial doses IV. Decrease dose if renal or hepatic impairment exists. After 1-4 weeks, taper dose and discontinue after platelet count is >100,000/µl. Serious bleeding secondary to thrombocytopenia and hemorrhagic cystitis can occur; use cautiously.

e) For rheumatoid arthritis: In conjunction with a glucocorticoid (predniso(lo)ne); give CTX PO once daily in the AM for 4 consecutive days each week at 2.5 mg/kg if weighs <10 kg, 2 mg/kg if 10-35 kg, and 1.5 mg/kg if >35 kg. Discontinue: 1 month after remission of synovial inflammation (determined from joint tap), after 4 months of treatment, or if hemorrhagic cystitis develops. If cystitis develops, switch to azathioprine.

f) For polymyositis: In conjunction with steroids, if steroids alone are ineffective: 1 mg/kg PO once daily for 4 days, then off 3 days. Decrease concurrent prednisone dose to 1 mg/kg/day.

Doses for cats:

For susceptible neoplastic diseases:

a) For advanced mammary carcinoma: Doxorubicin: 30 mg/m2 IV every 3 weeks up to 4-8 treatments. Cyclophosphamide: 100 mg/ m2 PO once daily on days 3, 4, 5, and 6 after doxorubicin.

As an immunosuppressant:

a) Give 2.5 mg/kg once daily PO for 4 consecutive days out of 7 for up to 3 weeks. Alternatively, 7 mg/kg IV may be given once a week.

b) For immune-mediated hemolytic anemia: 50 mg/ m2 for 4 consecutive days per week. May be overtreatment; efficacy not proven.

c) For rheumatoid arthritis: In conjunction with a glucocorticoid (predniso(lo)ne); give CTX PO once daily in the AM for 4 consecutive days each week at 2.5 mg/kg. Discontinue 1 month after remission of synovial inflammation (determined from joint tap), after 4 months of treatment, or if hemorrhagic cystitis develops. If cystitis develops, switch to azathioprine.

Doses for sheep:

As a chemical defleecing agent:

a) 25 mg/kg PO once.

Monitoring Parameters

1) Efficacy. See the Protocol section or refer to the references from the Dosage section above for more information.

2) Toxicity, see Adverse Effects above. Regular hemograms and urinalyses are mandatory.

Client Information

Clients must be briefed on the possibilities of severe toxicity developing from this drug, including drug-related mortality. Clients should contact veterinarian should the animal exhibit any symptoms of abnormal bleeding and/or bruising.

Although no special precautions are necessary with handling intact tablets, direct exposure should be avoided to split or crushed tablets, oral elixir, or the animal’s urine or feces. Should exposure occur, wash the area thoroughly with soap and water.

Dosage Forms – Preparations – FDA Approval Status – Withholding Times

Veterinary-Approved Products:

None

Human-Approved Products:

Cyclophosphamide Tablets 25 mg, 50 mg; Cytoxan® (Mead Johnson Oncology); (Rx)

Cyclophosphamide Powder for Injection 100 mg, 200 mg, 500 mg, 1 g and 2 g vials; Cytoxan® (with sodium chloride) and Cytoxan® Lyophilized (with mannitol) (Mead Johnson Oncology) (Rx), Neosar® (Pharmacia & Upjohn) (Rx)