Biomedical subjects

J M Cline

Publications and source records attributed to J M Cline.

61 records · Page 4Linked to original sources

PubMedDate not supplied

Naturally occurring and experimental diabetes in cynomolgus monkeys: a comparison of carbohydrate and lipid metabolism and islet pathology.

Diabetes is a major health problem of increasing incidence in the United States. Diabetes research has been limited by lack of availability of good animal models, particularly for the study of comorbidities associated with diabetes. We investigated the use of cynomolgus monkeys as an animal model of both type 1 and type 2 diabetes and compared these naturally occurring diseases with streptozotocin-induced diabetes. Both type 1 diabetics and streptozotocin-induced diabetics present with sudden onset of hyperglycemia and are ketosis prone without exogenous insulin. Type 2 diabetics can have a very long period of moderate hyperglycemia and hypertriglyceridemia and only require exogenous insulin therapy if pancreatic islet reserves are depleted. Type 2 diabetes is preceded by a relatively long period of insulin resistance that is associated with obesity and dyslipidemia. As insulin resistance progresses, islet size and insulin content increases initially. However, with sustained periods of insulin resistance, islet amyloid polypeptide (IAPP) is deposited in islets and can replace normal islet architecture, resulting in an insulin-deficient state. Appearance of IAPP also occurs in human type 2 diabetics but not in conventional rodent models. Unlike type 2 diabetes, neither type 1 nor streptozotocin-induced diabetes is associated with IAPP. Rather, islets can appear normal histologically, but have decreased insulin secretion and immunostaining. Further, the amount of insulin present in the islet is correlated with plasma insulin levels following glucose challenge. Studies are ongoing to determine the pathogenic changes associated with the progression of diabetes and to find novel drug treatments for diabetics.

Animals↗

PubMedDate not supplied

Is maintenance chemotherapy appropriate for the management of canine malignant lymphoma?

A retrospective study was conducted between two groups of dogs with histopathologically diagnosed multicentric malignant lymphoma to determine if treatment with either short-term or continuous chemotherapy resulted in a significant difference in first-remission length or survival time. One group was treated with single agent, short-term (three cycles) of doxorubicin. Dogs obtaining complete remission while receiving doxorubicin were given no further chemotherapy. The other group received combination agent, long-term chemotherapy consisting of cyclophosphamide, vincristine sulfate, and prednisone (COP). Dogs obtaining complete remission on COP by the end of 6 weeks were given maintenance chemotherapy of cyclophosphamide, prednisone and methotrexate. One hundred and five dogs were treated. Thirty-eight dogs received doxorubicin and 67 received COP. All dogs were evaluated at 6 weeks for response to chemotherapy and followed until death. No significant differences were observed in first-remission length or survival time when comparing dogs treated with either short-term doxorubicin or long-term COP (P greater than 0.05). Sex, weight, age, clinical stage, performance status, histopathologic cell type, and grade were not significant factors for determining the responsiveness to either chemotherapy protocol. However, within either treatment group, significant differences in first-remission length were observed in dogs evaluated histopathologically by the Keil and NCI working formulation and in survival time when evaluated by performance status (P less than 0.05).

Animals↗

PubMedDate not supplied

Phase III evaluation of doxorubicin and whole-body hyperthermia in dogs with lymphoma.

Sixty-one dogs with histologically confirmed, untreated, high-grade lymphoma were evaluated and treated with doxorubicin (DOX, 30 mg/m2) alone. Forty-seven dogs (77%) achieved a complete response. Forty-six of the 47 dogs were randomized to receive five additional treatments with doxorubicin +/- whole-body hyperthermia (WBH). Median disease-free survival for the group treated with DOX alone (n = 22) was 189 days and for the DOX plus WBH (n = 24) was 239 days (p = 0.17). After the analysis was adjusted for stratification variables (i.e. institution, weight, stage), the effect of heat on disease-free survival remained statistically insignificant (p = 0.10), but suggested a tendency towards increased disease-free survival in hyperthermic dogs. Intact male dogs had significantly shorter disease-free survival than neutered males and neutered females (178 days vs 266 days, respectively; p = 0.013). No intact females were treated. Body weight, when evaluated as a continuous variable, was found to be a negative prognostic factor (p = 0.036). Tumour volume, stage and institution were not significant. Clinical incidence of cardiac dysfunction was not increased in dogs receiving DOX and WBH; however, post-mortem histological analysis of cardiac tissue suggested that the combined therapy of DOX and WBH was associated with greater myocyte degeneration (p = 0.012) and a tendency for increased cardiac fibrosis (p = 0.08). We concluded that continued refinement of DOX-WBH protocols is warranted, and may ultimately result in significant therapeutic improvement.

Animals↗

PubMedDate not supplied

Serious toxicity associated with annular microwave array induction of whole-body hyperthermia in normal dogs.

Using a regional annular microwave array it was possible to produce a systemic temperature of 42 degrees C in approximately 80 min with applied net power levels of approximately 150 W. Resulting temperature distributions were non-uniform. Sites within the array were above systemic temperature during heating but approximated systemic temperature during the plateau phase. Sites outside of the array were lower than systemic temperature during heating and plateau phases. Dogs allowed to recover from the procedure experienced severe toxicity consisting of lumbar muscle haemorrhage, pain and swelling, and pelvic limb paralysis. Histologically, there was severe myopathy and haemorrhage and oedema in neural tissue in the caudal lumbar spine. Acute necrosis of lymphoid tissue was observed in all dogs. Temperatures in muscle reached 43-46 degrees C and were higher than at other measured sites. Spinal canal temperatures were essentially equal to rectal temperature, approximating 42-43 degrees C during heating and plateau phases. These data suggest regionally induced whole-body hyperthermia may result in: (1) power deposition non-uniformity leading to muscle and spinal canal temperatures which exceed systemic temperature and which are sufficient to cause serious toxicity; (2) systemic temperature non-uniformity which is undesirable for systemic thermochemotherapy; and (3) possible immunological dysfunction associated with lymphoid necrosis. Extreme caution must be exercised in administering energy to localized regions of human patients with the intent of elevating systemic temperature.

Animals↗

PubMedDate not supplied

Effect of whole-body hyperthermia on the pharmacokinetics and toxicity of lonidamine in dogs.

The pharmacokinetics and toxicity of intravenous lonidamine were investigated in dogs receiving four cycles of lonidamine (400 or 800 mg/m2) +/- whole-body hyperthermia (WBH). Clearance and volume of distribution in dogs receiving lonidamine during WBH increased 1.6-2.3 and 1.9-3.5-fold respectively, relative to dogs receiving lonidamine under euthermic conditions (p < 0.02). In dogs receiving lonidamine under euthermic conditions or 400 mg/m2 + WBH, the area under the lonidamine concentration versus time curve (AUC) measured during the fourth treatment was 21-58% lower than the first treatment AUC. However, in dogs receiving 800 mg/m2 + WBH, the fourth treatment AUC was four-fold higher than the first treatment AUC (p < 0.02). This suggests repeated exposure to 800 mg/m2 lonidamine and WBH impairs lonidamine metabolism. Weakness, hypoglycaemia, and elevations in amylase, alanine aminotransferase, alkaline phosphatase and bilirubin were more severe or occurred exclusively in dogs receiving 800 mg/m2 + WBH. Since these changes were attributable to marked AUC increases, which occurred secondary to repeated exposure to 800 mg/m2 lonidamine during WBH, 400 mg/m2 was identified as the maximum tolerable dose to be administered intravenously to dogs during WBH.

Alanine Transaminase↗

PubMedDate not supplied

Effect of whole-body hyperthermia on lonidamine and doxorubicin pharmacokinetics and toxicity in dogs.

Six cycles of the maximum tolerable intravenous doses of lonidamine (400 mg/m2) and doxorubicin (30 mg/m2) were administered to three normothermic dogs and three dogs undergoing whole-body hyperthermia (WBH) (42 degrees C X 90 min), at 3-week intervals. Lonidamine pharmacokinetics was unaltered by WBH. WBH increased doxorubicin clearance 1.6-fold, however this trend was not statistically significant. WBH resulted in a 2.4-fold increase in the volume of distribution (Vdss) of doxorubicin relative to dogs treated under euthermic conditions (p < 0.001). This finding suggests tissue extraction of doxorubicin was increased by WBH. The specific tissues in which this occurred is unknown, but myelosuppression and cardiotoxicity were only minimally increased. Therefore, doxorubicin uptake in critical normal tissues was probably unaffected. The biochemical and haematologic toxicities observed 6 h and 1 week after each treatment did not appear to differ in character or severity from that reported in dogs receiving lonidamine +/- WBH or doxorubicin +/- WBH. These results suggest WBH did not decrease the maximum tolerable dose of doxorubicin when given with lonidamine, and that the antitumour activity of this combination should be assessed.

Animals↗

PubMedDate not supplied

Potential complications associated with normothermic lonidamine infusion and with systemic acidosis in dogs receiving lonidamine during whole body hyperthermia (WBH).

The vascular toxicosis of lonidamine (40 mg/h) or vehicle infusion was investigated in six dogs. Vasculitis and thrombosis were observed in veins infused with lonidamine but not in veins infused with vehicle. This finding suggests that it may not be possible to use lonidamine infusion to circumvent therapeutic limitations associated with the oral lonidamine formulation currently used in patients. We also investigated the systemic toxicosis of lonidamine (400 mg/m2; rapid intravenous bolus) or vehicle in six other dogs that developed systemic acidosis (pH < or = 7.0) during whole body hyperthermia (42 degrees C x 90 min). Gross and histologic haemorrhage was observed in all dogs; however, haemorrhagic lesions in acidotic dogs receiving lonidamine + WBH were more severe than changes observed in acidotic dogs receiving vehicle + WBH. These observations confirm the results of in vitro studies which suggest that the combined effect of lonidamine and hyperthermia is enhanced under acidic conditions. Furthermore, these findings indicate that acid-base status of patients receiving lonidamine during WBH must be monitored carefully to avoid serious complications.

Acidosis↗