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Biomedical subjects

H B Lewis

Publications and source records attributed to H B Lewis.

At least 19 recordsLinked to original sources
PubMed1999

Atypical antipsychotic-induced neutropenia in dogs.

DMP 406 is an atypical antipsychotic, antischizophrenic drug, biochemically related to clozapine, which exerts its desired pharmacologic effects through selective antagonism of 5-hydroxytryptamine and dopamine-receptor subtypes. Clozapine therapy is clinically associated with severe granulocytopenia in a small subset of patients. In the course of a 3-month toxicity study in dogs, severe neutropenia, thrombocytopenia, marked myeloid and erythroid left-shifted bone marrow hyperplasia with increased erythrophagocytosis, positive Coombs' tests, and hypergammaglobulinemia occurred in individual females dosed with 30 mg/kg/day of DMP 406. Related but less severe changes were also observed in males. Sera or purified immunoglobulins from affected and control dogs were tested in methylcellulose-based, canine hematopoietic colony-forming unit (CFU) assays with or without DMP 406. Neither size nor number of erythroid or myeloid CFUs differed between cultures containing control or affected dog serum components. Sera from individual affected dogs but not controls resulted in moderate numbers of fibroblast-like CFUs, suggesting DMP 406-associated marrow stromal cell-modifying, serum activities to be present. DMP 406 alone resulted in a concentration-dependent reduction of erythroid and myeloid CFUs with an approximate IC50 of 3.0 microg/mL. Taken together, DMP 406-induced granulocytopenia and bone marrow dyscrasia appear likely to result from both immune-mediated and direct drug-induced myelotoxicity.

Animals↗
PubMed1988

The effect of human recombinant tissue-type plasminogen activator on clinical and laboratory parameters of hemostasis and systemic plasminogen activation in the dog and the rat.

The effect of human recombinant tissue-type plasminogen activator (rt-PA) on parameters of hemostasis and systemic plasminogen activation was studied in the dog and rat. Effects on screening coagulation times, fibrinogen concentration, fibrin/fibrinogen degradation products, and plasminogen and alpha 2-antiplasmin (alpha 2-AP) activities in plasma were examined following single bolus injections of 0.5-5.0 mg/kg, single and repeated 3 hr infusions of 0.75-7.5 mg/kg and 24 hr infusions of 6.0 and 30.0 mg/kg administered intravenously to dogs. Rats receiving single or 14 daily injections of 5.0-30.0 mg/kg i.v. were similarly monitored. Systemic fibrinogenolysis (greater than 50% decrease in fibrinogen, plasminogen or alpha 2-AP values) was observed in dogs receiving greater than or equal to 1.0 mg/kg as a bolus, greater than or equal to 3.75 mg/kg (20.8 micrograms or 1.19 x 10(4) IU kg-1min-1) as a 3 hr infusion and greater than or equal to 6 mg/kg (4.2 micrograms or 2.42 x 10(3) IU kg-1min-1) as a 24 hr infusion; and in rats treated with bolus injections of 30 mg/kg rt-PA. Clinical and laboratory indications of impaired hemostasis and bleeding (anemia, prolonged coagulation times and post-mortem evidence of hemorrhage) were associated with these effects, which together were dose-dependent and influenced by the rate of infusion. The incidence of major hemorrhage was variable and limited to animals receiving prolonged (24 hr) or repeated infusions.

Animals↗
PubMed1988

Cephalosporin-induced immune cytopenia in the dog: demonstration of erythrocyte-, neutrophil-, and platelet-associated IgG following treatment with cefazedone.

Cephalosporin treatment in man has been associated with a low incidence of hemolytic anemia, thrombocytopenia, and neutropenia; some cases have been shown to be immune-mediated. This triad of blood dyscrasias was also demonstrated in our laboratory in a series of toxicity studies in dogs of two cephalosporin compounds, cefonicid and cefazedone; these studies provided evidence for drug-associated immune hemolytic anemia, based on conventional laboratory tests. To further investigate possible immune mechanisms of the cephalosporin-induced cytopenias, we measured erythrocyte-associated, platelet-associated (PAIgG), and serum antineutrophil IgG over the course of cephalosporin treatment, using highly sensitive 125I-staphylococcal protein A (SPA) assays, as well as the direct antiglobulin test; we compared these findings with the hematologic changes. Intravenous treatment with high doses of cefazedone (540 mg/kg/day, increased to a maximum of 840 mg/kg/day for 4 months or until hematologic effects were evident) resulted in a high incidence of anemia (7/14), thrombocytopenia (11/14), and neutropenia (7/14). Of the affected dogs examined, 6/7 with anemia, 9/9 with thrombocytopenia, and 7/7 with neutropenia showed increased levels of the respective cell-associated antibody, compared with untreated controls. Unaffected dosed animals generally did not show these changes. In 3/3 dogs examined following remission of thrombocytopenia, PAIgG returned to levels comparable with controls; as one of these dogs suffered a relapse, increased PAIgG was again observed. Animals sacrificed during cytopenic episodes showed cytologic and histologic evidence of increased hemophagocytosis. We conclude that antibody-mediated blood cell destruction contributes to all three cephalosporin-induced cytopenias in the dog.

Anemia, Hemolytic↗
PubMed1987

The hematologic effects of cefonicid and cefazedone in the dog: a potential model of cephalosporin hematotoxicity in man.

Cephalosporin antibiotics cause a variety of hematologic disturbances in man, the pathogeneses and hematopathology of which remain poorly characterized. There is a need for a well-defined animal model in which these blood dyscrasias can be studied. In four subacute toxicity studies, the intravenous administration of cefonicid or cefazedone to beagle dogs caused a dose-dependent incidence of anemia, neutropenia, and thrombocytopenia after 1-3 months of treatment. A nonregenerative anemia was the most compromising of the cytopenias and occurred in approximately 50% of dogs receiving 400-500 mg/kg cefonicid or 540-840 mg/kg cefazedone. All three cytopenias were completely reversible following cessation of treatment; the time required for recovery of the erythron (approximately 1 month) was considerably longer than that of the granulocytes and platelets (hours to a few days). Upon rechallenge with either cephalosporin, the hematologic syndrome was reproduced in most dogs tested; cefonicid (but not cefazedone)-treated dogs showed a substantially reduced induction period (15 +/- 5 days) compared to that of the first exposure to the drug (61 +/- 24 days). This observation, along with the rapid rate of decline in red cell mass parameters of affected dogs, suggests that a hemolytic component complicated the red cell production problem and that multiple toxicologic mechanisms contributed to the cytopenia. We conclude that the administration of high doses of cefonicid or cefazedone to dogs can induce hematotoxicity similar to the cephalosporin-induced blood dyscrasias described in man and thus provides a useful model for studying the mechanisms of these disorders.

Anemia↗
PubMed1987

The hematopathology of cefonicid- and cefazedone-induced blood dyscrasias in the dog.

Cephalosporin treatment in man has been associated with blood dyscrasias that include a time- and dose-related anemia, neutropenia, and thrombocytopenia, the hematopathology of which remains poorly characterized. A similar hematologic syndrome can be produced in dogs following daily intravenous injections of 540-840 mg/kg cefazedone or 400-500 mg/kg cefonicid for 1-3 months. Using this animal model, histologic and cytologic changes in blood, bone marrow, spleen, and liver were studied over the course of the cephalosporin-induced cytopenias. Peripheral blood cytologic observations included an absence, generally, of erythroid regenerative changes, increased numbers of macroplatelets, spherocytosis, erythroblastemia, and toxic neutrophil morphology. Interim and postmortem cytologic and histologic observations of bone marrow included hypoplastic and toxic changes, primarily in cytopenic dogs receiving high doses of cefonicid, and regenerative changes in hematopoietic tissue of affected cefazedone-treated animals. The latter included variable erythroid hyperplasia, increased megakaryocytes, and decreased marrow fat and was accompanied by evidence of extra-medullary hematopoiesis and increased hemosiderin and hemophagocytosis in liver and splenic tissue. The incidence and severity of these changes were dose-dependent, corresponded with the cytopenias observed peripherally, and, like the cytopenias, were fully reversible. These observations suggest that the hematologic syndrome associated with cephalosporin treatment in the dog has multiple toxicologic mechanisms, which include peripheral cytotoxic effects and bone marrow damage with depressed or ineffective hematopoiesis.

Animals↗
PubMed1985

Effect of diet particle size and feeding of H2-receptor antagonists on gastric ulcers in swine.

Four experiments were conducted to evaluate the effect of diet and the administration of H2-antagonists in feed on gastric ulcer formation and performance of growing-finishing swine. Pigs receiving a finely ground diet (less than lmm) grew faster (.73 vs .68 kg/d, P less than .01) and had better feed utilization (3.47 vs 3.76, P less than .01) than pigs receiving a cracked corn-based diet. Incidence of ulcers in the esophageal region of the stomach of pigs fed the finely ground diet was greater (P less than .01) than in pigs fed cracked corn. The average daily gain of pigs receiving the finely ground diet was inversely related to ulcer incidence (r = .403, P less than .01, df = 59). The addition of 5, 10, 20 or 100 ppm of the H2-antagonist, metiamide, or 6, 18 or 54 ppm of SK&F 93479 to the finely ground diet did not improve pig performance or affect the incidence of gastric ulceration. The addition of 2, 6 and 18 ppm of SK&F 93479 to a corn-soy diet containing 4.5% alfalfa meal caused a reduction in gastric ulceration (P less than .05) and improved feed utilization by 3.2% (P less than .05). These data suggest that finely ground diets improve the performance of growing-finishing swine, but increase the incidence of ulcers in the esophageal region of the stomach. Severe gastric ulceration adversely affects swine performance. Feeding H2-antagonists does not reduce the ulcerogenic properties of finely ground diets, suggesting factors other than gastric acid secretion are involved in ulcerogenesis. The use of H2-antagonists in corn-soy diets improves feed utilization and reduces ulceration.

Animal Feed↗
PubMed1985

Arterial medial necrosis and hemorrhage induced in rats by intravenous infusion of fenoldopam mesylate, a dopaminergic vasodilator.

Fenoldopam mesylate, a selective, postsynaptic, dopaminergic vasodilator, was administered to rats for assessment of its clinical, toxicologic, and pathologic effects. Groups of 8 male and 8 female rats received 5, 25, 50, or 100 micrograms/kg/min by intravenous infusion for 24 hours. Groups of 12 male and 12 female rats received 2, 8, 16, or 20 mg/kg/day by intravenous injection once daily for 12 days. Tissues were examined by light microscopy. Rats infused for 24-hours with 5-100 micrograms/kg/min of fenoldopam had lesions of renal and splanchnic arteries characterized by medial necrosis and hemorrhage. None were seen in control rats or those administered the compound by intravenous injection. Arteries with four to five layers of medial smooth-muscle cells were most severely and frequently affected. Lesions were particularly severe in interlobular pancreatic arteries and subserosal gastric arteries. They occurred first at 4 hours, were present at low incidence at 8 hours, were induced in unrestrained rats, and were not caused by the experimental procedures employed. The nature and disposition of this novel arterial lesion in the rat suggests that its pathogenesis may be related to the pharmacologic activity of fenoldopam mesylate at the dopamine receptor.

Animals↗
PubMed1981

Red cell fragmentation in the dog: an editorial review.

Red blood cell fragments in blood smears from dogs are described morphologically and pathogenetically. Categories include microangiopathic fragmentation, spherocytic fragmentation. Heinz body fragmentation, metabolic fragmentation associated with systemic disease, and artifactual fragmentation. Microangiopathic fragmentation is associated with direct physical damage to normal circulating red blood cells as they pass through abnormal capillary beds. Spherocytic fragmentation is a common feature of immune-mediated hemolytic anemia and results from the removal of portions of antibody-coated erythrocyte plasma membranes by phagocytes of the reticuloendothelial system. Heinz body fragmentation occurs when rigid particles of oxidized hemoglobin are torn from affected red cells as they circulate through the spleen. Metabolic fragmentation is an ill-defined syndrome most commonly associated with cholesterol loading of red cell membranes caused by lipid metabolism abnormalities. Resulting spiculated red cells are more susceptible to traumatic disruption. All the types of red cell fragmentation described in dogs have been observed and documented in man.

Animals↗
PubMed1976

Interrelations between ABO blood group, plasminogen, alpha1-antitrypsin, alpha2-macroglobulin and the platelet count in blood donors.

The level of plasminogen alpha1-antitrypsin, alpha2-macroglobulin and the platelet count were measured in 511 blood donors. The mean level of alpha1-antitrypsin was significantly lower in men of group B compared with that of group O. No other differences between the blood groups reached statistical significance. Woman had higher mean levels of alpha1-antitrypsin and alpha2-macroglobulin and a higher platelet count than men. The levels of plasminogen and alpha1-antitrypsin were significantly higher in women using oral contraceptive compared with those who were not. The level of alpha2-marcoglobulin fell with age until the 60-64 year age-group in men and the 40-49 year age-group in women. A positive correlation existed between the alpha1-antitrypsin and the alpha2-macroglobulin level and between the platelet count and the plasminogen level.

ABO Blood-Group System↗