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Biomedical subjects

J S MacDonald

Publications and source records attributed to J S MacDonald.

At least 37 records · Page 2Linked to original sources
PubMed1991

Decreased fertility in male rats administered the 5 alpha-reductase inhibitor, finasteride, is due to deficits in copulatory plug formation.

Oral administration of 80 mg/kg/day of finasteride, a potent specific inhibitor of 5 alpha-reductase, to sexually mature male Sprague-Dawley rats for 24 to 38 weeks caused an approximate 30% to 40% decrease in fertility. There were no effects on mating indices or implants per pregnant female. From the mating trials, a selected group of treated males with poor reproductive performance was compared to a selected group of control males with good reproductive performance. Observed matings showed no qualitative effects on mating behavior or ejaculation. However, finasteride-treated males did not form or formed small and improperly positioned copulatory plugs, which are required in rats to transport sperm into the uterus. Intrauterine insemination of epididymal sperm from males that were nonfertile by natural mating resulted in similar numbers of embryos and unfertilized oocytes recovered from controls and finasteride-treated males, confirming that there was no effect of finasteride on the ability of sperm to fertilize. Decreased fertility of finasteride-treated males was due to failure to form copulatory plugs and is related to decreased weight of seminal vesicles and prostate, an expected pharmacologic effect. Testes weight was unaffected. Decreased fertility in male rats after finasteride administration is considered a species specific effect. The mechanism of the decrease in rats is not likely to be relevant to species that do not form copulatory plugs.

5-alpha Reductase Inhibitors↗
PubMed1991

Studies on the mechanism of simvastatin-induced thyroid hypertrophy and follicular cell adenoma in the rat.

Female Sprague-Dawley rats were treated with either simvastatin (a novel competitive inhibitor of HMG CoA reductase) or phenobarbital (positive control) to ascertain the possible relationship between the effects of simvastatin on hepatic metabolism and the thyroid hypertrophy and follicular cell adenomas which it produces in this strain of rat. The test compounds were administered orally at doses of 100 mg/kg (divided doses at 50 mg/kg, b.i.d.). (This dose of simvastatin represents approximately 250 times the human dose.) After 5 weeks of treatment, either simvastatin or phenobarbital produced significant increases (35% and 39% above control, respectively) in serum thyroid stimulating hormone (TSH), a significant increase (39% and 120% above control, respectively) in the systemic clearance of 125I-thyroxine, and slight decreases in serum thyroxine levels. Statistically significant increases in liver and thyroid weights were associated with phenobarbital treatment. With simvastatin, increased liver weights occurred. At the microscopic level, thyroid hypertrophy was observed in all phenobarbital-treated rats and to a lesser degree in most simvastatin-treated animals. Simvastatin did not markedly alter liver microsomal enzyme activities with the exception of the anticipated induction of HMG CoA reductase (which increased approximately 4.4-fold). Conversely, phenobarbital produced large increases in liver microsomal enzymes, including glucuronosyl transferase, but did not affect the activity of HMG CoA reductase. Therefore, the increased clearance of thyroxine in simvastatin-treated female rats was not associated with enzyme induction but may have been related to the increase in functional liver mass produced by this compound at this dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗
PubMed1991

HMG-CoA reductase inhibitor-induced myopathy in the rat: cyclosporine A interaction and mechanism studies.

Recent clinical evidence indicates a potential for skeletal muscle toxicity after therapy with HMG-CoA reductase inhibitors (HMGRIs) in man. Although the incidence of drug-induced skeletal muscle toxicity is very low (0.1-0.2%) with monotherapy, it may increase following concomitant drug therapy with the immunosuppressant, cyclosporine A (CsA), and possibly with certain other hypolipidemic agents. In the Sprague-Dawley rat, very high, pharmacologically comparable dosages (150-1200 mg/kg/day) of structurally similar HMGRIs (lovastatin, simvastatin, pravastatin and L-647, 318) produced dose-related increases in the incidence and severity of skeletal muscle degeneration. Physical signs included inappetence, decreased activity, loss of body weight, localized alopecia and mortality. To evaluate the interaction between HMGRIs and CsA, a rat model of CsA-induced cholestasis was developed. In this 2-week model, the skeletal muscle toxicity of the HMGRIs was clearly potentiated by CsA (10 mg/kg/day). Doses of HMGRIs which did not produce skeletal muscle toxicity when given alone caused between 75 and 100% incidence of myopathy (very slight to marked skeletal muscle degeneration) when CsA was coadministered. Typical light microscopic changes included myofiber necrosis with interstitial edema and inflammatory infiltration in areas of acute injury. Histochemical characterization of the muscle lesion indicated that type 2B fibers (primarily glycolytic white fibers) were most sensitive to this toxicity but that, with prolonged administration, all fiber types were ultimately affected. Results of pharmacokinetic studies in rats treated with various HMGRIs +/- CsA indicated that coadministration of CsA alters the disposition of these compounds, resulting in increased systemic exposure (e.g., increased area under the plasma drug concentration vs. time curve-AUC) and consequent (up to 13-fold) increases in skeletal muscle drug levels. Evaluation of the potential interaction between the HMGRI, lovastatin and CsA at the level of hepatic microsomal metabolism indicated that CsA did not inhibit the metabolism of lovastatin in isolated microsomes from female rats. In light of the above findings, it appears that HMGRI-induced myopathy is a class effect in the rat, which is potentiated by CsA as the result of altered clearance and resultant increased tissue exposure. Cholestasis associated with CsA and HMGRIs may form the basis for decreased elimination and the resultant elevated systemic exposure. Furthermore, this toxicity is muscle fiber-selective and may be associated with impaired skeletal muscle energy metabolism.

Animals↗
PubMed1990

External genitalia abnormalities in male rats exposed in utero to finasteride, a 5 alpha-reductase inhibitor.

A series of studies was conducted to determine the developmental toxicity of the 5 alpha-reductase inhibitor finasteride (MK-0906) in rats. This compound was administered orally once daily to pregnant rats during various extended treatment periods during gestation. F1 offspring were evaluated on Day 20 of gestation as well as postnatally through mating to produce an F2 generation. MK-0906 treatment induced dosage-related incidences of hypospadias (penischisis) in male offspring with a threshold dosage level near 0.1 mg/kg/day and a 100% effect level of 100 mg/kg/day (with dosing through Day 20 of gestation). MK-0906 also caused decreased anogenital distance in male offspring. The dosage response for this effect (ranging from a 4.2% decrease at 0.003 mg/kg/day to a 38% decrease at 100 mg/kg/day) was more shallow than that for hypospadias. The decreases in anogenital distance were at least partially reversible postnatally with essentially complete recovery at dosages up to 0.1 mg/kg/day. There was also a dosage-related, temporary induction of nipples in F1 males. All of these effects were apparent following treatment on Days 6 through 17 of gestation but were more pronounced when dosing extended to Day 20 of gestation. Slight maternal toxicity consisting of minor decreases in body weight gain occurred only at dosages of 3 mg/kg/day and higher, indicating the selective nature of the developmental toxicity. The 5 alpha-reductase enzyme located in the rat fetal genital tubercle was studied in vitro and compared to that in the adult ventral prostate. The values for Km, Vmax, and IC50 for inhibition by MK-0906 were similar in the two tissues, suggesting that the enzymatic proteins in the genital tubercle and ventral prostate may be similar.

5-alpha Reductase Inhibitors↗
PubMed1990

High-dose cisplatin in disseminated melanoma: a comparison of two schedules.

A total of 38 patients with metastatic melanoma received monthly chemotherapy with cisplatin at a dose of 200 mg/m2, per cycle; 14 received 20 mg/m2 cisplatin i.v. on days 1-5 and 24 were given 100 mg/m2 i.v. on days 1 and 8. Objective responses were seen in 2/14 treated on days 1-5 and in 5 of 22 evaluable subjects receiving cisplatin on days 1 and 8, for an overall response rate of 22%. The median survival of all patients was 6 months, with no significant difference observed between the two schedules. Severe neurotoxicity and myelosuppression were more common in patients treated on days 1-5. Two patients treated in this manner were bedridden due to neurotoxicity and four developed grade 4 leukopenia after the first cycle of chemotherapy. Only one patient treated with the divided-dose schedule became leukopenic during the first cycle, and none of the patients were debilitated by neurotoxicity. Thrombocytopenia was statistically more severe. Nausea and vomiting, fatigue, ototoxicity, and paresthesia were seen with equal frequency. Very high doses of cisplatin can be delivered with acceptable toxicity using a divided-dose schedule. As the response rate on this schedule appeared to be comparable with that achieved on the more toxic consecutive 5-day schedule, the former deserves to be tested in diseases known to show a dose response to cisplatin. However, in melanoma, administration of 200 mg/m2 per course did not appear to be associated with a markedly improved response rate, compared with cisplatin alone at "standard" doses.

Adult↗
PubMed1990

On the etiology of subcapsular lenticular opacities produced in dogs receiving HMG-CoA reductase inhibitors.

The administration of high dosages of various hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors has resulted in the development of subcapsular lenticular opacities in dogs. While dogs receiving cataractogenic doses of HMG-CoA reductase inhibitors experienced profound decreases in circulating serum cholesterol concentrations (40-60% reductions in total serum cholesterol), a causal relationship between serum cholesterol lowering and cataractogenesis was not established. A strong relationship was demonstrated, however, between the systemic exposure to inhibitor (plasma drug levels) and the cataractogenic potential of the various compounds studied. Analysis of lenses from dogs chronically dosed with various HMG-CoA reductase inhibitors revealed the presence of low drug levels in the lens (less than 500 ng equivalents g-1), but no correlation was observed between the amount of drug associated with the lens after chronic treatment and cataract development. In addition, no abnormalities in cholesterol content or sterol composition were observed in clear and/or cataract containing lenses from dogs chronically dosed with HMG-CoA reductase inhibitors. The kinetics of drug appearance in the aqueous and lens cortex was assessed after doses of various HMG-CoA reductase inhibitors, and suggested somewhat higher but not statistically significant peak concentrations of inhibitor were achieved by compounds which produced a higher incidence of cataracts. These data have suggested that high doses of HMG-CoA reductase inhibitors may increase lenticular exposure to drug via the aqueous humor by producing a substantial systemic exposure to drug substance. This may result in an increased concentration of inhibitor in the outer cortical region of the lens where cholesterol synthesis is critical, thereby resulting in the development of opacities. The production of lenticular changes by a HMG-CoA reductase inhibitor of diverse chemical structure establishes, with reasonable assurance, that these lens changes are mechanism based (i.e. a product of the biochemical mechanism of action of this class of compounds). An extrapolation of these findings to patients receiving therapeutic dosages enables a favorable risk evaluation since the doses to be employed clinically are much lower and result in a far lower systemic exposure to drug substance.

Animals↗
PubMed1990

Maternotoxicity and fetotoxicity of an angiotensin-converting enzyme inhibitor, enalapril, in rabbits.

When enalapril, an angiotensin-converting enzyme (ACE) inhibitor, was orally administered to inseminated rabbits at dosages of 0.1 to 30 mg/kg/day for 13 days in a range-finding study, nephrotoxicity, as measured by elevated serum urea nitrogen concentrations, occurred at 1 mg/kg/day and higher dosages and significant (p less than or equal to 0.05) increases in fetal wastage were observed at dosages as low as 3 mg/kg/day. Saline supplementation during treatment prevented this rise in urea nitrogen. Fetal wastage was significantly (p less than or equal to 0.05) increased in the absence of maternotoxicity when saline-supplemented females were treated with enalapril at 30 mg/kg/day. A developmental toxicity study of enalapril in saline-supplemented rabbits produced no evidence of teratogenicity at 3, 10, and 30 mg/kg/day. The period of sensitivity of fetuses to the toxic effects of enalapril was found to be limited to middle-to-late gestation (Gestational Days 14-27). A single oral dose of enalapril (30 mg/kg) on Day 26 of gestation resulted in 100% fetal deaths. On the basis of the work done by Broughton Pipkin et al. [1982, J. Physiol. (London) 323, 415-422] and Broughton Pipkin and Wallace (1986, Brit. J. Pharmacol. 87, 533-542), which demonstrated that the sheep fetus becomes markedly hypotensive when the dam is treated with captopril or enalapril during late pregnancy, we believe that the observed fetotoxicity of enalapril in rabbits is also due to fetal hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Animal safety and toxicology of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase inhibitors.

Simvastatin, a hydroxy-methylglutaryl-coenzyme A reductase inhibitor intended for use as a hypocholesterolemic agent, has undergone a thorough preclinical toxicology evaluation. This review describes preclinical toxicology findings associated with simvastatin administration in animals and provides the rationale for our conclusion that these changes are not indicative of potential human toxicity. Although it was not surprising to find that a potent inhibitor of this key biochemical pathway produces toxicity at high dosages in animals, none of the observed changes poses a significant risk to humans at clinical dosages. Many of the toxicities produced by high dosage levels of simvastatin in animals are directly related to the drug's biochemical mechanism of action and are the result of a profound, sustained inhibition of the target enzyme that is not anticipated at clinical dosages. Furthermore, several of the simvastatin-induced changes are species-specific responses to this agent and are not relevant to human risk assessment. Of the treatment-related changes reported for simvastatin, the development of cataracts in dogs has received considerable attention. The available data demonstrate a wide margin of safety in terms of dosage levels required to elicit this response as well as the plasma concentrations associated with the development of these ocular lesions. The data suggest that the development of lenticular opacities at clinical doses of simvastatin is highly improbable. Overall, simvastatin is highly improbable. Overall, simvastatin was well-tolerated by animals in preclinical toxicology studies, and no findings contraindicating its use in humans were identified.

Animals↗
PubMed1989

Toxicity of the HMG-coenzyme A reductase inhibitor, lovastatin, to rabbits.

Lovastatin, a specific inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase, has been shown to be highly effective in lowering serum cholesterol in animals and humans and thus represents a promising approach to the treatment and prevention of cardiovascular disease. During the preclinical safety assessment of lovastatin, oral doses that were tolerated by dogs, rats and mice were found to be lethal to rabbits in subacute studies. Postmortem findings in rabbits consisted of centrilobular hepatic necrosis, frequently accompanied by renal tubular necrosis and occasionally gallbladder necrosis. The liver lesions were associated with up to 300-fold elevations in serum aspartate and alanine aminotransferase activities, whereas the kidney lesions resulted in accumulations of serum urea nitrogen and creatinine. The organ damage was preceded by a progressive decline in food consumption and loss of body weight. All histopathological and serum biochemical changes induced by lovastatin were completely prevented by coadministration of mevalonate, the product of the inhibited HMG-CoA reductase enzyme. In addition, administration of mevalonate after the onset of lovastatin-induced hepatotoxicity effectively reversed the toxicity despite continued drug treatment. These findings indicated that the toxicity of high doses of lovastatin to rabbits is a consequence of a highly exaggerated pharmacologic action in blocking mevalonate synthesis. However, supplementation of lovastatin-treated rabbits with oral doses of the major product of mevalonate metabolism, cholesterol, paradoxically enhanced the liver and kidney damage, which suggested that the toxicity of lovastatin stemmed from depletion of a nonsterol metabolite(s) of mevalonate critical for cell viability.

Animals↗
PubMed1988

Preclinical evaluation of lovastatin.

Administration of lovastatin to animals at high dosage levels produces a broad spectrum of toxicity. This toxicity is expected based on the critical nature of the target enzyme (HMG CoA reductase) and the magnitude of the dosage levels used. The information reviewed in this paper demonstrates that these adverse findings in animals do not predict significant risk in humans. The reason for this derives from the fact that all the available evidence suggests that the adverse effects observed are produced by an exaggeration of the desired biochemical effect of the drug at high dosage levels. The presence of clear and high no-effect doses for these toxic effects along with the fact that most of the changes observed are clearly mechanism-based (directly attributable to inhibition of mevalonate synthesis) indicate that it is unlikely that similar changes will be observed at the therapeutic dosage levels in humans. This hypothesis is supported by the extensive human safety experience described by Tobert in the following report.

Animals↗
PubMed1988

Mechanism of action and biological profile of HMG CoA reductase inhibitors. A new therapeutic alternative.

Lovastatin (MK-803, mevinolin) and simvastatin (MK-733, synvinolin), 2 highly potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, have been heralded as breakthrough therapy for the treatment of atherosclerotic disease. This paper discusses the biochemical attributes of these HMG CoA reductase inhibitors, their structures and inhibitory properties in a variety of biological systems and presents the rationale for their therapeutic use. Not only do lovastatin and simvastatin potently inhibit cholesterol biosynthesis; they also can result in the induction of hepatic low density lipoprotein (LDL) receptors, thus increasing the catabolism of LDL-cholesterol. Lovastatin and simvastatin are the first HMG CoA reductase inhibitors to receive regulatory agency approval for marketed use. Their safety profiles are reviewed and 2 aspects of this evaluation are stressed. First, the objective in the clinical use of these inhibitors is to normalise plasma cholesterol levels in hypercholesterolaemic individuals. This contrasts with the profound reductions in cholesterol obtained when normocholesterolaemic animals are treated by the high doses of these drugs required for toxicological assessment. Second, both lovastatin and simvastatin are administered as prodrugs in their lactone forms. As lactones, they readily undergo first-pass metabolism, hepatic sequestration and hydrolysis to the active form. Consequently, lovastatin and simvastatin achieve lower plasma drug levels than do other HMG CoA reductase inhibitors in clinical development. Low plasma levels have been established as an important determinant of safety in the use of HMG CoA reductase inhibitors in both animal and human studies.

Anticholesteremic Agents↗
PubMed1988

Brain and optic system pathology in hypocholesterolemic dogs treated with a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase.

The cholesterol lowering compound lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (EC 1.1.1.34 HMG CoA reductase), was given in nine separate experiments to normocholesterolemic dogs at rates up to 180 times the maximum therapeutic dose in man (1 mg/kg/day). Mean serum total cholesterol concentrations were reduced as much as 88% below normal. Clinical evidence of neurotoxicity occurred in up to 37% of animals given 180 mg/kg/day lovastatin for 11 or more days, especially in one laboratory where the dosing regime resulted in higher concentrations of plasma drug levels. Dogs receiving 60 mg/kg/day or less never exhibited neurologic signs. The central nervous system (CNS) of affected dogs exhibited endothelial degeneration and hemorrhagic encephalopathy. Focal extravasation of horseradish peroxidase occurred frequently (6/8) in the retrolaminar optic nerve of asymptomatic or clinically affected dogs given 180 mg/kg/day lovastatin, with endothelial degeneration and discrete optic nerve degenerative lesions interpreted as ischemic. The association between the degree of hypocholesterolemia and occurrence of clinical signs was not exact. Total brain cholesterol was similar in treated and control dogs. Hypocholesterolemic dogs had proportionally lowered serum concentrations of alpha-tocopherol, but oral supplementation of this vitamin did not prevent the neurologic syndrome. Endothelial degeneration in the CNS and optic nerve may have reflected in vitro morphologic effects of HMG CoA reductase inhibitors due to extreme inhibition of nonsterol isoprene synthesis. Retinogeniculate axonal (Wallerian-like) degeneration occurred in greater than or equal to 12% of dogs given 60 mg/kg/day or more lovastatin, with central chromatolysis of occasional retinal ganglion cells. These neuroaxonal changes may have been secondary to vascular effects, but superimposed direct neurotoxic action at the high dosage levels of lovastatin could not be excluded. There was no evidence of drug induced adverse effects in the CNS of dogs given up to 30 mg/kg/day lovastatin for 2 years.

Animals↗
PubMed1985

Carbapenems, a new class of beta-lactam antibiotics. Discovery and development of imipenem/cilastatin.

The discovery of Streptomyces cattleya and its antibiotic product, thienamycin, has ushered in a new era of beta-lactam agents, the carbapenems. Numerous carbapenems were subsequently discovered; however, none had the potency, broad-spectrum activity, and lack of cross-resistance exhibited by thienamycin. Chemical instability encountered with thienamycin was overcome by the N-formimidoyl derivative, imipenem. Imipenem is distinguished from other beta-lactams by its outstanding activity against gram-positive organisms as well as against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides. However, development was hindered by extensive renal metabolism of imipenem, resulting in low urinary concentrations of antibiotic. A renal dipeptidase, dehydropeptidase-I, was responsible for hydrolyzing imipenem and other carbapenems. To counter its action, a specific inhibitor, cilastatin, was developed. Coadministered with imipenem in a one-to-one ratio, cilastatin provides prolonged, reversible blockade of imipenem metabolism, dramatically improving urinary recoveries to therapeutically significant levels. Cilastatin also contributes to the safety of imipenem, since its coadministration prevents proximal tubular necrosis which has been observed in sensitive animals receiving imipenem alone in high doses. Thus, the combination imipenem and cilastatin overcame the pharmaceutical and metabolic challenges presented by thienamycin, and allowed for the evaluation in humans of the outstanding antimicrobial activity of this new class of beta-lactam antibiotics.

Animals↗