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J D Rogers

Publications and source records attributed to J D Rogers.

At least 73 records · Page 4Linked to original sources
PubMed1993

Evaluation of sustained/controlled-release dosage forms of 3-hydroxy-3-methylglutaryl-coenzyme a (HMG-CoA) reductase inhibitors in dogs and humans.

Seven sustained/controlled-release dosage forms were designed for gastrointestinal delivery of lovastatin or simvastatin, two potent HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia. The in vivo performance of these formulations was evaluated in dogs and healthy volunteers in terms of the cholesterol lowering efficacy and/or systemic concentrations of HMG-CoA reductase inhibitors. Results from the present and previous studies suggest that, through the controlled release of HMG-CoA reductase inhibitors, sustained lower plasma concentrations of HMG-CoA reductase inhibitors may result in an equal or better therapeutic efficacy.

Adult↗
PubMed1993

Oral pharmacokinetics and food interaction of the leukotriene D4 receptor antagonist verlukast.

The influence of dose and food on the pharmacokinetic profile of orally administered verlukast, a leukotriene D4 receptor antagonist, was investigated in 12 healthy male volunteers. This was an open, four-period, single dose, randomised, crossover design including the following doses: one 75 mg tablet, one 250 mg tablet, 500 mg (2 x 250 mg) and 500 mg immediately following a standard meal. There were dose-related increases in the AUC, although after 500 mg verlukast this was disproportionately greater than with 75 mg (P = 0.04). Similarly, there were dose-related increases in C(max). No differences were observed in the t(max) between treatments. With respect to food, there was a 22% decrease (P = 0.02) in C(max) after 500 mg, and the AUC was 13% less (P = 0.052). The differences in the plasma concentration profiles betweeen fasted and fed states are not considered to be of clinical importance.

Administration, Oral↗
PubMed1992

Comparative pharmacokinetics of lovastatin, simvastatin and pravastatin in humans.

Twelve healthy male volunteers received single market-image 40-mg oral doses of lovastatin and simvastatin (both lactone prodrugs), or pravastatin (a beta-hydroxyacid) at 1 week intervals in a three-way crossover study to quantify HMG-CoA reductase inhibitors in plasma. Multiple plasma samples were collected up to 24 hours after the dose and assayed for active and total HMG-CoA reductase inhibitors. After equal oral doses, higher plasma concentrations of HMG-CoA reductase inhibitory activity after pravastatin than after either lovastatin of simvastatin (2-3 fold greater area under the concentration-time curve) suggest a greater potential availability of pravastatin-related inhibitory activity to peripheral tissues.

Administration, Oral↗
PubMed1992

Plasma drug profiles and tolerability of MK-571 (L-660,711), a leukotriene D4 receptor antagonist, in man.

We have studied the tolerability and plasma drug profiles of a leukotriene D4 receptor antagonist, MK-571, given intravenously and as an oral solution in two separate trials. Study I (i.v.) involved 2 panels of 6 healthy men in a double-blind, alternating, incrementally increasing dose study with single doses up to 1500 mg. There was good tolerability at all doses. Plasma was assayed stereospecifically by HPLC for the S(+) and R(-) enantiomers of MK-571. For each enantiomer AUC values increased more than proportionately with increasing dose, suggesting nonlinear kinetics. The S(+) enantiomer was cleared more rapidly than the R(-) enantiomer. The apparent initial volume of distribution was less than 101 for both enantiomers. Study II (oral) involved 18 healthy subjects in 3 parallel groups who took multiple oral doses of 100, 300, and 600 mg t.i.d. for 31 doses. MK-571 administration was well tolerated, with only mild to moderate gastrointestinal discomfort at the highest dose. Total MK-571 (plasma samples assayed nonstereoselectively) was rapidly absorbed after oral administration, reaching peak concentrations at 1-2 h. Mean 8 h AUC increased from dose 1 to dose 31 in all subjects at all doses, suggesting a modest extent of accumulation (about 50%) of total MK-571 in plasma with a t.i.d. dosage regimen.

Administration, Oral↗
PubMed1992

Dose-dependent kinetics of the enantiomers of MK-571, and LTD4-receptor antagonist.

The disposition of the enantiomers of MK-571 (MK-0679 and L-668,018) following single i.v. doses of MK-571 (L-660,711) was studied in a three way cross-over study in 12 healthy male volunteers. Each volunteer received 75 mg, 300 mg and 600 mg i.v. doses of MK-571 at weekly intervals. The disposition of both enantiomers appeared dose-dependent, since the AUC increased disproportionately faster than the dose. The dose dependency was much more pronounced for L-668,018: its AUC increased 6-fold from the 75 to the 300 mg dose, 16-fold from 75 to 600 mg and 2.7 fold from 300 to 600 mg. For MK-0679, the corresponding increases in AUC were 4.8-, 11-, and 2.3 fold. Regardless of dose, the elimination of L-668,018 was more rapid than that of MK-0679. The disposition of MK-0679 needs to be investigated independently to detect any potential influence of L-668,018 on its disposition.

Adult↗
PubMed1992

Influence of age and gender on the plasma profiles of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitory activity following multiple doses of lovastatin and simvastatin.

The effects of age and of gender on the plasma profiles of HMG-CoA reductase inhibitors following separate once-a-day dosage regimens (17 days) of lovastatin (80 mg/day) and simvastatin (40 mg/day) were studied in hypercholesterolemic patients. In general, plasma concentrations of active and total HMG-CoA reductase inhibitors were higher in elderly individuals (age, 70 to 78 years) and in females for both drugs. However, the Tmax of these inhibitors was not significantly affected by either age or gender. Following the last dose of lovastatin, the mean steady-stage plasma concentrations of total and active HMG-CoA reductase inhibitors were 30-60% higher in the elderly than in young individuals (age, 19 to 30 years). Also, the mean plasma concentrations were 20-50% higher in female than in male patients. Similarly, following the last dose of simvastatin, the mean plasma concentrations of HMG-CoA reductase inhibitors were 40-60% higher in the elderly than in young patients and were 20-50% higher in female than in male patients. These age- and gender-related differences do not appear to be large enough to warrant modification of dosage regimens, because plasma concentrations of these inhibitors are not necessarily indicative of efficacy and the therapeutic windows for lovastatin and simvastatin are broad.

Adult↗
PubMed1992

Pharmacokinetics of imipenem/cilastatin sodium in children with peritonitis.

Fifteen children (3-12 years) with peritonitis were given imipenem/cilastatin intravenously (15 or 25 mg/kg) every six hours for 3-14 days. One day during treatment days 2-8, multiple blood and urine samples were collected from each individual over a six hour dosing interval. Twelve children completed the study. The urinary recovery of imipenem and cilastatin averaged 50-70% of the administered dose. The plasma t1/2 for imipenem averaged 55 min. while that for cilastatin was even more rapid (approximately 38 min.). Little or no accumulation of either imipenem or cilastatin was observed for this regimen in this age group of paediatric patients. Steady state conditions prevailed within 2 days of initiation of therapy. The pharmacokinetics of imipenem and cilastatin in paediatric patients 3-12 years of age appear similar to those observed for adults.

Child↗
PubMed1991

Intracerebral Hodgkin's disease in a human immunodeficiency virus-seropositive patient.

Intracerebral involvement of Hodgkin's disease (HD) is rarely described, with only 42 cases in the literature. Since the outbreak of the acquired immune deficiency syndrome (AIDS) epidemic, there has been an increasing number of human immunodeficiency virus (HIV)-infected (HIV+) persons who have diffuse non-Hodgkin's lymphoma and, more recently, atypical aggressive HD. The authors report the case of a patient with a history of intravenous drug abuse (IVDA) and Stage IVB HD who, after a drug-induced clinical remission, had intracerebral mixed-cellularity HD. This appears to be the first report of intracerebral HD in a person who is HIV+.

Adult↗
PubMed1991

Density-related expression of caldesmon and vinculin in cultured rabbit aortic smooth muscle cells.

Quantitative immunoblotting techniques were used to study the effects of seeding density on the expression of caldesmon and vinculin variants, which are sensitive markers of vascular smooth muscle cell (SMC) phenotypic modulation in culture. Rabbit aortic SMC were seeded at different densities: 13 x 10(4) cells/cm2 (high density), 3 x 10(4) cells/cm2 (medium density), and 0.2 x 10(4) cells/cm2 (low density) and cultured in the presence of 5% fetal calf serum. Irrespective of cell density and growth phase, caldesmon150 was gradually and irreversibly substituted by caldesmon77, but at high seeding density this substitution proceeded at a slower rate. The fraction of meta-vinculin (smooth muscle variant of vinculin) was reduced after seeding SMC in culture, but was reestablished when the cells reached confluency. Thus, high SMC seeding density is essential but not sufficient to keep vascular SMC cultured in the presence of serum in the contractile phenotype.

Animals↗
PubMed1991

Quantification of imipenem's primary metabolite in plasma by postcolumn chemical rearrangement and UV detection.

Imipenem (thienamycin formamidine) is an antibiotic active against a broad spectrum of bacteria. Its primary metabolite arises from cleavage of the lactam ring. The metabolite can be formed in-vitro by acid-catalyzed or enzymatic hydrolysis. In animals and man, this metabolite can be generated systemically as well as in the kidneys following the excretion of imipenem into the urine. In man, this dehydropeptidase-catalyzed renal metabolism is minimized by the coadministration of cilastatin, a competitive inhibitor. A specific HPLC assay has been developed to evaluate the disposition of this metabolite in humans having normal or end-stage renal function. The assay employs ion-pair, reversed-phase chromatography, and post-column acid treatment of the analyte for ultraviolet detection.

Chromatography, High Pressure Liquid↗
PubMed1991

Steady-state pharmacokinetics of intramuscular imipenem-cilastatin in elderly patients with various degrees of renal function.

We studied the concentrations in plasma and pharmacokinetics of imipenem and cilastatin in elderly patients (greater than 65 years old) who had various degrees of renal function and who were hospitalized with soft tissue infections. Three groups of patients received imipenem-cilastatin (500/500 mg) intramuscularly every 12 h: group I consisted of eight patients with a creatinine clearance (CLCR) of greater than 50 ml/min (range, 51 to 84 ml/min; mean, 65.8 ml/min); group II consisted of three patients with a CLCR of 20 to 50 ml/min; and group III consisted of two patients with a CLCR of less than 20 ml/min. Imipenem and cilastatin concentrations were measured at steady state on day 5. Mean peak and trough plasma imipenem concentrations were 5.28 +/- 1.78 and 1.43 +/- 0.76 micrograms/ml in group I, 6.25 +/- 0.78 and 2.50 +/- 0.00 micrograms/ml in group II, and 14.3 +/- 0.71 and 6.85 +/- 1.06 micrograms/ml in group III, respectively. Mean peak and trough plasma cilastatin concentrations were 11.8 +/- 2.85 and 0.31 +/- 0.43 microgram/ml in group I, 15.5 +/- 2.48 and 2.03 +/- 2.05 micrograms/ml in group II, and 24.5 +/- 6.72 and 10.7 +/- 5.94 micrograms/ml in group III, respectively. Mean imipenem AUCss (area under the concentration-time curve over a dosage interval at steady state) values were 38.7 +/- 7.9 micrograms.h/ml for group I, 52.3 +/- 7.3 micrograms.h/ml for group II, and 143.7 +/- 11.9 micrograms.h/ml for group III. Mean cilastatin AUCss values were 45.6 +/- 12.5 micrograms.h/ml for group I, 93.8 +/- 51.2 micrograms.h/ml for group II, and 217.5 +/- 57.8 micrograms.h/ml for group III. Cilastatin mean apparent body clearance values (normalized to weight) were 2.78 +/- 0.67 ml/min for group I, 1.43 +/- 0.81 ml/min for group II, and 0.71 +/- 0.24 ml/min for group III. Imipenem open-lactam metabolite levels were all below the level of detective of the assay (<3.9 micrograms/ml). There was a progressive increase in plasma imipenem and cilastatin levels and AUCss and there was a decline in body clearance as renal function declined.

Aged↗
PubMed1991

Imipenem/cilastatin: evolution of the sustained-release intramuscular formulation.

Since 1983, numerous studies have confirmed the efficacy of imipenem/cilastatin as monotherapy for polymicrobial and multiresistant infections. Doses range from 1 to 4 g/day, usually given in 3-4 intravenous infusions. Recently, a sustained-release, intramuscular formulation of imipenem/cilastatin sodium has been developed. Investigations in both animals and healthy human volunteers have shown that this formulation maintains plasma concentrations of imipenem above susceptibility breakpoints for nearly twice the duration provided by similar intravenous doses. Although peak concentrations are lower with the intramuscular formulation, current research suggests that the efficacy of beta-lactam antibiotics is more closely related to the duration that levels are sustained above minimum inhibitory concentrations, rather than to the magnitude of peak concentrations over minimum inhibitory concentrations. Hence, the intramuscular formulation of imipenem/cilastatin sodium holds promise as an efficient, effective regimen in patients with serious infections of mild to moderate severity.

Biological Availability↗
PubMed1985

The nucleus basalis of Meynert in neurological disease: a quantitative morphological study.

The recent finding of neuronal degeneration in the nucleus basalis of Meynert (nbM) in Alzheimer's disease suggests a possible role of this nucleus and the cholinergic system in dementing illness. We assessed neuronal population and density in two anatomical levels of the nbM in 38 coded brains from patients with a broad variety of neurological disorders. We found the most striking nbM degeneration in Alzheimer's and Parkinson's diseases. An intermediate loss of neurons was noted in the transmissible dementia Creutzfeldt-Jakob disease and in progressive supranuclear palsy. The usually nondementing diseases amyotrophic lateral sclerosis and multiple sclerosis showed cell counts comparable to those in a control group of nondemented patients with cerebrovascular disease. Characteristic neuropathological changes of Alzheimer's, Parkinson's, and Creutzfeldt-Jakob diseases, progressive supranuclear palsy, and subacute sclerosing panencephalitis were also found in the nbM. Most previous studies of the nbM have been based on small numbers of cases compared with controls. In our large series we used consistent methodology and a multiple-comparison statistical procedure to avoid overreporting of statistical significance. Our comparison of the nbM not only confirms the marked degeneration of the nbM in Alzheimer's disease, but also places such degeneration into perspective in a spectrum of dementing and nondementing neurological diseases. Larger case studies, using appropriate statistical techniques for multiple group comparisons, are needed to establish the significance of nbM degeneration in neurological disease.

Adult↗
PubMed1984

Physical model approach to gastrointestinal absorption of prostaglandins III: In situ rat intestinal absorption of dinoprostone.

In situ absorption studies with dinoprostone in the rat jejunum were carried out to provide a quantitative mechanistic insight of the absorption process. The variables included buffer pH (3.5-9.5), buffer capacity, hydro-dynamics in the lumen, and concentration. The disappearance kinetics from the lumen was first order. The rate decreased with increasing pH in a sigmoidal manner and reached a minimum at about pH 9. These results indicate the effects of the partitioning of nondissociated species in the lipoidal membrane and transport across aqueous pores. The rate was higher with the higher degree of agitation of the lumenal solution. Between two hydrodynamic situations, the differences in the rates were large at pH 4.5 where the transport was largely aqueous diffusion controlled and then tended to become smaller with increasing pH where the transport became effectively membrane controlled. The 15-oxo- and 13,14-dihydro-15-oxo metabolites of dinoprostone were found. The physical model was applied to quantify the permeability coefficients of the aqueous diffusion layer and the aqueous pores of the membrane and the effective membrane transport-bioconversion permeability coefficient at various pH values. The overall absorption dinoprostone was similar to that of the less lipophilic dinoprost reported earlier and also more rapid. Hence, baseline absorption studies were completed with two major reference prostaglandins from which estimations of intestinal absorption can be made for their analogues and derivatives.

Animals↗
PubMed1984

Disposition of radiolabeled imipenem and cilastatin in normal human volunteers.

In the first of two successive studies, four healthy male subjects received 500 mg of 14C-labeled imipenem alone and together with 500 mg of unlabeled cilastatin sodium. In the second study, the same subjects were given 250 mg of 14C-labeled cilastatin sodium alone and together with 250 and 1,000 mg of cold imipenem. Concentrations of imipenem and cilastatin in plasma, urine, and feces were assayed by high-pressure liquid chromatography and radiometry. Plasma concentrations of imipenem assayed radiometrically were higher than those measured by high-pressure liquid chromatography. In one subject studied at the end of drug administration, the open lactam metabolite of imipenem represented 9% of the radioactivity. Plasma levels of cilastatin determined by high-pressure liquid chromatography and radiometry were virtually identical. Urinary recovery of imipenem varied between 12 and 42% of the dose when that drug was given alone but increased to between 64 and 75% when administered with cilastatin sodium at a 1:1 ratio. Almost all radioactivity of imipenem was recovered in the urine within 96 h after drug administration. The open lactam metabolite, resulting from the metabolism of imipenem in the kidneys by a dipeptidase, dehydropeptidase-I, represented 80 to 90% of the effluent radioactivity when imipenem was given alone and about 20% when cilastatin sodium was coadministered. Renal excretion of cilastatin followed closely that of imipenem. Almost all of the administered radioactivity was recovered in 24 h, and about 75% of the dose was recovered as unchanged cilastatin within 6 h. The N-acetyl metabolite of cilastatin was found to represent about 12% of the total radioactivity.

Adult↗
PubMed1983

Pharmacokinetics and tolerance of N-formimidoyl thienamycin (MK0787) in humans.

The pharmacokinetics of intravenously administered N-formimidoyl thienamycin (MK0787) were studied in 14 healthy male subjects in a single-dose study, in which the volunteers received N-formimidoyl thienamycin with and without probenecid, and in a multiple-dose study, in which the subjects were given 250 or 500 mg every 8 h for 10 doses. High dose-related plasma concentrations of N-formimidoyl thienamycin were achieved; co-administration with probenecid resulted in only minor increases in these concentrations. No accumulation in plasma was seen after multiple doses. The plasma half-life of N-formimidoyl thienamycin was slightly less than 1 h and did not increase significantly with the coadministration of probenecid. The urinary recovery of N-formimidoyl thienamycin varied between 6.0 and 38.4% of the dose with a marked intersubject variability. Variations in individual subjects were small, however, when the urinary recoveries after repeated doses were compared. These results were in agreement with previous animal studies showing a renal metabolism of N-formimidoyl thienamycin. Probenecid administration resulted in a marked decrease in N-formimidoyl thienamycin urinary recovery. In vitro experiments showed that the decay of N-formimidoyl thienamycin in spiked pretreatment urine samples was 2 to 5%/h with more rapid degradation at acidic than at basic pH.

Adult↗