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Biomedical subjects

A Karim

Publications and source records attributed to A Karim.

At least 109 records · Page 6Linked to original sources
PubMed1995

Verapamil stereoisomerism: enantiomeric ratios in plasma dependent on peak concentrations, oral input rate, or both.

OBJECTIVE: To determine if R/S enantiomeric ratios of verapamil in plasma are affected by the changes in plasma concentration-time profiles of total verapamil, which result from administration of oral formulations with different input rates. METHODS: Twelve young (19 to 37 years old) healthy men received 240 mg single oral doses of racemic verapamil as immediate-release (fasting) and sustained-release (fed) formulations in a randomized, crossover (7-day washout) study. Serial blood samples were taken over a 48-hour period, and PR intervals were measured at times close to blood drawings for the first 16 hours. RESULTS: Marked enantiospecific disposition of verapamil occurred, with oral clearance values of 40.8, 25.3, and 121 ml/min/kg for the total verapamil, R-verapamil, and S-verapamil, respectively. Wide input-rate differences also occurred between the immediate- and sustained-release formulations (mean [% coefficient of variation]; peak concentration [Cmax] [total], 327 [44%] versus 73 [58%] ng/ml; time to reach Cmax [total], 1.71 [36%] versus 10.8 [62%] hours). The mean extent of total verapamil bioavailability from the sustained-release formulation was 73.3% of the immediate-release formulation. The R/S ratios at Cmax (total) and at several other time periods were lower, with the immediate-release formulation for both verapamil (R/S = 4.52 [13%] versus 5.83 [18%]; p < 0.01) and norverapamil (R/S = 2.48 [16%] versus 3.04 [19%]; p < 0.01). CONCLUSIONS: Significantly different R/S ratios of verapamil occurred in the plasma with oral formulations that had substantially different rates of input. With the immediate-release formulation the total verapamil Cmax was higher than that observed with the sustained-release formulation, and the percentage of the pharmacologically more active S-verapamil in the total was also higher (lower R/S ratio). These findings were attributed to the concentration- and/or input-rate-related saturable hepatic first-pass metabolism of the S-verapamil.

Administration, Oral↗
PubMed1995

Species dependent esterase activities for hydrolysis of an anti-HIV prodrug glycovir and bioavailability of active SC-48334.

PURPOSE: The in vitro fate of an ester prodrug, glycovir, was studied to determine if the species differences in the bioavailability of pharmacologically active SC-48334 observed after glycovir administration and not observed after SC-48334 administration is due to species differences in ester hydrolysis rate or species differences in absorption of the prodrug itself, and to determine the site(s) of ester hydrolysis which contributes most to species differences in the bioavailability of SC-48334 if any. METHODS: Glycovir was incubated with small intestinal mucosa, liver S9 fractions, whole blood, red blood cells (RBC) and plasma of the rat, dog, monkey (cynomolgus and rhesus) and man, and glycovir concentrations were determined by HPLC. RESULTS: The relative bioavailabilities of SC-48334 after prodrug administration to the rat, dog, monkey and man were 99, 15, 42 and 37%, respectively. After SC-48334 administration, SC-48334 was rapidly and similarly well absorbed in all species. The hydrolysis rate in the small intestinal mucosa was well correlated with the relative bioavailability of SC-48334 after prodrug administration. Among different species the hydrolysis rate of glycovir in liver S9 fractions, blood, RBC and plasma did not parallel those in the mucosa of the small intestine. CONCLUSIONS: The species differences in bioavailability of SC-48334 with the prodrug were due to species differences in hydrolysis rates of the prodrug in small intestinal mucosa. The monkey was a good animal model for prediction of esterase activity in human small intestine and relative bioavailability in man.

1-Deoxynojirimycin↗
PubMed1995

Metabolism of a novel antiarrhythmic agent, bidisomide, in man: use of high resolution mass spectrometry to distinguish desisopropyl bidisomide from desacetyl bidisomide.

1. Metabolism of bidisomide, a novel antiarrhythmic agent, was studied in man, and was not extensive as evidenced by the fact that approximately 60 and 70% of the radioactive doses were recovered as the parent drug after i.v. and oral administration respectively. 2. The mass spectra of bidisomide metabolites indicate that the two major metabolic pathways of bidisomide were hydroxylation of the piperidine ring and N-dealkylation. The latter occurred on the side chain containing the piperidine ring or the isopropyl group. The N-dealkylated metabolite on the side chain containing the piperidine ring was cyclized to result in a pyrrolidone metabolite. 3. The N-dealkylated metabolite, desisopropyl bidisomide, was identified by comparing its high resolution mass spectrum to that of authentic desacetyl bidisomide. 4. In the hydroxylation pathway, both mono- and dihydroxylated metabolites of the piperidine ring were observed. The exact location of the hydroxyl groups on the piperidine ring was not determined.

Administration, Oral↗
PubMed1994

Rapid and quantitative analysis of recombinant protein expression using pyrolysis mass spectrometry and artificial neural networks: application to mammalian cytochrome b5 in Escherichia coli.

Recombinant Escherichia coli clones encoding between 0 and 6 copies of the mammalian cytochrome b5 gene were subjected to pyrolysis mass spectrometry (PyMS). To deconvolute the pyrolysis mass spectra so as to obtain quantitative information on the amount of cytochrome b5 produced fully-interconnected feedforward artificial neural networks (ANNs) were studied. It was found that the combination of PyMS and ANNs could be used to predict the amount of cytochrome b5 expressed in E. coli. PyMS is a novel, convenient and rapid method for the screening and analysis of microbial and other cultures producing recombinant proteins.

Animals↗
PubMed1994

Effect of salicylic acid on the plasma protein binding and pharmacokinetics of misoprostol acid.

The in vitro serum protein binding and erythrocyte uptake of [3H]misoprostol acid ([3H]MPA; SC-30695), an active metabolite of the prostaglandin E1 (PGE1) analogue misoprostol, was determined in the blood of young (20-40 years) and elderly subjects (64 years or older) at concentrations ranging between 20 and 5000 pg/mL. The effect of selected other drugs on the displacement of [3H] MPA from the binding sites was also investigated. [3H]MPA serum binding (between 81 and 89 %) was similar and concentration independent in the young and elderly subjects and the erythrocyte partitioning coefficient was about 1, indicating the absence of a significant accumulation of MPA in red blood cells. Both the plasma and serum protein binding of [3H] MPA were substantially reduced in the presence of high (> 100 microg/mL) concentrations of salicylic acid. In an in vivo study, the single-dose pharmacokinetics of MPA did not change significantly when misoprostol (200 microg) was given alone or concomitantly with 975 mg of aspirin. These findings indicate that MPA is displaced from its protein binding sites only by high concentrations of salicylic acid and that this displacement is unlikely to be of clinical significance with the usual therapeutic doses of aspirin.

Adult↗
PubMed1993

Processing of chimeric mammalian cytochrome b5 precursors in Escherichia coli: reaction specificity of signal peptidase and identification of an aminopeptidase in post-translocational processing.

A chimeric precursor interlinked by an arginine residue between the full-length signal sequence of alkaline phosphatase and the eukaryotic cytoplasmic cytochrome b5 was constructed. Expression of the chimeric precursor protein in Escherichia coli resulted in efficient export of spectrally authentic cytochrome b5 into the periplasm [Karim, Harding, Evans, Kaderbhai and Kaderbhai (1993) Bio/Technology 11, 612-618]. On sequencing, the apparent absence of arginine at the N-terminus of the secreted cytochrome b5 implied that the chimera was either miscleaved by signal peptidase or further processed following signal excision by an uncharacterized peptidase. The influence of the N-terminal region of cytochrome b5 on the unusual processing of the chimeric precursor was investigated by engineering a number of variant forms in which the region between Arg+1 and the mature portion of cytochrome b5 was extended and varied. Observations of the in vivo processed patterns of these variant cytochrome b5 forms exported into the periplasm revealed that the absence of arginine was due to neither miscleavage of the translocated precursor by the signal peptidase nor the nature of the early region of cytochrome b5. In fact, the selective excision of the arginine residue occurred subsequent to signal sequence deletion by an aminopeptidase which was sensitive to the metal chelator o-phenanthroline. We show that this aminopeptidase also participates in the trimming of the N-terminal arginine residue of the bacterial alkaline phosphatase to generate the three isoenzymes in the periplasm.

Amino Acid Sequence↗
PubMed1993

Pharmacokinetics of a novel antiarrhythmic drug, actisomide.

The pharmacokinetics of a novel antiarrhythmic drug, actisomide, were examined in the rat, dog, monkey, and human. The terminal half-life of actisomide was similar (1.15-1.89 hr) across species, regardless of dose. The total plasma clearance was higher in the monkey (13.5-16.4 mL/min/kg) than in the dog (9.01-9.32 mL/min/kg), rat (8.6-9.8 mL/min/kg), or human (6.79 +/- 1.07 mL/min/kg). Excretion of the parent drug was higher in urine than in feces in the dog and rat, whereas in the monkey and human, urinary and fecal excretions of actisomide were similar. In humans, atypical plasma concentration-time curves with double peak concentrations were observed following oral doses. Systemic availability of actisomide was higher in the dog than in the rat, monkey, and human. Further, the systemic availability appeared to increase with dose in the rat and monkey. The species-dependent systemic availability appeared to be due primarily to species-dependent absorption of actisomide, and not to species-dependent first-pass metabolism, biliary excretion, and/or renal elimination. The absorption of actisomide in the rat and its in vitro uptake in CaCo-2 cells were pH dependent. The higher systemic availability of actisomide observed in the dog may be due partly to the higher pH in the gastrointestinal (GI) tract of the dog. However, the pH differences in the GI tract of the different species alone did not appear to be enough to explain the difference in systemic availability of actisomide.

Administration, Oral↗
PubMed1993

Absorption and disposition of a new antiarrhythmic agent bidisomide in man.

Absorption and disposition of bidisomide were studied in 12 healthy male subjects after a 20-min iv (1 mg/kg; N = 6) infusion and oral (2 mg/kg; N = 6) administration of the 14C-labeled drug. The oral absorption profile of unlabeled bidisomide was also studied after administration of a solution by a nasoenteric tube to different sites of the gastrointestinal tract (stomach, duodenum, jejunum, and ileum). The systemic availability was 61%. Absorption was slow initially and then rapid, achieving peak plasma concentrations between 2 and 4 hr. Less than complete systemic availability was attributed to incomplete absorption rather than first-pass metabolism. When the drug solution was delivered directly to the stomach, two distinct peak plasma levels were found. This was attributed to the more rapid absorption of bidisomide in the duodenum and ileum (and/or possibly colon). Following an iv dose, plasma levels of the drug declined with mean half-lives of 0.11, 2.0, and 12 hr for alpha, beta, and gamma phases, respectively, and a plasma clearance of 380 mL/min. The percentages of the dose recovered as bidisomide in urine and feces were 19 +/- 1 and 29 +/- 4 for the iv dose and 9.1 +/- 0.9 and 48 +/- 5 for the oral dose. Bidisomide did not exhibit substantial enantioselective pharmacokinetics in plasma regardless of the route of administration. The mean urinary excretion of the (-) enantiomer was, however, slightly higher than that of the (+) enantiomer, with (-)/(+) enantiomeric ratios of 1.2 and 1.3 after iv and oral administration, respectively. The enantiomeric ratio of bidisomide recovered in the feces was approximately 1.

Absorption↗
PubMed1993

Efficient bacterial export of a eukaryotic cytoplasmic cytochrome.

The soluble core domain of cytochrome b5 of liver endoplasmic reticulum was appended at its amino terminus to full-length alkaline phosphatase secretory signal sequence including the ribosomal binding site. The chimeric precursor gene was placed under the transcriptional control of the native pho promoter in a prokaryotic expression vector. Induction of Escherichia coli by growth in a phosphate-limited medium resulted in abundant synthesis of cytochrome b5 as detected spectrophotometrically and by visual transformation of the bacteria to a pink color. The signal-appended cytochrome b5, but not the corresponding signal-deficient derivative, was translocated across the bacterial inner membrane and processed to yield authentic, haem-assembled cytochrome b5 within the periplasm. The eventual processing of the chimeric cytochrome b5 precursor was unusual regarding the known reaction specificity of signal peptidase. The exported, mature haemoprotein was biochemically indistinguishable from its native mammalian counterpart. At peak induction, approximately 6 mg of correctly matured cytochrome b5 per liter of culture was exported. This amount of cytochrome b5 constituted 6% (w/w) of the periplasmic protein. The appearance of the exported apo-cytochrome b5 preceded the formation of holo-protein. Thus the eukaryotic cytoplasmic protein was efficiently exported from E. coli and post-translocationally modified to generate a functional haemoprotein in the periplasm.

Amino Acid Sequence↗
PubMed1993

Pharmacokinetics of diclofenac and misoprostol when administered alone or as a combination product.

The pharmacokinetics of a new diclofenac/misoprostol combination dosage form have been investigated. Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that has been commercially available for many years and its pharmacokinetics are well documented. Similarly, misoprostol is a prostaglandin analogue with well documented pharmacokinetics. It is available commercially as both an effective treatment for peptic ulceration and as prophylaxis of NSAID-induced gastric and duodenal damage. The aim of studies of the diclofenac/misoprostol combination dosage form has been to determine the potential for drug-drug interactions between the 2 drugs when they are coadministered. A single dose crossover study in young healthy volunteers showed no statistically significant differences between the plasma concentrations of either diclofenac or misoprostol when the drugs were each administered alone and those after administration of the combination dosage form. Although not statistically significant, slight variations in plasma diclofenac concentrations appeared to occur between dosage forms. Use of a replicate design study in which the same dosage of diclofenac was administered in 2 different treatment periods to elderly volunteers showed that this variation was due to interindividual variations in the disposition of diclofenac. The latter study had both single and multiple dose components and confirmed the lack of interaction between misoprostol and diclofenac at steady-state. Thus, diclofenac and misoprostol may be given in a combination dosage form without either drug altering the pharmacokinetics of the other.

Administration, Oral↗
PubMed1993

Importance of pharmacokinetic and physicochemical data in the discovery and development of novel anti-arrhythmic drugs.

1. The importance of pharmacokinetics and physicochemical data in the discovery and development of a new mono-cationic antiarrhythmic agent, bidisomide (pKa 9.3), structurally related to the di-cationic anti-arrhythmic disobutamide (pKa of 8.6 and 10.2) and a mono-cationic drug disopyramide (pKa 10.4), is described. 2. In man, the di-cationic disobutamide was slowly eliminated with a mean terminal phase half-life of 54 +/- 18 h, a value > 7 times longer than disopyramide. The long terminal phase half-life of disobutamide is attributed to high accumulation of the drug in the tissues, a phenomenon attributed to the di-cationic nature. 3. Structural modification of disobutamide resulted in the mono-cationic agent bidisomide, designed to minimize drug accumulation in the tissues. Human studies with bidisomide confirmed that the terminal phase elimination of this drug was much faster than that of disobutamide, with a half-life of about 11h. The absolute bioavailability of bidisomide was 45-62% which is lower than that of disopyramide (60-90%). 4. Unlike disopyramide, absorption of bidisomide was complex, characterized by a lag period (0.75-1.5 h) before absorption, followed by occurrence of two peaks in the plasma concentration-time curves. 5. The characteristic double peaks found with bidisomide was attributed to two rapid absorption sites of the drug in the gastrointestinal tract.

Adolescent↗
PubMed1992

Quantitation and mapping of integrated human papillomavirus on human metaphase chromosomes using a fluorescence microscope imaging system.

Integrated human papillomavirus type 16 (HPV-16) DNA was directly visualized on metaphase chromosomes in the two human cervical carcinoma cell lines SiHa and CaSki by fluorescence in situ hybridization with a biotinylated DNA probe (7.9 kb). The fluorescence intensities of hybridization signals from single copies and dispersed clusters of integrated HPV-16 DNA were quantified using a microscope equipped with a cooled-CCD camera that was interfaced to an image processor and host computer. Hybridization signals were localized on chromosomes using separate, registered images of 4',6-diamidino-2-phenylindole (DAPI) or propidium iodide stained metaphase chromosome spreads. In both SiHa and CaSki spreads, a single fluorescein signal was observed on one or both chromatids of chromosome 13, which was identified by simultaneous hybridization with a biotinylated centromere probe specific for chromosomes 13 and 21. Ratios of the distance from 13pter to the HPV-16 signals to the entire chromosome length were approximately 0.63 +/- 0.05 in both SiHa and CaSki cells, indicating the possibility of a common integration domain on chromosome 13. In SiHa cells, no additional signals were observed on other chromosomes. This observation, taken together with literature reports that SiHa cells contain 1 to 2 copies of the HPV-16 genome in this region of chromosome 13, suggests that each fluorescein signal on chromosome 13 represents one equivalent of the HPV-16 genome. The total integrated fluorescence intensity in isolated CaSki metaphase chromosome spreads was approximately two orders of magnitude greater than that of a single copy of HPV-16 DNA in SiHa cells, indicating an increase in HPV-16 copy number.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Temporal bone resections for carcinoma of the middle ear and the external ear canal.

Petrosectomy has been used in the management of carcinoma of the external ear canal and the middle ear for the last 45 years. In recent years, there have been conflicting reports; some authors advocate a conservative approach, whereas others support an ultraradical approach. Most retrospective studies report patients who have been treated with radiotherapy or surgery as having undergone the primary modality depending on where the patient first presented. No selection criteria seem to have been employed. Although radiotherapy was used postoperatively, the problems of wound healing were not addressed. This study presents our experience with temporal bone resection as described by Lewis and shows that, in combination with patient selection and proper choice of incision, reconstruction and timely postoperative radiotherapy can achieve better results, and the patient's quality of life can be preserved.

Combined Modality Therapy↗
PubMed1992

Bidisomide (SC-40230), a new antiarrhythmic agent: initial study of tolerability and pharmacokinetics.

Forty-nine healthy male volunteers received the test article for bidisomide (SC-40230) in a double-blind, placebo-controlled, dose-ranging study. Intravenous doses ranged from 0.03 to 2.5 mg/kg. There was a close relationship between the dose and the peak plasma concentration. The PR, QRS, QT, RR, and QTc intervals each demonstrated a statistically significant response to the dose administered. The PR and QRS intervals lengthened and the other intervals shortened (although to a lesser degree). The compound was well tolerated, with mild symptoms only at higher doses. Bioavailability was studied in 12 male volunteers, with each receiving 2.0 mg/kg of bidisomide, both orally and intravenously, in an open-label crossover trial. After a 10-minute zero-order intravenous infusion, bidisomide plasma levels could best be described in terms of a three-compartment pharmacokinetic model with the mean half-life values of alpha, beta, and gamma phases of 0.12, 1.77, and 12.3 hours, respectively. The mean absolute oral bioavailability was 43%.

Administration, Oral↗