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Biomedical subjects

J D Rogers

Publications and source records attributed to J D Rogers.

At least 55 records · Page 3Linked to original sources

Pharmacokinetics and tolerability of intravenous rizatriptan in healthy females.

The pharmacokinetics and tolerability of intravenous (i.v.) rizatriptan (MK-0462), a novel 5-HT1D/1B receptor agonist for the acute oral treatment of migraine, were examined in an open, single-dose, four-period, randomized crossover study in healthy females. Results of this study indicated that i.v. rizatriptan (0.5-5 mg) was well tolerated. The disposition kinetics of rizatriptan were linear for i.v. doses up to and including 2.5 mg. Relative to the 0.5 mg dose, geometric mean dose-adjusted AUC ratios were 1.04, 1.09, and 1.18 for 1, 2.5, and 5 mg doses, respectively. Apparent plasma clearance (Cl) ranged between 859 and 941 mL min(-1) from 0.5 to 2.5 mg, but dropped to slightly below 800 mL min(-1) for the 5 mg dose. Therefore, the elimination of rizatriptan appears somewhat dose dependent at the high end of this dose range. Mean plasma half-life (t1/2) was 1.5-2.2 h across all doses while mean residence time in the body (MRT) and steady state volume of distribution (Vss) of rizatriptan remained relatively invariant across doses. Urinary excretion of rizatriptan (Ue) ranged from 14.5 to 34.6% of dose.

Adult↗

Sri Lanka. Political violence and ethnic conflict.

In recent years, Sri Lanka has experienced 2 violent rebellions in which youths have played a prominent role, 1 in the majority Sinhala community and 1 in the minority Tamil community. The former was crushed, but the latter remains ongoing, with the Liberation Tigers of Tamil Eelam, who claim to represent the Tamil minority, battling the Sinhala-dominated government. Prospects for peace in the short- and medium term appear poor. These events have generated an impressive body of interdisciplinary interpretation, but several important topics have received relatively little attention. Most ongoing research is being carried out by anthropologists, historians, and political scientists, but psychological insights would offer important complementary perspectives.

Civil Disorders↗

Species-specific oligonucleotides for enumeration of Pseudomonas putida F1, Burkholderia sp. strain JS150, and Bacillus subtilis ATCC 7003 in biodegradation experiments.

Species-specific sequences were identified within the V4 variable region of 16S rRNA of two bacterial species capable of aromatic hydrocarbon metabolism, Pseudomonas putida F1 and Burkholderia sp. strain JS150, and a third, Bacillus subtilis ATCC 7003, that can function as a secondary degrader. Fluorescent in situ hybridization (FISH) with species-specific oligonucleotides was used for direct counting of these species throughout a phenol biodegradation experiment in batch culture. Traditional differential plate counting methods could not be used due to the similar metabolism and interactions of the primary degraders and difficulties in selecting secondary degraders in mixed culture. In contrast, the FISH method provided reliable quantitative results without interference from those factors.

Bacillus subtilis↗

Delusional misidentification in association with parkinsonism.

The delusional misidentification syndrome (DMS) has been associated with a range of neurological conditions. Three cases of DMS in patients with Parkinson's disease and dementia, treated with dopaminergic medications, are presented. It is postulated that DMS associated with parkinsonism results from a combination of dopaminergic psychosis and cognitive dysfunction involving the frontal lobe in particular. DMS in the setting of parkinsonism may be more frequent than commonly supposed.

Aged↗

Stereoselective determination of R-(+)- and S-(-)-remoxipride, a dopamine D2-receptor antagonist, in human plasma by chiral high-performance liquid chromatography.

A stereoselective high-performance liquid chromatographic (HPLC) method is described for the selective and sensitive quantitation in human plasma of R-(+)- and S-(-)-enantiomers of remoxipride. Remoxipride was extracted from basified plasma into hexane-methyl-tert.-butyl ether (20:80, v/v), washed with sodium hydroxide (1.0 M), then back-extracted into phosphoric acid (0.1 M). A structural analog of remoxipride was used as an internal standard. The sample extracts were chromatographed using a silica-based derivatized cellulose chiral column, Chiralcel OD-R, and a reversed-phase eluent containing 30-32% acetonitrile in 0.1 M potassium hexafluorophosphate. Ultraviolet (UV) absorbance detection was performed at 214 nm. Using 0.5-ml plasma aliquots, the method was validated in the concentration range 0.02-2.0 microg/ml and was applied in the investigation of systemic inversion of remoxipride enantiomers in man.

Capsules↗

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers.

A study was conducted to (i) characterize the multiple-dose pharmacokinetics of oral montelukast sodium (MK-0476), 10 mg d-1 in healthy young subjects (N = 12), (ii) evaluate the pharmacokinetics of montelukast in healthy elderly subjects (N = 12), and (iii) compare the pharmacokinetics and oral bioavailability of montelukast between elderly and young subjects. Following oral administration of montelukast sodium, 10 mg d-1 (the therapeutic regimen for montelukast sodium) for 7 d, there was little difference in the plasma concentration-time profiles of montelukast in young subjects between day 1 and day 7 dosing. On average, trough plasma concentrations of montelukast were nearly constant, ranging from 18 to 24 ng mL-1 on days 3-7, indicating that the steady state of montelukast was attained on day 2. The mean accumulation ratio was 1.14, indicating that this dose regimen results in a 14% accumulation of montelukast. In elderly subjects, mean values of plasma clearance (Cl), steady-state volume of distribution (Vss), plasma terminal half-life (t1/2), and mean residence time in the body (MRTIV) following a 7 mg intravenous (5 min infusion) administration of montelukast sodium in the elderly were 30.8 mL min-1, 9.7 L, 6.7 h, and 5.4 h, respectively. Following a 10 mg oral dose, the bioavailability of montelukast in healthy elderly averaged 61%, very close to that (62%) determined previously in healthy young subjects. Also following the 10 mg oral administration, the mean values of AUC0-->infinity, Cmax, tmax, and t1/2, and the mean plasma concentration-time profile of montelukast in the elderly, were generally similar to those in young subjects, indicating that age has little or no effect on the pharmacokinetics of montelukast. There is no need to modify dosage as a function of age.

Acetates↗

Determination of montelukast (MK-0476) and its S-enantiomer in human plasma by stereoselective high-performance liquid chromatography with column-switching.

A steoreoselective high-performance liquid chromatographic method was developed for the quantification of montelukast (free acid of Singulair, or MK-0476), a potent and selective leukotriene D4 (cysLT1) receptor antagonist, and it S-enantiomers (L-768,232). The method involves protein precipitation and fluorescence detection. Chromatographic separation of the enantiomers from endogenous components in plasma and chiral resolution of the enantiomers are achieved by using column switching HPLC and an alpha-acid glycoprotein chiral column. The assay is linear in the range of 28.9-386 ng ml-1 of free acids of montelukast and L-768,232. The intraday precision (% relative standard deviation) values of this method were in the range of 2.5-9.1% for montelukast, and 2.4-6.8% for L-768,232, while the intraday accuracy values were in the range of 97-103% for montelukast and 96-104% for L-768,232. The interday precision values of this method at 48.2 and 193 ng ml-1 were 5.3 and 3.6%, respectively, for montelukast, and 4.2 and 3.7%, respectively, for L-768,232, while the interday accuracy values at these concentrations were 97 and 103%, respectively, for montelukast and 99 and 102%, respectively, for L-768,232. The utility of the methodology was demonstrated by analysis of plasma samples from a study in which healthy volunteers received 10 mg per day of montelukast orally for 7 days. Results of this study indicate that there is no apparent bioinversion of montelukast to its S-enantiomer in humans.

Acetates↗

Metabolic profiles of montelukast sodium (Singulair), a potent cysteinyl leukotriene1 receptor antagonist, in human plasma and bile.

Montelukast sodium [1-([(1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)- ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio]methyl)cyclopropylacetic acid sodium salt] (MK-476, Singulair) is a potent and selective antagonist of the cysteinyl leukotriene (Cys-LT1) receptor and is under investigation for the treatment of bronchial asthma. To assess the metabolism and excretion of montelukast, six healthy subjects received single oral doses of 102 mg of [14C]montelukast, and the urine and feces were collected. Most of the radioactivity was recovered in feces, with </=0.2% appearing in urine. Based on these results and the reported modestly high oral bioavailability of montelukast, it could be concluded that a major part of the radioactivity was excreted via bile. A second clinical study was conducted to identify biliary metabolites of montelukast. The bile was aspirated using a modified procedure involving a nasogastric tube placed fluoroscopically near the ampulla of Vater, after an oral dose of 54.8 mg of [14C]montelukast. This technique appears to be a new application for drug metabolism studies. The study was conducted with fasted and nonfasted subjects, with the bile being aspirated continuously under suction over periods of 2-8 hr and 8-12 hr after the dose, respectively. Two hours before the end of the collection procedure, cholecystokinin carboxyl-terminal octapeptide was administered iv to stimulate gallbladder contraction. Plasma samples also were collected periodically over 10 hr. Due to the nature of the collection procedure and the limited sampling time, recovery of radioactivity in bile was incomplete and varied from 3 to 20% of the dose. Radiochromatographic and LC-MS/MS analyses of bile showed the presence of one major and several minor metabolites, along with small amounts of unchanged parent drug. The minor metabolites were identified, by LC-MS/MS comparison with synthetic standards or by NMR, as acyl glucuronide (M1), sulfoxide (M2), 25-hydroxy (a phenol, M3), 21-hydroxy (diastereomers of a benzylic alcohol, M5a and M5b), and 36-hydroxy (diastereomers of a methyl alcohol, M6a and M6b) analogs of montelukast. The major metabolite was characterized as a dicarboxylic acid (M4), a product of further oxidation of the hydroxymethyl metabolite M6. Chiral LC-MS/MS analyses of M4 revealed that this diacid, like M5 and M6, was formed in both diastereomeric forms. The levels of metabolites in the systemic circulation were low in the fed as well as fasted subjects, with <2% of the circulating radioactivity being due to metabolites M5a, M5b, M6a, and M6b. Overall, this bile aspiration technique, which is less invasive than either T-tube drainage or fine-needle percutaneous puncture, provided a convenient and expedient means of identifying the biliary metabolites of montelukast, relatively free of contributions from colonic microflora.

Acetates↗

Pharmacokinetics and food interaction of MK-462 in healthy males.

A study was conducted to assess the safety, tolerability, and pharmacokinetics of single intravenous (IV) doses of 5-90 micrograms kg-1 of MK-462, and the effect of food on the pharmacokinetics of MK-462 administered orally to healthy males. Results of this study indicate that IV doses of MK-462 from 5 to 90 micrograms kg-1 are well tolerated. The disposition kinetics of MK-462 were linear for IV doses up to and including 60 micrograms kg-1. The values of the plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/2), and mean residence time in the body (MRT) of MK-462 averaged 1376 mL min-1, 140 L, 1.8 h, and 1.7 h, respectively, and remained essentially constant over the dosage range of 10-60 micrograms kg-1 of IV MK-462. However, as the dose increased from 60 to 90 micrograms kg-1, the mean value of the apparent CL decreased from 1376 to 807 mL min-1. Thus, elimination of MK-462 was dose dependent in this dosage range. Based on the disposition decomposition analysis (DDA), it was shown that the Vss value of MK-462 remained essentially constant over the dosage range of 10-90 micrograms kg-1 of IV MK-462. The following values of two dose-independent parameters were also calculated by using DDA: distribution clearance (CLd) = 2028 mL min-1, and mean transit time in the peripheral tissues (MTTT) = 0.74 h. The mean values of AUC, Cmax, tmax, and apparent t1/2 of MK-462 in 12 subjects each receiving a 40 mg tablet of MK-462 without breakfast were 330 ng.h mL-1, 77 ng mL-1, 1.6 h, and 1.8 h, respectively. Although administration of a standard breakfast prior to dosing increased the AUC value (by approximately 20%) of MK-462 and delayed its absorption, there were no significant effects of the meal on the values of Cmax and apparent t1/2 of MK-462.

Absorption↗

Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females.

PURPOSE: The safety, tolerability, and pharmacokinetics of intravenous *i.v.) montelukast sodium (Singulair, MK-0476), and the oral bioavailability of montelukast sodium in healthy males and healthy females were studied. METHODS: This was a two-part study. Part I was a four-period study in males of rising i.v. doses of montelukast sodium (3, 9, and 18 mg) administered as 15-minute constant-rate i.v. infusions (Periods 1-3), followed by a 10-mg oral tablet dose of montelukast sodium (Period 4) under fasting conditions. Part II was a four-period study in females of i.v. montelukast sodium (9 mg) infused over 15 and 5 minutes (Periods 5 and 6, respectively) or injected as a bolus over 2 minutes (Period 7), followed by a 10-mg oral tablet dose of montelukast sodium (Period 8). Plasma samples were collected and analyzed by HPLC. RESULTS: In males (N = 6), as the i.v. dose of montelukast sodium increased from 3 to 18 mg, the area under the plasma concentration-time curve of montelukast sodium from time 0 to infinity (AUC) increased proportionately. The mean values of plasma clearance (CL), steady-state volume of distribution (Vss), plasma terminal half-life (t1/12), and mean residence time in the body (MRTi.v.) of montelukast sodium were 45.5 ml/min, 10.5 1, 5.1 hr, and 3.9 hr, respectively, and remained essentially constant over the i.v. dosage range. Following oral administration of a 10-mg tablet of montelukast sodium, the AUC, maximum plasma concentration (Cmax), time when Cmax occurred (Tmax), apparent t1/12, mean absorption time (MAT), and bioavailability (F) of montelukast sodium averaged 2441 ng.hr/ml, 385 ng/ml. 3.7 hr, 4.9 hr, 3.4 hr, and 66%, respectively. Following i.v. administration of 9 mg of montelukast sodium to females (N = 6), the values of CL, Vss, t1/2, and MRT i.v. averaged 47.6 ml/min, 9.6 1, 4.5 hr, and 3.6 hr, respectively. Following oral administration of a 10-mg tablet to females, the mean AUC, Cmax, Tmax, apparent t1/2, MAT and F were 2270 ng.hr/ml, 350 ng/ml, 3.3 hr, 4.4 hr, 2.6 hr, and 58%, respectively. These parameter values were similar to or slightly smaller than those in healthy males receiving the same i.v. and oral doses. CONCLUSIONS: The disposition kinetics of montelukast sodium were linear. Gender had little or no effect on the kinetics of montelukast sodium. Safety results from this study indicate that intravenous doses of montelukast sodium from 3 to 18 mg and a 10-mg oral dose are well tolerated.

Acetates↗

Immunotherapy of established murine tumors with large multivalent immunogen and cyclophosphamide.

Plasma membrane vesicles isolated from tumor cells can be incorporated onto 5-microns diameter microspheres and antigen in this form, termed large multivalent immunogen (LMI), augments generation of tumor-specific cytotoxic T lymphocyte (CTL) responses in vivo. Treatment of mice with LMI at the time of challenge with tumor significantly reduced growth of several tumors in their syngeneic hosts. Our report describes the effects of LMI on established progressing tumors, including P815 solid tumor and two fibrosarcomas in a lung-metastasis model. Treatment of mice bearing established tumors (7 to 12 days) with LMI alone did not significantly reduce tumor growth or extend host survival, but highly synergistic effects of combined treatment with cyclophosphamide (Cy) and LMI were found. Cy alone reduced the size of P815 solid tumors, but within a few days, the tumors began to grow progressively, and survival was only marginally extended. However, Cy followed 2 to 3 days later by a single injection of LMI resulted in prolonged reduction of tumor growth and significant extension of survival; in some experiments, tumors became undetectable in the majority of treated mice, and the mice survived indefinitely. Essentially the same results were obtained in experiments examining survival of mice bearing established MCA-203 fibrosarcoma. LMIs were uniquely effective in acting synergistically with Cy; antigen in the form of irradiated tumor cells or plasma membrane in adjuvant were ineffective, and free plasma-membrane antigen (not on microspheres) had only marginal effects. There has been considerable interest in the possibility of using tumor antigen to enhance tumor-specific immune responses, and clinical trials using this approach are showing some promise. The results described here suggest that altering the form of antigen by purifying plasma membranes and incorporating them onto microspheres might significantly improve the efficacy of tumor immunotherapy with antigen.

Animals↗

Enantioselective high-performance liquid chromatographic determination of omeprazole in human plasma.

A new stereoselective HPLC assay was developed to isolate omeprazole enantiomers from human plasma using C2 solid-phase extraction cartridges and an analogue was used as internal standard. Recoveries of the (+)-isomer were 83.4 and 89.7% at 100 and 250 ng/ml, respectively. Recoveries of the (-)-isomer were 78.4 and 82.8%, respectively. Recovery of the internal standard averaged 77.2%. Direct chiral separation of the enantiomers is achieved on a Resolvosil BSA-7 chiral column (15 cm x 4 mm I.D.) and a matching guard column. The mobile phase is a variable amount of n-propanol (0.05-1.0%) in 0.05 M ammonium phosphate buffer (pH 7.0) and the flow-rate is 1.5 ml/min. Drug absorbance is monitored at 302 nm. Standard curves are linear from 15 to 250 ng/ml for each enantiomer. The coefficients of variation for intra-day precision at each concentration over the range of the standard curve were between 0.98 and 10.87%. The coefficients of variation for inter-day precision for the analyses of omeprazole enantiomers in plasma (30 and 175 ng/ml) were less than 10% over a four month interval.

Chromatography, High Pressure Liquid↗

Determination of MK-0476 in human plasma by liquid chromatography.

A simple and accurate assay for quantitating MK-0476 [sodium 1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)-(ethenyl)phenyl)(3-(2-(1- hydroxy-1-methylethyl)phenyl)propyl)thio)-methyl)cyclopropane)acetate], which is a potent and selective leukotriene D4-receptor antagonist, in human plasma has been developed. The method involves precipitation of protein and reversed-phase liquid chromatography with fluorescence detection. The assay is linear in the range of 30-3000 ng ml-1 of MK-0476, and the limit of detection is 5 ng ml-1. The interday precision (% relative standard deviation) values of this method at 51 and 2040 ng ml-1 are 10 and 3%, respectively. The interday accuracy values at these concentrations are 94 and 104%, respectively. The absolute recovery of MK-0476 is 99%. The utility of this method to determine plasma concentrations of MK-0476 in humans receiving the drug orally was demonstrated.

Acetates↗

The bioavailability and nonlinear pharmacokinetics of MK-679 in humans.

MK-679 (R(-)-3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)(3- (dimethylamino)-3-oxo-propyl)thio)methyl)thio)propanoic acid) is a potent and specific LTD4-receptor antagonist. The disposition of MK-679 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma concentration-time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two-compartment model with linear tissue distribution and Michaelis-Menten elimination from the central compartment, indicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-dependent when given together with its S(+)-isomer, L-668,018. Thus, the disposition of MK-679 in humans is dose-dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK-679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg 14C-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nearly quantitative.

Administration, Oral↗

Pharmacokinetics and bioinversion of ibuprofen enantiomers in humans.

An open, randomized, six-way crossover study was conducted in 12 healthy males to assess pharmacokinetics and bioinversion of ibuprofen enantiomers. The mean plasma terminal half-life (t1/2) of R(-)ibuprofen was 1.74 hr when intravenously infused as a racemic mixture and was 1.84 hr when intravenously infused alone. The mean t1/2 of S(+)ibuprofen was 1.77 hr when dosed as S(+)ibuprofen. Examination of values of both the absorption and disposition parameters of R(-)ibuprofen revealed that the kinetics of R(-)ibuprofen were not altered by concurrent administration of S(+)ibuprofen. In this study, there was little or no presystemic inversion of R(-)ibuprofen to its S(+)isomer. Also, 69% of the intravenous dose of R(-)ibuprofen was systemically inverted and 57.6% of the oral dose of R(-)ibuprofen lysinate was bioavailable as S(+)ibuprofen. These results indicate that the bioinversion of R(-)ibuprofen administered orally is mainly systemic. Because bioinversion of R(-)ibuprofen is not complete, S(+)ibuprofen produced higher bioavailability of S(+)ibuprofen (92.0%) than either racemic ibuprofen (70.7%) or R(-)ibuprofen (57.6%). However, bioavailability of R(-)ibuprofen (83.6%) when dosed alone was not significantly different from when dosed as racemic mixture (80.7%).

Administration, Oral↗

The clinical spectrum of unruptured intracranial aneurysms.

OBJECTIVE: A retrospective study was performed to delineate the clinical characteristics of symptomatic unruptured aneurysms. DESIGN: Patient histories, operative reports, and angiograms in 111 patients with 132 unruptured aneurysms were reviewed. SETTING: Tertiary care university hospital. PATIENTS: One hundred eleven patients with 132 unruptured intracranial aneurysms were studied. There were 85 women and 26 men, with a mean age of 51.2 years (age range, 11 to 77 years). Many patients were referred by community neurologists and neurosurgeons for further evaluation and neurosurgical management. RESULTS: Fifty-four symptomatic patients were identified. Group 1 (n = 19; mean aneurysm diameter, 2.1 cm) had acute symptoms: ischemia (n = 7), headache (n = 7), seizure (n = 3), and cranial neuropathy (n = 2). Group 2 (n = 35; mean aneurysm diameter, 2.2 cm) had chronic symptoms attributed to mass effect: headache (n = 18), visual loss (n = 10), pyramidal tract dysfunction (n = 4), and facial pain (n = 3). Group 3 (n = 57; mean aneurysm diameter, 1.1 cm) had asymptomatic aneurysms. CONCLUSIONS: Acute severe headache, comparable to subarachnoid hemorrhage headache, but without nuchal rigidity, was associated with the following mechanisms: aneurysm thrombosis, localized meningeal inflammation, and unexplained. Unruptured aneurysms may be misdiagnosed as optic neuritis or migraine, or serve as a nidus for cerebral thromboembolic events. Internal carotid artery and posterior circulation aneurysms were more likely to cause focal symptoms from mass effect than were anterior cerebral artery and middle cerebral artery aneurysms. Weeks to years may elapse before their diagnosis. The absence of subarachnoid blood does not exclude an aneurysm as a cause for acute or chronic neurologic symptoms.

Acute Disease↗

Synthesis and expression of smooth muscle phenotype markers in primary culture of rabbit aortic smooth muscle cells: influence of seeding density and media and relation to cell contractility.

Rabbit aortic smooth muscle cells (SMC) were seeded at moderate or high densities and grown either in the presence of serum or in the serum-substitution formula Monomed. Expression and synthesis of marker proteins caldesmon, calponin, smooth muscle myosin, and vinculin were monitored during SMC cultivation. Contractility was tested by the ability of cultured SMC to deform silicone membranes following ionomycin treatment. The results show that cells of moderate density grown in Monomed, as opposed to those grown in 5% serum, have the smooth muscle isoform of caldesmon 1.6-fold higher, calponin 1.4-fold and smooth muscle myosin 1.4-fold higher on Day 14 of cultivation. Synthesis of these proteins corresponded to their expression in SMC. The metavinculin:vinculin ratio slightly decreased over the first days with a following reestablishment on Day 8. Contraction was observed until Day 13, compared with Day 7 for cells grown in the presence of serum. High seeding density also prevented a decrease in the expression of smooth muscle markers with the exception of smooth muscle caldesmon whose content in the high density SMC culture was not significantly different from that in the moderate density culture. The period of contractility of SMC in the high density culture was also similar to that in the moderate density culture in the presence of serum. We conclude that cultivation of primary SMC in Monomed allows the maintenance of cells in the contractile phenotype more effectively than high initial seeding density.

Animals↗