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Biomedical subjects

J Posner

Publications and source records attributed to J Posner.

At least 37 records · Page 2Linked to original sources
PubMed1997

Peripheral vascular effects and pharmacokinetics of the antimigraine compound, zolmitriptan, in combination with oral ergotamine in healthy volunteers.

Members of the new class of antimigraine compounds, 5HT1B/1D agonists, as well as ergotamine, may cause vasoconstriction through stimulation of 5HT receptors on peripheral vessels. The cardiovascular effects of 20 mg oral zolmitriptan (Zomig, formerly 311C90), 2 mg oral ergotamine and the combination were assessed in a randomized double-blind, placebo-controlled crossover study in 12 healthy subjects. Pharmacodynamic measures included oscillometric blood pressure, systolic blood pressure at the toe and arm using a strain gauge technique, stroke volume and cardiac output using bioimpedance cardiography, high-resolution ultrasound to measure brachial arterial diameter and a novel Doppler method to measure blood flow velocity. Both drugs produced small degrees of peripheral vasoconstriction, including increases in diastolic blood pressure and blood flow velocity and decreases in arterial diameter and toe-arm systolic pressure gradient. These effects were generally additive with the combination but of no clinical importance. There were no significant changes in cardiac output, stroke volume heart rate or ECG. Zolmitriptan, at eight times the likely therapeutic dose, was generally well tolerated both alone and in combination with ergotamine. Ergotamine had no clinically important effects on zolmitriptan pharmacokinetics.

Administration, Oral↗
PubMed1997

1457 years of microsurgical experience.

Microsurgery is a relatively new field of surgery involving various methods and practices that are currently evolving. Our goal was to register the current practices employed by the members of the American Society for Reconstructive Microsurgery. A survey was mailed to the 319 members of the society, resulting in a response rate of 33 percent (106 of 319). The data reflect the combined experience of 10,839 free-tissue transfers and 3487 digital and upper and lower extremity replants over a 4-year period between 1990 and 1994. Practices employed, such as pharmacologic adjuvant therapy, monitoring techniques, flap types, and success rates reported by the members of the American Society for Reconstructive Microsurgery, were analyzed.

Anticoagulants↗
PubMed1997

Comparison of the pharmacokinetics of lamotrigine in patients with chronic renal failure and healthy volunteers.

AIMS: The aim of this study was to compare the pharmacokinetics of the anti-epileptic agent, lamotrigine, in patients with chronic renal failure and healthy volunteers. METHODS: Non-compartmental pharmacokinetics of a single oral dose (200 mg) of the anti-epileptic agent, lamotrigine, and its main metabolite, lamotrigine N2-glucuronide, were determined for 10 patients with chronic renal failure of mean estimated creatinine clearance 18 ml min-1 and a control group of 11 healthy volunteers, matched for age and gender. RESULTS: For lamotrigine, there were no significant differences in Cmax, tmax, AUC, t1/2,z, CL/F and amount excreted in urine although t1/2,z tended to be longer for the renal failure group with a mean (+/-s.d.) of 35.9 +/- 10.7 h vs 27.8 +/- 4.3 h for the control group. For the renal failure group. VZ/F was 18% higher (95% CI 1% to 39%) compared with controls and CLR was reduced to 61% (95% CI 46% to 80%) of the control group value. For lamotrigine glucuronide, Cmax was increased 4-fold (95% CI 3.1 to 5.3) and AUC 7.8-fold (95% CI 6.0 to 10.1) in the renal failure group compared with controls. CLR was approximately 9-fold lower and apparent t1/2 was increased by 53% (95% CI 27% to 84%). Concentrations of an N2-methylated cardio-active metabolite, previously observed in dogs, were below the limit of detection (2 ng ml-1) of the ASTED/h.p.l.c. assay in the renal failure group as well as controls. CONCLUSIONS: These results indicate that impaired renal function will have little effect on the plasma concentrations of lamotrigine achieved for a given dosing regimen.

Administration, Oral↗
PubMed1997

Disposition of atovaquone in humans.

Atovaquone is an antiprotozoal compound with good in vitro stability against metabolic inactivation. Previous human studies which did not involve radiolabelling had not accounted for a substantial proportion of the dose. The possible metabolism of atovaquone in men was examined in a radiolabelling study involving four healthy male volunteers. Radioactivity was eliminated almost exclusively via the feces. All radioactivity in plasma, urine, and feces was accounted for by atovaquone, with no evidence of metabolites. Radiolabelled atovaquone was administered to a patient with an indwelling biliary tube after surgery. Biliary radioactivity was approximately 10- to 40-fold higher than that in plasma and was accounted for by atovaquone. Atovaquone is not significantly metabolized in humans but is excreted into bile against a high concentration gradient.

Adult↗
PubMed1997

Quality improvement in neurology residency programs. Report of the Quality Improvement Committee of the Association of University Professors of Neurology.

The neurology residency programs in the United States are facing a crisis of quality. The Association of University Professors of Neurology (AUPN) approved the Quality Improvement Committee to examine this situation and make recommendations, which have been accepted by the AUPN. The recommendations are (1) that the educational goals of neurology residency training be dissociated from patient-care needs in academic medical centers and (2) that minimum levels of quality be applied to residents in neurology residency programs and to these programs themselves. These minimum criteria should include minimum educational criteria for entry into the program, minimum criteria for advancement from one year to the next in the program, and minimum criteria for performance of the graduates of neurology residency programs for program accreditation. The implementation of these recommendations will require a shift of funding of the care of indigent patients from the graduate medical education budget to direct patient-care sources. These recommendations will significantly improve the quality of neurologists and neurologic care in the United States.

Academic Medical Centers↗
PubMed1996

Inhibition of dihydropyrimidine dehydrogenase by 5-propynyluracil, a metabolite of the anti-varicella zoster virus agent netivudine.

OBJECTIVE: To study the effects of the anti-herpetic drug netivudine on dihydropyrimidine dehydrogenase activity in elderly volunteers and to relate them to concentrations of netivudine and its metabolite 5-propynyluracil. METHODS: Three groups of eight elderly volunteers received 400 or 800 mg netivudine or placebo once daily for 8 days. Plasma netivudine, 5-propynyluracil, and uracil, an indirect measure of dihydropyrimidine dehydrogenase activity, were assayed before the first dose and on days 2, 3, 5, 7 and 8. Full plasma profiles of netivudine and 5-propynyluracil were determined after the last dose. RESULTS: Plasma uracil was unquantifiable in all subjects before the first dose and at all time points in the placebo group. In recipients of netivudine it reached a plateau between days 3 and 5, with mean values of 23.2 and 23.5 mumol/L on day 8 in the subjects who received 400 and 800 mg. Plasma netivudine concentrations were approximately dose proportional, but 5-propynyluracil concentrations were similar in both groups. The half-maximal rise in plasma uracil occurred after a cumulative 5-propynyluracil exposure of 120 mumol/L.hr; such exposures will be achieved even after doses as low as 50 to 100 mg daily. CONCLUSIONS: Netivudine dosing produces complete inhibition of plasma dihydropyrimidine dehydrogenase. Coadministration with the antimetabolite 5-fluorouracil will require a substantial reduction in 5-fluorouracil dose to avoid toxicity but may also improve the therapeutic index of 5-fluorouracil.

Aged↗
PubMed1996

The HuD paraneoplastic protein shares immunogenic regions between PEM/PSN patients and several strains and species of experimental animals.

Patients with small-cell carcinoma of the lung and paraneoplastic encephalomyelitis develop antibodies (anti-Hu) against HuD, a member of a family of neuronal specific RNA-binding proteins, which are also expressed by the tumor. In order to determine if the human HuD paraneoplastic antigen shares immunogenic regions between patients and several strains and species of animals, we immunized animals with HuD and several deletion constructs of this protein. All immunized animals developed high titers of anti-HuD antibodies, comparable to the antibody titers found in paraneoplastic patients. Using immunohistochemistry and Western blot analysis of human and mouse cerebral cortex, the pattern of reactivity of these antibodies could not be differentiated from the human paraneoplastic anti-Hu antibodies. None of the immunized animals developed neurologic symptoms. Western blot analysis of HuD deletion constructs demonstrated that the first and second RNA binding domains were the main immunodominant regions, and that the animal immune response was both strain and species dependent.

Animals↗
PubMed1996

Pharmacokinetics of 619C89, a novel neuronal sodium channel inhibitor, in acute stroke patients after loading and discrete maintenance infusions.

1. This was a multi-centre, placebo controlled, randomized, dose-escalating design study in which five dosing regimens of 619C89/placebo were evaluated in 48 stroke patients. Loading infusions of 0.5, 1, 1.5, 2 and 2.5 mg kg-1 over 1 h were followed by respective maintenance infusions of 0.25, 0.5, 0.75, 1 and 1.25 mg kg-1 over 30 min at 8 hourly intervals for 3 days. 2. Plasma concentrations of 619C89 and its N-oxide, 341C90, and N-demethylated, 78C90, metabolites were assayed using an LC-MS-MS method. Plasma concentration-time profiles after the final maintenance infusion were subjected to conventional noncompartmental pharmacokinetic analysis. 3. For 619C89, geometric CL means ranged between 0.71 and 0.99 1 h-1 kg-1 for maintenance infusions up to 1.25 mg kg-1 over 30 min, with an overall mean of 0.85 l h-1 kg-1 (95% CI: 0.70-1.04 l h-1 kg-1). Geometric Vss means ranged between 13.2 and 27.9 l kg-1 for the same doses, with an overall mean of 22.5 l kg-1 (95% CI: 16.4-30.9 l kg-1). The ANOVA results revealed that neither CL, Vss nor t1/2 were significantly different across the five dosing regimens (P values: 0.82, 0.54 and 0.61, respectively). 4. Average AUC for 341C90 was 270% and that for 78C90 was 62% of the AUC for 619C89. The AUCm/AUCp-ratios were similar at all dose levels for each metabolite. Values of t 1/2 for 341C90 were similar to those of 619C89 whereas t1/2 for 78C90 was about three-fold longer than that of parent drug. 5. In conclusion, the pharmacokinetics of 619C89 are independent of dose in acute stroke patients. The pharmacokinetics of 341C90 are probably formation rate-limited and those of 78C90 are elimination rate-limited and are also dose-independent.

Aged↗
PubMed1996

Atovaquone has no effect on the pharmacokinetics of phenytoin in healthy male volunteers.

The potential pharmacokinetic interaction between atovaquone and phenytoin was investigated in 12 healthy male volunteers. Each volunteer received a single 600 mg oral dose of phenytoin in the two treatment periods. On one occasion phenytoin was taken alone and on the other pre-treatment with 2000 mg atovaquone taken as two doses of 1000 mg as a microfluidized suspension. The mean (+/- s.d.) peak plasma concentrations (Cmax), apparent total clearance (CL/F) and terminal half-life (t1/2) for phenytoin when administered alone were 10.6(1.8) mg 1(-1), 24.3 (7.7) ml min-1 and 25(8) h, respectively. When administered together with atovaquone, phenytoin Cmax, CL/F and t1/2,z were 10.9 (2.0) mg 1(-1), 23.8 ml min-1 and 24(6) h, respectively. There were no statistically significant differences in any of these plasma pharmacokinetic parameters. There were also no statistically significant differences in the fraction of circulating drug not bound to plasma protein or urinary excretion of 5-hydroxyphenyl-phenyl-hydantoin. In conclusion, there was no effect of atovaquone on the pharmacokinetics of phenytoin or its major metabolite after a single dose.

Adult↗
PubMed1996

Tucaresol increases oxygen affinity and reduces haemolysis in subjects with sickle cell anaemia.

The primary pathophysiological event in sickling is the intracellular polymerization of deoxygenated haemoglobin S. Tucaresol (589C80;4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid), a substituted benzaldehyde, was designed to interact with haemoglobin to increase oxygen affinity and has been shown to inhibit sickling in vitro. We administered tucaresol to sickle cell patients in the steady state to examine the anti-sickling effect in vivo. Oral doses of tucaresol or placebo were given to nine stable sickle cell patients (aged 17-39 years; tucaresol, six; placebo, three) for 10 d. The first two patients on tucaresol were scheduled to receive a loading dose of 800 mg or 1200 mg (depending on bodyweight) for the first 4 d, followed by maintenance doses of 200 or 300 mg for the next 6 d. Due to concerns over the sharp rise in haematocrit in one patient, subsequent cohorts received 300 mg tucaresol daily throughout the dosing period. The oxygen affinity of haemoglobin S was increased in all patients receiving tucaresol, with between 10% and 24% of the haemoglobin modified, dependent on dose. In all patients on tucaresol, haemolysis was reduced with rises in haemoglobin of 0.9- 3.7 g/dl (mean 2.2 g/dl), falls in lactate dehydrogenase of 16-52%, and a halving of the irreversibly sickled cell counts. These effects were apparent within a few days and persisted for 1-2 weeks following discontinuation of the drug. Three of the six patients on tucaresol developed fever and cervical lymphadenopathy, with onset between days 7 and 11 from start of drug. Further evaluation of the tolerability and efficacy of tucaresol in sickle cell patients is necessary.

Adolescent↗
PubMed1996

Evaluation of non-invasive techniques to assess vasoconstriction in healthy volunteers using methoxamine as a probe drug.

Non-invasive methods for assessment of the vascular effects of antimigraine drugs were evaluated with respect to their utility, variability and sensitivity in a double-blind, placebo-controlled, three-period crossover study in six healthy volunteers using an intravenous vasoconstrictor, methoxamine, as a probe drug. Changes in the internal diameter of the brachial and radial arteries were measured using ultrasound which had low between-day and within-day coefficients of variation. Peak systolic velocity (PSV), time-averaged velocity (TAV), total flow, resistance (RI) and pulsatility indices (PI) were measured by Doppler from one arterial wave form. Whilst PSV and TAV increased with methoxamine, because of bradycardia, changes in PI and RI were difficult to interpret. An automatic oscillometric cuff, a mercury-in-silastic strain gauge method and the "Finapres", finger arterial blood pressure monitor were used to follow changes in systolic blood pressure (SBP). The strain gauge technique underestimated arm SBP compared to the oscillometric method but clearly showed drug-related increases whilst the Finapres did not reflect changes in blood pressure detected by the other methods.

Adult↗
PubMed1996

Lack of interaction between valaciclovir, the L-valyl ester of acyclovir, and Maalox antacid.

Valaciclovir is rapidly and extensively converted to acyclovir. In this study we investigated the potential interaction between oral valaciclovir and Maalox. On each of three occasions 18 healthy volunteers received a single oral dose of 1000 mg valaciclovir, or 30 mL Maalox 65 min after valaciclovir administration, or 30 mL Maalox 30 min before valaciclovir. Acyclovir plasma concentrations and pharmacokinetic parameters were not significantly affected by administration of Maalox before or after valaciclovir. Therefore, there is no need for restriction of valaciclovir dosing in patients receiving antacid medication.

Acyclovir↗
PubMed1996

Pharmacokinetics of netivudine, a potent anti-varicella zoster virus drug, in patients with renal impairment.

The pharmacokinetics of a single oral 200 mg dose of netivudine (1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil), a nucleoside analogue under development for use in varicella zoster virus infections, were studied in 12 renal failure (RF) subjects (creatinine clearance 15 +/- 7 mL/min) and 12 age-matched healthy subjects with normal creatinine clearance. Blood and urine samples were collected up to nine days after drug administration. Concentrations of netivudine and of its main metabolite, the pyrimidine base 5-(1-propynyl)uracil (5 PU), were determined by a specific high performance liquid chromatography assay. The mean peak plasma concentrations of netivudine, Tmax, and volume of distribution were not significantly affected by RF. The elimination half-life of netivudine was approximately 15 h in subjects with normal renal function and 60 h in RF patients. Plasma and renal clearances of netivudine were significantly reduced in RF patients and AUC was three to four times higher in these patients. Cmax and AUC of 5 PU were higher in RF patients, and the half-life was also significantly longer. However, the half-life of this metabolite was much lower than that of the parent compound. Tmax and the lag time were similar in the two groups. There were highly significant correlations for netivudine and 5 PU between half-life and creatinine clearance and between renal clearance and creatinine clearance. These findings suggest that netivudine dosage may need to be reduced in patients with severe renal failure, and confirm that formation of the 5 PU is independent of the elimination of netivudine from plasma.

Administration, Oral↗
PubMed1996

The tolerability and pharmacokinetics of the novel antimigraine compound 311C90 in healthy male volunteers.

1. 311C90 is a novel and selective agonist at 5-HT1D receptors, with central and peripheral actions, currently in development for the acute oral treatment of migraine. 2. The pharmacokinetic and tolerability profiles of single oral doses from 1-50 mg 311C90 were investigated in 12 healthy male volunteers in a double-blind, placebo-controlled, dose-escalating study. 3. 311C90 was well tolerated with most adverse experiences of mild and transient nature. 4. Absorption was rapid with dose-independent kinetics. Median tmax was 2-4 h although 50-85% of eventual Cmax was attained within 1 h. The t1/2 was 2.5-3 h with a high apparent plasma clearance (CL/F > 2000 ml min-1) and apparent volume of distribution (Vz/F) of 400-500 l. 5. Three metabolites were detected in plasma and urine, one of which, the N-desmethyl metabolite, has 5-HT1D agonist activity. 6. 311C90 showed no clinically significant effects on blood pressure, heart rate, ECG or laboratory variables at any dose and demonstrated a tolerability and pharmacokinetic profile compatible with an acute oral migraine treatment.

Administration, Oral↗
PubMed1996

Single-dose and steady-state pharmacokinetics of a novel microfluidized suspension of atovaquone in human immunodeficiency virus-seropositive patients.

The single- and multiple-dose pharmacokinetics of and tolerability to a new microfluidized suspension of atovaquone were studied in human immunodeficiency virus-seropositive patients with CD4 counts of < or = 200 cells per mm3 in order to define a dosing regimen for the treatment of Pneumocystis carinii pneumonia. This was an open study with groups of six patients each. In the first part of the study, six subjects received escalating single doses of 500, 1,000, and 1,500 mg after an overnight fast at weekly intervals. In the second part of the study, groups of six subjects were dosed for 14 days according to three regimens: 1,000 mg twice daily fasting, twice daily with a high-fat meal, or once daily with a high-fat meal. Plasma atovaquone levels were assayed by high-performance liquid chromatography. Pharmacokinetic parameters were determined by noncompartmental methods, and statistical comparison of parameters for single doses was performed by analysis of variance. Plasma drug concentrations increased with single doses from 500 to 1,000 mg but were no higher with a dose of 1,500 mg. Thus, 1,000 mg was selected for multiple administration. A regimen of 1,000 mg twice daily with food resulted in a 93% increase in the average trough steady-state concentration compared with 1,000 mg once daily with food. Food increased the bioavailability of atovaquone 1.4-fold over that in the fasting state. All patients who received 1,000 mg twice daily with food achieved target steady-state concentrations in plasma of 15 to 25 micrograms/ml. Multiple-dose regimens were generally well tolerated, but the higher levels in plasma achieved by 1,000 mg twice daily with food were associated with an increased incidence of rash. In conclusion, target plasma atovaquone concentrations for the treatment of P. carinii pneumonia can be achieved in most patients with 1,000 mg twice daily in a fasting state and in all patients with 1,000 mg twice daily administered with food, but at higher concentrations in plasma, there may be an increased risk of rash.

Adult↗
PubMed1995

The tolerability, pharmacokinetics and lack of effect on plasma cholesterol of 447C88, an AcylCoA: Cholesterol Acyl Transferase (ACAT) inhibitor with low bioavailability, in healthy volunteers.

447C88 (N-Heptyl-N'-(2,4 difluoro-4-6-(2(-4-(2,2 dimethylpropyl)phenyl)ethyl)phenyl)urea) is an inhibitor of human microsomal AcylCoA: Cholesterol acyltransferase (ACAT) with an IC50 of 10.2 ng.ml-1 (23 nM). It is poorly absorbed but 5 mg.kg-1.day-1 completely abolishes the rise in plasma cholesterol in cholesterol-fed rats. In this study, twelve healthy, male volunteers received single, oral doses of 25, 50, 100, 200, 400 and 800 mg of 447C88 (n = 8) or placebo (n = 4) with food in a double-blind study with at least a week between occasions. The 400 mg dose was repeated after an overnight fast. Subsequently, fourteen different volunteers received a single 200 mg dose of 447C88 (n = 8) or placebo (n = 6) with food and, a week later, the same dose twice daily for 10 days; all doses were given with food. All doses were well tolerated with no significant changes in vital signs, full blood counts or plasma biochemical profiles. Plasma concentrations of 447C88 were unquantifiable after the fasting dose and low after all other doses. Mean Cmax and AUC were 1.8 ng.ml-1 and 9.0 ng.ml-1.h after 200 mg rising to 5.4 ng.ml-1 and 23.8 ng.ml-1.h respectively after 800 mg; t1/2 was 1.3 to 5.2 h. After 10 days dosing, plasma 447C88 concentrations were higher in the evening than the morning probably due to administration of the evening dose with more food. There were no significant changes in plasma triglcerides or total, LDL- or HDL-cholesterol after dosing with 447C88.

Adolescent↗