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Biomedical subjects

J Posner

Publications and source records attributed to J Posner.

At least 19 recordsLinked to original sources
PubMed2004

Clinical pharmacology studies in UK Phase 1 units: an AHPPI survey 1999-2000.

AIMS: This study, conducted by the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI), was designed to determine the amount of Phase 1 activity in the UK in the period 1999-2000, the timelines involved for submissions to ethics committee and responses from ethics committees. METHODS: A questionnaire was completed by AHIPPI members from pharmaceutical companies with in-house phase 1 units, by Clinical Research Organizations (CRO's) and by academic centres. A few responses were also vailable from organisations that were not AHPPI members. Results were rendered anonymous and grouped by category. RESULTS: The response rate was > 98% and indicated that the vast majority of early drug research in humans is now CRO-based (82%). The total number of studies (as indicated by protocol numbers) was notably similar across the 2 years--629 in 1999 and 606 in 2000. Turnaround time for ethics committee review was a mean of 14 days. CONCLUSIONS: These data set important benchmarks for early-phase drug research in the UK where regulatory approval is not currently required. Furthermore, the information should be used as a guide if the competitive nature of such work in the UK is to be maintained as new national legislation is implemented following publication of the European Union (EU) Clinical Trials Directive.

Biomedical Research↗
PubMed2002

Multiple interactions of cimetidine and probenecid with valaciclovir and its metabolite acyclovir.

The effects of probenecid and cimetidine on the pharmacokinetics of valaciclovir and its metabolite acyclovir have been investigated. Twelve healthy male volunteers participated in this open single-dose study with a four-way-crossover randomized and balanced design. At the first of four administrations, volunteers in four groups received 1 g of valaciclovir alone, valaciclovir with 1 g of probenecid, valaciclovir with 800 mg of cimetidine, or valaciclovir with a combination of probenecid and cimetidine. At three subsequent administrations, drug regimens were alternated among groups so that each group received each regimen. Probenecid and cimetidine increased the mean maximum concentrations in serum (C(max)) of valaciclovir by 23 and 53% and the areas under the concentration-time curves (AUC) for valaciclovir by 22 and 73%, respectively; probenecid and cimetidine also increased the mean acyclovir C(max) by 22 and 8% and its AUC by 48 and 27%, respectively. The combination had a greater effect than either drug alone. Their effects may be due to competitive inhibition of membrane transport of valaciclovir and acyclovir in the liver and kidney. Neither cimetidine nor probenecid affected the absorption of valaciclovir. Both probe drugs reduced the rate of valaciclovir metabolism but not its extent. These pharmacokinetic modifications did not affect the tolerability of valaciclovir.

Acyclovir↗
PubMed2001

Stroke in young adults and children.

Data from studies of 337 children and 1606 young adults are summarized to identify the major causes of stroke in these age groups. In children under 15 years of age, stroke occurs in patients with congenital heart disease, nonatherosclerotic vasculopathies, infection, and hematologic defects like sickle cell disease. In patients 15 to 35 years of age, dissection, cardioembolism, nonatheroslerotic vasculopathies, and prothrombotic states cause a significant percentage of strokes. In adults over 35 years of age, traditional atherosclerotic risk factors predominate. Lifestyle choices (e.g., cigarette smoking, alcohol consumption, and illicit drug use) can significantly increase the rate of stroke among young adults in a community. Limited access to healthcare may increase the role of infectious disease and peripartum complications.

Adult↗
PubMed2000

Who can give a pediatric trauma history for children injured in bicycle crashes?

Emergency Departments are important sites for injury surveillance but the quality of data collected has not been evaluated. This prospective cohort study assessed the ability of various respondents to provide circumstantial information following pediatric bicyclist trauma. A semi-structured survey tool was administered in the Emergency Department of a Level One Pediatric Trauma Center for 448 child bicyclists. The injured child provided more complete information when compared to witnesses and Emergency Medical Services personnel. No one respondent type provided the complete history. To obtain thorough injury circumstantial information, multiple respondents should be interviewed utilizing a semi-structured questionnaire.

Abbreviated Injury Scale↗
PubMed1999

Bilateral optic neuropathy with IgGkappa multiple myeloma improved after myeloablative chemotherapy.

A 49-year-old woman with immunoglobulin GK multiple myeloma developed progressive visual loss with bilateral upper and lower central arcuate scotomas. Funduscopic and electrophysiologic studies indicated bilateral optic neuropathy. The immunoglobulin G fraction of the patient's serum reacted with retinal ganglionic cells in bovine retina. The visual abnormalities remitted after myeloablative chemotherapy and disappearance of the paraprotein.

Animals↗
PubMed1999

Effects of lamotrigine on pain-induced chemo-somatosensory evoked potentials.

Lamotrigine, a sodium channel blocker that selectively inhibits the neuronal release of glutamate, has been shown to produce analgesia in acute and chronic pain models in rats without causing noticeable sedation. After oral administration it also reduces pain scores, as assessed by the cold pain test, in volunteers. The purpose of this study was to determine the analgesic effect of lamotrigine given by mouth to healthy volunteers as evidenced by alterations in chemo-somatosensory evoked potentials. The following factors were measured: latency to N1 and P100 peak (ms); amplitude between the N1 and P100 peak (microV); visual analogue pain intensity scores. A double-blind, randomised and crossover design was used in which 12 volunteers received either placebo or lamotrigine 300 mg on separate occasions as determined by the randomisation schedule. Volunteers were tested before and 2 h after the treatment. The plasma lamotrigine concentration was measured immediately after the end of the experimental sessions. Lamotrigine produced a significantly higher latency to P100 values at 2 h postdrug than placebo (p < 0.05) but had no significant effects on the other factors. Although plasma concentrations were similar to those observed in the cold pain test, we conclude that lamotrigine 300 mg by mouth had no analgesic effect in this acute pain model.

Administration, Oral↗
PubMed1998

Lack of an effect of zolmitriptan (Zomig, 311C90) on psychometric task performance: results of a placebo-controlled study in healthy volunteers.

The novel selective 5-hydroxytryptamine (5-HT)1B/1D agonist, zolmitriptan (Zomig, formerly known as 311C90), has shown good efficacy in the acute oral treatment of migraine. Zolmitriptan acts both centrally and peripherally, therefore it is important to assess central nervous system effects. At single doses of 25-50 mg (up to 8 times the likely therapeutic dose), zolmitriptan can cause sedation; therefore, a study was designed to examine the dose-response. A double-blind, randomized, placebo-controlled, six-limb crossover study in 13 healthy volunteers compared the effects of single oral doses of zolmitriptan (5, 10, 15 or 20 mg) and lorazepam (2 mg) on various psychometric tests. Zolmitriptan doses less than 20 mg had no statistically significant effects on choice reaction time, the Stroop test, visual analog scale (VAS) assessments of physical sedation, tranquilization and other types of feelings, the logical reasoning test or the adaptive tracking test. There was a mild transient increase in the subjective assessment on VAS of mental sedation which was dose related and occurred mainly with the highest zolmitriptan dose and were not reflected in objective measures of drug effects. In contrast, lorazepam (used as a positive control) was associated with statistically significant impairment in all tests (except tranquilization) for up to 10 h after dosing. The results demonstrate that therapeutic doses of zolmitriptan are unlikely to cause clinically significant impairment in psychometric performance.

Adolescent↗
PubMed1998

The pharmacodynamics and pharmacokinetics of the 5HT1B/1D-agonist zolmitriptan in healthy young and elderly men and women.

OBJECTIVE: Zolmitriptan is a selective 5HT1B/1D-agonist for the treatment of migraine. In this study we investigated the cardiovascular and central nervous system effects and the pharmacokinetics of zolmitriptan in young and elderly adults. METHODS: Twelve young adult and 12 elderly volunteers received single doses of 5, 10, and 15 mg zolmitriptan during a randomized, double-blind, placebo-controlled study. Blood pressure, heart rate, ECG, and central nervous system effects were monitored, and pharmacokinetic parameters of zolmitriptan and its metabolites calculated. RESULTS: Zolmitriptan did not affect heart rate and had little effect on systolic blood pressure in the young adults. In the elderly, mean peak supine systolic blood pressure values were 9 to 16 mm Hg higher after zolmitriptan than after placebo. Mean peak diastolic pressure was 6 to 10 mm Hg higher in both age groups. These changes were transient. Postural changes in blood pressure were unaffected. There was a dose-related increase in sedation, but the magnitude of the effects was small. Mean observed peak plasma concentration (Cmax) and area under the plasma concentration-time profile [AUC(0-infinity)] for zolmitriptan and its active N-desmethyl metabolite were similar in both age groups but higher in young women than in young men. Metabolite/parent ratios probably the result of greater first-pass metabolism in young men. Zolmitriptan half-life was 2.8 to 3.6 hours in the elderly compared with 2.7 to 2.9 hours in young adults. Mean Cmax and AUC(0-infinity) for the inactive, N-oxide, and the indole acetic acid metabolites were higher in the elderly, associated with lower renal clearance. CONCLUSIONS: Zolmitriptan was well tolerated, with an effect of age on its effects on blood pressure and the pharmacokinetics of its metabolites. The data suggest no need for dose adjustment for age. In young subjects, concentrations were higher in women than in men, but the differences were insufficient to justify dosage adjustment.

Adult↗
PubMed1998

Perceptions of danger: a psychological mediator of neighborhood demographic characteristics.

Associations between neighborhood characteristics and adjustment of 168 urban fifth-grade children were explored. High neighborhood risk was associated with parent and teacher reports of child misconduct, and with parent and child reports of child psychological distress, while child and parent perceptions of neighborhood dangers appeared to mediate these associations. Specific neighborhood aspects were also related to child adjustment: higher violent crime rates with higher child misconduct rates, and lower neighborhood incomes with greater child psychological distress. Implications for research and intervention are discussed.

Chi-Square Distribution↗
PubMed1998

Effect of food and gender on the pharmacokinetics of tucaresol in healthy volunteers.

AIMS: The potential effects of food and gender on the pharmacokinetics of tucaresol were investigated in healthy volunteers. METHODS: Ten males (mean weight 76.5 kg, age 27-42 years) and eight females (mean weight 58.9 kg, age 18-44 years) received a single oral dose of 200 mg tucaresol on two occasions in random order. On one occasion, tucaresol was given after an overnight fast and on the other, immediately after ingestion of a standard breakfast. RESULTS: There were no significant differences in standard pharmacokinetic parameters between the two occasions but the rate of tucaresol absorption was faster after food intake. Female subjects had higher Cmax (ratio 1.25 with 95% CI 1.10-1.44) and AUC (ratio 1.25 with 95% CI 1.05-1.49) values than males but the differences were due to the higher body weights of the males; weight-adjusted apparent total clearance values (CL/F) were not different between genders (ratio 1.03 with 95% CI 0.87-1.21). CONCLUSIONS: Food intake and gender have no significant effect on the exposure to orally administered tucaresol.

Absorption↗
PubMed1998

Lack of interaction between valaciclovir, the L-valyl ester of aciclovir, and digoxin.

AIMS: Changes in both digoxin and aciclovir renal clearance following coadministration with some other renally eliminated drugs have been reported. The potential interaction of valaciclovir, with its antiherpetic metabolite aciclovir, and digoxin was investigated. METHODS: Twelve healthy volunteers (seven males, five females) participated in an open, randomized, four-period crossover study. Valaciclovir, 1000 mg, was given alone on one occasion, and on another, after the second of two 0.75 mg digoxin doses administered 12 h apart. Blood samples and all urine were collected up to 12 h following the valaciclovir dose for aciclovir radioimmunoassay. On a third occasion, digoxin was given alone and on a fourth, with 1000 mg valaciclovir three times/day for 8 days starting 12 h before the first digoxin dose. Blood samples were taken up to 168 h and all urine collected up to 24 h following the second dose for digoxin radioimmunoassay. RESULTS: There were no clinically significant differences in digoxin or aciclovir pharmacokinetic parameters when digoxin or valaciclovir was given alone or in combination. CONCLUSIONS: No dosage adjustment is required when valaciclovir and digoxin are coadministered.

Acyclovir↗
PubMed1998

Median cleft lip with associated midline sinuses.

Midline upper lip sinuses alone are rare entitities, with less than 25 cases reported previously. Midline upper lip sinuses with associated cleft lip are even more rare. A patient report of median cleft lip with associated upper lip sinuses in a 16-year-old boy is presented. Controversy exists as to whether these abnormalities are related. This report demonstrates the plausibility of a cause-and-effect relationship between midline clefts and sinuses.

Adolescent↗
PubMed1997

The novel anti-migraine compound zolmitriptan (Zomig 311C90) has no clinically significant interactions with paracetamol or metoclopramide.

OBJECTIVE: This study investigated potential pharmacokinetic or pharmacodynamic interactions between the novel anti-migraine compound zolmitriptan (Zomig, formerly 311C90) and paracetamol and/or metoclopramide. METHODS: In an open-label, randomised, crossover study, 15 healthy volunteers received single oral doses of 10 mg zolmitriptan alone, 1 g paracetamol alone, 10 mg zolmitriptan + 1 g paracetamol, 10 mg zolmitriptan + 10 mg metoclopramide or 10 mg zolmitriptan + 1 g paracetamol + 10 mg metoclopramide on five separate occasions. RESULTS: Metoclopramide had no significant effects on the pharmacokinetics of zolmitriptan or the active zolmitriptan metabolite 183C91, nor did it affect interactions between zolmitriptan and paracetamol. Paracetamol marginally increased the maximum plasma concentration (Cmax) (11%) and the area under the curve (AUC) (11%) and reduced the renal clearance of zolmitriptan (9%); similar small effects were seen on 183C91. The AUC, Cmax and half-life of paracetamol were reduced by concomitant zolmitriptan (by 11%, 31% and 8%, respectively), whilst the mean residence time showed a small increase (+0.7 h). There was a trend towards a transient increase in blood pressure following all regimens containing zolmitriptan; this effect was small, was consistent between all zolmitriptan regimens as well as with previous studies, and was considered to be clinically insignificant. Zolmitriptan was well tolerated after all treatment regimens. CONCLUSION: Concomitant administration of zolmitriptan and paracetamol resulted in a slight increase in bioavailability of zolmitriptan and a reduced rate and extent of paracetamol absorption. These findings are considered to be of no clinical significance and there is no reason to avoid concomitant administration of paracetamol and/or metoclopramide with zolmitriptan.

Acetaminophen↗
PubMed1997

The pharmacokinetics and effects on blood pressure of multiple doses of the novel anti-migraine drug zolmitriptan (311C90) in healthy volunteers.

AIMS: Zolmitriptan (311C90), a novel, selective, centrally and peripherally acting 5-HT1D-receptor agonist is under development as an acute treatment for migraine. The tolerability, pharmacokinetics and effects on blood pressure and heart rate of multiple doses of 5 or 10 mg (5 doses administered over 24 h) were compared, in healthy adult volunteers, with those after placebo and single doses of zolmitriptan. METHODS: Twelve subjects participated in a randomized, balanced, crossover comparison. Plasma and urine concentrations of zolmitriptan and its metabolites, pulse rate and blood pressure were measured at intervals after drug. Ten volunteers completed the study. RESULTS: Zolmitriptan was well tolerated after single and multiple doses throughout the study. There was no evidence of significant changes in the pharmacokinetic parameters of zomitriptan or its metabolites after the last dose compared to the first, except for an expected rise in peak concentrations and a small, apparent increase in the amount of drug excreted in urine and hence in CLR. After the last 10 mg dose, mean dosing interval zolmitriptan AUC was 80.3 ng ml-1 h compared with 86.5 ng ml-1 h after the single 10 mg dose (95% CI for ratio 0.76-1.13). There was no evidence of changes in the pharmacokinetic parameters of zolmitriptan and its metabolites after 10 mg compared with 5 mg, except a small increase in zolmitriptan CLR. There were no statistically significant increases in peak systolic or diastolic blood pressure after the last doses of zolmitriptan compared to placebo or in peak blood pressure after the last dose compared to the first. There were no significant differences between blood pressure immediately before the first and last doses of each multiple dose regimen. Peak erect systolic blood pressure after the last 10 mg dose (137 mmHg) was significantly lower than that after placebo (147 mmHg, 95% CI for difference -18, -2) and that after the last 5 mg dose (148 mmHg, 95% CI -19, -3). CONCLUSIONS: Repeated doses of 5 or 10 mg zolmitriptan are well tolerated despite higher plasma concentrations than expected from single doses.

Administration, Oral↗
PubMed1997

Population pharmacokinetics of lamotrigine monotherapy in patients with epilepsy: retrospective analysis of routine monitoring data.

AIMS: To examine the population pharmacokinetics of lamotrigine in patients newly diagnosed with epilepsy and receiving oral lamotrigine monotherapy for up to 48 weeks. METHODS: The population consisted of 158 Caucasians and 5 Asians of whom 81 were males and 82 females. Age and weight ranged between 14 and 76 years and 41-107 kg, respectively. A one-compartment compartment model with first-order absorption and elimination was fitted to plasma lamotrigine concentration-time profiles from retrospective drug monitoring, using non-linear mixed effect modelling (NONMEM), with first-order estimation. Oral clearance (CLo), apparent volume of distribution (V/F) and absorption rate constant (Ka) were the main pharmacokinetic parameters. RESULTS: CLo was not significantly influenced by body weight, age, gender, oral contraceptives and dose. However, due to auto-induction CLo increased by 17.3% during the 48 weeks of therapy, from 1.94 to 2.28 l h(-1), and was 28.7% lower in Asians than Caucasian. The final magnitude in interpatient variability was 32%. The effect of the covariates weight, age, race and gender on V/F was examined and none was statistically significant. The final population estimate of V/F was 77.4 l with an interpatient variability of 34%. CONCLUSIONS: In view of the wide therapeutic margin of lamotrigine and the 21% residual variability in plasma concentrations, the modest significant effects of race and auto-induction on clearance are unlikely to be clinically significant and, thus, no dosage adjustment is warranted for these effects.

Adolescent↗
PubMed1997

The absolute bioavailability and metabolic disposition of the novel antimigraine compound zolmitriptan (311C90).

AIMS: Two open studies in healthy volunteers were conducted to determine the absolute bioavailability and metabolic disposition of zolmitriptan (311C90), a novel 5HT1D agonist for the acute treatment of migraine. METHODS: After an initial test i.v. infusion, bioavailability was assessed by comparison of AUC after an i.v. infusion (3.5 mg) and an oral tablet (10 mg), in six men and six women using a randomised, crossover design. Disposition was studied by administration of a 25 mg capsule, labelled with 100 microCi [14C]-zolmitriptan, to five men and one woman on a single occasion. RESULTS: Zolmitriptan was well tolerated by both i.v. and oral routes. Adverse events were mostly mild, consistent with earlier studies and characteristic of this class of drug. Reports were similar in nature and number after both oral and i.v. dosing. Mean +/- s.d. oral bioavailability was 0.49 +/- 0.24 (0.38 +/- 0.16 in men and 0.60 +/- 0.28 in women). After oral dosing, Cmax and AUC values in women were approximately double those in men. Relative to zolmitriptan concentrations, metabolite concentrations were higher after oral dosing than after i.v., and higher in men compared with women. Half-life was significantly longer after oral dosing (mean 22%, 95% CI 6-35%). Mean +/- s.d. values for CL, V2 and t1/2,z after i.v. dosing (all subjects) were 8.7 +/- 1.7 ml min-1 kg-1, 122 +/- 321 and 2.30 +/- 0.59 h respectively. Following administration of 25 mg [14C]-zolmitriptan, 91.5% of the dose was recovered in 7 days, 64.4 +/- 6.5% in urine and 27.1 +/- 6.0% in faeces. Less than 10% was recovered unchanged in urine, with 31.1 +/- 6.4% recovered as the inactive indole acetic acid metabolite. Most of the faecal material was unchanged zolmitriptan, representing unabsorbed drug. Plasma concentrations of [14C] were slightly higher than those of the summed concentrations of known analytes zolmitriptan, the active N-desmethyl metabolite (183C91), the inactive N-oxide (1652W92) and indole acetic acid (2161W92) metabolites, which accounted for 86% of total plasma radioactivity. No other significant metabolites were detected in plasma. Some minor additional metabolites were detected in urine, none of which contributed more than 5% of the dose. CONCLUSIONS: The data suggest that zolmitriptan undergoes first-pass metabolism and this is more extensive in men than in women. Zolmitriptan has suitable bioavailability for an acute oral migraine treatment and there are no significant unidentified metabolites in man.

Absorption↗
PubMed1997

The interaction between propranolol and the novel antimigraine agent zolmitriptan (311C90).

AIMS: Zolmitriptan (Zomig, formerly known as 311C90), a selective 5HT1B/1D agonist is under development as an acute oral treatment for migraine. Despite the use of prophylactic medication, such as propranolol, breakthrough attacks often occur in patients. Consequently we investigated the effects of propranolol on the pharmacokinetics of, and cardiovascular responses to, zolmitriptan. METHODS: A double-blind, randomized, crossover study of the effects of pre-treatment with propranolol 160 mg daily for 7 days or placebo on the pharmacokinetics and effects on blood pressure of a single 10 mg dose of zolmitriptan in 12 healthy volunteers. RESULTS: Propranolol increased mean zolmitriptan Cmax and AUC by 56% and 37% respectively; mean t1/2 was prolonged from 3.1 to 4.0 h. Mean Cmax and AUC of the pharmacologically active N-desmethyl metabolite were reduced by 24% and 11% respectively and the metabolite:parent AUC ratio (AUCm/AUCp) fell from 0.46 to 0.26. Mean Cmax and AUC for the inactive indole acetic acid metabolite were both reduced by 13% and AUCm/AUCp from 1.04 to 0.59. A small pressor effect of short duration was observed following zolmitriptan with mean peak rises of 13 and 11 mmHg in systolic and diastolic pressures respectively; propranolol had no effect on the pressor response. CONCLUSIONS: The results suggest that propranolol inhibits biotransformation of zolmitriptan but with no change in the small pressor response to zolmitriptan. It is therefore unlikely that the pharmacokinetic changes will lead to clinically important changes in pharmacological effects and dosage adjustment of zolmitriptan is not required in patients taking propranolol for migraine prophylaxis.

Adrenergic beta-Antagonists↗