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Biomedical subjects

J Posner

Publications and source records attributed to J Posner.

At least 55 records · Page 3Linked to original sources
PubMed1995

The bioavailability and disposition of 1-(beta-D-arabinofuranosyl)-5-(1-propynyl)uracil (882C87), a potent, new anti-varicella zoster virus agent.

1. The bioavailability and disposition of 882C87, an anti-varicella zoster virus (VZV) agent, have been investigated in healthy young and elderly volunteers. 2. The mean bioavailability of a 200 mg tablet was 21.1% in the young (range 13.3-33.0%, n = 10) and 24.6% in the elderly (range 14.4-38.4%, n = 8), which is sufficient to achieve plasma concentrations well above the IC50 for anti-VZV activity. 3. Plasma concentrations of 882C87 after 50 mg i.v. were higher in the elderly than in the young, associated with a significantly longer half-life (13.7 vs 11.8 h) and decreased renal clearance (0.11 vs 0.14 ml min-1 kg-1) and total clearance (0.15 vs 0.17 ml min-1 kg-1). 4. After intravenous administration, the main route of elimination of 882C87 was renal with 81.6% recovered unchanged in urine in the young and 71.2% in the elderly. The pyrimidine base, 5-propynyluracil (5-PU) was unquantifiable in plasma and only present in trace amounts in urine. 5. After oral administration to four healthy volunteers, only 17% of a dose of [14C]-882C87 was recovered unchanged in urine and 58% as 5-PU, with total recovery in urine accounting for 86% of the dose. There was a lag of 4-12 h before the appearance of 5-PU in plasma, peak concentrations were one-third to a half those of 882C87. The data suggest that 5-PU is formed from unabsorbed 882C87 in the gut lumen and then absorbed and excreted in urine. 6. 882C87 is a potential once daily treatment for shingles.

Administration, Oral↗
PubMed1995

Pharmacokinetics and pharmacodynamics of tucaresol, an antisickling agent, in healthy volunteers.

1. Tucaresol is an orally administered antisickling agent which increases the oxygen affinity of haemoglobin. 2. The pharmacokinetics, effects on moderate graded exercise and psychometric performance of tucaresol were examined in a double-blind, placebo-controlled, parallel groups study in 12 healthy men. 3. Three doses of tucaresol were given at 48 h intervals intended to modify 15, 25 and 32.5% of a subject's haemoglobin to a high affinity form (%MOD). 4. Mean peak %MOD was 34%. Mean Cmax values in plasma and erythrocytes were 81.4 and 1459 micrograms ml-1, respectively. 5. Heart rate, compared with baseline, increased in the tucaresol group with the greatest changes at the highest %MOD and workload. There were no differences between groups in psychometric test performance. 6. Three volunteers on active drug developed fever, rash and tender cervical lymphadenopathy with onset 7-10 days from the start of dosing, suggesting an immune mechanism. 7. The acute increase in oxygen affinity with tucaresol is physiologically well-tolerated, but the utility of tucaresol in the management of sickle cell disease will depend on the identification of a dosing regimen with a lower incidence of drug allergy.

Administration, Oral↗
PubMed1995

Pharmacokinetics and tolerability of single oral doses of 882C87, a potent, new anti-varicella-zoster virus agent, in healthy volunteers.

882C87 is a nucleoside analog with potent, specific activity against varicella-zoster virus. It is approximately seven times as potent as acyclovir with an in vitro 50% inhibitory concentration of 1 to 2 microM. The tolerability and pharmacokinetics of single doses of 882C87 have been investigated in a series of studies with healthy young and elderly adult volunteers. The young received 50 to 1,600 mg, and the elderly received 50 and 100 mg. Concentrations of 882C87 and its main metabolite, the pyrimidine base 5-(1-propynyl)uracil (5PU), in plasma and urine were assayed by an automated sequential trace enrichment of dialysate-high-performance liquid chromatography procedure, and noncompartmental pharmacokinetic parameters were derived from the data. Concentrations of 882C87 in plasma increased proportionally for doses of up to 400 mg, but after higher doses the increase was less than dose proportional. In young adults, after 200, 400, and 1,600 mg, the maximum concentrations of the drug in plasma were 9.0, 16.3, and 34.7 microM, respectively, and the areas under the concentration-time curve (AUC) from 0 h to infinity were 166.6, 333.7, and 822.9 microM.h, respectively. Elimination half-life was 11.3 to 13.0 h after 50 to 400 mg, increasing to 15.3 h after 1,600 mg, associated with a small decrease in renal clearance. In healthy elderly volunteers concentrations of 882C87 in plasma after 50 and 100 mg were similar to those in young adults after twice the dose; apparent clearance and renal clearance were significantly reduced, and half-life was significantly longer at 15 h. Administration of 882C87 with food produced a small, nonsignificant reduction in mean AUC from 0 h to infinity, but in subjects with a low fasting AUC there was an increase after food and in subjects with a high fasting AUC there was a decrease. Concentrations of 5PU in plasma were one-third to one-half those of 882C87 and, in most subjects, were not dose proportional. There was a lag of at least 5 h after dosing with 882C87 before 5PU was detectable in plasma.

Administration, Oral↗
PubMed1995

Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans.

Valaciclovir (Valtrex), the L-valyl ester of acyclovir, is undergoing clinical development for the treatment and suppression of herpesviral diseases. The absolute bioavailability of acyclovir from valaciclovir and the metabolic disposition of valaciclovir were investigated with healthy volunteers in two separate studies. In a randomized, crossover study, 12 fasting healthy volunteers each received 1,000 mg of oral valaciclovir and a 1-h intravenous infusion of 350 mg of acyclovir. The mean absolute bioavailability of acyclovir was 54.2%, a value three to five times that obtained previously with oral acyclovir. A similar estimate of 51.3% was made from urinary recovery of acyclovir. In the second study, four fasting volunteers received a single oral dose of 1,000 mg of [14C]valaciclovir. The majority of plasma radioactivity was accounted for by acyclovir, with very low plasma valaciclovir concentrations (mean maximum concentration of drug in plasma = 0.19 microM), which were undetectable after 3 h postdose. By 168 h, more than 90% of the administered radioactive dose was recovered, with approximately 45% in urine and 475 in feces. More than 99% of the radioactivity recovered in urine corresponded to acyclovir and its known metabolites, 9-(carboxymethoxymethyl)guanine and 8-hydroxy-9- [(2-hydroxyethoxy)methyl]guanine, with valaciclovir accounting for less than 0.5% of the dose. Acyclovir, but no valaciclovir, was detected in fecal samples. These studies show that after oral administration to humans, valaciclovir is rapidly and virtually completely converted to acyclovir to provide a high level of acyclovir bioavailability in comparison with that following oral administration of acyclovir. The plasma acyclovir exposure obtained following oral administration of valaciclovir is similar to that achieved with doses of intravenous acyclovir, which are effective in the treatment and suppression of the less susceptible herpesviral diseases.

Acyclovir↗
PubMed1994

Sera from some patients with antibody-associated paraneoplastic encephalomyelitis/sensory neuronopathy recognize the Ro-52K antigen.

Screening a small cell lung cancer cDNA library with serum from a patient with antibody-associated paraneoplastic sensory neuronopathy (Anti-Hu syndrome) resulted in the isolation of a cDNA clone encoding the Ro-52 kD antigen. The Ro-52 kD antigen is one of the major antigens recognized by the sera of patients with Sjögren's syndrome and systemic lupus erythematosus. Further investigation revealed that the sera of only a small percentage (4%) of patients with the Hu syndrome reacted with Ro-52 kD antigen. The cross-reactivity may result from a domain of high homology between Ro-52 kD and HuD antigen. These results emphasize the necessity of using recombinant antigens whenever possible when assaying for assaying for specific antibodies.

Amino Acid Sequence↗
PubMed1994

Examination of some factors responsible for a food-induced increase in absorption of atovaquone.

1. Atovaquone is a potent antiprotozoal slowly and irregularly absorbed after administration as tablets to fasting volunteers. A series of studies was performed to investigate the effects of food, bile and formulation on atovaquone absorption. 2. In 18 healthy male volunteers, a high-fat breakfast administered 45 min before 500 mg atovaquone as tablets increased AUC by 3.3-fold (95% CI 2.8-4.0) and Cmax 5.3-fold (4.3-6.6) compared with fasting. 3. The absorption of atovaquone from tablets was examined in 12 healthy male volunteers after an overnight fast, following toast alone, toast with 28 g butter (LOFAT), or toast with 56 g butter (HIFAT). Compared with absorption when fasted, toast had no significant effect but LOFAT increased AUC 3.0-fold (2.1-4.2) and Cmax 3.9-fold (2.6-5.8). HIFAT increased AUC 3.9-fold (2.7-5.5) and Cmax 5.6-fold (3.8-8.4). 4. The absorption of atovaquone was examined in nine healthy fasting male volunteers from tablets, an aqueous suspension, and an oily solution/suspension in miglyol (fractionated coconut oil). Compared with tablets, AUC following the aqueous suspension was increased 1.7-fold (1.0-2.7) and Cmax 2.4-fold (1.7-3.5). Following miglyol, AUC was increased to the same extent but Cmax was only increased 1.8-fold (1.2-2.6). 5. Atovaquone absorption was examined in eight healthy fasting male volunteers following an i.v. infusion of cholecystokinin octapeptide (CCK-OP) which decreased gallbladder volume by 82% (73%-90%) on occasion 1 or saline on occasion 2. AUC(0,12) was increased following CCK-OP by 1.6-fold (1.1-2.4) and Cmax by 1.5-fold (0.98-2.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

The pharmacokinetics, tolerability and pharmacodynamics of tucaresol (589C80; 4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid), a potential anti-sickling agent, following oral administration to healthy subjects.

1. Tucaresol (589C80; 4[2-formyl-3-hydroxyphenoxymethyl] benzoic acid) interacts stoichiometrically with haemoglobin to increase oxygen affinity. By decreasing the proportion of insoluble deoxy sickle haemoglobin at capillary oxygen concentrations, tucaresol may be of therapeutic benefit in sickle cell anaemia. 2. In this study, which involved the first administration to man, the pharmacokinetics and pharmacodynamics of tucaresol were studied in healthy male volunteers following oral doses of 200-3600 mg. 3. Peak drug concentrations in plasma and erythrocytes were linearly related to dose; mean (s.d.) values were 95.8 (26.1) and 1035 (67) micrograms ml-1, respectively, at the highest dose. Median tmax in plasma was 6.5 h and in erythrocytes 24.5 h, when approximately 60% of the administered dose was in the target tissue. Plasma drug concentrations fell biexponentially with commencement of the apparent terminal elimination phase at approximately 24 h. The terminal elimination half-life from plasma increased with dose (r = 0.77; P < 0.0001) from 133-190 h at 400 mg to a mean (s.d.) of 289 (30) h at 3600 mg. Erythrocyte drug concentrations declined mono-exponentially with a half-life that was always shorter than the apparent terminal half-life in plasma: overall mean (95% CI) of t1/2 erythrocyte/t1/2 plasma ratio was 0.57 (0.53, 0.61). The erythrocyte AUC/plasma AUC ratio increased with dose (r = 0.67; P < 0.001). 4. The proportion of haemoglobin modified to a form with high oxygen affinity (%MOD) increased in a dose-related manner above doses of 800 mg reaching 19-26% after the 3600 mg dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1992

Measuring exercise-induced adaptations and injury with magnetic resonance spectroscopy.

We compared the metabolic capacity of calf muscles in young normal subjects who performed endurance training to highly trained track athletes, older subjects, and subjects with several metabolic diseases. Metabolic capacity was measured as the rate of phosphocreatine (PCr) recovery following submaximal exercise. PCr levels were measured using magnetic resonance spectroscopy (MRS). Exercise consisted of repeated plantar flexion against resistance. MRS calculated metabolic capacity agreed well with rates from muscle biopsies. Short term endurance training resulted in a 14% increase in metabolic capacity. This adaptation was small compared to the metabolic capacities of endurance athletes (70% greater than control subjects), and changes due to aging (20% and 55% declines by 66 and 80 years of age, respectively). Exercise training is also associated with muscle injury. Muscle injury was seen as a transient elevation of Pi/PCr at rest in response to an acute bout of exercise. The elevation of resting Pi/PCr persisted during continued training. Metabolic capacity as measured by the rate of phosphocreatine recovery increased with endurance training and decreased with normal aging and metabolic disease. Small levels of persistent muscle injury is a natural by product of strenuous endurance training.

Adaptation, Physiological↗
PubMed1992

The effect of a prostaglandin DP-receptor partial agonist (192C86) on platelet aggregation and the cardiovascular system in healthy volunteers.

1. PGD2 (DP)-receptors mediate inhibition of platelet aggregation and vasodilatation. If receptor reserve were greater on platelets it might be possible to separate these effects. To determine whether such a difference in receptor reserve exists, we have examined the effects of a highly selective DP-receptor partial agonist 192C86 on platelet aggregation and the cardiovascular system in healthy volunteers. 2. Using an open, dose-escalating study design, four male volunteers received constant rate intravenous infusions of 192C86 for up to 60 min. Ex vivo platelet aggregation to ADP and collagen in platelet-rich plasma (PRP) and whole blood (WB) was studied at baseline, after 15, 30 and 60 min of each infusion and at 180 min post-infusion. Heart rate (HR), systolic and diastolic (DBP) blood pressure were measured at frequent intervals. Adverse experiences were monitored by checklist. Facial flushing was assessed by the volunteer using a visual analogue scale, by an observer using a numerical scale and by full-face colour photographs. Blood was taken for assay of plasma 192C86 concentrations by radio-immunoassay (r.i.a.). 3. 192C86 (0.007-0.058 micrograms kg-1 min-1) inhibited platelet aggregation to ADP and collagen both in PRP and WB in a dose-dependent manner. However, this was always accompanied by a decrease in DBP, increase in HR and facial flushing. Plasma concentrations of 192C86 were at or below the limits of sensitivity of the r.i.a. (0.5 ng ml-1). 4. The highest infusion rate was stopped after 20 min due to symptomatic hypotension on standing.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Surrogate decision-maker preferences for medical care of severely demented nursing home patients.

BACKGROUND: In the absence of advanced directives, physicians treating demented patients rely on surrogates to help make medical care decisions. METHOD: We surveyed family members of severely demented nursing home residents to determine preferences for medical intervention in five hypothetical situations involving tube feeding, hospitalization, intensive care unit admission, mechanical ventilation, and cardiopulmonary resuscitation. RESULTS: Only 11.8% of surrogates rejected all interventions. Cardiopulmonary resuscitation and tube feeding were accepted least frequently (31.6% and 36.4%, respectively). Mechanical ventilation, hospitalization, and intensive care unit admission were accepted by 43.6%, 63.4%, and 75.2%, respectively. There was no correlation between previous surrogate experience with an intervention and its acceptance. Nearly 70% of surrogates indicated that decisions were independent of any previously expressed resident views. CONCLUSIONS: In this study, surrogates of even the most demented nursing home patients prefer hospital level services including intensive care unit care for the treatment of acute illness. Efforts to control access to services on ethical or economic grounds may meet with resistance.

Aged↗
PubMed1991

The effect of 443C81, a mu opioid receptor agonist, on the response to inhaled capsaicin in healthy volunteers.

Activation of mu opioid receptors on sensory nerves in the lung represents an attractive mechanism for reducing cough and reflex bronchoconstriction. We have examined the effect of the peptide 443C81, a peripherally acting mu opioid agonist, on the cough and reflex increase in respiratory resistance (Rrs) produced by capsaicin in nine healthy male volunteers. Using a randomised, double-blind crossover design, each subject inhaled either saline, 1 mg ml-1 443C81 or 4 mg ml-1 443C81 for 10 min from an ultrasonic nebuliser. The cough response to a range of doses of inhaled capsaicin and the increase in Rrs caused by inhalation of a single subtussive dose of capsaicin were measured before and after each treatment. There was no evidence of an effect of either 1 or 4 mg ml-1 443C81 on cough or increase in Rrs produced by capsaicin when compared with the saline placebo. It is concluded that inhalation of this mu opioid receptor agonist had no effect on capsaicin-induced cough or reflex bronchoconstriction in healthy volunteers.

Administration, Inhalation↗
PubMed1990

Analgesic, central, cardiovascular and endocrine effects of the enkephalin analogue Tyr-D.Arg-Gly-Phe(4NO2)-Pro-NH2 (443C81) in healthy volunteers.

443C81 is a synthetic enkephalin thought to act on peripheral opiate receptors. The analgesic, central, cardiovascular and endocrine effects of two i.v. doses of 443C81 were investigated in 12 healthy male volunteers. Its effects were compared with those of placebo and the classical opiate dipipanone given orally using a double dummy design. 443C81 produced dose-related analgesia; dipipanone 10 mg had a greater effect than the high dose 443C81. In contrast to dipipanone, 443C81 did not cause significant miosis or reduce minute volume on rebreathing CO2 and there was no evidence of sedation. Dry mouth was reported frequently and associated with reduced salivation after all active treatments. Both 443C81 and dipipanone increased circulating prolactin and growth hormone and reduced cortisol levels. This novel enkephalin appears to possess analgesic activity and some other properties of opiates but is devoid of clinically relevant narcotic effects.

Adult↗
PubMed1990

The onset of effect of the H1-antagonist acrivastine ("Semprex") assessed by histamine bronchial challenge in volunteers.

The onset of effect of acrivastine, a new H1-antagonist, has been assessed using antagonism of histamine-induced bronchoconstriction in sensitive volunteers. Acrivastine administered 30, 45, 60 or 90 min before challenge produced a right-shift of the histamine dose-response curve of at least 8-fold indicating that a clinically desired degree of H1-antagonism was present within 30 min of ingestion of the recommended therapeutic dose.

Administration, Oral↗
PubMed1990

Cardiovascular effects of a novel enkephalin analogue, 443C81, in humans.

The cardiovascular effects of a novel enkephalin analogue, 443C81 (Tyr-D-Arg-Gly-Phe(4NO2)-Pro.NH2), were studied in healthy volunteers. According to a double-blind, cross-over, randomised, balanced design, six men received two different doses of 443C81 or saline as intravenous (i.v.) infusions on three occasions. Mean +/- SD plasma concentrations achieved at steady state were 0.46 +/- 0.11 microgram/ml after low-dose 443C81 and 1.0 +/- 0.2 microgram/ml after high-dose 443C81. In the supine position, low and high doses produced mean transient increases in diastolic blood pressure (DBP) of 5 and 4 mm Hg and heart rate (HR) of 5 and 12 beats/min, respectively. With the higher dose, these changes were followed by a mean decrease in DBP of 8 mm Hg while HR returned to control values. When the subjects were tilted, the pressor effect was not observed, and hypotension occurred earlier and was more pronounced. Both doses reduced forearm and systemic vascular resistance, and there was a dose-related increase in supine forearm venous capacitance; venoconstriction associated with tilting was unaffected by 443C81. Plasma renin activity and elevation of epinephrine concentrations on tilting were increased by the enkephalin, which also caused a diuresis through an increase in free water clearance.

Adult↗
PubMed1989

The pharmacokinetics of lamotrigine (BW430C) in healthy subjects with unconjugated hyperbilirubinaemia (Gilbert's syndrome).

A single oral dose of lamotrigine was administered to seven volunteers with Gilbert's Syndrome (unconjugated hyperbilirubinaemia). Plasma samples were assayed by high performance liquid chromatography (h.p.l.c.) and pharmacokinetic parameters were compared with those of a group of nine normal volunteers. In the subjects with Gilbert's Syndrome mean oral clearance (CLpo) was 32% lower (P less than 0.01) and the plasma elimination half-life (t1/2) was 37% lower (P less than 0.02) than in the normal controls. The amount of unchanged lamotrigine excreted in the urine was 30% greater in the Gilbert's subjects (P less than 0.01) although this only amounted to 9.5% of the administered dose. Subjects with Gilbert's Syndrome have some impairment of lamotrigine elimination but this is unlikely to be clinically important.

Adult↗
PubMed1989

Comparison of the onset of H1-antagonism with acrivastine and terfenadine by histamine bronchial challenge in volunteers.

The speed of onset of H1-antagonism by 8 mg acrivastine and 60 mg terfenadine was compared by bronchial challenge of volunteers with histamine. Active treatments or placebo were administered 1 or 2 h before challenge in a double-blind, randomized, balanced crossover manner to 10 subjects. Acrivastine and terfenadine significantly attenuated the response to inhaled histamine compared to placebo. The effects of acrivastine at 1 and 2 h before challenge, and terfenadine at 2 h were indistinguishable, but that of terfenadine at 1 h was significantly less, indicating that acrivastine has a faster onset of action than terfenadine.

Adult↗