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Biomedical subjects

P Jacob

Publications and source records attributed to P Jacob.

At least 145 records · Page 8Linked to original sources
PubMed1993

Nicotine and cotinine elimination pharmacokinetics in smokers and nonsmokers.

Published research suggests that smokers metabolize nicotine and its major metabolite cotinine more rapidly than nonsmokers. To evaluate this possibility, we studied the disposition pharmacokinetics of intravenous deuterium-labeled nicotine in 11 smokers (administered 2.0 and 0.5 micrograms/kg/min x 30 minutes) and in 11 nonsmokers (0.5 micrograms/kg/min). Smokers did not metabolize nicotine more rapidly; the clearance of nicotine normalized for body weight was significantly slower in smokers than in nonsmokers. Cotinine elimination rates were similar in the two groups. The disposition pharmacokinetics of nicotine was similar for the low and high doses in the smokers, indicating that metabolism is dose-independent. Our findings argue against "metabolic tolerance" as a mechanism for the dose escalation observed in smokers after initiation of smoking. Our findings suggest that nicotine and cotinine kinetic parameters for smokers may be extrapolated to nonsmokers for estimating exposures to environmental tobacco smoke in nonsmokers.

Adult↗
PubMed1993

Bioavailability and absorption kinetics of nicotine following application of a transdermal system.

1. The absolute bioavailability and absorption kinetics of nicotine were investigated in 13 healthy adult male smokers following single and multiple applications of a nicotine transdermal system (NTS), designed to release nicotine at an approximate rate of 1.5 mg h-1 over 24 h. The absorption of nicotine from the single NTS application was calculated with reference to a simultaneous intravenous infusion (i.v.) of deuterium-labelled nicotine. 2. The mean input time (MIT) and mean absorption time (MAT) for nicotine following application of NTS for 24 h were 7.7 and 4.2 h, respectively. 3. Following NTS removal, the mean apparent nicotine elimination half-life was 2.8 h, compared with 2.0 h following i.v. nicotine, reflecting continued absorption of nicotine following NTS removal. 4. The mean amount of nicotine absorbed from the NTS after the 24 h application was 20.9 mg, which represents about 68% of the amount released from the system; the remaining 32% was lost from the system during daily activities. 5. The ratio of AUC values for the metabolite cotinine relative to nicotine was similar whether nicotine was administered transdermally or intravenously. 6. Following i.v. administration, the mean nicotine clearance was 72 l h-1 (coefficient of variation 29%). Since coefficients of variation in AUC values following NTS and i.v. treatments were similar, transdermal administration of nicotine was not associated with increased interindividual variability in plasma nicotine concentrations. 7. No significant changes were seen in the pharmacokinetics of nicotine between single and multiple applications of NTS. 8. As expected from the higher total plasma nicotine concentrations, the incidence of adverse effects was higher following simultaneous intravenous and transdermal administration of nicotine. The most frequently reported systemic side effects were nervousness and headache: mild itching was the most frequent topical effect.

Administration, Cutaneous↗
PubMed1993

Botulinum toxin in the treatment of paralytic strabismus and essential blepharospasm.

As an alternative to conventional medical and surgical modalities that have met little success in the treatment of paralytic strabismus and essential blepharospasm, we explored the use of botulinum toxin as a treatment of choice in these two disorders. We used botulinum toxin in three patients with paralytic strabismus and in nine patients with essential blepharospasm. In three patients with paralytic strabismus, the botulinum toxin was injected into the ipsilateral antagonist of the paralysed muscle. The preinjection deviations ranged from 18 to 60 prism diopters. Two of these three patients achieved orthotropia around the thirtieth day and thereafter maintained it. The third patient became orthotropic on the eighteenth day, but deviation recurred and therefore required another injection of toxin. In nine patients with essential blepharospasm, botulinum toxin was injected into the orbicularis oculi muscles. Both objective and subjective improvement occurred in all nine patients within seven days and the effect lasted 12 to 15 weeks. Further injection of the toxin produced extremely beneficial results. However, the only significant complication that we encountered in both groups of strabismus and blepharospasm was ptosis, which was usually partial and temporary. From our experience, we advocate the use of botulinum toxin in the treatment of essential blepharospasm.

Adult↗
PubMed1993

Anterior capsular support for posterior chamber intraocular lenses following vitreous loss in endocapsular surgery.

We used anterior capsular support for posterior chamber intraocular lenses (PC IOLs) in fourteen eyes with large posterior capsular ruptures. An endocapsular technique preserved the anterior capsule and facilitated implantation. With a median follow up of 8.5 months, all patients had a visual acuity of 6/9 or better. One lens was lost in the vitreous and one patient had a clinically significant cystoid macular edema. In the event of a posterior capsular rupture we suggest this technique as an alternative to anterior chamber or scleral-fixated lenses.

Adolescent↗
PubMed1993

Releasable suture technique for trabeculectomy.

We studied the effect of the releasable suture technique on immediate postoperative intraocular pressure (IOP). Nine eyes of nine patients with glaucoma had trabeculectomy with a releasable suture. In the six eyes that did not receive antimitotics, the suture was released by the fifth postoperative day; in the others suture release was delayed up to the fourteenth day. Of the nine patients, one had an acceptable postoperative IOP and did not need suture release; in another the suture broke and could not be released. In the remaining seven patients, the difference between the pre-release and post-release IOP was statistically significant (p < 0.001). The complications of this technique include failed suture release, subconjunctival hematoma and a distinctive "windshield wiper" keratopathy.

Corneal Diseases↗
PubMed1993

Fluoxetine for cocaine dependence in methadone maintenance: quantitative plasma and urine cocaine/benzoylecgonine concentrations.

Cocaine abuse is a common clinical problem among opioid-dependent patients who are in methadone maintenance treatment. In an open prospective study, 16 DSM-III-R, cocaine-dependent, methadone maintenance treatment patients were treated with fluoxetine, at a mean dose of 45 mg/day for 9 weeks. Eleven subjects (69%) were infected with the human immunodeficiency virus. Cocaine use was significantly reduced by the end of treatment, although most subjects did not achieve abstinence. Comparison of intake to week 9 showed a significant decrease in self-reported cocaine use, craving, and quality of high. Actual cocaine use was measured by a quantitative analysis of cocaine and benzoylecgonine (BE) concentrations in plasma and urine. Median BE and cocaine concentrations in urine decreased significantly from intake to week 9 of fluoxetine treatment. This decrease would not have been detected if BE had been measured only qualitatively, as present or absent in the urine. Fluoxetine was well tolerated in combination with methadone and did not appear to alter methadone concentrations in plasma. Few adverse effects were noted. No subjects had to discontinue fluoxetine. Fluoxetine may be a promising treatment approach for cocaine abuse in methadone maintenance patients. Quantitative determination of exact cocaine and BE concentrations in biofluids may be a more accurate method of measuring cocaine use outcome than qualitative urinalysis.

Adult↗
PubMed1992

Determination of the nicotine metabolite trans-3'-hydroxycotinine in urine of smokers using gas chromatography with nitrogen-selective detection or selected ion monitoring.

A gas chromatographic method for the determination of the nicotine metabolite trans-3'-hydroxycotinine is described. The method involves conversion of the metabolite to the tert.-butyldimethylsilyl derivative, chromatography on a fused-silica capillary column, and determination using nitrogen-phosphorus detection or electron ionization mass spectrometry with selected ion monitoring. A structural analogue, trans-3-hydroxy-1-methyl-5-(2-pyridyl)pyrrolidin-2-one (trans-3'-hydroxy-ortho-cotinine), was used as an internal standard. Using selected ion monitoring, good precision and accuracy were obtained for determination of trans-3'-hydroxycotinine in urine over the concentration range 10-10,000 ng/ml. There was a good correlation between concentrations determined by selected ion monitoring and by nitrogen-phosphorus detection in urine of smokers, although low concentrations determined using nitrogen-phosphorus detection tended to be somewhat higher, suggesting some interference from urinary constituents. Concentrations and 24-h excretion of trans-3'-hydroxycotinine in the urine of 22 cigarette smokers are reported and compared to concentrations and excretion of nicotine, cotinine, nicotine 1'-N-oxide, nornicotine, and cotinine N-oxide.

Chromatography, Gas↗
PubMed1992

Comparison between thallium-201 and technetium-99m methoxyisobutyl isonitrile defect size in single-photon emission computed tomography at rest, exercise and redistribution in coronary artery disease.

Defect size on myocardial tomograms was measured in 30 patients who underwent 2 separate studies, 1 with thallium-201 (TI-201), the other with technetium-99m-methoxyisobutyl isonitrile (MIBI). A group of 15 patients with myocardial infarction was studied at rest and received both tracers on the same day. The other 15 patients had documented coronary artery disease. They were were given injections of TI-201 at peak exercise and underwent imaging immediately after exercise and again 4 hours later. They then received a dose of MIBI for imaging at rest. A week later they underwent a second exercise test with the same work load and received a second dose of MIBI. Defect size on single-photon emission computed tomographic images was measured and repeated twice. Results were expressed in percentage of the volume of the whole myocardium. Reproducibility of the defect size measurement was high for TI-201 (r = 0.978; SEE = 1.59) as well as for MIBI (r = 0.981; SEE = 0.80). In patients with coronary artery disease the mean size of the defects was significantly larger with TI-201 than with MIBI at exercise (6.7 +/- 5.2 vs 4.6 +/- 5.2%, respectively, p less than 0.05) and at redistribution (5.1 +/- 4.4 vs 2.8 +/- 3.2%, respectively, p less than 0.05), where no difference was seen in patients with myocardial infarction studied only at rest (11.2 +/- 10.4 vs 12.0 +/- 11.5%, respectively, p = not significant). Smaller MIBI defect sizes, when compared with TI-201, in the exercise and redistribution studies were not due to technical artefacts since there was no difference when they were compared at rest.

Adult↗
PubMed1992

Effect of heparin and enoxaparin on platelet interaction with fibrin clots.

It has been recently shown that platelet-rich thrombi are particularly resistant to thrombolysis. Since unfractionated heparin was reported to enhance fibrinogen binding to platelets responsible for the hyperaggregating effect of this drug, the purpose of this work was to determine whether or not heparin could also modulate platelet interaction to whole blood clot. We have therefore investigated the retention to a standard clot of 111In-labelled platelets suspended in plasma in presence of saline (control), heparin or a low molecular weight heparin (Enoxaparin). We have shown that the platelet interaction to the clot was significantly increased by heparin but not by enoxaparin used at the same anti Xa activity. In conclusion, this difference may favor the use of enoxaparin over heparin in clinical situation associated with platelet retention to fibrin clot, such as thrombolysis.

Blood Platelets↗
PubMed1992

Intravenous nicotine retards transdermal absorption of nicotine: evidence of blood flow--limited percutaneous absorption.

For most drugs delivered by the transdermal route, percutaneous absorption is limited by the rate of release of the drug from the device or by diffusion across the stratum corneum. However, systemic absorption also requires that the drug be taken up by dermal blood vessels. As part of a bioavailability study of a transdermal delivery system, we observed that a concomitant intravenous infusion of nicotine had a marked effect on the absorption kinetics of transdermal nicotine. Plasma concentrations of nicotine rose less rapidly, reached a lower peak, and peaked at a later time, indicating delayed absorption of transdermal nicotine after intravenous nicotine versus after transdermal nicotine administered alone. Nicotine is known to produce cutaneous vasoconstriction. The likely explanation for our observation is that intravenous nicotine constricts dermal blood vessels, thereby limiting percutaneous absorption. Other vasoconstrictor drugs would be expected to retard the absorption of transdermal nicotine and perhaps other transdermal drugs as well.

Administration, Cutaneous↗
PubMed1992

In-situ determination of deposited radionuclide activities: improved method using derived depth distributions from the measured photon spectra.

When applying the standard method of in-situ gamma spectrometry to determine deposited radionuclide activities, an assumption is needed regarding the depth distribution of radionuclides in the ground. The method can be improved by assessing, from information contained in the spectrum, the attenuation of the radiation by the soil and vegetation. By comparing the count rates of the x ray and the gamma-ray lines of its daughter nuclide 137mBa, the 137Cs activity per area can be determined. The range of applicability of the method is discussed by means of an uncertainty analysis, and the method is applied to post-Chernobyl measurements. A comparison with the results of the standard method of in-situ spectrometry demonstrates the progress achieved by the proposed method. Nevertheless, the method still has some shortcomings for the peak analysis that could be improved by better detector resolution or better computer software.

Cesium Radioisotopes↗
PubMed1992

The correlation of age of onset with CTG trinucleotide repeat amplification in myotonic dystrophy.

The gene for myotonic dystrophy (DM) has recently been isolated and amplification of an unstable CTG trinucleotide repeat, located within the DM gene, has been identified in virtually all patients studied to date. A high proportion of DM families who are studied show a progressively earlier age of onset with succeeding generations and, in the few pedigrees reported so far, an increasing degree of amplification of the CTG repeat has been noted to parallel this trend. It has been implicit in several of the original reports on the nature of the changes in the DM gene that knowledge of CTG amplification status at the DM locus of a person will provide useful information concerning prognosis. However, no studies of genotype-phenotype correlation have been reported and there are no specific data on which to base such counsel. In this paper we report the correlation between the degree of CTG amplification and age of onset in 109 DM gene carriers from 17 families. Included are parent-child and sib-sib comparisons which provide a framework in which to incorporate DNA diagnostic studies when counselling subjects and families at risk for DM.

Adolescent↗
PubMed1991

Selected ion monitoring method for determination of nicotine, cotinine and deuterium-labeled analogs: absence of an isotope effect in the clearance of (S)-nicotine-3',3'-d2 in humans.

A method for simultaneous determination of nicotine, its metabolite cotinine, and the stable isotope-labeled analogs nicotine-3',3'-d2 and cotinine-4',4'-d2 in human plasma has been developed. The method utilizes capillary column gas chromatography with detection by electron impact mass spectrometry and selected ion monitoring. Sensitivity is adequate for determination of nicotine and nicotine-d2 at concentrations as low as 1 ng ml-1, and cotinine and cotinine-d2 at concentrations as low as 10 ng ml-1 with good precision and accuracy. The method has been used to compare the elimination kinetics of (S)-nicotine-3',3'-d2 with natural nicotine in human subjects. Total clearance of nicotine-3',3'-d2 was virtually identical to the total clearance of natural nicotine, which validates the use of the deuterium-labeled analog in quantitative studies of nicotine metabolic disposition.

Adult↗
PubMed1991

A comparison of the binding of nicotine and nornicotine stereoisomers to nicotinic binding sites in rat brain cortex.

Both stereoisomers of nicotine and nornicotine were tested for their ability to competitively displace 3H-(-)-nicotine and 3H-acetylcholine (in the presence of atropine), in rat cortex tissue. 3H-acetylcholine was displaced from two binding sites, super-high and high, by (+)-nicotine, (-)-nornicotine and (+)-nornicotine but from a high affinity site by (-)-nicotine. 3H-nicotine was displaced from two sites, high and low affinity by nicotine and nornicotine stereoisomers. The high-affinity 3H-(-)-nicotine binding site showed similar binding characteristics to one of the sites labelled by 3H-acetylcholine. IC50 values showed (-)-nicotine to be 13 and 25-fold more potent than (+)-nicotine for displacing 3H-(-)-nicotine and 3H-acetylcholine, respectively, but no difference was observed for nornicotine stereoisomers. While (-)-nicotine preferentially bound to the high affinity site of 3H-(-)-nicotine (+)-nicotine preferred the low affinity site. The study provides further evidence for multiple nicotine receptors in brain.

Animals↗
PubMed1991

Effects of caffeine with repeated dosing.

We have recently demonstrated dose-dependency of caffeine metabolism under multiple dosing conditions. Whether there are persistent pharmacodynamic actions of caffeine under such circumstances is the focus of this report. Nine healthy subjects were given, in randomized 5 day blocks, placebo, 4.2 (low) and 12 (high) mg.kg-1.day-1 of caffeine in 6 divided doses. After 5 days, complete tolerance developed to the effects of caffeine on blood pressure, heart rate and plasma glucose concentrations. The 24-h area under the curve (AUC) for plasma norepinephrine and the AUC for the total sum of free fatty acids (FFA) both demonstrated a trend to increase with the high dose caffeine treatment. When the AUC for norepinephrine was split into 12 h time periods, a significant difference between the placebo and the high dose treatment block was seen. We conclude that regular consumption of 12 mg.kg-1 of caffeine per day (equivalent to approximately 6 to 11 cups of coffee per day) may produce pharmacodynamic effects not completely compensated for by the development of tolerance. Mechanisms of tolerance may be overwhelmed by the nonlinear accumulation of caffeine and other methylxanthines in the body when caffeine metabolism becomes saturable.

Adult↗
PubMed1991

Proximal esophageal pH-metry in patients with 'reflux laryngitis'.

Fiberoptic laryngoscopic examinations were performed on 40 patients with gastroesophageal reflux disease, 25 of whom had persistent laryngeal symptoms (dysphonia, cough, globus sensation, frequent throat clearing, or sore throat) and 15 without laryngeal symptoms who served as disease controls. Ten patients with laryngeal symptoms but none of the controls had laryngoscopic findings consistent with reflux laryngitis. Dual-site ambulatory pH recordings were obtained with the pH electrodes spaced 15 cm apart and with the proximal sensor positioned just distal to the upper esophageal sphincter. Patients in the three groups (disease controls: group 1; patients with symptoms but without laryngoscopic findings: group 2; and patients with both laryngeal symptoms and findings: group 3) were comparable in terms of age, smoking habit, the presence of esophagitis, and distal esophageal acid exposure. Proximal esophageal acid exposure was, however, significantly increased in groups 2 and 3, and nocturnal proximal esophageal acidification occurred in over half of these patients but in none of the group 1 patients. We conclude that the subset of reflux patients who experience laryngeal symptoms show significantly more proximal esophageal acid exposure (especially nocturnally) and often have laryngoscopic findings of posterior laryngitis not observed in control reflux patients.

Adult↗
PubMed1991

Stable isotope method for studying transdermal drug absorption: the nicotine patch.

A stable isotope-labeled drug method was used to determine the absolute bioavailability and absorption kinetics of a transdermal nicotine-delivery system (TTS). TTSs are being developed as an adjunct to smoking-cessation therapy. Deuterium-labeled nicotine was infused for 24 hours simultaneously to TTS application in cigarette-abstinent smokers. In 11 subjects with good patch adhesion, an average systemic dose of 19 mg nicotine was delivered, with average absolute bioavailability of 82%. The rate of nicotine absorption was maximal between 6 and 12 hours after TTS application and declined thereafter, plateauing between 16 and 24 hours at 62% of the maximal rate. Ten percent of nicotine was absorbed after the TTS was removed, demonstrating a reservoir for nicotine in the skin. Our study demonstrates the applicability of stable isotope methods in understanding the clinical pharmacology of transdermal drugs.

Administration, Cutaneous↗