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Biomedical subjects

A F Cohen

Publications and source records attributed to A F Cohen.

At least 109 records · Page 6Linked to original sources
PubMed1996

Anthropometric analysis of the female Latino nose. Revised aesthetic concepts and their surgical implications.

OBJECTIVE: To determine whether the present aesthetic concepts set forth for rhinoplasty in white patients can be applied to the ethnic variations seen in Latino women and, if not, to develop a reproducible means of analysis to serve as a guide for surgical correction. DESIGN: Cohort analytic study; criterion standard analysis of nasal aesthetics. PARTICIPANTS: Ninety-seven Latino women and 40 white women. INTERVENTIONS: Patients were separated according to geographic area of origin, either the Caribbean, Central America, or South America. Anthropometric measurements were obtained and nasal indexes were calculated. Results were compared with previously reported data for African Americans and whites. All patients underwent complete nasal photographic analysis. RESULTS: Caribbean subjects showed the greatest divergences from whites and resembled African-American anthropometric norms, whereas Central and South American subjects more closely resembled white norms. Two new aesthetic concepts were developed, the dorsal nasal breakpoint and the horizontal nasal axis, which have implications for aesthetic rhinoplasty. The breakpoint is a pivotal point along the nasal dorsum, structurally determined, which was found at different locations in all the groups studied. Caribbean subjects had breakpoints approximately halfway down the dorsum. Central and South Americans had breakpoints about two thirds of the way down the dorsum, and whites had breakpoints three fourths of the way down the dorsum. The horizontal rotation axis is present along a plane that connects the top of the ala with the tip. Rotation of the tip about this axis affects both the characteristics of the dorsal breakpoint and the final appearance of the nose. CONCLUSIONS: In general, Latino noses can be anthropometrically categorized as mesorrhine. When the geographically derived groups were examined individually, the Latino nose ranged from subplatyrrhine to paraleptorrhine. Surgical correction should be individualized, as each group requires correction of different nasal features. The dorsal breakpoint and the horizontal axis plane can act as nasal profile guides for surgical modifications that would achieve the current concept of the aesthetic nose.

Adult↗
PubMed1996

Ectopic thyroid tissue presenting as a midline neck mass.

Ectopic thyroid tissue can be found anywhere between the foramen cecum and the normal position of the thyroid gland. Although very uncommon, it is most often found in the region of the foramen cecum, in patients in whom the gland fails to descend. Extralingual thyroid tissue is most commonly located in the anterior cervical area, the region of the thyroglossal duct. It must be differentiated from thyroglossal duct cyst, in that it frequently represents the only source of thyroid tissue. In the majority of patients with lingual thyroid tissue, this is the only functioning thyroid. We present the case of a thirteen year old male child with a midline cervical mass first noted at one year of age. Since its early presentation, this midline mass had increased and decreased in size, and over the last three months had been associated with odynophagia and anterior neck swelling. A presumptive diagnosis of thyroglossal duct cyst was made. A preoperative thyroid scan revealed that this midline mass was in fact the only functioning thyroid tissue; therefore no surgery was performed. This case demonstrates the essential role of a thyroid scan in the preoperative evaluation of a midline neck mass. Recognizing that ectopic thyroid tissue may present as a thyroglossal duct cyst and may be the only functioning thyroid avoids subjecting the child to inappropriate surgery and a life of replacement therapy.

Adolescent↗
PubMed1996

Effects of increased liver blood flow on the kinetics and dynamics of recombinant tissue-type plasminogen activator.

OBJECTIVE: To investigate the influence of increased liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue-type plasminogen activator (rt-PA) and to study the changes in endogenous urokinase-type plasminogen activator (u-PA). METHODS: This open, randomized, crossover trial was carried out in a clinical research unit. Eight healthy, nonsmoking volunteers received linear infusions of 24 mg rt-PA and 92 mg indocyanine green over 160 minutes. Sixty minutes after the infusions were started, the subjects consumed a standardized meal to increase liver blood flow on one occasion and abstained from taking food on the other occasion. Plasma concentrations of indocyanine green, tissue-type plasminogen activator (t-PA) antigen, t-PA activity, total u-PA antigen, plasmin-activatable single-chain u-PA (scu-PA), active two-chain u-PA (tcu-PA), fibrinogen, total fibrin, and fibrinogen/fibrin degradation products (TDP), and alpha 2-antiplasmin were measured. RESULTS: After the consumption of the meal, the area under the curve (AUC) was 35% (95% confidence interval [CI]: 25%, 43%) lower for indocyanine green, 15% (CI: 6%, 24%) lower for t-PA antigen, and 11% (CI: 2%, 19%) lower for t-PA activity compared to the AUC after subjects abstained from food. No changes were observed in fibrinogen, TDP, or alpha 2-antiplasmin concentrations that were attributable to the intake of food. The infusion of rt-PA caused a fivefold increase in the concentration of active tcu-PA and a concomitant decrease in scu-PA concentrations by more than 50%. CONCLUSIONS: Increased liver blood flow results in an increase in t-PA clearance. The conversion of the inactive zymogen scu-PA to the active tcu-PA is increased by an infusion of rt-PA, but total u-PA antigen concentrations remain unchanged.

Adult↗
PubMed1996

Pharmacokinetic and pharmacodynamic profiles of sumatriptan in migraine patients with headache recurrence or no response.

OBJECTIVES: Sumatriptan is effective in the acute treatment of migraine. However, about 15% of patients with migraine do not experience headache relief after sumatriptan, and up to 40% may experience recurrence of headache within 24 hours. We studied whether pharmacokinetic or pharmacodynamic differences may explain these different clinical effects. METHODS: We compared the pharmacokinetic profiles of subcutaneous sumatriptan in 14 patients who consistently had headache relief without headache recurrence, in 12 patients who had headache recurrence in every attack, and in six patients who did not have headache relief after sumatriptan. Because the antimigraine action of sumatriptan may be mediated through vasoconstriction of cranial blood vessels, we also compared in these patients changes in blood vessel diameter and blood velocity in the common, internal, and external carotid arteries. RESULTS: Despite sufficient power of the study, no important differences in pharmacokinetic and pharmacodynamic profiles between the three patient groups were detected. CONCLUSION: Headache recurrence and lack of headache relief after sumatriptan do not appear to be explained by pharmacokinetic or pharmacodynamic differences between patients, which may be an important finding for the development of novel antimigraine drugs.

Adolescent↗
PubMed1996

Estimating impossible curves using NONMEM.

1. On fitting model equations to experimental data, the situation may arise that individual subjects provide insufficient information to obtain adequate parameter estimates due to the fact that not all aspects are exhibited by all subjects or that the models are simply too complex. This may be solved by applying nonlinear mixed effect modelling to the data, which integrates the information provided by different subjects. 2. We aim to provide insight into the methodology and its use in these situations, illustrated by three examples: determination of pharmacokinetics in a rising dose design, where the lower doses provide insufficient information (due to assay limitations) to estimate terminal half-life; determination of the kinetics of the low molecular weight heparin enoxaparine (Clexane) using anti-Xa activity, effectively dealing with lingering low/basal activity; simultaneous estimation of the pharmacokinetics and pharmacodynamics of the low molecular weight heparin dalteparin (Fragmin) after subcutaneous and intravenous administration.

Antihypertensive Agents↗
PubMed1996

Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol.

1. Interaction between alcohol and bretazenil (a benzodiazepine partial agonist in animals) was studied with diazepam as a comparator in a randomized, double-blind, placebo controlled six-way cross over experiment in 12 healthy volunteers, aged 19-26 years. 2. Bretazenil (0.5 mg), diazepam (10 mg) and matching placebos were given as single oral doses after intravenous infusion of alcohol to a steady target-blood concentration of 0.5 g l-1 or a control infusion of 5% w/v glucose at 1 week intervals. 3. CNS effects were evaluated between 0 and 3.5 h after drug administration by smooth pursuit and saccadic eye movements, adaptive tracking, body sway, digit symbol substitution test and visual analogue scales. 4. Compared with placebo all treatments caused significant decrements in performance. Overall, the following sequence was found for the magnitude of treatment effects: bretazenil+alcohol > diazepam+alcohol > or = bretazenil > diazepam > alcohol > placebo. 5. There were no consistent indications for synergistic, supra-additive pharmacodynamic interactions between alcohol and bretazenil or diazepam. 6. Bretazenil with or without alcohol, and diazepam+alcohol had marked effects. Because subjects were often too sedated to perform the adaptive tracking test and the eye movement tests adequately, ceiling effects may have affected the outcome of these tests. 7. No significant pharmacokinetic interactions were found. 8. Contrary to the results in animals, there were no indications for a dissociation of the sedative and anxiolytic effects of bretazenil in man.

Administration, Oral↗
PubMed1996

Self-medication of a single headache episode with ketoprofen, ibuprofen or placebo, home-monitored with an electronic patient diary.

1. The objective of this study was to investigate the efficacy of home-medicated non-steroidal anti-inflammatory (NSAID) analgesics, using an electronic patient diary. Single doses of ketoprofen 25 mg and ketoprofen 50 mg were compared with ibuprofen 200 mg and placebo in the treatment of a single occasion of episodic tension-type headache, using a double-blind, randomized, parallel group design. 2. A total of 166 patients with headache compatible with episodic tension-type headache and no refractory headaches or contraindications to NSAIDs were contacted by advertisements and selected by questionnaires. Patients performed the study at home, using an electronic diary for headache assessment, with a form to allow comments and corrections. Visual analogue scales (VAS 10 cm) of headache severity, five-item headache relief rating (HRR) scales, and time of intake of 'escape' analgesics were scored regularly, for 4 h following intake of trial medication. 3. VAS-scores (n = 1407) and HRRs (n = 452) were returned by 159 patients. Of these scores, 1.5% were inadvertently omitted from the electronic diary or modified on the comment forms. 4. Headache (VAS and HRR) improved more with all three NSAIDs than with placebo, although the effect of ibuprofen was significant for HRR only. After 2 and 4 h respectively, the reduction in VAS-ratios was 17 and 19% with placebo, 18 and 53% with ibuprofen 200 mg, 41 and 61% with ketoprofen 25 mg, and 47 and 59% with ketoprofen 50 mg. After 4 h, headache improved strongly (highest HRR) in 18% of patients on placebo, 39% on ibuprofen 200 mg, 62% on ketoprofen 25 mg, and 55% on ketoprofen 50 mg. Headache disappeared completely (VAS-score = 0) in one patient (3%) with placebo (after 180 min), 10% with ibuprofen 200 mg (average 211 min), 18% with ketoprofen 25 mg (159 min), and 28% with ketoprofen 50 mg (146 min). 5. The effects of ketoprofen 50 mg were more pronounced than those of ibuprofen 200 mg, which seemed to start later. Ketoprofen 25 mg and 50 mg were very similar, suggesting a maximal effect of the lower dose. Mild to moderate adverse events were reported by 9% of the patients, half of which occurred with ketoprofen 50 mg. Treatment of headache with ketoprofen can start with 25 mg, and possibly less. 6. Although a direct comparative study would be necessary to determine the relative benefits of the novel electronic patient diaries over traditional paper-and-pencil methods, this study has shown the usefulness of this newer technique to detect differences in efficacy between low doses of analgesics under ambulant conditions, with very limited loss of data. Electronic patient diaries appear to be an important new attribute for the efficacy assessment of self-medicated drugs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Assessment of changes in liver blood flow after food intake--comparison of ICG clearance and echo-Doppler.

Echo-Doppler measurements of portal venous blood flow in intrahepatic branches and indocyanine green (ICG) clearance after continuous i.v. infusion as measure for liver blood flow were compared to evaluate the increase in splanchnic blood flow after food intake. It was shown that both methods assessed the changes in flow in a similar manner. Changes in blood flow in intrahepatic portal vein branches measured with echo-Doppler adequately predicted the change in ICG concentrations. Hence, echo-Doppler measurements of hepatic portal blood flow in intrahepatic branches can be used to estimate changes in total liver blood flow.

Humans↗
PubMed1996

Specific stimulation of brain serotonin mediated neurotransmission by dexfenfluramine does not restore growth hormone responsiveness in obese women.

OBJECTIVE: Growth hormone release in response to all known stimuli of GH secretion is blunted in obese subjects. Several studies, using d,l-fenfluramine (d,l-FF) as a serotoninergic tool, suggest that brain serotonin plays a role in the pathogenesis of this phenomenon. However, the effect of d,l-FF appears to be dependent on the stimulus used to induce GH release. Furthermore, d,l-FF has catecholamingergic properties apart from its capacity to stimulate serotonin release and to block its re-uptake. In this study, we investigated whether subchronic treatment with the highly selective serotoninergic drug dexfenfluramine (d-FF) affects the GH response to galanin or GHRH in obese subjects. DESIGN: The study had a randomized, cross-over, placebo controlled design. d-FF was administered in a dose of 15 mg twice daily during 6 days. On days 5 and 6 of treatment (with either d-FF or placebo) an i.v. bolus injection of 100 micrograms hGHRH(1-44) or a continuous infusion of p-galanin (40 pmol/kg/min over 40 minutes) were administered in randomized order. All tests were performed in the follicular phase of two consecutive menstrual cycles. PATIENTS: Eight obese women (body mass index (BMI) 34.5 +/- 3.6 kg/m2); 7 normal weight (BMI 21.9 +/- 1.9 kg/m2) age-matched control women. All women had a regular menstrual cycle. None used oral contraceptive drugs. MEASUREMENTS: GH response to either stimulus was measured both during treatment with d-FF and during treatment with placebo. RESULTS: The GH response to galanin and the response to GHRH were significantly smaller in obese subjects. d-FF significantly reduced the galanin induced GH secretion in obese subjects, but not in normal weight controls. It did not significantly affect GH release in response to GHRH in either group. CONCLUSION: This study confirms that GH secretion in response to stimuli with varying mechanisms of action is blunted in obese subjects. A decrease of central serotonin mediated neurotransmission does not appear to play a role in the pathogenesis of this phenomenon.

Adult↗
PubMed1995

Plasma amino acid ratios related to brain serotonin synthesis in response to food intake in bulimia nervosa.

Fifteen bulimic women (BN) and 19 healthy female controls (CO) were studied. The subjects were cross-over treated with either fluoxetine (FXT) or placebo during 4 days. They received, in randomized order, a breakfast containing pure carbohydrate (CHO) or a protein-rich (PROT) breakfast following day 3 and 4 of each treatment period. Twenty-nine different food items were offered for lunch. The fasting serum glucose and insulin concentrations and the fasting plasma tryptophan (Trp)/large neutral amino acid (LNAA) ratio were slightly higher in BN. The changes of these metabolic parameters in response to a CHO or PROT breakfast were similar in both groups. Across breakfast type, the plasma (Trp)/(LNAA) ratio at 120 min after breakfast was higher in BN. Total caloric intake at lunchtime was less in BN. In CO, less carbohydrate was selected at lunchtime following the CHO breakfast, an effect that was abolished by FXT. Breakfast type or FXT did not have any apparent effect on food intake at lunchtime in BN. This might indicate that bulimic subjects are less sensitive to serotoninergic stimuli than control subjects.

Adult↗
PubMed1995

Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril.

The pharmacokinetics and pharmacodynamics of the prodrug ramipril and its active ACE-inhibiting metabolite ramiprilat were investigated in an open, randomised, three-way cross-over study in 12 healthy male volunteers. Subjects received 2.5 mg ramipril orally, 2.5 mg ramipril intravenously and 2.5 mg ramiprilat intravenously. The absolute bioavailability as judged by ramipril plasma AUC was 15%, by ramiprilat plasma AUC, 44%. Ramiprilat formation from intravenous ramipril was 53% and from oral ramipril 28%. Urinary recovery of oral ramipril was 23%, i.v. ramipril 49%, and i.v. ramiprilat 68% of the given dose. Maximum ACE inhibition was highest (100%) after i.v. ramiprilat; it was 99% after i.v. ramipril and 84% following oral ramipril. ACE inhibition over 24 h was highest after i.v. ramipril, 2% less with i.v. ramiprilat and 34% less with oral ramipril. Ramiprilat renal clearance was concentration dependent. The biological availability of ramipril can best be judged by ramiprilat AUC, urinary recovery of ramipril and metabolites, or ACE inhibition over 24 h. It is concluded that the bioavailability of oral ramipril seems to be in the range of 44-66%.

Biological Availability↗
PubMed1995

Tolrestat pharmacokinetic and pharmacodynamic effects on red blood cell sorbitol levels in normal volunteers and in patients with insulin-dependent diabetes.

OBJECTIVES: To examine the effect of diabetes mellitus on the pharmacokinetics of tolrestat and to investigate its effect on red blood cell sorbitol levels according to a new pharmacodynamic model for this class of drugs. METHODS: Single and multiple doses of tolrestat (200 mg/twice a day) were administered to 12 patients with insulin-dependent (type I) diabetes and 12 healthy volunteers in an open parallel trial. RESULTS: Tolrestat disposition was characterized by first-order absorption and biexponential disposition: In normal subjects the terminal disposition half-life (t1/2) was 13 +/- 3 hours (mean +/- SD) and the apparent oral clearance (CL/F) was 48 +/- 9 ml/hr/kg, similar to the values in patients with type I diabetes mellitus (t1/2 = 14 +/- 4 hours; CL/F = 55 +/- 10 ml/hr/kg). Red blood cell sorbitol concentrations, which declined because of tolrestat's inhibition of aldose reductase, were characterized by an indirect-response model including a 50% inhibition constant (IC50) for production of sorbitol by aldose reductase. The removal of sorbitol (kout) was slower in patients with diabetes. The plasma IC50 averaged 2.0 +/- 1.3 micrograms/ml in normal subjects and 2.5 +/- 1.9 micrograms/ml in patients with diabetes. IC50 values expressed in free (unbound) concentrations (fu = 0.64%), which ranged from 12 to 16 ng/ml, were similar to the in vitro IC50 for inhibition of sorbitol accumulation in human red blood cells. CONCLUSIONS: Tolrestat pharmacokinetics were similar in normal subjects and in patients with diabetes; however, the patients with diabetes had higher baseline sorbitol levels (11 versus 5 nmol/ml for normal subjects) and slower sorbitol efflux rates. The proposed biochemically realistic, dynamic model characterized well the red blood cell sorbitol response patterns after administration of single and multiple doses of tolrestat.

Adult↗
PubMed1995

The effect of grapefruit juice on cyclosporine and prednisone metabolism in transplant patients.

OBJECTIVE: To estimate the effect of grapefruit juice on cyclosporine and prednisone metabolism. METHODS: This was an open, placebo-controlled, two-way crossover study performed in the academic departments of clinical pharmacology and nephrology. On two study occasions, 12 kidney transplant patients with stable cyclosporine trough levels received either grapefruit juice or water every 3 hours for a period of 30 hours. The main outcome measures were peak concentration and time to peak, area under the concentration-time curve, the ratio of the area under the curve of the metabolites/area under the curve of the parent drug, terminal half-life, and 24-hour trough levels of cyclosporine. RESULTS: Grapefruit juice increased the peak concentration of cyclosporine by 185 ng/ml (95% confidence interval, 60 to 310; p = 0.008). The ratio of the area under the curve of the metabolites of cyclosporine to the area under the curve of cyclosporine was reduced by 0.137 on the grapefruit day (95% confidence interval, -0.221 to -0.054; p = 0.004). After grapefruit juice, no significant changes were observed in the area under the curve and the time to peak of cyclosporine, prednisone, and prednisolone. Cyclosporine trough levels were unchanged by grapefruit juice. CONCLUSIONS: Grapefruit juice inhibits the metabolism of cyclosporine for a brief period after administration, which may be explained by the inhibition of cytochrome P450 enzymes in the gut wall and to a lesser extent by inhibition of these enzymes in the liver. Grapefruit juice can be one of the factors leading to intraindividual variability in the pharmacokinetics of cyclosporine. Grapefruit juice had no significant effect on the metabolism of prednisone or prednisolone.

Adult↗
PubMed1995

Effects of changing liver blood flow by exercise and food on kinetics and dynamics of saruplase.

OBJECTIVE: To investigate the influence of changes in liver blood flow on the pharmacokinetics and pharmacodynamics of single-chain unglycosylated urokinase-type plasminogen activator. METHODS: This open, randomized, crossover trial was carried out in the clinical research unit. Infusions of 37.5 mg saruplase and 90 mg indocyanine green were administered over 150 minutes to 10 healthy male volunteers. After 60 minutes the subjects consumed a standardized meal to increase liver blood flow or performed an exercise test (20 minutes) to decrease liver blood flow. Indocyanine green concentrations, total urokinase-type plasminogen activator (u-PA) antigen, two-chain u-PA activity, fibrinogen, total degradation products, alpha 2-antiplasmin, and factor XII-dependent fibrinolytic activity were measured. Blood flow was measured after food intake in a portal vein branch with Doppler echography. RESULTS: The weighted average indocyanine green concentration after exercise was increased by 29% compared with baseline (steady-state concentration) values (95% confidence intervals [CI]: +6%, +56%). After food, the concentration was 27% lower compared with baseline values (95% CI: -35%, -19%), and portal vein flow was increased by a maximum of 103% (95% CI: +71%, +136%). Average maximal concentrations of u-PA antigen after exercise were increased by 130 ng/ml compared with baseline concentrations (95% CI: +65, +195 ng/ml) and, unexpectedly, 156 ng/ml higher after food (95% CI: +59, +253 ng/ml). Although not significant, an increase in average u-PA antigen concentration compared with baseline values was detected after both exercise (7%) and food (13%). This tendency toward a larger effect after food compared with the effect after exercise was reflected by minor changes in the pharmacodynamics. CONCLUSIONS: u-PA plasma concentrations were increased by reduced liver blood flow induced by exercise. Food intake produced an unexpected increase in u-PA concentrations despite increases in liver blood flow.

Adult↗
PubMed1995

The Neurotoxicity Scale: the validity of a patient-based scale, assessing neurotoxicity.

The validity of a patient-based scale, presumably measuring adverse effects of drugs on cognitive function, was examined in a normal volunteer study. Thirty subjects were randomly assigned to placebo or one of two doses of a benzodiazepine, temazepam (10 mg and 20 mg), in a double-blind placebo-controlled parallel group design. Plasma samples were taken before the scale was completed and up to 8 hours post-dose. After administration of the medication the subjects were asked to maintain their normal daily routine as much as possible (reading, studying, conversations). The inventory was administered twice, at 50 minutes and 2 hours post-dose (peak level). The overall score was different between the three groups, only for the second assessment, 2 h post-dose (ANOVA, P < 0.02). Multiple t-testing between the three groups revealed statistically significant differences between placebo and the 10 mg temazepam group (P = 0.02) and between placebo and the 20 mg temazepam group (P = 0.006). No significant difference was found between the two temazepam groups. Analysis of the separate questions showed least sensitivity for questions related to the domain of 'hyperexcitability' and most sensitivity for 'fatigue' and 'slowing.' The overall score appeared to be sensitive already for the lower toxicity range suggesting an 'all or nothing effect'. The subjective reports, collected by using this scale, may therefore be used for the detection of gross overall changes in cognitive functioning.

Adult↗
PubMed1995

Human immunodeficiency virus--associated non-Hodgkin's lymphoma presenting as an auricular perichondritis.

AIDS-related NHL is an aggressive neoplasm, usually of high or intermediate grade, frequently extranodal at initial treatment, and often the first manifestation of AIDS. Although complete remissions have been reported, they occur in only a minority of patients. We describe a patient with NHL of the external ear that masqueraded as an auricular perichondritis. This is the first case reported in which AIDS-related NHL first appeared in the ear, and this should alert physicians who treat patient with AIDS to be aware of the protean manifestations of this disease.

Adult↗