Biomedical subjects

A F Cohen

Publications and source records attributed to A F Cohen.

At least 55 records · Page 3Linked to original sources

PubMed2001

Continuous intravenous furosemide in haemodynamically unstable children after cardiac surgery.

OBJECTIVE: The commonly used continuous intravenous (i.v.) furosemide dosing schedule after cardiac surgery in children is largely empirical and may not be optimal. This may even be more marked in children after cardiac surgery who are haemodynamically unstable, and in whom transient renal insufficiency may occur. A study was performed to obtain an impression regarding which clinically applicable measures may be used to design a rational scheme for continuous i.v. furosemide therapy in children after cardiac surgery. SUBJECTS AND METHODS: Twelve paediatric patients (5F/7 M, age 0-33 weeks) post-cardiac surgery, who were to receive 3 days of continuous i.v. furosemide treatment, were included in an open study. Blood and urine samples were taken for furosemide, creatinine, and electrolyte levels, and fractionated urinary output was measured. Furosemide in blood and urine was measured using high performance liquid chromatography (HPLC). RESULTS: The mean starting dose of continuous i.v. furosemide was 0.093 (+/- 0.016) mg/kg per hour. The mean dose was increased to 0.175 (+/- 0.045) mg/kg per hour per hour on day 2, and changed to 0.150 (+/- 0.052) mg/kg per hour on day 3. Infusion rates were increased from day 1 to day 2 in ten cases, and decreased from day 2 to day 3 in three cases. Serum furosemide levels never exceeded ototoxic levels. The urinary furosemide excretion rate was inversely related to serum creatinine levels. CONCLUSIONS: This study extends the observation of the beneficial effects of continuous i.v. furosemide also to those children who are haemodynamically unstable after cardiac surgery. However, as the effects of furosemide are dependent on renal function, it can be hypothesised that the dosing schedule may be optimised. Contrary to the currently used dosage schedule in which the dose of furosemide is gradually increased over time, it may be more rational to start with a higher dose and adapt this dose (downward) guided by the observed effect (urine output). Because the infusion rate was increased to 0.2 mg/kg per hour in nine out of 12 patients on day 2 and was never increased further, this suggests that a starting rate of 0.2 mg/kg per hour may be optimal.

Cardiac Surgical Procedures↗

PubMed2001

The effect of warfarin on the pharmacokinetics and pharmacodynamics of napsagatran in healthy male volunteers.

OBJECTIVE: The effect of oral warfarin on the pharmacokinetics and pharmacodynamics of the synthetic direct thrombin inhibitor napsagatran was investigated. METHODS: In an open, randomised, two-way crossover study, 12 healthy male volunteers were infused napsagatran (80 micrograms/min) for 48 h. Each subject was administered 25 mg warfarin (Coumadin) at the start of the infusion in either the first or second treatment period. Sampling was performed regularly over the treatment period and 24 h thereafter for measurement of plasma levels of napsagatran, activated partial thromboplastin time (APTT) and prothrombin time (PT). RESULTS: The pharmacokinetic parameters of napsagatran were not significantly influenced by co-administration of warfarin. Napsagatran administration was followed by increases in APTT and PT. Co-administration of warfarin increased the AUEC (area under the effect curve) calculated for the period 0-48 h (corrected for baseline) for APTT by 45% (95% CI: 28-65%) and for PT by 438% (95% CI: 272-678%) compared to the treatment with napsagatran alone. CONCLUSION: Warfarin has no effect on the pharmacokinetics of napsagatran, but has a marked influence on the pharmacodynamic parameters (APTT, PT) of napsagatran. In clinical practice, this interaction between the two compounds should be taken into account. The PT cannot be used to monitor the effect of oral anticoagulants during the switch from this group of direct thrombin inhibitors to full oral anticoagulant therapy.

Adult↗

PubMed2001

Influence of a microemulsion vehicle on cutaneous bioequivalence of a lipophilic model drug assessed by microdialysis and pharmacodynamics.

PURPOSE: The aim of the study was to investigate the cutaneous bioequivalence of a lipophilic model drug (lidocaine) applied in a novel topical microemulsion vehicle, compared to a conventional oil-in-water (O/W) emulsion, assessed by a pharmacokinetics microdialysis model and a pharmacodynamic method. METHODS: Dermal delivery of lidocaine was estimated by microdialysis in 8 volunteers. Absorption coefficients and lag times were determined by pharmacokinetic modelling of the microdialysis data. Subsequently, the anaesthetic effect of the treatments was assessed by mechanical stimuli using von Frey hairs in 12 volunteers. RESULTS: The microemulsion formulation increased the cutaneous absorption coefficient of lidocaine 2.9 times (95% confidence interval: 1.9/4.6) compared with the O/W emulsion-based cream. Also, lag time decreased from 110 +/- 43 min to 87 +/- 32 min (P = 0.02). The compartmental pharmacokinetic model provided an excellent fit of the concentration-time curves with reliable estimation of absorption coefficient and lag time. A significant anaesthetic effect was found for both active treatments compared to placebo (P < 0.02), but the effect did not diverge significantly between the two formulations. CONCLUSIONS: The microemulsion vehicle can be applied to increase dermal drug delivery of lipophilic drugs in humans. The microdialysis technique combined with an appropriate pharmacokinetic model provides a high sensitivity in bioequivalence studies of topically applied substances.

Administration, Topical↗

PubMed2001

Concentration-effect relationships of two infusion rates of the imidazoline antihypertensive agent rilmenidine for blood pressure and development of side-effects in healthy subjects.

AIMS: The aim of this study was to compare the effect profiles of i.v. administered rilmenidine aimed at the same target plasma concentration, but attained with different rates. METHODS: The study was placebo-controlled, randomized, double-blind, double-dummy, three-way, cross-over in nine healthy volunteers. All subjects randomly received either a fast infusion, a slow infusion or a placebo infusion. The target concentration was set at 8 ng ml-1 with a fivefold difference in the time to reach the maximum concentration. Saccadic eye movements, electroencephalography (EEG), blood pressure and heart rate were measured every half hour. Drug plasma concentrations, adverse events, salivary flow and visual analogue scales were obtained every hour. RESULTS: Changes in systolic/diastolic blood pressure at the end of the infusion were (mean +/- s.d.) 13.3 +/- 16.4/7.9 +/- 7.5 mmHg with the fast infusion and 16.3 +/- 12.7/10.2 +/- 7.9 mmHg during the slow infusion, compared with 0.0 +/- 13.2/1.3 +/- 8.3 mmHg for the placebo occasion. Decrease of saccadic peak velocity (SPV) at the end of the infusion was 18.0 +/- 5.2% during the fast infusion, 23.0 +/- 7.0% with the slow infusion, and 6.1 +/- 5.2% with placebo. PK/PD analysis showed similar concentration-dependent linear reduction in SPV and blood pressure up to the maximum observed rilmenidine plasma level for both the fast and the slow infusion. CONCLUSIONS: The rate of infusion of rilmenidine in healthy volunteers does not influence the PK/PD relationship of saccadic eye movements and blood pressure up to the maximum observed rilmenidine plasma concentrations. Rilmenidine causes clear concentration-dependent blood pressure reductions in healthy volunteers.

Adult↗

PubMed2001

The sugar absorption test in the evaluation of the gastrointestinal intolerance to bisphosphonates: studies with oral pamidronate.

UNLABELLED: RATIONALE AND AIMS Some bisphosphonates induce gastrointestinal side effects, but the localization in the gastrointestinal tract and the underlying mechanism are unknown. The feasibility of the sugar absorption test was investigated to assess the gastrointestinal effects of oral enteric-coated pamidronate. The sugar absorption test measures the urinary excretion of lactulose, mannitol, and sucrose after oral intake. Increases in the lactulose/mannitol ratio and sucrose excretion indicate increased small intestinal permeability and gastroduodenal disease, respectively. SUBJECTS AND METHODS: Twelve volunteers (5 women and 7 men) participated in a randomized, double-blind, 4-way crossover study. The sugar absorption test was performed 2 hours after the final drug intake following a 3-day course of enteric-coated pamidronate (300 mg daily), placebo, or acetylsalicylic acid (3 g daily). The lactulose/mannitol ratio and sucrose excretion were measured in urine collected for 5 hours after ingestion of the solution. The fourth treatment consisted of intravenous administration of pamidronate. Treatment comparison was with paired t tests after log-transformation. RESULTS: The lactulose/mannitol ratio after pamidronate and acetylsalicylic acid administration was 54% and 118% higher than that after placebo (95% confidence intervals [CI], +8%, +119%, and +69%, +182%). The lactulose/mannitol ratio after pamidronate administration was 29% lower (95% CI, -54%, +3%) than that after acetylsalicylic acid. Compared with placebo the sucrose excretion was 290% higher after acetylsalicylic acid (95% CI, +46%, +518%) but only 8% higher after pamidronate (95% CI, -41%, +97%). The absorption of pamidronate was below 1%, and there was no relationship with the increased lactulose/mannitol ratio. CONCLUSION: Oral enteric-coated pamidronate increases intestinal but not gastroduodenal permeability. There was no relationship between intestinal permeability and absorption of pamidronate. It appears that the sugar absorption test is an appropriate, noninvasive method for evaluation of gastrointestinal effects of bisphosphonates in humans.

Absorption↗

PubMed2001

Endothelial function in patients with hyperthyroidism before and after treatment with propranolol and thiamazol.

Hyperthyroidism is associated with a higher incidence of arterial thromboembolism; increasing age, atrial fibrillation, and mitral valve abnormalities are risk factors. However, the contribution of endogenous coagulation parameters is unclear. Because thyroid hormone influences receptor and transcription factors, it can be expected that it will influence proteins involved in coagulation processes synthetised in many cells. Fourteen hyperthyroid patients were studied untreated, after 1 week of treatment with propranolol, and after therapeutic treatment with thiamazol. Fourteen matched controls were used for comparison. On each occasion, endothelial marker proteins, coagulation/fibrinolysis factors, and inflammatory (liver) markers were measured. Excess thyroid hormone was associated with elevated levels of most endothelium-associated proteins. In addition, plasma fibronectin and fibrinogen were increased, while plasminogen was decreased. No evidence was found that hyperthyroidism was associated with coagulation/fibrinolysis activation, or with increased levels of the inflammation markers interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) or C-reactive protein (CRP). Propranolol treatment only lowered the von Willebrand factor propeptide, and slightly increased plasminogen. Treatment with thiamazol returned all parameters to normal. Hyperthyroidism increased the plasma levels of most endothelial marker proteins, and of some liver-synthetized proteins. No evidence for coagulation/fibrinolysis activation was found. However, it appears that endothelial activation, which is indicative of a procoagulant state, is present in hyperthyroidism. This may explain the association between hyperthyroidism and thromboembolism especially if other risk factors are present. von Willebrand factor II (vWF:Ag-II) levels may be suitable markers to evaluate acute changes in endothelial function because this parameter responds more rapidly to changes in endothelial function than other factors.

Adrenergic beta-Antagonists↗

PubMed2001

Disagreement between bedside and laboratory activated partial thromboplastin time and international normalized ratio for various novel anticoagulants.

During studies on warfarin, heparin and various anticoagulants with novel mechanisms of action, the activated partial thromboplastin time (aPTT) and the (apparent) international normalized ratio (INR) from a bedside monitor (Coagucheck Plus(R)) were compared with laboratory assay results. Data were compared using the Bland and Altman method of comparison where systematic differences result in significant slopes of the regression line. During heparin treatment, the bedside monitor largely underestimated the aPTT (slope = -0.80). During treatment with the direct thrombin inhibitor napsagatran (slope = 0.99), the pentasaccharides Org31540/SR90107A (slope = 0.77) and SanOrg34006 (slope = 0.35), and warfarin (slope = 0.60), the bedside monitor underestimated the aPTT at lower aPTT levels, while at higher aPTT levels it overestimated the laboratory values. The bedside monitor slightly overestimated the INR during treatment with warfarin (slope = 0.33). Apparent INR was largely overestimated during treatment with Org31540/SR90107A (slope = 1.38), SanOrg34006 (slope = 0.97), Napsagatran (slope = 1.23), and recombinant tissue factor pathway inhibitor (slope = 1.48, P < 0.001 for all regression lines). These results indicate that a substantial disagreement in aPTT or (apparent) INR exists between the bedside monitor and laboratory assay during treatment with the studied 'classic' and novel anticoagulants. The amount of disagreement depended on the anticoagulant given.

Anticoagulants↗

PubMed2001

Biomarkers for the effects of antipsychotic drugs in healthy volunteers.

Studies of novel antipsychotics in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. A useful biomarker should meet the following requirements: a consistent response across studies and antipsychotics; a clear response of the biomarker to a therapeutic dose; a dose-response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. In the current review, all individual tests found in studies of neuroleptics in healthy volunteers since 1966 were progressively evaluated for compliance with these requirements. A MedLine search yielded 65 different studies, investigating the effects of 23 different neuroleptics on 101 different (variants of) neuropsychological tests, which could be clustered into seven neuropsychological domains. Subjective and objective measures of alertness, and of visual-visuomotor-auditory and motor skills were most sensitive to antipsychotics, although over half of all the studies failed to show statistically significant differences from placebo. The most consistent effects were observed using prolactin response and saccadic eye movements, where 96% and 83% of all studies resp. showed statistically significant effects. The prolactin inducing dose equivalencies relative to haloperidol of 19 different antipsychotic agents correlated with the lowest recommended daily maintenance dose (r(2) = 0.52). This relationship could reflect the clinical practice of aiming for maximum tolerated levels, or it could represent a common basis behind prolactin release and antipsychotic activity (probably D2-receptor antagonism). The number of tests used in human psychopharmacology appears to be excessive. Future studies should look for the most specific and sensitive test within each of the domains that are most susceptible to neuroleptics.

Antipsychotic Agents↗

PubMed2001

Cardiovascular side effects of inhaled salbutamol in hypoxic asthmatic patients.

BACKGROUND: Beta-2 adrenoceptor agonists have been associated with sudden death in asthma patients but the cause and underlying mechanism are unclear. Animal experiments indicate that the combination of hypoxia and beta2 agonists may result in detrimental cardiovascular effects. A study was undertaken to investigate the effect of hypoxia on the systemic vascular effects of salbutamol in patients with asthma who are hypoxic by assessing forearm blood flow (FBF) as a measure of peripheral vasodilatation. METHODS: Eight men with mild asthma underwent the following treatments: normoxia + placebo (NP), normoxia + salbutamol (NS), hypoxia + placebo (HP), and hypoxia + salbutamol (HS). The period of mask breathing started at t=0 minutes, lasted for 60 minutes, and at 30 minutes 800 microg salbutamol was inhaled. The experiment was completed 30 minutes after the inhalation (t=60 minutes). For the hypoxia treatment the SpO2 level was 82%. Differences between treatments were sought using factorial ANOVA on percentage change from the pretreatment value. RESULTS: There were no significant differences in blood pressure and potassium levels between the treatments. After 60 minutes the increase in FBF was 13% (95% CI -12 to 39) more for HP treatment than for NP, 21% (95% CI -5 to 46) more for NS than for NP, and 32% (95% CI 7 to 58) more for HS than for HP (p=0.016). The inhalation of salbutamol during hypoxia resulted in a significant increase in FBF of 45% (95% CI 20 to 71) compared with NP (p=0.001). CONCLUSION: Patients with asthma who are hypoxic and inhale beta2 agonists have serious systemic vascular side effects which may be an additional explanation for the association between asthma treatment and sudden death.

Administration, Inhalation↗

PubMed2001

Sympathovagal imbalance in hyperthyroidism.

We assessed sympathovagal balance in thyrotoxicosis. Fourteen patients with Graves' hyperthyroidism were studied before and after 7 days of treatment with propranolol (40 mg 3 times a day) and in the euthyroid state. Data were compared with those obtained in a group of age-, sex-, and weight-matched controls. Autonomic inputs to the heart were assessed by power spectral analysis of heart rate variability. Systemic exposure to sympathetic neurohormones was estimated on the basis of 24-h urinary catecholamine excretion. The spectral power in the high-frequency domain was considerably reduced in hyperthyroid patients, indicating diminished vagal inputs to the heart. Increased heart rate and mid-frequency/high-frequency power ratio in the presence of reduced total spectral power and increased urinary catecholamine excretion strongly suggest enhanced sympathetic inputs in thyrotoxicosis. All abnormal features of autonomic balance were completely restored to normal in the euthyroid state. beta-Adrenoceptor antagonism reduced heart rate in hyperthyroid patients but did not significantly affect heart rate variability or catecholamine excretion. This is in keeping with the concept of a joint disruption of sympathetic and vagal inputs to the heart underlying changes in heart rate variability. Thus thyrotoxicosis is characterized by profound sympathovagal imbalance, brought about by increased sympathetic activity in the presence of diminished vagal tone.

Adult↗

PubMed2001

Estimation of growth hormone secretion rate: impact of kinetic assumptions intrinsic to the analytical approach.

We compared four common mathematical techniques to determine daily endogenous growth hormone (GH) secretion rates from diurnal plasma GH concentration profiles in 24 women (16 upper- or lower-body obese and 8 normal-weight individuals). Two forms of deconvolution analysis and two techniques based on a priori determined GH clearance estimates were employed. Deconvolution analyses revealed significant differences in the 24-h GH secretion rate between normal-weight and upper-body obese women, whereas the other two techniques did not. Moreover, deconvolution analyses predicted that the reduction in mean plasma GH concentrations in upper-body obese women was accounted for by impaired GH secretion, whereas the other methods suggested that obesity increases GH metabolic clearance. Thus we infer that disparate conclusions concerning GH secretion can be drawn from the same primary data set. The different inferences likely reflect dissimilar kinetic assumptions and the particular limitations intrinsic to each analytical approach. Accordingly, we urge caution in the facile comparison of calculated GH secretion data in humans, especially when kinetic and secretion measurements are performed under different conditions. The most appropriate way to determine the GH secretion rate in humans must be balanced by the exact intent of the experiment and the acceptability of different assumptions in that context.

Adult↗

PubMed2001

Altered neuroregulation of GH secretion in viscerally obese premenopausal women.

We used deconvolution analysis of 24-h plasma GH concentration profiles (10- min sampling intervals) to appraise GH secretion rates and elimination kinetics in obese (body mass index, approximately 34 kg/m2) premenopausal women with large visceral fat area (LVFA; n = 8) vs. small visceral fat area (SVFA; n = 8) as determined by magnetic resonance imaging. The subjects were matched for body mass index, body fat percentage, and age. The impact of the loss of 50% of prestudy weight excess induced by caloric restriction was assessed as well. The results were compared with those obtained in normal weight control women (n = 8). LVFA subjects manifested markedly (4-fold) reduced mean plasma GH levels, which was brought about by jointly diminished basal and pulsatile GH secretion. Moreover, visceral obesity was associated with loss of regularity of GH release, as established by the approximate entropy statistic. In contrast, SVFA subjects produced normal daily amounts of GH and exhibited mean 24-h plasma GH concentrations that were similar to those in normal weight controls. GH half-life and distribution volume were not different among the study groups. Importantly, weight loss did not affect the daily GH secretion rate in LVFA women, so that their mean plasma GH concentration remained considerably reduced (approximately 50%) compared with controls (despite the loss of approximately 40% of visceral fat). Normal GH kinetics in SVFA women were not significantly influenced by weight reduction. Thus, GH neuroregulation appears to be particularly altered in obese women with a tendency to store fat in their visceral adipose depot. Because weight loss did not reverse GH secretion rate in viscerally obese women, we speculate that relative hyposomatotropism is a primary feature of these women, which could be involved in their tendency to preferentially store excess fat in visceral adipose tissue.

Adipose Tissue↗

PubMed2001

Food choice in hyperthyroidism: potential influence of the autonomic nervous system and brain serotonin precursor availability.

We explored energy and macronutrient intake in patients with Graves' hyperthyroidism. We specifically hypothesized that hyperthyroidism is associated with increased appetite for carbohydrates, because of enhanced sympathetic tone and diminished serotonin mediated neurotransmission in the brain. To test this hypothesis, we measured food intake by dietary history and food selected for lunch in the laboratory in 14 patients with Graves' hyperthyroidism. Twenty-four-hour catecholamine excretion was used as a measure of activity of the sympathetic nervous system (SNS) and the plasma [Trp]/[NAA] ratio was measured to estimate (rate limiting) precursor availability for brain 5-hydroxytryptamine synthesis. All measurements were repeated after the subjects had been treated to establish euthyroidism. In addition, the effects of nonselective beta-adrenoceptor blockade upon these parameters were studied to evaluate the influence of beta-adrenergic hyperactivity on food intake. Hyperthyroidism was marked by increased SNS activity and reduced plasma [Trp]/[NAA] ratio. Accordingly, energy intake was considerably and significantly increased in hyper vs. euthyroidism, which was fully attributable to enhanced carbohydrate consumption, as protein and fat intake were not affected. These results suggest that hyperthyroidism alters the neurophysiology of food intake regulation. Increased SNS activity and reduced Trp precursor availability for 5-hydroxytryptamine synthesis in the brain may drive the marked hyperphagia and craving for carbohydrates that appears to characterize hyperthyroid patients. Because propranolol did not affect food intake in hyperthyroidism, the potential effect of catecholamines on food intake might be mediated by alpha-adrenoceptors.

Autonomic Nervous System↗

PubMed2000

Dexamethasone concentration in the subretinal fluid after a subconjunctival injection, a peribulbar injection, or an oral dose.

PURPOSE: To determine dexamethasone concentrations in the subretinal fluid of patients after a peribulbar injection, a subconjunctival injection, or an oral dose of dexamethasone and to compare the results with those of previous similar studies of dexamethasone concentrations in the vitreous. DESIGN: Prospective, nonrandomized, comparative trial. PARTICIPANTS: One hundred forty-eight patients with a rhegmatogenous retinal detachment. METHODS: Fifty patients received a peribulbar injection of 5 mg dexamethasone disodium phosphate, 49 received a subconjunctival injection of 2.5 mg dexamethasone disodium phosphate, and 49 received an oral dose of 7. 5 mg dexamethasone at various time intervals before surgery. At the time of surgery, a subretinal fluid sample was taken from each patient. MAIN OUTCOME MEASURES: The dexamethasone concentration in the subretinal fluid measured by radioimmunoassay. RESULTS: The estimated maximum dexamethasone concentrations in the subretinal fluid after the peribulbar injection, the subconjunctival injection, and the oral dose were, respectively, 82.2 ng/ml (standard error, 17. 6), 359 ng/ml (standard error, 80.2), and 12.3 ng/ml (standard error, 1.61). Corrected for dose, the maximum dexamethasone concentrations after subconjunctival injection and peribulbar injection were, respectively, 120 (95% confidence interval, 54/180) and 13 (95% confidence interval, 6.8/20) times greater than after oral administration. CONCLUSIONS: A subconjunctival injection of dexamethasone disodium phosphate is more effective in delivering dexamethasone into the subretinal fluid of patients with a rhegmatogenous retinal detachment compared with peribulbar injection or oral administration. The subretinal dexamethasone concentrations were higher than concentrations measured in the vitreous in previous studies with a similar setup after all three delivery methods.

Administration, Oral↗

PubMed2000

Sorbitol as a marker for drug-induced decreases of variable duration in liver blood flow in healthy volunteers.

OBJECTIVE: Sorbitol has been suggested as a suitable marker to assess liver blood flow (LBF), after it was shown to adequately reflect prolonged changes in LBF but changes of a shorter duration have not been investigated. We therefore used sorbitol to evaluate drug-induced decreases in LBF of variable duration with i.v. infusions of somatostatin and its synthetic analogue octreotide. METHODS: In a double-blind, placebo controlled, randomised study, six healthy males received sorbitol for 170 min. At sorbitol steady state, which was at 45 min after the start of the infusion (t=0), somatostatin or octreotide was infused for 30 min. Sampling for sorbitol assay and echo-Doppler hepatic portal vein flow measurements were done regularly and treatments were compared using ANOVA. RESULTS: The sorbitol AUC over the 30-min intervention period was 15% (95% C.I.: +4, +22%) and 13% (+5, +24%) higher compared to placebo after somatostatin and octreotide respectively. The decline of sorbitol levels after termination of the intervention was faster for somatostatin compared to octreotide, demonstrated by the difference in the AUC (0-2 h) with placebo which was 8% (-3, +19%) lower after somatostatin, and 15% (+5, +26%) after octreotide. Portal venous blood flow decreased during the 30-min interventions; after somatostatin 27% (-14, -40%) and after octreotide 29% (-17, -42%). Portal flow was lower than placebo during the entire experiment after octreotide 30% (-10, -50%), but not after somatostatin 13% (-33, +7%). Changes in sorbitol levels and portal venous blood flow occurred simultaneously and were well correlated for each individual, making it likely that the interventions did not interfere with metabolism. CONCLUSION: Sorbitol can be used to adequately assess decreases in LBF of variable duration in healthy volunteers.

Adult↗

PubMed2000

The influence of the hand circulation on the assessment of venous distensibility of the human forearm with venous occlusion plethysmography.

AIMS: To determine the influence of the hand circulation on the determination of venous distensibility with venous occlusion plethysmography. METHODS: In a randomised study, duplicate measurements of forearm venous distensibility, with and without a wrist cuff, were made over occlusion periods of 3 and 12 min in eight volunteers. Treatments were compared with paired Student's t-tests and differences are presented as 95% confidence intervals (CI). Intra-subject variability was assessed with analysis of variance. RESULTS: Non-significant differences in increases in forearm volume between the occlusions with and without wrist cuff were found for the 3 min occlusion (CI: -0.4, + 0.2%) and the 12 min occlusion period (CI: -0.7, + 0.2%). However, the coefficient of variation was lower with the use of a wrist cuff; after 3 min occlusion (12% vs 19%) and after 12 min of occlusion (14% vs 24%). Forearm volume after 12 min of venous occlusion was 0.5% (CI: + 0.4, + 0.7) higher than after 3 min. CONCLUSIONS: Although venous distensibility was equal when assessed with and without wrist cuff, exclusion of the hand circulation reduces intraindividual variability. Equilibrium in forearm volume is not reached after 3 min period of venous occlusion, as often assumed. The magnitude of the additional increase after prolonged occlusion stresses the need for well-controlled studies.

Adult↗

PubMed2000

The influence of reduced liver blood flow on the pharmacokinetics and pharmacodynamics of recombinant tissue factor pathway inhibitor.

OBJECTIVES: Recombinant tissue factor pathway inhibitor (rTFPI) has been shown to be an effective treatment in animal models of sepsis and is under investigation for human use. Reduced liver blood flow during septic shock may substantially alter the pharmacokinetics of rTFPI because clearance of rTFPI approaches liver blood flow. The aim of this study was to examine the effect of exercise-induced reduction in liver blood flow on the pharmacokinetics and pharmacodynamics of rTFPI. METHODS: This was a two-way, open-label, randomized crossover study in eight healthy male volunteers. The subjects in both treatment groups received a continuous intravenous infusion of rTFPI (0.2 mg/kg/h) concurrently with intravenous sorbitol (50 mg/min) for 4 hours. Sorbitol was used as a biomarker for liver blood flow. The subjects were randomized to remain supine or to exercise on a bicycle ergometer for 30 minutes starting at the beginning of the third hour of the infusion. RESULTS: Exercise reduced liver blood flow (mean +/- SEM) from 1.44 +/- 0.06 L/min to 0.40 +/- 0.03 L/min. The average clearance of rTFPI decreased from 0.73 +/- 0.04 L/min in the supine position to 0.25 +/- 0.02 L/min during exercise. This decrease in rTFPI clearance resulted in an 80% (95% confidence interval [CI], 60% to 102%) increase in plasma rTFPI levels during exercise. The average maximal prothrombin time and activated partial thromboplastin time values during exercise were 1.4 (95% CI, 0.4 to 2.5) and 4.4 (95% CI, 2.7 to 6.1) seconds higher compared with the supine steady-state level. CONCLUSIONS: Reduction in liver blood flow by exercise markedly increased rTFPI concentrations and induced a slight but variable prothrombin time and activated partial thromboplastin time increase at the rTFPI dose studied.

Adult↗

PubMed2000

A pharmacodynamic Markov mixed-effects model for the effect of temazepam on sleep.

BACKGROUND: A hypnogram shows how sleep travels through its various stages in the course of a night. The sleep stage changes can be quantified to study sedative drug effects. METHODS: Hypnograms from 21 patients with primary insomnia were collected during a randomized, placebo-controlled crossover study of 20 mg temazepam. A separate daytime session was performed to determine the pharmacokinetics of 20 mg temazepam and its effect on saccadic eye movement and electroencephalogram. A first-order Markov model was developed to describe the probability of sleep stage changes as a function of time after drug intake and time after last sleep stage change. The influence of temazepam concentration on the probability to change sleep stage was incorporated into the model. RESULTS: Transitions between sleep stages were profoundly influenced by the time of the night and by the time since the last change of sleep stage. Temazepam reduced the time spent awake. This effect could be attributed to four mechanisms: (1) transition to "deeper" sleep was facilitated, (2) transition to "lighter" sleep was inhibited, (3) regardless of sleep stage, the transition to wake state was inhibited, and (4) return to sleep was facilitated. Daytime sensitivities to temazepam, measured with the surrogate markers saccadic peak velocity and electroencephalogram beta activity, each correlated with one of the transition probabilities influenced by temazepam. CONCLUSIONS: By the development of a Markov model for these non-ordered six categorical data, the effect of temazepam on the sleep-wake status could be interpreted in terms of known mechanisms for sleep generation and benzodiazepine pharmacology.

Adolescent↗