Comparative evaluation of the efficacy and safety of two doses of terbinafine (500 and 1000 mg day(-1)) in the treatment of cutaneous or lymphocutaneous sporotrichosis.

The aim of this study was to evaluate the safety and efficacy of oral terbinafine (500 and 1000 mg day(-1)) in the treatment of cutaneous or lymphocutaneous sporotrichosis. A culture for Sporothrix schenckii was required for inclusion into this multicentre, randomized, double-blind, parallel-group study. Patients received either 250 mg b.i.d. or 500 mg b.i.d. oral terbinafine for up to a maximum of 24 weeks and were assessed up to 24 weeks post-treatment. The main efficacy outcome measure was cure, defined as no lesion and absence of adenopathy at the end of follow-up. Adverse events (AEs), laboratory tests, vital signs and ophthalmological examinations were also assessed. Sixty-three patients (14-85 years of age) were treated with 500 mg day(-1) (n = 28) or 1000 mg day(-1) terbinafine (n = 35). The majority of patients were cured after 12-24 weeks of treatment, and the response was dose-dependent throughout the study and at the end of follow-up. The cure rate was significantly higher in patients treated with 1000 mg day(-1) terbinafine compared with those treated with 500 mg day(-1) terbinafine (87% vs. 52%, respectively; P = 0.004). There were no cases of relapse after 24 weeks of follow-up in the 1000 mg day(-1) terbinafine group, compared with six relapses in the terbinafine 500 mg day(-1) group. Terbinafine was well tolerated and the frequency of drug-related AEs was slightly higher in the 1000 mg treatment group. Both doses of terbinafine were well-tolerated and effective for the treatment of sporotrichosis. The 1000 mg day(-1) terbinafine dose was more efficacious than 500 mg day(-1) in the treatment of cutaneous or lymphocutaneous sporotrichosis.

Short-duration oral terbinafine for the treatment of tinea pedis in HIV-positive patients.

Management of tinea pedis in patients who have the human immunodeficiency virus (HIV) is problematic; in those patients, dermatophytoses may be more difficult to treat than in the general population. This prospective, open-label, multicenter, randomized study evaluated the efficacy and safety of a short course of oral terbinafine for tinea pedis in patients who are HIV positive. Twenty-seven patients were randomized to receive oral terbinafine 250 mg once daily for 2 or 4 weeks; 17 patients with positive initial cultures and follow-up cultures were evaluable for efficacy at week 8. Mycological cure (defined as negative potassium hydroxide [KOH] microscopy and culture results) occurred in 47% (8) of patients; and modified mycological cure (defined as negative follow-up cultures) occurred in 65% (11) of patients. All 27 patients were evaluated for safety. Clinical cure (defined as minimal residual signs and symptoms) occurred in 82% (14) of patients. Oral terbinafine was well tolerated, indicating that regimens of 2 or 4 weeks are safe and effective for the treatment of tinea pedis in patients who are HIV positive.

Alterations of host defence system after sleep deprivation are followed by impaired mood and psychosocial functioning.

In healthy humans, sleep deprivation (SD) has consistently been demonstrated to impair different parameters of the host defence system and of psychosocial functioning. However, the individual timing of these alterations and their possible association have remained unknown so far. We therefore investigated functional measures of the individual host defence system as well as of subjective well-being and psychosocial performance in 10 healthy male adults before and after SD, as well as after recovery sleep. In detail, we examined the number of leukocytes, granulocytes, monocytes, lymphocytes, B cells, T cells, T helper and cytotoxic T cells, natural killer (NK) cells as well as the interleukin-1 beta (IL-1 beta) release from platelets after serotonin (5-HT) stimulation. Mood and psychosocial performance (excitement, energy, ability to work and timidity) were measured by visual analogue scales. Taken together, SD induced a deterioration of both mood and ability to work, which was most prominent in the evening after SD, while the maximal alterations of the host defence system could be found twelve hours earlier, i.e., already in the morning following SD. Our findings therefore suggest an SD-induced alteration of these psychoimmune response patterns in healthy humans preceding deterioration of mood and psychosocial functioning.

White blood cells and cortisol after sleep deprivation and recovery sleep in humans.

Sleep deprivation (SD) has enriched our treatment programme for major depression. SD has been demonstrated to modify different host defence activities. There is some evidence that there are reciprocal relationships between immune function and increased hypothalamic-pituitary-adrenocortical (HPA) axis activity in depression. We therefore investigated the number of leukocytes, granulocytes, monocytes, lymphocytes, B cells, T cells, helper T cells, cytotoxic T cells, NK cells and salivary cortisol in 10 healthy men before and after total SD (TSD) as well as after recovery sleep. Blood samples were drawn on 3 consecutive days at 7 am, 1 pm and 7 pm, respectively. Comparison of the 7 am values by contrast analysis yielded significant differences for granulocytes (p = 0.044) and NK cells (p = 0.001) after SD and recovery sleep. NK cells decreased and granulocytes increased after SD and after recovery sleep. Significant differences between single points in time across the day were found for granulocytes (p = 0.022), monocytes (p = 0.031), T cells (p = 0.005), helper T cells (p = 0.004), cytotoxic T cells (p = 0.005) and NK cells (p = 0.017). No significant difference could be detected for leukocytes, lymphocytes and B cells counts. These results favour the thesis that SD and recovery sleep lead to changes in the distribution of peripheral leukocytes, especially in a reduction of NK cells after SD and recovery sleep. The cortisol rhythm was affected neither by SD nor recovery sleep.

Platelet aggregation during abdominal surgery in an experimental pig model: the effects of presurgical antibiotic protocols and volume replacement with hydroxyethyl starch.

The effect of presurgical antibiotic protocols in combination with hemodilution on platelet aggregation was studied. Thirty pigs were randomly assigned to three groups. Group 1 received amoxicillin/clavulanic acid, group 2 metronidazole+cefuroxime, and group 3, as a control, sodium chloride. They underwent laparotomy, massive blood loss, and volume replacement with hydroxyethyl starch 200, followed by an anaphylactoid reaction. Platelet aggregation was measured by the turbidometric method. Neither antibiotic protocols had any effect on platelet aggregation as compared with the control group. In all three groups, aggregation to ADP and collagen was significantly reduced after volume replacement with hydroxyethyl starch. In contrast, the sensitivity to the aggregating effects of collagen was increased as assessed by a higher frequency of responses to low concentrations of collagen and a shortened latency of the aggregation response after collagen addition. Further in vitro studies revealed that dilution of plasma with hydroxyethyl starch specifically induced the changes seen after in vivo volume replacement. The results suggest that the plasma substitute hydroxyethyl starch 200 increases the sensitivity to low doses of collagen, an effect never described before and considered of clinical relevance.

Effect of repeated immobilization on serotonin metabolism in different rat brain areas and on serum corticosterone.

The effect of daily repeated 10 min immobilization on the serotoninergic neurotransmission and serum corticosterone levels was studied. Male Lewis rats were immobilized for a 10 min period daily once or on 5 consecutive days. Serotoninergic neurotransmission was followed using differential in vivo pulse voltammetry with carbon fibre electrodes measuring extracellular 5-hydroxyindoleacetic acid (5-HIAA) levels. Recordings were performed in brain areas involved in the control of behaviour, mood, and stress response such as the frontal cortex, the hippocampal CA-3 and dentate gyrus, the striatum, and the raphe nuclei dorsalis (NRD) and medialis (MRN). The first immobilization resulted in an increase of the extracellular 5-HIAA levels in all areas under study, except the striatum where no reaction was observed. The major effect was recorded in the frontal cortex, showing an increase of about 400% as compared to control, which lasted for 3h after the end of the immobilization period. Beginning on day 2 in all areas, except the striatum, a consecutive habituation to the stressor seemed to occur, since the stress-induced increase in the voltammetric signal was found to be reduced after consecutive immobilization. Serum corticosterone levels were measured directly after a single and after 5 daily immobilization periods. After single immobilization the serum corticosterone level was found to be about 270 ng/ml. After the 5th immobilization about 300 ng/ml were detected. These differences were not found to be significant. In summary, our data indicate that the serotonin metabolism shows habituation in nearly all brain areas after repeated immobilization, though the corticosterone level at the end of the immobilization period was comparable after single and repeated immobilization.

Effect of hypochlorite (HOCl)-modified low density lipoproteins and high density lipoproteins on platelet function.

As hypochlorous acid (HOCl) might be a potential candidate for generation of modified (lipo)proteins in vivo , the present study was aimed at investigating the effects of HOCl-modified lipoproteins on platelet function in vitro. Lipoproteins modified with HOCl at concentrations that occur physiologically did not induce spontaneous platelet aggregation. However, low density lipoproteins (LDL; 100 to 500 microg protein/ml) increased platelet aggregation and fluorescence anisotropy in response to ADP (1 and 10 microM) and thrombin (0.1 and 0.5 U/ml) as well as malondialdehyde (MDA) formation as a function of increasing HOCl-concentrations (0.2 to 1.6 mM). HOCl-modified high density lipoprotein subfraction 3 (HDL3) had no effect on platelet function.

Analysis of GTP-binding proteins, phosphoproteins, and cytosolic calcium in functional heterogeneous human blood platelet subpopulations.

The biochemical basis for the functional heterogeneity of human blood platelets was investigated in terms of protein phosphorylation, cytoplasmic calcium ([Ca2+]i), the ratio of 46 and 50 kDa vasodilator-stimulated protein (VASP), and GTP-binding proteins (G-proteins). Platelets were fractionated by density. Comparing resting low-density platelets (LDP) to high-density platelets (HDP) revealed higher phosphorylation of proteins in the 47, 31, and 24 kDa ranges. A higher phosphorylation of the 20 kDa protein in LDP compared to HDP was related to an enhanced [Ca2+]i, an increased ADP-ribosylation of the inhibitory G-protein (G(i alpha1-3)) and rhoA, and a decreased ADP-ribosylation of the stimulatory G-protein (G(s alpha)). The differences in the ribosylation patterns of the subpopulations were not influenced by thrombin stimulation or exposure to prostaglandin E1 (PGE1). An 18 kDa phosphoprotein was more highly phosphorylated in resting HDP than in LDP. Thrombin exposure caused dephosphorylation of the 18 kDa phosphoprotein in the HDP, but generally increased phosphorylation of both HDP and LDP in the 47, 31, 24, and 20 kDa bands. Preincubation with prostaglandin E1 or sodium nitroprusside diminished the subsequent thrombin-induced increase in phosphorylation, particularly in HDP. In unstimulated HDP, the 50 kDa VASP phospho form was enhanced, whereas in unstimulated LDP the 46 kDa VASP dephospho form was increased. Our findings suggest that the functional heterogeneity of platelets is partly derived from differences in signal transduction mechanisms reflected in varying phosphoprotein patterns and G-protein properties of platelet stimulatory and inhibitory pathways.

Alterations of blood platelet MAO-B activity and LSD-binding in humans after sleep deprivation and recovery sleep.

Sleep deprivation (SD) is an effective, however short-lived, method of treatment of depression. Preliminary findings suggest that the antidepressive effect of sleep deprivation is mediated by serotoninergic (5-HT) mechanisms. We therefore assessed serotoninergic activity before and after total SD (TSD) as well as after the following night sleep by investigating platelet LSD-binding, MAO B-activity, and 5-HT-content as well as plasma norepinephnne (NE) in 10 healthy men (age: 27.4 +/- 2.8 years). Blood samples were drawn on three consecutive days at 0700, 1300 and 1900 h, respectively. After TSD, a significant increase of LSD-binding KD and Bmax as well as of MAO-B KM and plasma NE could be observed, which, however, vanished after consecutive night sleep. Our findings favour an increased serotoninergic transmission after TSD and thus support the hypothesis, that sleep deprivation exerts its antidepressant effects by pro-serotoninergic mechanisms.

Decreased platelet membrane anisotropy in patients with adrenoleukodystrophy treated with erucic acid (22:1)-rich triglycerides.

Low platelet count and bleeding diathesis have been observed in patients with adrenoleukodystrophy (ALD) treated with erucic acid (22:1)-rich triglycerides ("Lorenzo's oil'). To investigate possible alterations of biophysical membrane properties, we measured platelet membrane anisotropy, which is inversely related to membrane fluidity, in 16 patients with and in 3 patients without treatment. In patients on treatment, platelet membrane anisotropy was significantly decreased. Additionally, we found increased platelet concentrations of 22:1 and compromised in vitro platelet aggregation response. The decrease of platelet membrane anisotropy is probably a main cause of bleeding diathesis. Long-term haematological side-effects must be considered in ALD patients treated with Lorenzo's oil.

Effects of interferon-gamma, interleukin-1 beta, and tumor necrosis factor-alpha on the serotonin metabolism in the nucleus raphe dorsalis of the rat.

The effects of the cytokines interferon (IFN)-gamma, interleukin (IL)-1, and tumor necrosis factor (TNF)-alpha on the serotoninergic transmission in the nucleus raphe dorsalis (NRD) were studied after peripheral and central application. The studies were performed in the freely moving rat using differential pulse voltammetry with multicarbon fibre electrodes to study the extracellular levels of the serotonin (5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA). The extracellular 5-HIAA levels were not changed in the NRD after peripheral application of rat recombinant IFN-gamma, but elevated by the cytokines IL-1 beta and TNF-alpha. After intracerebroventricular (i.c.v.) application the cytokines IFN-gamma, IL-1 beta and TNF-alpha stimulated the serotoninergic transmission in the NRD. Our data suggest that the effect of peripherally elevated cytokine concentrations on the serotonin metabolism in the NRD of the rat is cytokine-dependent. In this respect the T-cell and NK-cell cytokine IFN-gamma acts clearly different when compared to the mainly macrophage-derived cytokines IL-1 beta and TNF-alpha, and plays a different role in the communication between immune and central nervous system.

The antagonism of ipsapirone induced biobehavioral responses by +/- pindolol in high and low impulsives.

The present study was conducted to investigate whether +/- pindolol antagonizes ipsapirone induced biobehavioral changes in a personality dependent way. Our previous work demonstrated that high impulsives show higher immune cell responses than low impulsive subjects upon treatment with ipsapirone. A total number of 80 healthy male volunteers received placebo (N = 20) or 10 mg ipsapirone (N = 20), 30 mg +/- pindolol (N = 20), or a combination of 30 mg +/- pindolol and 10 mg ipsapirone (N = 20). Each group consisted of 10 low and 10 high impulsive subjects. Since 5-HT related drugs induce thermoregulatory responses, the study took place in a climate chamber with a constant ambient temperature. Blood samples (for measurement of CD4+ cell counts) were drawn from an indwelling catheter invisibly for the subjects. The results clearly demonstrate that the ipsapirone induced decreases in body temperature and number of peripheral CD4+ cells are more pronounced in high impulsives. +/- Pindolol antagonizes thermoregulatory and CD4+ cell responses. The results are discussed with respect to mechanisms of alteration in 5-HT function related to impulsivity.

Platelet serotonin and interleukin-1 beta after sleep deprivation and recovery sleep in humans.

Sleep deprivation (SD) represents a well-established therapy for major depression. Recent findings suggest that the antidepressive effects of sleep deprivation are mediated at least in part by pro-serotoninergic mechanisms. Furthermore, SD has been demonstrated to modify different host defense activities. We therefore investigated the serotonin (5-HT) content in platelets, platelet density distribution and 5-HT-induced IL-1 beta release from platelets in 10 healthy men before and after total SD (TSD) as well as after recovery sleep. Blood samples were drawn on 3 consecutive days at 7.00 h, 13.00 h, and 19.00 h, respectively. In addition, the psychophysiological parameters tiredness and wakefulness were assessed. After TSD the normal daily variation of IL-1 beta release with high morning levels and low evening levels was found to be significantly inverted. The release of IL-1 beta corresponded positively to the subjectively experienced tiredness of the probands. Analysis of platelet density distribution indicated a significant daily variation of low density platelets with low levels in the morning and high levels in the evening, which was absent after TSD. Our findings favour an increased pro-serotoninergic effect after TSD, which comprises respective variations of the host defense system, but is abolished by consecutive recovery sleep.

Changes in lipids and membrane anisotropy in human spermatozoa during epididymal maturation.

Previously it was demonstrated that immature and immotile human spermatozoa from the caput epididymides developed a good progressive motility after in-vitro stimulation with phosphatidylcholine (PC). In order to define the role of PC and membrane anisotropy in epididymal maturation and to determine the exact lipid composition of human spermatozoa during epididymal maturation, spermatozoa from seven epididymides from patients who underwent orchiectomy because of prostatic cancer were investigated. Lipids were determined by high-performance thin-layer chromatography and gas chromatography. Membrane anisotropy was measured by fluorescence polarization. The ratio between PC and phosphatidylserine (PS) plus phosphatidyl ethanolamine (PE) plus sphingomyelin (SM) was significantly higher in spermatozoa from the cauda compared to those from the caput and corpus. This was due to an increase of PC and a decrease of the concentration of PS plus PE plus SM. With regard to fatty acids, those with saturated chains predominated in caput spermatozoa while the highest concentration of unsaturated long-chain fatty acids was in cauda spermatozoa. A lower membrane anisotropy of cauda spermatozoa compared with caput or corpus spermatozoa was found. In conclusion, during epididymal maturation human spermatozoa integrate lipids, particularly PC, which is strongly associated with the induction of progressive motility. A change in the pattern of fatty acids and a decrease in the cholesterol/phospholipid molar ratio cause a decrease in membrane anisotropy in cauda spermatozoa.

Involvement of guanylate cyclase and phosphodiesterases in the functional heterogeneity of human blood platelet subpopulations.

Cyclic nucleotides are involved in the regulation of platelet activation, shape change, and aggregation. In this study we have investigated the role of guanylate cyclase and phosphodiesterase in three functional heterogeneous human blood platelet subpopulations separated according to density. In low-density platelets aggregation was enhanced and inhibited less when cyclic GMP was increased by sodium nitroprusside, compared to high-density platelets. Low-density platelets possessed a lower basal level of cyclic GMP and exhibited a small increase in cyclic GMP after stimulation with sodium nitroprusside. Cyclic GMP-dependent phosphodiesterase activity was similar in high, low, and intermediate-density platelets. In contrast, the activity of the cyclic AMP-dependent phosphodiesterase was higher in low-density compared to high and intermediate-density platelets. These results suggest that regulation of cyclic GMP and cyclic AMP levels plays an important role in the functional heterogeneity of human blood platelets.

Lowering of body temperature affects human platelet functions and norepinephrine release.

The effect of lowering body temperature on plasma epinephrine, norepinephrine, and platelet density distribution and volume was studied in a placebo-controlled double-blind study. Lowering of body core temperature was induced by either exposure to a cold environment at a temperature of 5 degrees C (CT) or by a single dose of the 5-HT1A agonist ipsapirone (IPS). A third group exposed to an ambient temperature of 28 degrees C was given placebo (PLAC). All of the three groups were investigated in a climate chamber. In the CT group the density distribution of blood platelet subpopulations was shifted to an increase in less dense platelets that were more sensitive towards aggregation-inducing agents. The mean platelet volume in this subpopulation was decreased. Epinephrine was not affected, whereas the increase of norepinephrine was correlated with an increase of platelets that were more sensitive to aggregation-inducing agents in the CT group but not in the PLAC and IPS groups.

Increased number of high sensitive platelets in hypercholesterolemia, cardiovascular diseases, and after incubation with cholesterol.

The number of low density platelets was found to be increased in patients with hypercholesterolemia, as compared with the number in controls. The percentage increase of the low density platelet subpopulation was even more pronounced in patients with hypercholesterolemia when compared with that in patients suffering from myocardial infarction or angina. In vitro studies with control platelets incubated with cholesterol rich liposomes showed also an increase in the subpopulation of low density platelets. After incubation of control platelets with cholesterol rich liposomes, a higher membrane anisotropy and a higher cholesterol to phospholipid (C/P) molar ratio of the plasma membrane were found. Furthermore, cholesterol-enriched platelets were more sensitive upon thrombin stimulation. The results suggest that a shift of platelet subpopulations to a higher number of low density platelets could be caused by either the level of plasma cholesterol or an in-vitro incubation with cholesterol rich liposomes.