Dissociation between peripheral and central heat loss mechanisms induced by neonatal capsaicin

Fifty-eight 4-day-old male rats were studied. Peripheral desensitization was induced in 36 rats by sc administration of capsaicin in increasing doses (350, 700, 1,400, 2,100, and 2,800 micrograms) on 5 consecutive days. When adult, 9 treated and 5 control rats were chronically implanted with a lateral intracerebroventricular (icv) guide cannula. This tube was used for icv capsaicin injection. Eleven treated rats and 6 controls were implanted with a hypothalamic thermode. Hypothalamic heating was activated with the aid of this water-perfused thermode. Twenty-eight rats, 12 control and 16 treated, were injected ip and sc with capsaicin. Results showed that in control rats, icv, ip, and sc capsaicin injections produced a fall in body (core) temperature and an increase in cutaneous temperature. These changes are attributed to cutaneous vasodilation. In capsaicin-treated rats, sc and ip injections had no effect on body temperature. However, neonatal treatment did not inhibit the effect of capsaicin on body temperature. Furthermore, in these rats thermoregulatory behavior for fresh air was identical to that of controls at all ambient temperatures before and during hypothalamic heating. These results suggest that the central heat receptors responsible for autonomic and behavioral thermoregulation in the treated rats function normally when icv capsaicin is injected or when the hypothalamus is heated. In contrast, neonatal injection of capsaicin produced an inhibition of the heat loss mechanisms induced by ip or sc capsaicin, i.e., by stimulation of the peripheral nervous system.     

Increased dopamine content in lymphocytes from high-dose L-Dopa-treated Parkinson's disease patients

OBJECTIVES: The intracellular (i.c.) content of dopamine and its metabolites was measured in the peripheral blood lymphocytes (PBLs) of Parkinson's disease (PD) patients and healthy controls. METHODS: Catecholamine levels of PBLs were measured using capillary electrophoresis in healthy controls and PD patients receiving different doses of L-dihydroxyphenylalanine (L-Dopa). RESULTS: Higher i.c. dopamine content was found in lymphocytes from PD patients receiving a high dose of L-Dopa (700 +/- 30 mg/day) as compared to lymphocytes from the healthy controls (p = 0.002) and from PD patients treated with a low dose of L-Dopa (400 +/- 30 mg/day) (p = 0.022). The dihydroxyphenylacetic acid to dopamine ratio was significantly lower in the high-dose L-Dopa-treated PD patients than in the controls (p = 0.013). CONCLUSIONS: These findings suggest that the dopamine content and metabolism in the peripheral lymphocytes of PD patients are influenced by L-Dopa administration. This is the first study in which a dose-related effect of L-Dopa treatment was found in lymphocytes from PD patients.     

Diffuse colonic ganglioneuromatous polyposis

Ganglioneuromatous polyposis is a very rare intestinal disease which differs from isolated polypoid ganglioneuroma and from diffuse ganglioneuromatosis. Its clinical, endoscopic, microscopic and evolutive features are poorly known. We report three cases of colonic ganglioneuromatous polyposis that illustrated an uncommon diffusion pattern in two men and one woman aged 63-72 who presented with chronic diarrhea. Endoscopic features suggesting the diagnosis were diffuse polyposis predominating in the cecum and right colon, with hyperhemic flat lesions enhanced after indigocarmin instillation. Histological study of the biopsies, and of colectomy specimens, showed a diffuse mucosal ganglioneuromatous proliferation with a few adenomatous polyps. Search for multiple endocrine neoplasia (MEN) type 2b was negative. In conclusion, this polypoid type of diffuse ganglioneuromatosis can be suspected in patients with chronic diarrhea by the special endoscopic aspect of the colonic polyposis. Pathologists should be aware of the distinctive features; diagnosis requires search for adenomas and/or neoplasia by total colopsy in addition to search for MEN 2b.     

Tolerance of riluzole in a phase IIIb clinical trial

Within the framework of an early drug access programme launched in 1995, a multicentre open study was initiated in France in order to assess, inter alia, the safety of riluzole (50 mg twice a day) in a total of 2069 patients from 28 centres. This programme, a phase IIIb study with direct individual benefit, had two main objectives: to enable patients to receive riluzole therapy pending regulatory approval and commercial availability and to provide further data on the safety of riluzole in a broader ALS population. The most frequent adverse events related to riluzole treatment were: asthenia, nausea and elevation of serum transaminase levels. These observations, similar to data derived from previous pivotal clinical trials, confirm that riluzole has a satisfactory tolerability profile.     

The relative pharmacokinetics of two oral formulations of chlormadinone acetate: Lutéran 5mg. and Lutéran tablet 10 mg

The bioavailability of a new formulation of chlormadinone acetate (one 10 mg Lutéran tablet) was compared with that of the reference formulation (two 5 mg Lutéran tablets) in a randomised crossover open trial after single oral administration of a 10 mg dose to 12 healthy female volunteers. Measurements of chlormadinone acetate plasma samples were performed by combined gas chromatography/mass spectrometry. Blood samples were collected before administration and up to 144 hours after administration. No significant difference was found between the two formulations in pharmacokinetic parameters. The bioavailability of the two formulations was equivalent in terms of time to maximum concentration (tmax [mean tmax about 2.5 h]) and area under the concentration-time curve (AUC0-infinity) [Weslake's symmetric confidence interval: 19.24%, Schuirmann two one-sided tests procedure: p < 0.05]. No difference was found between the two formulations with regard to clinical safety parameters.     

The effect of intestinal ischemia and reperfusion injury on ICAM-1 expression,endothelial barrier function,neutrophil tissue influx,and protease inhibitor levels in rats

Multiple organ dysfunction syndrome (MODS) is mediated by complex mechanisms in which interactions between activated leukocytes and endothelial cells play a central role. ICAM-1 (intercellular adhesion molecule-1) mediates firm adhesion and transendothelial migration of activated leukocytes from postcapillary venules into the tissue. The present study evaluated the ICAM-1 expression in various organs after 40 min of intestinal ischemia and 1, 3, 6, 12 h of reperfusion (I/R) in the rat, using a dual monoclonal antibody technique (n = 36). Endothelial barrier permeability, using the vascular leakage of radiolabeled human serum albumin was also assessed (n = 12). Neutrophil sequestration in the lungs was quantitated by myeloperoxidase activity and plasma protease inhibitor levels were measured with electroimmunoassay. Significant regional differences were found in ICAM-1 expression between organs, both constitutively and after I/R-injury. The highest constitutive levels were observed in the liver and lungs, followed by the kidneys. The constitutive ICAM-1 expression in the intestines and in the heart was about 1/20 compared with that found in the liver and lungs. The brain and muscle had levels of about 1/150 of that in the liver and lungs. After intestinal I/R, significant increases (17-45%) were found in the lungs, intestines, brain, heart, and muscle. Albumin leakage index (ALI) in all examined organs and myeloperoxidase activity in the lungs increased after I/R-injury. Serum levels of albumin and most protease inhibitors decreased significantly after I/R challenge. Intestinal I/R results in an increase of systemic ICAM-1 expression with marked organ variability. The upregulation of ICAM-1 could represent a crucial step in the adherence- and migration process of activated leukocytes and potentially in the development of tissue injury.     

Study of the microencapsulation of camu-camu (Myrciaria dubia) juice

The camu-camu, like many other Amazonian fruits, shows an excellent potential for use due to its high vitamin C content, and the use of these natural resources could result in greater development of the Amazonian region. Few studies have been conducted with this fruit, and such studies are necessary in order to develop the required technology to allow for its utilization, thus avoiding or at least decreasing wastage of such a rich raw material. The principle objective of this study was to develop a process for the microencapsulation of camu-camu juice, optimizing the operational conditions. The processing conditions consisted of blanching at a temperature of 95 +/- 2 degrees C for 2 min, followed by cooling in an ice bath and juice extraction using a brush type depulper. The juice was dried with gum arabic or malt dextrin in a mini-spray dryer using an air entry temperature of between 100-160 degrees C and wall material concentration varying between 5-35%, in accordance with a factorial experimental design. Both the air entry temperature and the amount of wall material, plus the interaction between the two, gave significant positive effects at the level of 5% probability on the yield of juice powder. The optimum conditions for juice yield and vitamin C retention were established as 15% wall material and an air entry temperature of 150 degrees C.     

Amyotrophic lateral sclerosis: progress and prospects for treatment

Fifteen years ago, a role for excitotoxic damage in the pathology of amyotrophic lateral sclerosis (ALS) was postulated. This stimulated the development of riluzole, the only available treatment for the disease. Since then, the identification of abnormal forms of superoxide dismutase as the genetic basis of certain familial forms of ALS has provided a huge impetus to the search for new effective treatments for this devastating disease. Transgenic mouse models have been developed expressing these aberrant mutants that develop a form of motor neurone disease the progress of which can be slowed by riluzole. Studies in these mice have provided evidence for a role for excitotoxic, apoptotic and oxidative processes in the development of pathology. The mice can be used for testing molecules targeting these processes as potential therapies, to allow the most promising to be evaluated in humans. Several such agents are currently in clinical trials. Many previous clinical trials in ALS were insufficiently powered to demonstrate any relevant effect on disease progression. This situation has been to some extent remedied in the more recent trials, which have recruited many hundreds of patients. However, with the exception of studies with riluzole, the results of these have been disappointing. In particular, a number of large trials with neurotrophic agents have revealed no evidence for efficacy. Nonetheless, the need for large multinational trials of long duration limits the number that can be carried out and makes important demands on investment. For this reason, surrogate markers that can be used for rapid screening in patients of potential treatments identified in the transgenic mice are urgently needed.     

High-dose intravenous immunoglobulin treatment in two patients with acquired factor V inhibitors

We report two patients who developed acquired factor V (FV) inhibitors not related to exposure to bovine thrombin. Associated conditions were found in one patient (surgery, antibiotic administration) but none in the other one. Bleeding complications occurred only in the patient with idiopathic FV inhibitor, leading to packed red cell infusion. Laboratory findings showed the presence of specific FV inhibitors with titers of 5.5 and 5 Bethesda units, respectively. These two patients received high-dose intravenous immunoglobulin and FV levels normalized within a few days with a concomitant disappearance of FV inhibitors.