Clinical trial of two antivenoms for the treatment of Bothrops and Lachesis bites in the north eastern Amazon region of Brazil

The efficacies of specific Bothrops atrox-Lachesis and standard Bothrops-Lachesis antivenoms were compared in the north eastern Amazon region of Brazil. The main aim was to investigate whether a specific antivenom raised against the venom of B. atrox, the most important Amazon snake species from a medical point of view, was necessary for the treatment of patients in this region. Seventy-four patients with local and systemic effects of envenoming by Bothrops or Lachesis snakes were randomly allocated to receive either specific (n = 38) or standard (n = 36) antivenoms. In 46 cases (24 in the standard antivenom group, 22 in the other) the snake was identified either by enzyme immunoassay or by examination of the dead snake, as B. atrox in 45, L. muta in one. Patients were similar in all clinical and epidemiological respects before treatment. Results indicated that both antivenoms were equally effective in reversing all signs of envenoming detected both clinically and in the laboratory. Venom-induced haemostatic abnormalities were resolved within 24 h after the start of antivenom therapy in most patients. The extent of local complications, such as local skin necrosis and secondary infection, was similar in both groups. There were no deaths. The incidence of early anaphylactic reactions was 18% and 19%, respectively for specific and standard antivenoms; none was life-threatening. Measurement of serum venom concentrations by enzyme immunoassay (EIA) confirmed that both antivenoms cleared venom antigenaemia effectively. EIA also revealed that one patient had been bitten by Lachesis muta, although the clinical features in this case were not distinctive.     

Effect of the antidepressant nefazodone on the density of cells expressing mu-opioid receptors in discrete brain areas processing sensory and affective dimensions of pain

Rationale The principal use of antidepressants is in the treatment of depression and affective disorders. Antidepressants have also been used as an adjuvant to analgesics in pain treatment. However, in chronic treatment, their antinociceptive and antidepressive effects coexist simultaneously. Antidepressants can interact with the opioid system, which is also involved in regulating nociceptive processing and affective state. Chronic antidepressants could act by increasing mu-opioid receptor expression in many brain areas involved in the regulation of nociception and affective state.Objectives The aim of this study was to evaluate the antinociceptive and antidepressant-like effects and the possible variations in mu-opioid receptor expression induced by a chronic nefazodone treatment in brain areas related to pain and affective state.Methods Wistar rats were chronically treated with nefazodone (10 and 25 mg/kg IP, twice a day, for 14 days). Twelve hours after the last day 14 dose of nefazodone, a tail-flick test was performed. After the administration of a daily dose of nefazodone, Porsolts test was carried out 12 h after last dose. Two hours after completion of 14 days treatment, other animals were processed for mu-opioid receptor immunocytochemistry using polyclonal antisera raised in rabbits. Several brain regions were analyzed: the frontal and cingulate cortex, the dorsal raphe nucleus and the periaqueductal gray.Results Chronic nefazodone treatment induced a significant increase in tail-flick latency and a significant decrease in immobility time at total doses of 20 and 50 mg/kg per day (P<0.05). In treated animals, the density of neural cells immunostained for mu-opioid receptor in the frontal and cingulate cortices, dorsal raphe nucleus and periaqueductal gray had increased after chronic nefazodone compared to controls.Conclusion Therefore, chronic nefazodone induces antinociceptive and antidepressant-like effects in rats and increases mu-opioid receptor expression in brain areas related to pain and affective state. These results suggest that antidepressants could be effective on somatic and affective dimensions of pain and this action could be related to its influence on the opioid system.     

Striatal dopamine D2 receptor density in neuroleptic-naive and in neuroleptic-free schizophrenic patients: an 123I-IBZM-SPECT study

Most post-mortem autoradiographic studies have described striatal dopamine D₂ receptor up-regulation due to chronic neuroleptic exposure. The aim of our study was to compare in-vivo striatal D₂ receptor density in neuroleptic-naive and neuroleptic-free schizophrenic patients. We included 28 young (mean age: 28±8 years) acute psychotic patients meeting DSM-IV criteria for schizophrenia or schizophreniform disorder. Enrolled patients were either first-episode neuroleptic-naive (n=12) or neuroleptic-free (n=16) after a minimum washout period of 7 days. All neuroleptic-free subjects had previously received neuroleptic treatment for a median period of 3.5 years. Both groups were evaluated using standard clinical scales. In-vivo striatal D₂ receptor binding was assessed by basal ganglia/frontal cortex ratios using ¹²³I-IBZM SPECT. No statistically significant differences were found in age or clinical assessment between neuroleptic-naive and neuroleptic-free schizophrenic patients. No differences were found in the basal ganglia/frontal cortex ratios of neuroleptic-naive (1.78±0.11) and neuroleptic-free (1.81±0.15) patients. No striatal uptake laterality was observed in either group. No correlation was demonstrated between BG/FC ratios and duration of illness, period of neuroleptic exposure or time of drug washout. We conclude that our neuroleptic-naive and neuroleptic-free schizophrenic patients did not show differences in striatal D₂ receptor binding, suggesting that IBZM-SPECT fails to detect D₂ receptor up-regulation induced by chronic exposure to neuroleptic drugs.     

Role of the sympathetic and renin angiotensin systems in the glucose-induced increase of blood pressure in rats

The pressor effect induced by acute hyperglycemia is not well understood, therefore, it was of interest to study the effect of intravenous glucose infusion on the mean arterial pressure of anesthetized Wistar rats. Animals received glucose (100 mg/kg/min, i.v.), mannitol or saline during 30 min, but only glucose increased the mean arterial pressure (about 40 mm Hg), plasma glucose, insulin and nitric oxide (NO). Pretreatment with reserpine or indorenate (a central antihypertensive) inhibited completely the pressor effect of glucose. Reserpine also decreased the plasma NO levels. Pretreatment with ramipril or with streptozotocin decreased the late phase of the glucose-induced pressor response and the NO levels, the latter treatment also abolishes insulin plasma concentrations. The present results suggest that the pressor effect induced by glucose has an early phase due to an increase of efferent sympathetic discharges and a delayed phase produced by the activation of the renin angiotensin system.     

Entry into a new class of potent proteasome inhibitors having high antiproliferative activity by structure-based design

Proteasome inhibition is a therapeutic concept of current interest in anticancer research. We report here the design, synthesis, and biological characterization of prototypes of a new class of noncovalent proteasome inhibitors showing high activity in biochemical and cellular assays.     

Development of GABAB subunits and functional GABAB receptors in rat cultured hippocampal neurons

Metabotropic gamma-aminobutyric acid receptors (GABA(B)Rs) play a critical role in inhibitory synaptic transmission in the hippocampus but the ontogeny of their subunit synthesis and synaptic localisation has not been determined. Here we report the distributions and developmental profiles of GABA(B1) and GABA(B2) subunits in cultured rat embryonic hippocampal neurons. Limited levels of GABA(B1) and GABA(B2) immunoreactivity were present at 3 days in vitro (DIV). At 7 DIV, when baclofen-evoked inwardly rectifying K(+) channel-mediated responses first appear in the cells, there was a more widespread expression within the soma and proximal dendrites. Levels of the K(+) channel GIRK 1 were relatively constant at all time points suggesting channel availability does not limit the appearance of functional GABA(B)Rs. At 14 DIV the staining displayed a punctate dendritic distribution and near maximal GABA(B)R-mediated electrophysiological responses were obtained. About half of the puncta for each GABA(B)R subunit in dendrites co-localised with the synaptic marker SV2a suggesting that these subunits are at or very near to synapses. Interestingly, at all ages strong GABA(B)R immunoreactivity was also present in the nuclei of neurons. These results provide an important developmental baseline for future studies aimed at investigating, for example, the trafficking and functional regulation of these receptors.     

Stability and ocular tolerance of cyclophosphamide-loaded nanospheres

The physical and chemical stabilities of several formulations of cyclophosphamide-loaded polybutylcyanoacrylate (PBCA) nanospheres developed for an ophthalmic application as an immunosuppressive agent were studied over 6 months of storage at 4, 25 and 40 degrees C in different experimental conditions. The physical stability of nanospheres was followed by the study of morphological (visual appearance) and morphometrical properties (mean particle size and polydispersity). The pH and tonicity of the suspensions and the association efficiency of the drug to polymeric system were also analysed to evaluate their chemical stability. The behaviour of colloidal suspensions with storage conditions was also followed by differential scanning calorimetry. The degradation of PBCA was affected by temperature and pH. The average particle size of all nanospheres remained practically unchanged throughout the study, with the polydispersity index being less than 0.1, corresponding to a monodisperse system. At 40 degrees C, a loss of 25.9% of the initial association efficiency, especially in non-buffered pH 7.2 medium, was observed. The type of polymer degradation (surface erosion) was also determined by photon correlation spectroscopy. The results obtained from in vivo study of ocular tolerance indicate a good ocular tolerance for drug loaded to nanospheres.     

Natural history of gastro-oesophageal reflux disease diagnosed in general practice

BACKGROUND: Cross-sectional studies indicate that gastro-oesophageal reflux disease symptoms have a prevalence of 10-20% in Western countries and are associated with obesity, smoking, oesophagitis, chest pain and respiratory disease. AIM: To determine the natural history of gastro-oesophageal reflux disease presenting in primary care in the UK. METHODS: Patients with a first diagnosis of gastro-oesophageal reflux disease during 1996 were identified in the UK General Practice Research Database and compared with age- and sex-matched controls. We investigated the incidence of gastro-oesophageal reflux disease, potential risk factors and comorbidities, and relative risk for subsequent oesophageal complications and mortality. RESULTS: The incidence of a gastro-oesophageal reflux disease diagnosis was 4.5 per 1000 person-years (95% confidence interval: 4.4-4.7). Prior use of non-steroidal anti-inflammatory drugs, smoking, excess body weight and gastrointestinal and cardiac conditions were associated with an increased risk of gastro-oesophageal reflux disease diagnosis. Subjects with gastro-oesophageal reflux disease had an increased risk of respiratory problems, chest pain and angina in the year after diagnosis, and had a relative risk of 11.5 (95% confidence interval: 5.9-22.3) of being diagnosed with an oesophageal complication. There was an increase in mortality in the gastro-oesophageal reflux disease cohort only in the year following the diagnosis. CONCLUSIONS: Gastro-oesophageal reflux disease is a disease associated with a range of potentially serious oesophageal complications and extra-oesophageal diseases.     

Chromosomal abnormalities are related to location and grade of osteoarthritis

OBJECTIVE: To investigate the frequency of numerical aberrations of chromosomes 7, X and Y in patients with osteoarthritis (OA) by performing fluorescent in situ hybridization (FISH) studies on articular cartilage, and to correlate the chromosomal changes with the degree and location of articular involvement. PATIENTS: Thirty-four women and 10 men with OA were included in the study. As a control group, 6 women and 5 men operated for orthopedic disorders other than OA were analyzed. METHODS: FISH studies were performed on hip or knee cartilage, using two-color centromere-specific probes for chromosomes 7 & X for women and 7 & Y for men. RESULTS: FISH analysis revealed that 46% of OA patients had numerical abnormalities of chromosomes 7, X or Y. An extra chromosome 7 (trisomy 7) was present in 35% of patients with chromosomal aberrations. All males with OA lost the Y chromosome while 15% of the women had loss of one chromosome X (monosomy X). Trisomy 7 was associated with hip OA (p=0.019) and advanced OA according to the Kellgren and Lawrence classification (p=0.05). None of the 11 controls showed abnormalities in the chromosomes analyzed. CONCLUSIONS: FISH analysis showed the presence of numerical chromosomal abnormalities in the articular cartilage of patients with OA.