Synthesis, structure-activity relationship and trypanocidal activity of pyrazole-imidazoline and new pyrazole-tetrahydropyrimidine hybrids as promising chemotherapeutic agents for Chagas disease.

Drug therapy for Chagas disease remains a major challenge as potential candidate drugs have failed clinical trials. Currently available drugs have limited efficacy and induce serious side effects. Thus, the discovery of new drugs is urgently needed in the fight against Chagas' disease. Here, we synthesized and evaluated the biological effect of pyrazole-imidazoline (1a-i) and pyrazole-tetrahydropyrimidine (2a-i) derivatives against relevant clinical forms of Trypanosoma cruzi. The structure-activity relationship (SAR), drug-target search, physicochemical and ADMET properties of the major active compounds in vitro were also assessed in silico. Pyrazole derivatives showed no toxicity in Vero cells and also no cardiotoxicity. Phenotypic screening revealed two dichlorinated pyrazole-imidazoline derivatives (1c and 1d) with trypanocidal activity higher than that of benznidazole (Bz) against trypomastigotes; these were also the most potent compounds against intracellular amastigotes. Replacement of imidazoline with tetrahydropyrimidine in the pyrazole compounds completely abolished the trypanocidal activity of series 2(a-i) derivatives. The physicochemical and ADMET properties of the compounds predicted good permeability, good oral bioavailability, no toxicity and mutagenicity of 1c and 1d. Pyrazole nucleus had high frequency hits for cruzipain in drug-target search and structure activity relationship (SAR) analysis of pyrazole-imidazoline derivatives revealed enhanced activity when chlorine atom was inserted in meta-positions of the benzene ring. Additionally, we found evidence that both compounds (1c and 1d) have the potential to interact non-covalently with the active site of cruzipain and also inhibit the cysteine proteinase activity of T. cruzi. Collectively, the data presented here reveal pyrazole derivatives with promise for further optimization in the therapy of Chagas disease.

[Survival of AIDS patients in a city in southeastern Brazil]. / Sobrevivência de pacientes com AIDS em uma cidade do sudeste brasileiro.

OBJECTIVE: To assess survival in patients diagnosed with AIDS in the city of Ribeirão Preto, Brazil, between 1986 and 1997. METHODS: The epidemiological records of 2,214 patients diagnosed during the study period were retrospectively reviewed. From those, 1,231 patients with at least 30 days of follow-up after the date of diagnosis were included in the study. Information concerning deaths was obtained from hospitals and vital-records offices. RESULTS: Survival for the group as a whole was 310 days (10.3 months) over the period of 1986 through 1997. Median survival was 362 days for 1986 to 1990, 260 days for 1991 to 1995, and 864 days for 1996 and 1997. The Kaplan-Meier survival curves and the log-rank test showed significant differences for the following variables: sex, age, period when diagnosis was made, and presence of candidiasis and of cerebral toxoplasmosis. Cox's regression showed an association between reduction of survival and the following variables: age (in comparison to individuals younger than 15 years, hazard ratio = 1.435 for age between 15 and 34 years, and 1.681 for age above 35 years); period of diagnosis (in comparison to the period of 1996 and 1997, hazard ratio = 1.682 for the period from 1986 to 1990, and 2.324 for the period from 1991 to 1995); and presence of candidiasis (hazard ratio = 1.391). The hazard ratio for the presence of cerebral toxoplasmosis was 1.063, with a probability value close to the limit of significance. CONCLUSIONS: Our results show a striking increase in survival in 1996 and 1997, coinciding with the availability and utilization of highly active antiretroviral drugs.

[Rabies epizootic in the urban area of Ribeirão Preto, São Paulo, Brazil]. / Epizootia de raiva na área urbana de Ribeirão Preto, SP, Brasil.

This report describes some epidemiological aspects of a rabies epizootic that started in 1995 in the urban area of Ribeirão Preto, SP, Brazil, and discusses its main causes. All laboratory confirmed cases were described according to a set of epidemiological variables. Simultaneously, information was raised concerning rabies vaccine coverage and epidemiological surveillance activities. In addition to one human case, 58 rabid animals were confirmed in 1995 (54 dogs, 3 cats. and 1 bat). There were 20 cases in 1996 (18 dogs and 2 cats). Geographical distribution was uneven in the city, with higher concentrations observed in the Western, Northern, and Southwestern sections, corresponding to the poorest areas. No seasonal variation was observed. The main reasons for the epizootic were low rabies vaccine coverage in animals and severe failures in epidemiological surveillance activities in the years immediately prior to 1995. This epizootic illustrates the risk of neglecting such activities, even in a city with a reasonably good health system, located in one of the most economically developed areas of the country. Vigorous preventive measures markedly reduced the number of cases.

A case of human rabies in the urban area of Ribeirã Preto, SP, Brazil.

A 39-year old male patient was admitted to the University Hospital of the Faculty of Medicine of Ribeirão, Preto with signs and symptoms of sudden dyspnea, generalized myalgia and behavioral disorders. The initial suspicion was alcohol abstinence syndrome and the patient was referred for psychiatric and neurologic care. The evolution of the patient with a worsening of signs and symptoms, presence of crises of tachypnea, agitation, difficulty to swallow, irritability and hydrophobia, and his report of having been bitten by a suspected dog raised the hypothesis of rabies. The diagnosis was confirmed by examination of a corneal impression, biological tests in the cerebrospinal fluid (CSF) and saliva and visualization of Negri bodies in nervous tissue (direct immunofluorescence). The patient evolved with agitation, aggressiveness, and worsening tachypnea intercalating with apnea, and died on the 4th day after admission.

Effects of synthetic salmon calcitonin therapy in children with osteogenesis imperfecta.

A total of four children with osteogenesis imperfecta, three with type I and one with type III forms of the disease, were treated with synthetic salmon calcitonin for 18-24 months. The annual fracture rate was decreased during calcitonin therapy compared with the period preceding it. No patient presented a marked inflexion in linear growth and a transient improvement was even noticed in two cases.

[Endogenous opioids in respiratory inhibition by laryngeal stimulation]. / Opioides endógenos en la inhibición respiratoria por estimulación laríngea.

The reflex effect elicited by mechanical stimulation of the glottis has been studied in dogs. The three components of the response--sudden apnea, constriction of the glottis and bradycardia--were modified by naloxone, although not in the same degree. These results suggest the existence of opioid interneurons between laryngeal afferent fibers and central inspiratory neurons.

[Respiratory effects of naloxone]. / Efectos respiratorios de la naloxona.

The respiratory effects of naloxone (200 micrograms X kg-1) on dogs, was studied measuring the parameters breath rate, inspiratory volume, breath minute volume, inspiratory time, total time of cycle, inspiratory volume/inspiratory time ratio, and inspiratory time/total time of cycle ratio. The statistical study was made by using the analysis of variance. Naloxone increases all the parameters studied as well as the response to CO2 while it decreases inspiratory time. The results suggest that there are opioid neurons in the respiratory centre. The blockade of the opioid receptors by naloxone almost explains the respiratory effects observed.

[Effect of naloxone on coughing]. / Efecto de la naloxona en la tos.

Naloxone at doses of 200 micrograms X kg-1 increases cough, in experiments carried out on dogs. With stimuli of the same intensity, after naloxone, a significant increase in the number of coughs in each fit, is observed. Changes in the first cough burst, compared with spontaneous respiration at rest, are statistically significant and they contribute to define the characteristics of the cough burst. The increase of cough by naloxone blockade of endorphinic neurons of the respiratory center shows that usually the activity of these inhibitory neurons, tonically depresses the tussive response. The antitussive opiates would seem to operate by activating these inhibitory synapses.