Clinical research and drug development in Latin America: weighing the pros and cons, talking about the future.

Two decades ago, clinical trials were carried out only in developed countries. Drug development and the need to speed up clinical trials lead the conduction of clinical trials to other countries. Among the regions of interest, Latin America (LA) has played its role successfully. LA has a large number of naive patients, qualified investigators, established regulatory systems and reasonable costs. Furthermore, LA might be also considered as a new option for any company looking for international patterns on drug research and development. The region has good professionals with scientific qualifications, well-established multinational pharmaceutical bases and an expansive pharmaceutical regional market. This work summarizes the recent advances that have occurred in drug research and development in the region and the expansion of the clinical trial market in the last couple of years.     

Right internal thoracic artery through the transverse sinus in myocardial revascularization

Background. A major concern in evaluating dynamic cardiomyoplasty has been whether the synchronous stimulation of latissimus dorsi muscle is essential for benefit or not. We studied 10 patients to determine the efficacy of the systolic augmentation generated by the synchronous electrical stimulation of the latissimus dorsi muscle.

Methods. Left ventricular ejection fraction, end-systolic and end-diastolic volume indexes, and stroke volume index obtained during resting, peak exercise, and recovery periods (“on” values) were compared with those obtained 1 week after cessation of electrical stimulus (“off” values). Double product and estimated total body oxygen consumption at peak exercise were also calculated and compared.

Results. Higher ejection fractions (0.36 ± 0.07 versus 0.33 ± 0.06 at rest, 0.40 ± 0.07 versus 0.33 ± 0.07 peak exercise, and 0.37 ± 0.06 versus 0.31 ± 0.06 at recovery) and lower end-systolic volume indexes with relatively constant end-diastolic volume indexes were observed with the cardiomyostimulator on. Further, exercise response was better with the cardiomyostimulator on. Double product indirectly reflected better myocardial oxygen supply/demand ratio when on at peak exercise (17 ± 2.2 mm Hg × beats/min × 10⁻³ for on versus 19 ± 2.6 mm Hg × beats/min × 10⁻³ for off). Estimated total body oxygen consumption was improved at peak exercise when the cardiomyostimulator was functional (12 ± 2.7 mL · kg⁻¹ · min⁻¹ versus 11 ± 2.6 mL · kg⁻¹ · min⁻¹).

Conclusions. Current data suggest a true systolic assist during synchronous contractions of the latissimus dorsi muscle. It is thought, therefore, that synchronous electrical stimulation is essential for maximum benefit and all the beneficial effect of cardiomyoplasty certainly cannot be attributed to simple wrapping itself.     

Adenosine administration produces an antidepressant-like effect in mice: evidence for the involvement of A1 and A2A receptors

This study investigated the effect of adenosine in the forced swimming test (FST) and the tail suspension test (TST) in mice, and the contribution of adenosine A1 and A2A receptors to adenosine's antidepressant-like effect. The immobility time in the FST was reduced by adenosine given either by i.p. (5-10 mg/kg) or i.c.v. (0.01-10 microg/site) route. Adenosine (1-10 mg/kg, i.p.) also produced an antidepressant-like effect in the TST. No treatment affected locomotion in an open-field. The anti-immobility effect of adenosine (10 mg/kg, i.p.) in the FST was prevented by i.p. pretreatment of mice with caffeine (3 mg/kg), DPCPX (2 mg/kg) and ZM241385 (1 mg/kg). CHA (0.05 mg/kg, i.p.) and DPMA (1-5 mg/kg, i.p.) also produced an antidepressant-like effect in the FST. This is the first report of an antidepressant-like effect of adenosine in mice, apparently mediated through an interaction with A1 and A2A receptors.     

Ontogenetic profile of glutamate uptake in brain structures slices from rats: sensitivity to guanosine

The excitotoxicity of the neurotransmitter glutamate has been shown to be connected with many acute and chronic diseases of the CNS. High affinity sodium-dependent glutamate transporters play a key role in maintaining adequate levels of extracellular glutamate. In the present study, we used slices of striatum, hippocampus and cortex from rat brain to describe the in vitro profile of glutamate uptake during development and ageing, and its sensitivity to guanosine. In all structures, glutamate uptake was higher in immature animals. There was a maximum decrease in glutamate uptake in striatum and hippocampus in 15-month-old rats, which later increased, while in cortex there was a significant decrease in rats aged 60 days old. The effect of guanosine seems to be age and structure dependent since the increase in basal glutamate uptake was only seen in slices of cortex from 10-day-old animals.     

Effect of losartan on sodium appetite of hypothyroid rats subjected to water and sodium depletion and water, sodium and food deprivation

The involvement of angiotensin AT1 receptors in sodium appetite was studied in hypothyroid rats treated with the angiotensin II antagonist losartan. Losartan was administered chronically by the oral route or acutely by the subcutaneous route after water and sodium depletion or water, sodium and food deprivation. Three days after addition of losartan to the food at the dose of 1.0 mg x g(-1), the rats significantly reduced (P < 0.02) their spontaneous intake of 1.8% NaCl. Increasing the dose of losartan to 2.0 and 4.0 mg x g(-1) did not reduce NaCl intake; in contrast, the intensity of the sodium appetite gradually returned to previous levels. The simultaneous administration of captopril, an angiotensin converting enzyme inhibitor, and losartan significantly increased (P < 0.05) NaCl intake and after captopril removal NaCl intake returned to the levels observed with losartan treatment alone. The administration of losartan 4 days after the beginning of captopril treatment significantly reduced (P < 0.0001) NaCl intake. Following acute administration of losartan, water- and sodium-depleted rats significantly reduced their NaCl and water intake (P < 0.001). The administration of losartan also induced a significant reduction in NaCl and water intake in water, NaCl and food-deprived rats (P < 0.0001 and P < 0.001, respectively). The present results show that chronic treatment with oral losartan inhibited spontaneous sodium appetite in hypothyroid rats. Continuation of treatment rendered rats resistant to the blockade of AT1 receptors. Water and sodium depletion and water, NaCl and food deprivation induced sodium appetite, which in the short term depends on cerebral angiotensinergic activity mediated by the activation of AT1 receptors.     

Synaptonemal complex analysis in spermatocytes and oocytes of rainbow trout,Oncorhynchus mykiss (Pisces,Salmonidae): the process of autosome and sex chromosome synapsis

The surface-spreading synaptonemal complex (SC) technique was employed to analyze spermatocytes and oocytes of rainbow trout in order to visualize the process of autosome and sex chromosome synapsis in this species. The structure of lateral elements (LEs) of the SC and the chromosome synapsis process at the stages of leptotene, zygotene and pachytene are described. Comparative analysis of SCs of spermatocytes and oocytes showed a difference in the synaptic process, i.e. in spermatocytes all LEs were synapsed before the appearance of centromeric regions in the biarmed elements, while in the oocytes some fully synapsed LEs, including the centromeric region of the biarmed elements, were found together with fully or partially unsynapsed LEs. In males the sex chromosome synapsis starts only after all autosomes have synapsed. Irregular synapses involving three or four LEs were found in 3.4% of the cells analyzed in mid or late zygotene. Multivalents were found in males and females. Some aspects of initial meiotic development and their implications in rainbow trout cytogenetics, genetics and evolution are discussed.