Cadralazine and chlorthalidone as a second-step drug with atenolol in hypertensive patients: Differences in blood pressure control during exercise

Summary The long-term efficacy of a new vasodilator, cadralazine (ISF 2469), and chlorthalidone have been compared in 20 hypertensive patients not adequately controlled by atenolol. After 4 weeks of treatment with atenolol 100 mg once daily, patients whose diastolic blood pressure was >95 mmHg were randomly divided into two groups to receive in addition to atenolol, either cadralazine 15 mg once daily or chlorthalidone 25 mg once daily. Both treatments were administered for 6 months. At the end of treatment with atenolol and after 3 and 6 months of combination therapy, blood pressure and heart rate were measured at rest and during bicycle exercise 24 h after the last dose. Compared to atenolol alone, both cadralazine and chlorthalidone caused a significant and similar reduction in resting blood pressure. Both groups showed an increase in diastolic blood pressure during exercise while receiving atenolol alone. The addition of chlorthalidone did not modify the pressor response to exercise, whereas patients taking cadralazine had a decrease in exercise diastolic blood pressure, which was fully evident after 6 months of therapy. The reduction in exercise diastolic blood pressure induced by cadralazine was proportional to the increase in exercise heart rate, suggesting a fall in peripheral vascular resistance. Chlorthalidone caused a significant increase in serum glucose and uric acid and a decrease in K⁺, whereas no change was observed during cadralazine It is concluded that cadralazine given once a day with atenolol has the same efficacy in controlling blood pressure at rest as the combination of atenolol and chlorthalidone, and in addition it improves the pressor response to dynamic exercise and does not cause unwanted metabolic effects.     

Hepatotoxicity in HIV-infected children and adolescents on antiretroviral therapy.

CONTEXT AND OBJECTIVE: Adverse drug reactions are a significant problem in patients on antiretroviral therapy (ART). We determined liver enzyme elevation frequencies in HIV-infected children and adolescents receiving ART, and their association with risk factors. DESIGN AND SETTING: Cross-sectional study, at the Pediatrics Immunodeficiency Division, University Hospital, Universidade Estadual de Campinas. METHODS: Medical records of 152 children and adolescents (54.6% male; median age 7.48 years) were analyzed, with a mean of 2.6 liver enzyme determinations per patient. Clinically, patients were classified in categories N (6), A (29), B (78) and C (39). Serum levels of aspartate aminotransferase and alanine aminotransferase were evaluated. Hepatotoxicity was scored as grade 1 (1.1-4.9 times upper limit of normality, ULN), grade 2 (5.0-9.9 times ULN), grade 3 (10.0-15.0 times ULN) and grade 4 (> 15.0 times ULN). To assess hepatotoxicity risk factors, odds ratios (OR) and adjusted odds ratios (aOR) for age, gender, TCD4+ cell count, viral load and medication usage were calculated. RESULTS: We observed grade 1 hepatotoxicity in 19.7 % (30/152) patients. No cases of grade 2, 3 or 4 were detected. There was a significant association between hepatotoxicity and use of sulfonamides (OR, 3.61; 95% confidence interval (CI), 1.50-8.70; aOR, 3.58; 95% CI, 1.44-8.85) and antituberculous agents (OR, 9.23; 95% CI, 1.60-53.08; aOR, 9.05; 95% CI, 1.48-55.25). No toxicity was associated with ART. CONCLUSIONS: One fifth of patients experienced mild hepatotoxicity, attributed to antituberculous agents and sulfonamides. Our results suggest that ART was well tolerated.     

Method of measuring deposition of unlabeled monodisperse microspheres in rat lungs

A system to simultaneously measure the total deposition of four different sizes of monodisperse microspheres in normal and damaged lungs of rats was developed and tested. The system reproducibly measured the deposition of microspheres in control rats, and the procedure was shown to be sufficiently sensitive to measure ozone-induced changes in deposition rates. Rats exposed to 1.2 ppm ozone 6 h/d for 2 consecutive days showed greater deposition of the 1.09-micron-, 2.02-micron-, and 2.99-micron- but not of the 0.48-micron-diameter microspheres when compared to controls. After 8 consecutive days of exposure to the same concentration of ozone, there were no differences in deposition rates between control and ozone-exposed rats. Respiratory physiology and lung histopathology data provided evidence that subtle changes in the airway architecture and/or aerodynamics were likely to be responsible for the differential deposition rates as a function of the duration of ozone exposure.     

Age, personality, and the Holtzman Inkblot Technique

Recent longitudinal studies using personality questionnaires and ratings have shown remarkable stability across the adult years. In an investigation of age changes and differences in personality as measured by the Holtzman Inkblot Technique (HIT), ninety-three men and women aged twenty-five to ninety were administered Form A of the HIT; forty-four of these were retested one to three years later. Stability coefficients ranged from .07 for Form Appropriateness to .73 for Form Definiteness, with most variables showing significant but moderate stability. Repeated measures analyses of variance showed increases in six variables and decreases in two others, but only one of these changes was paralleled by cross-sectional age differences. Correlations with self-report measures of the broad personality domains of neuroticism, extraversion, and openness to experience failed to show hypothesized relations, and the associations seen were attributable to chance. It was concluded that the HIT measures perceptual-cognitive variables that are moderately stable in adulthood.     

Evidence that peroxynitrite affects human osteoblast proliferation and differentiation.

Peroxynitrite (PN), a nitric oxide (NO*)-derived anion, has been associated with NO* damage in various cell types. We examined the effects of adding PN to cultured human osteoblast-like (hOB) cells obtained after hip arthroplasty. Exposure to PN (0.1-0.4 mM) decreased both hOB proliferation and differentiation, measured by [3H]thymidine uptake and alkaline phosphatase production, respectively. Incubation with 3-morpholinosydnonimine (SIN-1; 0.25-1 mM), an NO* and O2- donor that leads to PN release, also reduced both hOB proliferation and differentiation. Coincubation with both superoxide dismutase (SOD; 100 U/ml) and catalase (CAT; 50 U/ml), rendering SIN-1 a pure NO* donor, reversed its effects on hOB proliferation and differentiation. However, SIN-1-induced NO* production, measured by nitrite release to the hOB medium, was not altered by cotreatment with SOD and CAT. Expression of nitrotyrosine by hOB, a marker of PN action, was significantly increased after SIN-1 addition, as compared with untreated cells, as revealed by Western blot analysis. Interleukin-1alpha (IL-1alpha) and interferon gamma (IFN-gamma) but not tumor necrosis factor alpha (TNF-alpha) also significantly increased nitrotyrosine expression in these cells. These data show that PN is at least partially responsible for osteoblast derangement by NO* and that cytokines released during inflammatory arthropathies can induce PN production in hOB cells.     

Interaction of short chain aliphatic alcohols with muscarinic receptor-stimulated phosphoinositide metabolism in cerebral cortex from neonatal and adult rats.

Muscarinic receptor-stimulated phosphoinositide metabolism has been recently suggested as a possible target for the neurotoxic effects of ethanol during brain development. Since two other alcohols, tertiary butanol and n-propanol, have been shown to cause microencephaly in the rat when administered during the brain growth spurt, in the present study we investigated the in vitro effects of five short chain aliphatic alcohols on muscarinic receptor-stimulated phosphoinositide metabolism in cerebral cortical slices from 7 day-old rats. In neonatal animals all alcohols tested inhibited carbachol (1 mM)-stimulated [3H]inositol phosphates accumulation in a dose- and time-dependent manner. The order of potency was t-butanol greater than n-propanol greater than or equal to iso-propanol greater than ethanol greater than methanol. After 90 min of incubation, ethanol, n-propanol and t-butanol caused a significant inhibition of muscarinic receptor-stimulated inositol metabolism at doses as low as 15 - 50 mM, comparable to the blood concentrations reached after in vivo administration of doses able to induce developmental neurotoxicity. The inhibitory effect of ethanol was additive to that of iso-propanol or t-butanol. Differently from these effects in 7 day-old rats, in cortical slices from adult animals methanol and ethanol had no effect on carbachol-stimulated phosphoinositide metabolism, while the two propanol isomers and t-butanol were less effective than in neonatal animals. These results suggest that muscarinic receptor-coupled phosphoinositide metabolism might be a common neurochemical target for the developmental neurotoxicity of short chain aliphatic alcohols.     

Delayed increase of Ca2+ influx elicited by glutamate: role in neuronal death

The mechanism of delayed neurotoxicity, triggered by glutamate, was studied in 7-8-day-old primary cultures of rat cerebellar granule cells. Treatment of cultures for 15 min with 50 microM glutamate in Mg2+ -free medium, followed by removal of the excitoxin, resulted in neuronal death, which started to appear 2-3 hr after the termination of glutamate treatment. The number of dead neurons increased gradually in the next few hours and 80-85% of neurons were found dead 24 hr later. Antagonists of N-methyl-D-aspartate-sensitive glutamate receptors (phencyclidine) or 1.2 mM MgCl2, but not the antagonist of N-methyl-D-asparatate-insensitive glutamate receptors (6-cyano-7-nitroquinoxaline-2,3-dione), abolished the neurotoxic effect of kainate. Development of glutamate-induced neuronal death depends strongly on Ca2+. Removal of extracellular Ca2+ (with 1mM ethyleneglycol-bis-(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid) immediately after the termination of glutamate exposure and before the appearance of the early signs of neuronal death (post-glutamate period) dramatically reduced neuronal degeneration. Neurotoxic concentrations of glutamate induced sustained increase of 45Ca2+ uptake in the post-glutamate period. The delayed increase of 45Ca2+ uptake, as well as the delayed neurotoxicity, were not affected by post-glutamate treatment with phencyclidine, dibenzocyclohepteneimine; DL-2-amino-5-phosphonovalerate, or MgCl2 or with voltage-dependent Ca2+ channel blockers (nitrendipine, verapamil, diltiazem). Neurotoxic concentrations of glutamate also induced a delayed sustained increase of [3H]phorbol-12,13-dibutyrate binding, reflecting an increased translocation of protein kinase C (PKC) from cytosol to the cell membrane during the post-glutamate period. Pretreatment of neurons with the ganglioside GT1b (trisialosylgangliotetraglycosylceramide), followed by removal of free GT1b from the incubation medium, prevented PKC translocation, the sustained increase of 45Ca2+ uptake in the post-glutamate period, and the delayed neuronal death. We suggest that the sustained activation and translocation of PKC primed by glutamate receptor stimulation may be the triggering event causing the protracted increase of neuronal Ca2+ influx. This influx is insensitive to voltage-dependent Ca2+ channel blockers and glutamate receptor antagonists. It appears that this delayed increase of Ca2+ influx may be important in causing neuronal death.