Efficacy and tolerability of a ß-1 selective ß blocker, bisoprolol, as a first-line antihypertensive in Indian patients diagnosed with essential hypertension (BRIGHT): an open-label, multicentric observational study.

OBJECTIVES: This study was aimed to evaluate the efficacy and tolerability of bisoprolol, in Indian patients diagnosed with stage I essential hypertension as first-line drug. DESIGN: This was an open-label, phase IV, multicentric prospective study. SETTINGS: 239 outpatient centres across India. PARTICIPANTS: After ethical approval, patients who were willing to sign informed consent, who are newly diagnosed with JNC VII stage I essential hypertension (systolic blood pressure 140-159 mm Hg or diastolic blood pressure 90-99 mm Hg) and who are prescribed bisoprolol were enrolled in the study. Patients with significant organ disease or complications, women of childbearing age refusing reliable contraceptive method, patients with known contraindications (like symptomatic bradycardia, significant atrioventricular blockade, sick sinus syndrome) and patients with known hypersensitivity reactions to bisoprolol and unwilling patients were excluded. PRIMARY AND SECONDARY OUTCOMES MEASURES: The primary outcome measure was percentage of patients achieving blood pressure (BP) ≤140/90 mm Hg at the end of 12 weeks, while multiple secondary outcome measures were assessed. RESULTS: Of 2418 patients screened, 2161 patients were recruited (66.64% men, mean age 51.7±9.8 years, smokers 19.19%) and 2131 (96.44%) patients achieved BP control. There was significant reduction in systolic blood pressure (-25.29; SD: 13.22 mm Hg), diastolic blood pressure (-14.14; SD: 7.67 mm Hg) and heart rate (-12/min; SD: 6.15) compared with baseline (all p values <0.05). The median dose of bisoprolol and average period required for the response were 5 mg/day and 33 days, respectively. Bisoprolol was found to be well tolerated in the patients up to 10 mg/day. A total of 1.9% patients showed adverse events, which were mild to moderate in severity without any severe adverse event. None required treatment withdrawal. CONCLUSION: Bisoprolol is an effective and safe option to control BP. Thus, it can be used as one of the first-line antihypertensive in Indian patients.

Effect of vitamin D repletion on testicular function in vitamin D-deficient rats.

Freshly weaned 30-day-old male Wistar rats were fed a vitamin D-deficient diet adequate in calcium and phosphorus for 3 months. On the 120th day of age three different doses of vitamin D were injected intramuscularly into three groups of rats and maintained for another month with water and a normal diet ad libitum. One group was continued with a vitamin D-deficient diet up to the 150th day. One group of animals was killed by decapitation on the 120th day and testicular functions like sperm count in testis and epididymis, testicular glutamyl transpeptidase activity and Leydig cell count as well as body weight were noted. On the 150th day animals of all groups were killed and testicular function was studied. Body weight and testicular function decreased significantly on the 120th and 150th day of age in vitamin D-deficient rats as compared to age-matched normal control rats. Injection of lower doses of vitamin D on the 120th day of age improved testicular function after 1 month whereas administration of a high dose of vitamin D caused a deterioration of the testicular function. The result suggests that retardation of spermatogenesis due to disturbances in Sertoli and Leydig cell function in vitamin D deficiency is reversible and can be corrected by supplementing an optimal dose of vitamin D.

Transfer lung factor for Co (TLCO) and its components (DM & VC) in flour mill workers.

Tlco, Kco (Tlco/Va), Va, Vc and Dm were measured in 25 flour mill workers (non-smoker 9, smoker 16) and 50 healthy control subjects (25 non-smoker, 25 smoker) of similar anthropometric parameters and socio-economic status. Tlco (P < 0.05) was decreased significantly and rest of the parameters were decreased insignificantly in flour mill workers as compared to control subjects. In non-smoker flour mill workers none of the parameters altered significantly as compared to non-smoker control subjects. Statistically significant reduction was seen in smoker workers only in Tlco (P < 0.05) and its component Dm (P < 0.05) as compared to smoker control subjects. Further it has been observed that less duration of flour dust exposure (< 5 years) in all flour mill workers and smoker flour mill workers caused negligible fall in Tlco, whereas longer duration of flour dust exposure (> 5 years) in both the groups caused highly significant fall in Tlco (P < 0.01) which was contributed to by highly significant fall in Dm (P < 0.001).

Vasopressin antagonist disrupts the circadian rhythm of water intake on suprachiasmatic injection.

The present study makes an attempt to find out the action of arginine vasopressin (AVP) and its antagonist d-(CH2)5 Tyr (Me) AVP applied at the suprachiasmatic nuclei (SCN) on the circadian rhythm of water intake. Chronic implantation of a 22 G stainless steel cannula for injection was performed using a stereotaxic technique under Nembutal anesthesia. AVP and its antagonist were injected into the SCN of free-moving rats at the beginning of light and dark phases of the light-dark (LD) cycle. Injections of AVP during either phase did not disrupt the circadian pattern of water intake while the injections of the antagonist disrupted it. The findings are suggestive of the involvement of AVP as a mediator of the circadian rhythm of water intake at the level of the neural pacemaker, SCN.

Effect of graded doses of naloxone on renal function in canine hemorrhagic shock.

All the parameters of renal function (inulin clearance, para amino hippuric acid clearance and urine flow) which were depressed during experimentally induced hemorrhagic shock in dogs improved significantly in addition to improvement in mean arterial pressure (MAP) after bolus administration (iv) of 1 or 2 mg/kg naloxone. A smaller dose (0.5 mg/kg) of naloxone, however, did not improve the renal function. Even renal arterial injection of the same dose of naloxone showed no improvement in the renal function. In both these cases the improvement in the MAP was significantly less as compared to other groups of animals which received 1 or 2 mg/kg naloxone. It may be concluded that (a) naloxone at doses of 1 or 2 mg/kg improved the renal function by improving MAP and (b) naloxone has no direct action on renal vasculature.

Effect of vitamin D deficiency on testicular function in the rat.

To study the effect of vitamin D deficiency on testicular function, 30-day-old male rats were put on a vitamin-D-deficient diet. At 120 days of age, the testicular function of these animals was compared with that of rats of the same age group fed, ad libitum, a diet containing vitamin D and rats fed on a restricted amount of diet with vitamin D. In vitamin-D-deficient rats, there was a significant reduction in the total body weight, testicular and epididymal sperm count and testicular glutamyl transpeptidase activity (an index of Sertoli cell function) as compared to control group rats, but there was no difference in the testicular lactate dehydrogenase activity (an index of germ cell function). Histological examination of the testis in vitamin-D-deficient rats revealed a significant reduction in the Leydig cell count along with degenerative changes in the germinal epithelium. Histological examination of the tibia revealed excess of osteoid in vitamin-D-deficient rats only. On the other hand, in undernourished rats given a normal amount of vitamin D, the only significant change was a reduction in total body weight. These results suggest that vitamin D deficiency retards spermatogenesis by interfering with the function of Sertoli and Leydig cells.

Effect of vitamin D supplementation in lactating rats on the neonatal growth.

In lactating rats consuming a commercial diet adequate in calcium, phosphorus and vitamin D, the effect of supplementation of 3000 IU and 7,500 IU of vitamin D3 on the lactational performance of the dams and soft tissue and skeletal growth in the pups has been investigated. On 28th day of age, the pups in the supplemented groups were significantly heavier than in the control group. Study of the indices of cellular growth in the liver and gastrocnemius muscle revealed that the increase in the soft tissue weight was due to a significant increase in protein, RNA and DNA contents (cellular hyperplasia) without any change in protein/DNA ratio (cell size). In the tibia, compared to controls, the dry bone weight and ash weight were more in the supplemented groups, but ash weight/dry bone weight ratio was not altered. The improvement in the neonatal growth was most probably due to the greater milk yield observed in the dams in supplemented groups and not due to any anabolic effect in the pups since direct administration of 500 IU or 1,000 IU of vitamin D3 in 10 day old pups did not increase their body weight.

H-reflex latency and sensory conduction in the assessment of neuropathy in patients of chronic obstructive lung disease.

H-reflex latency, proximal conduction velocity and distal proprioceptive conduction velocity were studied along with distal motor and sensory conduction in 38 patients of chronic obstructive lung disease grouped according to age and duration of the disease, as well as in 35 age-matched smoker controls and 14 non-smoker controls. The mean values of all the parameters studied in all the patient groups were significantly different from those of the non-smoker control group. Smoker controls also showed significant abnormality in all the parameters except motor conduction velocity. Among the patients, significant abnormality (mean +/- greater than 2 SD) was seen in 44.7% in motor conduction, 86.8% in sural nerve distal latency, 97% in Ia conduction velocity, 78.9% in H-reflex latency and 60.5% in proximal conduction velocity, as compared to the non-smoker control values. Among the old patients with more than 10 years of the disease, 62.5% had all the parameters significantly abnormal. More than one parameter was affected in 97.4% of the patients. The intra-group and inter-group differences in all the parameters studied, except motor conduction velocity, were statistically significant indicating that age, chronicity of the disease and smoking can produce nerve conduction defects independently and collectively. It is suggested that though all parameters studied are highly sensitive to neuropathies, proximal H-latency studies are best suited for grading conduction defects in patients of chronic obstructive lung disease, since in many patients sural nerve action potential (52.63%) and distal H-reflex response for Ia conduction studies (81.52%) could not be elicited.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of vitamin D supplementation during pregnancy on the neonatal skeletal growth in the rat.

In rats on normal intakes of calcium, phosphorus and vitamin D3, 3,000 and 7,500 IU of vitamin D3 were injected on the 10th day of pregnancy and the pups were investigated for the skeletal growth on 28th day of age. Compared to controls, the pups in the supplemented groups showed significantly greater dry weight and ash weight of the tibiae. However, the ash weight/dry bone weight ratios in the supplemented groups were not different from controls. Histological examination of the upper ends of decalcified tibiae and plasma calcium estimations revealed no abnormality in any group. The results suggest that vitamin D3 supplementation in pregnancy enhances the skeletal growth of the pups which involves both the organic and inorganic components.

Vasopressin: its possible role in circadian time keeping.

In this review article an insight has been made into the strong possibility of the role of vasopressin (VP) in the control of circadian rhythms which has emerged from the results of the recent experiments in this field. A role for VP, which is identified in the suprachiasmatic nuclei (SCN) of mammals, as a neurotransmitter/neuromodulator in the central nervous system has been postulated for some time now. The presence of certain abnormalities in the circadian rhythms in VP deficient Brattleboro rats has suggested that this neuropeptide is a likely candidate in controlling circadian rhythms. The coexistence of VP and corticotropin releasing factor (CRF), their interrelation with reference to their role in the hypothalamus-pituitary-adrenocortical glucocorticoid axis not only in states of stress but also in day-to-day life has also been discussed. The possible role of dynorphin, which is co-synthesized with VP in the hypothalamic neurons, and other opioids in the control of circadian rhythms has been highlighted. The pineal, SCN relation in the process of development of circadian rhythms has also been reviewed briefly.

Effect of cold challenge on alveolar capillary blood volume in normal individuals.

The effect of immersion of both the hands and the feet in water at 10 degrees C on lung transfer factor for carbon monoxide (Tlco) and on pulmonary capillary blood volume (Vc) was investigated in 20 normal young adult males immediately, 60 min and 120 min after the end of the cold challenge. Vc was significantly reduced immediately and the reduction was aggravated at 60 min. Tlco was significantly reduced only at 60 min. All the values returned to baseline at 120 min. It is concluded that the cold-induced changes in Tlco and Vc are physiological responses and not unique to patients with Raynaud's phenomenon as suggested by some workers.

Comparison of effects of naloxone and catecholamines on acid-base balance in canine hemorrhagic shock.

The present study was conducted to compare the effect of naloxone, an opiate receptor antagonist, with catecholamines on acid-base status and survival in dogs subjected to hemorrhagic shock. Arterial lactic acid concentration which had increased during hemorrhage, decreased significantly (P less than 0.05) in naloxone treated animals but increased further in catecholamine treated dogs. Blood bicarbonate concentration and PCO2 which had markedly decreased 1 hr after hemorrhage recovered significantly (P less than 0.05) in naloxone group of animals. On the other hand bicarbonate and pH declined further in noradrenaline group and remained unchanged in dopamine group. These results as well as better survival rate observed in naloxone treated animals suggest the superiority of naloxone over dopamine and noradrenaline, as an adjunct to blood transfusion in the treatment of hemorrhagic shock.

Response of lung transfer components to grades of smoking.

Pulmonary functions were studied in 50 healthy, asymptomatic, 20 to 47 years, male smokers along with 50 healthy non-smokers matched for age, height, socio-economic status and physical activity. Smokers consumed 2-30 cigarettes per day with duration of smoking ranging from 2 to 26 years. In smokers FEF, V75. PEF and MVV were significantly reduced whereas FRC was increased significantly. Pulmonary diffusion function as assessed by TLCO showed significant reduction. While Vc showed progressive decrease with increasing duration and quantity of smoking, DM increased in the beginning but gradually declined later. TLCO showed a better negative correlation with quantity than with duration of smoking even when the effect of other factors was excluded. Decrease in TLCO is probably due to bronchoconstriction and reflex vasospasm of pulmonary vasculature. Co-efficient of diffusion KCO was also decreased in smokers.

Effect of ganglionic stimulating and blocking agents on the fast components of colonic myoelectrical activity in the rat.

The presence of two types of fast myoelectrical activities, medium fast activity and fast activity, has been demonstrated previously in the electromyogram of colon in normal children and in the rat by the authors. An absence of medium fast activity in Hirschsprung's disease and in experimental aganglionosis of colon in the rat has also been described. In the present study the fast components of colonic myoelectrical activity were analysed during the procedures affecting ganglionic transmission. It was observed that ganglionic stimulants, such as balloon inflation, and intra-arterial injections of acetylcholine and small amounts of nicotine, increased the spike activity and the frequency of medium fast activity without affecting fast activity. The intra-arterial injections of ganglionic blocking agents, such as nicotine in large amounts and pentolinium tartrate, completely abolished the medium fast activity. These observations suggest that the ganglionic activity is responsible for the genesis of medium fast activity and that the absence of cholinergic ganglionic transmission is the most important single factor for the reported altered electromyogram pattern in aganglionosis.

Long latency cutaneous reflex effect on H-reflex recovery in hemiplegics and paraplegics: a longitudinal study for the assessment of motor function.

H-reflex recovery by twin pulses was recorded serially in 10 paraplegics for 5 months and in 23 hemiplegics for 2 months after the lesion. Fifty-one normal subjects acted as controls. The effect of cutaneous tactile stimulation was also studied simultaneously by applying electrical stimuli synchronized with twin pulses to the skin over the lateral border of small toe. In paraplegics, the H-reflex recovery curves recorded serially showed a highly depressed pattern during the first two weeks, an almost normal pattern during the second and third months and a significantly elevated pattern during the fourth and fifth months. Whereas cutaneous stimulation in control subjects produced a highly significant late inhibition of H-reflex recovery between 600 ms and 600 ms, in paraplegics it failed to produce any significant effect, except in two, who besides having a normal H-reflex recovery curve even during the first week, showed a substantial amount of cutaneous inhibition of H-reflex recovery, 4 months after the lesion. A highly depressed pattern of H-reflex recovery was observed on the affected side of the majority of hemiplegics during the first week after the lesion, many of them showing similar pattern on the "unaffected side" also. The serial study showed very good improvement in all hemiplegics both in terms of H-reflex recovery pattern and the amount of cutaneous inhibition. The observations in present study suggest preservation and/or restoration of supraspinal influences in many hemiplegics and in at least two paraplegics. The study also shows that a serial recording of H-reflex recovery curve and the amount of cutaneous reflex effect on it, is a very sensitive method of assessing the supraspinal influences on the spinal motoneurones and so can be of immense help in the diagnosis and prognosis in hemiplegics and paraplegics.

Ventilatory and diffusion studies in smoker and non smoker flour-mill workers.

Various pulmonary function tests, FVC, FEV1/FVC%, PEFR, EFR25-75, MVV and Tlco were measured in 25 asymptomatic male flour mill workers and 50 healthy subjects not working at flour mill, to assess the effect of flour dust on lungs. All the subjects of different groups were well matched in their anthropometeric parameters and socio economic status. In smoker flour mill workers significant reduction was present in both ventilatory and diffusion functions of lungs, which was more pronounced in subjects who consumed larger quantity of tobacco and were exposed to flour dust for longer duration. On the other hand deterioration of pulmonary functions in non smoker flour mill workers was found to be statistically not significant. The relative strength of both the parameters viz tobacco and flour dust for impairment of pulmonary functions is discussed for being a pointer to further studies.

Lithium chloride SCN injection alters the circadian rhythm of food intake.

Effect of lithium injections through chronically implanted cannulae into the bilateral suprachiasmatic nuclei (SCN) on the circadian rhythm of food intake was investigated in the rat. It was observed that the circadian rhythm was disrupted by injections of lithium at the beginning of the light as well as the dark phase of the LD cycle. In either case the percentage of the food consumed during the 12-hr light period increased while that during the dark period decreased without any significant change in the total daily intake. Disruptions in the circadian rhythm of food intake failed to show any dose-response relation. Injections of saline into the SCN or lithium into the nearby SCN area did not produce a disruption of the circadian rhythm of food intake.