Glomerular size-selective dysfunction in NIDDM is not ameliorated by ACE inhibition or by calcium channel blockade.
BACKGROUND: In patients with insulin-dependent diabetes mellitus (IDDM) and overt nephropathy glomerular barrier size-selectivity progressively deteriorates with time and is effectively improved by angiotensin converting enzyme (ACE) inhibition. Whether similar glomerular functional changes develop in proteinuric patients with non-insulin-dependent diabetes mellitus (NIDDM), and whether antihypertensive agents can favorably affect glomerular filtration of macromolecules in these patients, has not been documented yet. METHODS: We investigated renal hemodynamics and fractional clearance of neutral dextrans of graded sizes, in nine proteinuric patients with NIDDM and renal biopsy findings of typical diabetic glomerulopathy. Six healthy volunteers served as controls. We also investigated the effects of an ACE inhibitor and of a calcium channel blocker, both given in doses targeted to achieve a comparable level of systemic blood pressure control, on glomerular hemodynamics and sieving function. Theoretical analysis of glomerular macromolecule transport was adopted to evaluate intrinsic glomerular membrane permeability properties. RESULTS: Fractional clearance of large macromolecules (42 to 66 A in radius) was significantly higher in diabetic patients than in controls, and the distribution of membrane pore radii was calculated to be shifted towards larger pore sizes in diabetics (mean radius increased from 55 to 60 A). Despite effective blood pressure control, neither antihypertensive affected glomerular hemodynamics to any significant extent. Fractional clearance of dextrans, as well as of albumin and IgG, and total urinary proteins were not modified by either treatments. CONCLUSIONS: These data indicate that patients with NIDDM and overt nephropathy develop abnormalities in size-selective function of the glomerular barrier and, at variance to IDDM, such changes were not ameliorated either by ACE inhibition or calcium channel blockade. (+info)
Energy cost of propulsion in standard and ultralight wheelchairs in people with spinal cord injuries.
BACKGROUND AND PURPOSE: Wheelchair- and subject-related factors influence the efficiency of wheelchair propulsion. The purpose of this study was to compare wheelchair propulsion in ultralight and standard wheelchairs in people with different levels of spinal cord injury. SUBJECTS: Seventy-four subjects (mean age=26.2 years, SD=7.14, range=17-50) with spinal cord injury resulting in motor loss (30 with tetraplegia and 44 with paraplegia) were studied. METHOD: Each subject propelled standard and ultralight wheelchairs around an outdoor track at self-selected speeds, while data were collected at 4 predetermined intervals. Speed, distance traveled, and oxygen cost (VO2 mL/kg/m) were compared by wheelchair, group, and over time, using a Bonferroni correction. RESULTS: In the ultralight wheelchair, speed and distance traveled were greater for both subjects with paraplegia and subjects with tetraplegia, whereas VO2 was less only for subjects with paraplegia. Subjects with paraplegia propelled faster and farther than did subjects with tetraplegia. CONCLUSION AND DISCUSSION: The ultralight wheelchair improved the efficiency of propulsion in the tested subjects. Subjects with tetraplegia, especially at the C6 level, are limited in their ability to propel a wheelchair. (+info)
Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids.
Ethambutol (EMB) is the most frequent "fourth drug" used for the empiric treatment of Mycobacterium tuberculosis and a frequently used drug for infections caused by Mycobacterium avium complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (+/- standard deviation) EMB maximum concentration of drug in serum (Cmax) of 4.5 +/- 1.0 micrograms/ml, time to maximum concentration of drug in serum (Tmax) of 2.5 +/- 0.9 h, and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) of 28.9 +/- 4.7 micrograms.h/ml. In the presence of antacids, subjects had a mean Cmax of 3.3 +/- 0.5 micrograms/ml, Tmax of 2.9 +/- 1.2 h, and AUC0-infinity of 27.5 +/- 5.9 micrograms.h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean Cmax of 3.8 +/- 0.8 micrograms/ml, Tmax of 3.2 +/- 1.3 h, and AUC0-infinity of 29.6 +/- 4.7 micrograms.h/ml. These reductions in Cmax, delays in Tmax, and modest reductions in AUC0-infinity can be avoided by giving EMB on an empty stomach whenever possible. (+info)
Antiproteinuric efficacy of verapamil in comparison to trandolapril in non-diabetic renal disease.
BACKGROUND: Non-dihydropyridine calcium antagonists such as verapamil are equally effective in reducing proteinuria as ACE inhibitors in hypertensive patients with diabetic nephropathy. To date it is unknown whether verapamil elucidates such an antiproteinuric capacity in non-diabetic renal disease. METHODS: We performed a double-blind, placebo-controlled, random cross-over study which compared the antiproteinuric effect of 6 weeks treatment with verapamil SR (360 mg) to that of the ACE inhibitor trandolapril (4 mg), and their fixed combination vera/tran (180 mg verapamil SR and 2 mg trandolapril) in 11 non-diabetic patients with proteinuria of 6.6 (5.1-8.8) g/day, a creatinine clearance of 87 (74-106) ml/min, and a 24-h blood pressure of 136/85 (126/76-157/96) mmHg at baseline. RESULTS: Twenty-four-hour mean arterial pressure did not change during verapamil, whereas both trandolapril and vera/tran induced a significant reduction in MAP. Verapamil showed no significant effects on renal haemodynamics. Trandolapril and vera/tran did not significantly change GFR, but ERPF increased and FF decreased during both treatments (P<0.05). The antiproteinuric response of verapamil was significantly less compared to that of trandolapril and vera/tran (-12% (-17/-1) vs -51% (-56/-25) and -41% (-50/-19) respectively). The blood pressure and antiproteinuric response during verapamil tended to be greater in hypertensive patients than in normotensive patients, although this difference was not significant. Baseline blood pressure was related to the change in blood pressure during verapamil (r = -0.70; P < 0.02). CONCLUSIONS: The antiproteinuric and antihypertensive response of verapamil is less than that of the ACE inhibitor trandolapril in patients with non-diabetic renal disease. In contrast to the antiproteinuric response of trandolapril, the antiproteinuric reponse of verapamil seems to be completely dependent from effective blood pressure reduction. The fixed combination of verapamil and ACE inhibition at half doses has similar effects as ACE inhibition at full dose. (+info)
A nicotine antagonist, mecamylamine, reduces cue-induced cocaine craving in cocaine-dependent subjects.
We have previously shown that nicotine enhances cue-induced cocaine craving. In the present study, the effects of a nicotine antagonist, mecamylamine, on cue-induced cocaine craving were investigated. Twenty-three cocaine-dependent patients, all cigarette smokers, were randomly assigned to mecamylamine (2.5 mg tablet) or placebo in a single-dose, placebo-controlled, crossover, double-blind study. Craving and anxiety were measured before and after cocaine cues with visual analog scales for desire to use cocaine and mood. Skin conductance, skin temperature and heart rate were recorded before and during cocaine cues. Following exposure to cocaine cues, all patients reported an increase in cocaine craving and anxiety relative to the precue measures. Cue exposure also produced an increase in skin conductance and decrease in skin temperature. The cue-induced increase in cocaine craving was reduced, while the cue-induced skin conductance and temperature responses were unaffected, by mecamylamine. These findings show that cue-induced cocaine craving is attenuated by mecamylamine. Further study on the use of mecamylamine in relapse prevention programs are suggested. (+info)
Airway inflammatory response to ozone in subjects with different asthma severity.
The aim of this study was to evaluate whether ozone exposure induces a similar airway inflammatory response in subjects with different degrees of asthma severity. Two groups of asthmatic subjects were studied: seven with intermittent mild asthma not requiring regular treatment (group A); and seven with persistent mild asthma requiring regular treatment with inhaled corticosteroids and long-acting beta2-agonists (group B). All subjects were exposed, in a randomized cross-over design, to air or O3 (0.26 parts per million (ppm) for 2 h with intermittent exercise); subjects in group B withdrew from regular treatment 72 h before each exposure. Before the exposure, and 1 and 2 h after the beginning of the exposure they performed a pulmonary function test, and a questionnaire was completed to obtain a total symptom score (TSS). Six hours after the end of the exposure, hypertonic saline (HS) sputum induction was conducted. Sputum cell percentages, eosinophil cationic protein (ECP) and interleukin (IL)-8 concentrations in the sputum supernatant were measured. TSS significantly increased and forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) significantly decreased after O3 exposure in comparison with air exposure in group A, whereas no changes were observed in group B except for a significant decrement of FEV1 2 h after the beginning of O3 exposure. Sputum neutrophil percentage was significantly higher after O3 exposure than after air exposure in both groups (Group A: 70.2% (28-87) versus 26.6% (8.6-73.2); Group B: 62.1% (25-82.4) versus 27.9% (14.4-54)). IL-8 was higher in sputum supernatant collected 6 h after O3 exposure than after air, only in group A. No change due to O3 has been found in sputum eosinophil percentage and ECP concentration in both groups. In conclusion, the degree of airway response to a short-term exposure to ozone is different in subjects with asthma of different severity. The available data do not allow elucidation of whether this difference depends on the severity of the disease or on the regular anti-inflammatory treatment. (+info)
The contribution of the swallowed fraction of an inhaled dose of salmeterol to it systemic effects.
Salmeterol is approximately eight times as potent as salbutamol for systemic effects. This may be because the drug is eight times more potent on receptors or there may be differences in systemic bioavailability. The systemic effects of salbutamol are limited by its fairly high first-pass metabolism, but the oral bioavailability of salmeterol is unknown. The contribution of the swallowed fraction of an inhaled dose of salmeterol to its systemic effects were analysed in a randomized, double-blind, crossover study. Twelve healthy subjects were given inhaled salmeterol 400 microg, inhaled salmeterol 400 microg plus oral activated charcoal or inhaled placebo plus oral activated charcoal on three separate days. Cardiac frequency (fC), Q-T interval corrected for heart rate (QTc), plasma potassium and glucose concentrations were measured for 4 h following the inhaled drug. Salmeterol with and without oral charcoal produced significant changes for all measures compared to placebo. The magnitude of effect following salmeterol alone was significantly greater than that following salmeterol plus charcoal for fC and glucose (mean (95% confidence interval) differences 8 (2-13) beats x min(-1), 0.59 (0.04, 1.13) mmol x L(-1), respectively) and nonsignificantly greater for QTc interval and potassium concentration. The differences between salmeterol given with and without charcoal suggest that 28-36% of the systemic response to salmeterol administered from a metered-dose inhaler are due to drug absorbed from the gastrointestinal tract. Thus, most of the systemic effects are due to the inhaled fraction of the drug. (+info)
Neonatal examination and screening trial (NEST): a randomised, controlled, switchback trial of alternative policies for low risk infants.
OBJECTIVE: To evaluate the effectiveness of one rather than two hospital neonatal examinations in detection of abnormalities. DESIGN: Randomised controlled switchback trial. SETTING: Postnatal wards in a teaching hospital in north east Scotland. PARTICIPANTS: All infants delivered at the hospital between March 1993 and February 1995. INTERVENTION: A policy of one neonatal screening examination compared with a policy of two. MAIN OUTCOME MEASURES: Congenital conditions diagnosed in hospital; results of community health assessments at 8 weeks and 8 months; outpatient referrals; inpatient admissions; use of general practioner services; focused analysis of outcomes for suspected hip and heart abnormalities. RESULTS: 4835 babies were allocated to receive one screening examination (one screen policy) and 4877 to receive two (two screen policy). More congenital conditions were suspected at discharge among babies examined twice (9.9 v 8.3 diagnoses per 100 babies; 95% confidence interval for difference 0.3 to 2.7). There was no overall significant difference between the groups in use of community, outpatient, or inpatient resources or in health care received. Although more babies who were examined twice attended orthopaedic outpatient clinics (340 (7%) v 289 (6%)), particularly for suspected congenital dislocation of the hip (176 (3.6/100 babies) v 137 (2.8/100 babies); difference -0.8; -1.5 to 0.1), there was no significant difference in the number of babies who required active management (12 (0.2%) v 15 (0.3%)). CONCLUSIONS: Despite more suspected abnormalities, there was no evidence of net health gain from a policy of two hospital neonatal examinations. Adoption of a single examination policy would save resources both during the postnatal hospital stay and through fewer outpatient consultations. (+info)