Independent measurement of the total active 8B solar neutrino flux using an array of 3He proportional counters at the Sudbury Neutrino Observatory.

The Sudbury Neutrino Observatory (SNO) used an array of 3He proportional counters to measure the rate of neutral-current interactions in heavy water and precisely determined the total active (nu_x) 8B solar neutrino flux. This technique is independent of previous methods employed by SNO. The total flux is found to be 5.54_-0.31;+0.33(stat)-0.34+0.36(syst)x10(6) cm(-2) s(-1), in agreement with previous measurements and standard solar models. A global analysis of solar and reactor neutrino results yields Deltam2=7.59_-0.21;+0.19x10(-5) eV2 and theta=34.4_-1.2;+1.3 degrees. The uncertainty on the mixing angle has been reduced from SNO's previous results.

Pharmacokinetics of lamivudine, zidovudine, and nevirapine administered as a fixed-dose combination formulation versus coadministration of the individual products.

The pharmacokinetics of 150 mg lamivudine, 300 mg zidovudine, and 200 mg nevirapine were assessed following single oral administration of a fixed-dose combination tablet and coadministration of the separate innovator products in healthy male subjects (n = 64) under fasting conditions in an open-label, randomized, 2-way crossover study. Multiple blood samples were collected up to 72 hours and plasma concentrations of antiretrovirals were assayed using liquid chromatography/tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods, and bioequivalence was assessed using an analysis of variance model. The ratio of the least squares mean (fixed-dose combination to individual products) and 90% confidence intervals of AUC(0-t), AUC(0-infinity), and C(max) for lamivudine, zidovudine, and nevirapine were all within 80.0% to 125.0%, suggesting a similar rate and extent of antiretroviral exposure in the bloodstream. Mean oral clearance (CL/F) values of lamivudine, zidovudine, and nevirapine for the fixed-dose combination were 23.7, 127, and 1.65 L/h, respectively. The fixed-dose combination and individual products were equally safe and well tolerated, with only a few subjects experiencing drug-related adverse events. The current fixed-dose combination of lamivudine, zidovudine, and nevirapine is expected to provide a similar efficacy/safety profile as coadministration of the individual products, a better adherence to treatment, and considerable cost savings in the treatment of HIV.

Bioequivalence of abacavir generic and innovator formulations under fasting and fed conditions.

OBJECTIVE: Abacavir sulfate is a synthetic carbocyclic nucleoside analogue indicated for the treatment of HIV-1 infection in combination with other antiretroviral agents. The objective of the current study was to determine the bioequivalence between a generic formulation of abacavir and the innovator product. MATERIAL AND METHODS: A total of 80 subjects were randomly assigned to receive a single 300 mg oral dose of abacavir sulfate as the generic (Ranbaxy-Abacavir, Ranbaxy Laboratories Ltd., equivalent to 300 mg of abacavir) and innovator (Ziagen, GlaxoSmithKline) tablet formulations in 2-way crossover studies performed under fasting (n=40) and fed (n=40) conditions. Multiple blood samples were collected over 14 hours and plasma concentrations of abacavir were assayed using an LC/MS/MS method with a limit of quantitation of 25.0 ng/ml. Pharmacokinetic (PK) parameters were calculated using noncompartmental methods. RESULTS: Under fasting conditions, geometric mean area under the curve from time 0 to the last measurable concentration (AUC(0-t)), area under the curve extrapolated to infinity (AUC(0-infinity) and maximum plasma concentrations (Cmax) of abacavir for the generic (5565 ng x h/ml, 5668 ng x h/ml and 2526 ng/ml, respectively) and innovator (5675 ng x h/ml, 5770 ng x h/ml and 2528 ng/ml, respectively) products were very similar. Under fed conditions, mean values of AUC(0-t) AUC(0-infinity) and Cmax for the generic (4487 ng x h/ml, 4571 ng x h/ml and 1841 ng/ml, respectively) and innovator (4574 ng x h/ml, 4654 ng x h/ml and 1781 ng/ml, respectively) formulations were also very similar. Ratios of LSM and 90% confidence intervals of PK parameters between the 2 formulations were within 80.0 - 125.0% under fasting and fed conditions, suggesting that the 2 tablet formulations resulted in similar rate and extent of bioavailability. Adverse events for the generic and innovator products were similar in nature and frequency in the fasting and fed studies. CONCLUSIONS Based on the above results, the generic tablet formulation of abacavir developed by Ranbaxy should be equally effective as the innovator product.

Comparative bioavailability study of zidovudine administered as two different tablet formulations in healthy adult subjects.

AIM: Zidovudine is a synthetic nucleoside analogue of thymidine with activity against the human immunodeficiency virus type 1 (HIV-1). In patients with HIV infections or the acquired immunodeficiency syndrome (AIDS), zidovudine is a first-line therapy that was shown to reduce morbidity, mortality, and hospitalization. A generic formulation of zidovudine offers the possibility of considerable savings to HIV/AIDS patients in developed and Third World countries. The objective of the current study was to characterize the pharmacokinetic and safety profiles of zidovudine administered as a generic tablet formulation relative to the innovator product. VOLUNTEERS AND METHODS: A total of 68 healthy adult volunteers received a 300 mg oral dose of zidovudine as the generic formulation (AVIRO-Z 300 mg tablet, Ranbaxy Laboratories Limited) and as the innovator product (Retrovir tablet, GlaxoSmithKline) in a randomized, 2-way crossover study. Multiple blood samples were collected over 12 hours and plasma concentrations of zidovudine were assayed using an LC/MS/MS method with an analytical range of 5.00 to 2,000 ng/ml. Pharmacokinetic parameters were calculated using non-compartmental methods. RESULTS: Mean plasma concentrations of zidovudine declined in a mono-exponential manner, with mean concentration values falling below the limit of quantitation 12 hours after administration of both formulations. Mean area under the curve from time 0 to the last measurable concentration (AUC(0-t)), mean area under the curve from time 0 to infinity (AUC(0-infinity)) and peak plasma concentrations (C(max)) of zidovudine for the generic tablet formulation (2,220.6 ng x h/ml, 2,236.0 ng x h/ml and 1,087.9 ng/ml, respectively) were very similar to those observed for the innovator product (2,139.7 ng x h/ml, 2,158.6 ng x h/ml and 1,066.5 ng/ml, respectively). Ratios of least-squares means and 90% confidence intervals of AUC(0-t) AUC(0-infinity) and C(max) between the 2 formulations were within 80-125%, suggesting that the two tablet formulations displayed similar rate and extent of bioavailability. The oral clearance (CL/F) of zidovudine for the generic and innovator formulations were 2.11 1/h/kg and 2.16 1/h/kg, respectively. For the two formulations, adverse events were similar in nature and frequency. CONCLUSION: Since the two formulations displayed similar in vivo delivery rate of zidovudine in the bloodstream, the generic tablet formulation of zidovudine developed by Ranbaxy should be equally effective as the innovator product and is expected to produce considerable cost-savings in AIDS patients worldwide.

Evaluating a support group for perinatal loss.

PURPOSE: This study attempted to determine if a support group intervention makes a difference in grief reactions of parents who have experienced a perinatal loss, and describes what parents perceived as being helpful and not helpful in handling the loss. DESIGN: A cross-sectional, retrospective, two-group research design was used. The independent variable was having attended or not having attended a perinatal loss support group. METHODS: A convenience sample of 121 participants (n = 67 in support groups; n = 51 not in support groups) was obtained from a mail survey to families who were on a perinatal loss support newsletter mailing list. The participants completed the Hogan Grief Reactions Checklist and a demographic questionnaire. RESULTS: There were no statistically significant differences in parents' grief reaction scores between the two groups, but there were some differences in grief scores by gender and ethnicity. In both groups, the parents perceived their spouse, their extended families, and their friends as "most helpful." Physicians were perceived as "least helpful." CLINICAL IMPLICATIONS: Grief is very individual, and not all individuals may benefit from a support group. When suggesting a support group or any intervention, timing and a caring approach are essential.

D-LysAsnProTyr tetrapeptide: a novel B-cell stimulant and stabilized bursin mimetic.

The tetrapeptide I (D-lysine-L-asparaginyl-L-prolyl-L-tyrosine or D-LysAsnProTyr), and analogue sequences, were synthesized and evaluated for the ability to stimulate immune cell subsets. These sequences were selected based on their perceived ability to readily adopt a beta-turn structure. In vitro immunological assays revealed a robust stimulation of mitogen activated B-cell proliferation and a modest to significant stimulation of cytotoxic T lymphocytes (CTLs). Further, this in vitro stimulation of B-cells was accompanied by an in vivo expansion of B-cells in C57BL/6 mice, as demonstrated by immunophenotyping experiments. Interestingly, a conformational analysis of the low energy conformers of I and the endogenous B-cell stimulant bursin (LysHisGlyNH2) shows that these molecules can be superimposed. However, I displayed significantly enhanced physiological stability. For a number of reasons, I may be a particularly useful vaccine adjuvant.

Faculty practice at a homeless shelter for women and children.

Homelessness in America has significantly increased in recent years. Exact numbers of homeless persons in the United States are difficult to assess, though estimates of homeless persons range from 250,000 to 3 million. The homeless population has shifted to include women and children, including two parent families. Providing health care for the homeless is one of the most important and challenging health issues today. There are many barriers to providing adequate health care. The purpose of this article is to describe the complexity of the role and the experiences of a pediatric nurse practitioner at a clinic in a homeless shelter that houses approximately 30 women and children.

Thioamides: synthesis, stability, and immunological activities of thioanalogues of Imreg. Preparation of new thioacylating agents using fluorobenzimidazolone derivatives.

Imreg (Tyr1-Gly2-Gly3) is a well-known immunostimulant. However, it possesses a short half-life. Stabilized analogues of Imreg were prepared by a regioselective insertion in which peptide bonds at position 1,2 or 2,3 were replaced by thioamide linkages. This was achieved by using new thioacylating agents based on thioacyl-fluoro-N-benzimidazolone. The synthesis and properties of these reagents are described herein. This peptide modification enhanced significantly the half-life of the thioanalogues relative to Imreg in blood. The thioanalogues and Imreg were tested in vitro in T and B cell proliferation assays and for their ability to stimulate cytotoxic T-lymphocytes (CTLs). Only thiotyrosyl glycyl glycine 11 displayed some activity as evidenced by a weak stimulation of CTLs. On the basis of this activity and the increased stability, an in vivo immunological evaluation was undertaken. Immunophenotyping of 11 revealed a significant increase in activated CTL and NK cell populations in the spleen. This expansion was also accompanied by a significant stimulation of NK cells and the B cell proliferative response. Thioanalogues of Imreg were generally nontoxic, as exemplified by 11. The latter is a promising immunostimulant which may be targeted for cancer and viral infections, where CTLs and NK cells play an important role, or as a vaccine adjuvant where stimulation of antibody-producing B cells is important.

Anti-ischaemic properties of amlodipine, a new calcium antagonist, in patients with severe coronary artery disease: a prospective trial.

Amlodipine significantly reduced both weekly anginal attack rate and consumption of glyceryl trinitrate tablets in patients with severe coronary artery disease. Exercise tolerance also significantly improved, with a 79% increase in the exercise time to onset of angina and a 59% decrease in ST-segment depression. Blood pressure was decreased, with no significant change in heart rate. No serious adverse events occurred in any patient during amlodipine treatment.

Iritis in children with varicella.

A prospective study that included 82 consecutive children seen over 2 years by five pediatricians was undertaken to determine the incidence of iritis in children with chickenpox. Twenty-one (25%) children without pox on their lids were found to have iritis. Follow-up of children with objective evidence of iritis revealed no long-term sequelae.

Long-term follow-up of Candida endophthalmitis in the premature infant.

In the March 1981 issue of the Journal of Pediatrics, Baley, Annable and Kleigman discussed the natural course of Candida endophthalmitis in the premature infant. We now have long-term follow-up on the three surviving infants along with follow-up on an additional eight patients. Though vitrectomy is routinely performed in adults, we recommended that it not be performed in premature infants with systemic candidiasis and associated vitreo-retinal pathology. These 11 infants with candidal endophthalmitis secondary to systemic candidiasis demonstrated minimal residual ocular pathology after having been treated with systemic antifungals alone. Neither vitreous taps nor intravitreal injections should be performed in infants with ocular candidiasis.

Lysosomal enzyme levels in corneal storage media. K-Sol versus McCarey-Kaufman.

Evidence indicates that lysosomal enzymes can carry out corneal autolysis during corneal storage and that they are damaging to the corneal endothelium. The authors investigated the release of lysosomal enzymes into two corneal storage media (K-Sol and McCarey-Kaufman [M-K]) by paired human donor corneas during 4 degrees C storage. The authors also studied the interaction of these media with lysosomal enzymes from human cornea. K-Sol and M-K stimulated (P less than 0.01) both beta-glucuronidase and alpha-galactosidase about equally. beta-N-Acetyl-glucosaminidase, a major catabolic enzyme of the cornea, was inhibited by the chondroitin sulfate in K-Sol by over 90% (P less than 0.01). Corneas stored in M-K released more lysosomal enzymes than corneas stored in K-Sol. At 4 days, the values approached significance (P less than 0.06) and by day 10 significantly higher values were found in the M-K media (P less than 0.01). Both storage methods showed a linear release. Individual corneas were found to vary in their release rates. Whether corneas that release more enzyme will show higher endothelial cell loss or produce less successful penetrating keratoplasty grafts deserves further study.

Comparative effects of aminophylline on diaphragm and cardiac contractility.

The mechanisms by which aminophylline increases inspiratory muscle contractility are unclear. The present study compared the effects of aminophylline on cardiac as well as on diaphragm contractility and examined the interaction of aminophylline with verapamil, a calcium channel-blocking agent, on both types of muscle. Experiments were performed in mongrel dogs anesthetized with pentobarbitone. Diaphragm contractility was assessed from transdiaphragmatic pressure (Pdi) developed during supramaximal electrical stimulation of the cervical phrenic rootlets, and cardiac contractility was assessed from peak left ventricular (LV) pressure and its rate of rise (dPv/dt). Measurements were made before and after each of 3 sequential IV infusions of aminophylline (6 mg/kg) and subsequent IV infusions of verapamil (0.1 mg/kg bolus and 0.02 mg/kg/min for 5 to 7 min.). Transient decreases in Pdi were frequently observed immediately after aminophylline infusion in association with decreases in mean arterial blood pressure. With recovery of mean blood pressure, Pdi increased above baseline values. Aminophylline increased Pdi in a dose-dependent fashion over the entire frequency range studied (1 to 40 Hz). Aminophylline increased the rate of rise of Pdi (dPd/dt) without affecting the period over which pressure was developed or dissipated during single twitches. Aminophylline increased both peak LV pressure and dPv/dt. The magnitude of the cardiac response was greater than the diaphragmatic response. Subsequent verapamil infusion completely reversed the effects of aminophylline on LV contractility but had only a small effect on diaphragm contractility.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of inspiratory resistive training on respiratory muscle function in patients with muscular dystrophy.

The effects of inspiratory resistive training on respiratory muscle function was evaluated in 11 patients with Duchenne, limb-girdle, and facio-scapulo-humeral (FSH) type muscular dystrophy. Muscle training consisted of breathing against an inspiratory resistance for two 15-minute sessions each day while at home. Following 6 weeks of training, there were significant increases in the maximum resistance that could be tolerated for at least 5 minutes (P < 0.01) and also in the maximum duration that ventilations equal to 30%, 50%, 70%, and 90% of the maximum voluntary ventilation could be sustained (P < 0.05). In six patients who trained for an additional 6-week period, respiratory muscle endurance increased even further. The degree of improvement in respiratory muscle endurance was positively correlated with baseline vital capacity (r = 0.84, P < 0.05) and maximal inspiratory pressure (r = 0.76, P < 0.05). Spirometry, functional residual capacity, and maximal inspiratory and expiratory pressures were not affected by training. We conclude that inspiratory resistive training improves respiratory muscle endurance in muscular dystrophy patients. Improvement in respiratory muscle function may serve to delay the onset of respiratory complications in patients with muscular dystrophy.

Effects of expiratory threshold loading on thoracoabdominal motion in cats.

Expiratory muscle activity may alter rib cage and abdominal configuration at end-expiration and thereby affect the pattern of thoracoabdominal motion during subsequent inspiration. In this study, expiratory muscles were stimulated by the application of a series of expiratory threshold loads (ETL) (range: 0 to + 10 cm H2O) in 10 cats lightly anaesthetized with pentobarbitone. Thoracoabdominal motion was monitored by inductance plethysmography. Peak internal intercostal and abdominal muscle electrical activity increased proportionately with the magnitude of the ETL, suggesting comparable activation of both expiratory muscle groups. Increases in end-expiratory abdominal volume, however, were greater than increases in end-expiratory rib cage volume, during ETL. This resulted in a shift of the end-expiratory thoracoabdominal position to the right of the relaxation characteristic. During ETL, there was inward movement of the abdomen in early inspiration and this decrease in abdominal volume correlated closely with the change in end-expiratory abdominal volume and the magnitude of the ETL (mean r = 0.95, P less than 0.01). In three animals, sectioning the abdominal muscles resulted in a further increase in end-expiratory abdominal volume for a given ETL. Deepening anesthesia progressively reduced and eventually abolished expiratory muscle activation and under these conditions, ETL increased end-expiratory rib cage and abdominal volume along the thoracoabdominal relaxation characteristic. The results of this study indicate that while abdominal muscle activation acts to decrease abdominal volume at end-expiration, the action of the expiratory intercostal muscles predominates during ETL to produce a smaller rib cage volume at the expense of an enlargement of abdominal volume.