An assessment of the in vivo efficacy of the glycogen phosphorylase inhibitor GPi688 in rat models of hyperglycaemia.

BACKGROUND AND PURPOSE: Studies in cultured hepatocytes demonstrate glycogen synthase (GS) activation with glycogen phosphorylase (GP) inhibitors. The current study investigated whether these phenomena occurred in vivo using a novel GP inhibitor. EXPERIMENTAL APPROACH: An allosteric GP inhibitor, GPi688, was evaluated against both glucagon-mediated hyperglycaemia and oral glucose challenge-mediated hyperglycaemia to determine the relative effects against GP and GS in vivo. KEY RESULTS: In rat primary hepatocytes, GPi688 inhibited glucagons-mediated glucose output in a concentration dependent manner. Additionally GP activity was reduced and GS activity increased seven-fold. GPi688 inhibited glucagon-mediated hyperglycaemia in both Wistar (65%) & obese Zucker (100%) rats and demonstrated a long duration of action in the Zucker rat. The in vivo efficacy in the glucagon challenge model could be predicted by the equation; % glucagon inhibition=56.9+34.3[log ([free plasma]/rat IC50)], r=0.921). GPi688 also reduced the blood glucose of obese Zucker rats after a 7 h fast by 23%. In an oral glucose tolerance test in Zucker rats, however, GPi688 was less efficacious (7% reduction) than a glycogen synthase kinase-3 (GSK-3) inhibitor (22% reduction), despite also observing activation (by 45%) of GS in vivo. CONCLUSIONS AND IMPLICATIONS: Although GP inhibition can inhibit hyperglycaemia mediated by increased glucose production, the degree of GS activation induced by allosteric GP inhibitors in vivo, although discernible, is insufficient to increase glucose disposal. The data suggests that GP inhibitors might be more effective clinically against fasting rather than prandial hyperglycaemic control.

The optimal approach for management of metachronous hernias in children: a decision analysis.

PURPOSE: Up to 30% of children undergoing unilateral hernia repair will later get a hernia on the contralateral side that requires repair. Three approaches have been used to address the potential for development of a metachronous hernia: (1) observation and repair of a contralateral hernia only if it later becomes apparent, (2) routine contralateral groin exploration, and (3) laparoscopy to evaluate the contralateral groin for a potential hernia. The purpose of this study was to use decision analysis to determine which approach resulted in the lowest morbidity, mortality, and cost. METHODS: A decision tree was constructed for the management of metachronous hernias that accounted for the occurrence of both nonincarcerated and incarcerated metachronous hernias. Baseline values were estimated from recent reports in the literature. Total charges for each approach were obtained from available hospital records and were used to estimate cost. RESULTS: Observation was favored over laparoscopy and laparoscopy over routine exploration with respect to preventing spermatic cord injury and preserving future fertility. Although a second operation may be required when observation is used, this approach was associated with only a small increase in anesthesia-related complications (1 in 17,847), cardiac arrests (1 in 62,500), and death (1 in 312,500). Although observation was the favored approach with respect to cost, laparoscopy was less expensive when the expected incidence of metachronous hernias was high. CONCLUSIONS: Observation is the preferred approach to metachronous hernias because it results in the lowest incidence of injury and cost for most patients and is associated with a minimal increase in anesthesia-related morbidity and mortality. Laparoscopy may be advantageous for patients at high risk for development of a contralateral hernia. As a strategy for preventing metachronous hernias without consideration for injury or cost, routine exploration should be limited to situations in which laparoscopy cannot be performed because of small patient size or a preference for spinal anesthesia.

Estimating the dollar value of health outcomes from drug-abuse interventions.

OBJECTIVES: People who abuse drugs suffer from a host of medical problems that impose costs on both the abusers and society as a whole. Drug-abuse treatment and other interventions can help alleviate these medical problems, leading to health status improvements for chronic drug users and reduced social costs. The authors' dual purpose here is to (1) propose a theoretically rigorous yet easy-to-apply methodology for estimating the health-related costs of drug abuse and (2) demonstrate the methodology by estimating the potential dollar value of avoiding adverse health consequences as a result of successful drug-abuse interventions. METHODS: The authors' proposed multiattribute quality-adjusted life year methodology for estimating the value of avoiding morbidity and mortality involves eight steps to be followed sequentially. The framework is based on developing a common unit of well-being (i.e., quality-adjusted life year) that can be applied to all types of health conditions. If all health states can be denominated in this common unit, then the process of valuation is straightforward and consistent across all types of illnesses and diseases. The methodology is relatively inexpensive to execute because the estimation procedures are not complicated technically and the data demands are modest. Also, this approach incorporates elements from several disciplines, including psychology, epidemiology, medicine, and economics. Finally, the proposed methodology is flexible enough to cover a wide range of illnesses and diseases so that consistent and comparable estimates can be generated. RESULTS: The authors estimate the dollar value of avoiding acute hepatitis B, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), hypertension, bacterial pneumonia, sexually transmitted diseases, and tuberculosis for a white male aged 32 years. The authors' results illustrate that estimated avoided morbidity values can vary significantly across the range of health consequences associated with drug abuse. At the upper end of the range, the value of avoiding only the morbidity associated with a single case of HIV/AIDS is approximately $157,811 for the period beginning with transmission of HIV, through late-stage HIV and AIDS, and ending just before death. CONCLUSIONS: People who abuse drugs suffer from many medical problems in addition to their addiction. The proposed approach for estimating the dollar value of avoiding adverse health consequences provides policy analysts, evaluators, and researchers a method to calculate theoretically based benefit estimates for use in a benefit-cost analysis of drug-abuse interventions.

Reproductive toxicity assessment by continuous breeding in Sprague-Dawley rats: a comparison of two study designs.

The protocol for Reproductive Assessment by Continuous Breeding (RACB) studies was originally designed to use mice as the test species. However, rats are commonly used for reproductive toxicity research and could be used in the basic RACB design. One of the studies reported below evaluated a standard murine RACB design using rats, which rears the fifth litter to test second generation fertility. The second design tested the logistics and feasibility of rearing the second litter for second generation fertility testing. The standard fifth litter design (L5) was modified slightly for rats by increasing the time allowed for gestation and delivery. Compared to rats rearing their second litter (L2), rats in this L5 design had more litters per pair during continuous breeding and maintained this fertility better over time, as evidenced by producing more pups per litter during the crossover mating segment. Both L2 and L5 rats gave sufficient pups to conduct the second generation fertility evaluation. In addition, the L5 design was easier to conduct and produced pups from gametes exposed to chemical throughout spermatogenesis, making it the preferred design for using rats in Continuous Breeding studies.

Qat use in North Yemen and the problem of addiction: a study in medical anthropology.

Travelers to North Yemen nearly invariably report that Yemeni people are universally addicted to the drug qat and that the problems of the country are related to this. On the other hand, the majority of Yemenis claim that qat is not only harmless, but that it has many virtues. After describing the chemistry of the drug and the customs of use, this paper addresses the question of the concept of addiction in terms of data gathered during an extensive field study of qat use. Questions of latency, tolerance and availability are discussed, while particular attention and data are devoted to an examination of the "analgesic hypothesis." It is concluded that a more complex theory is needed to deal with drug "dependencies" and that social and cultural perspectives must be added to concepts of the physiological and psychological effects of drugs if progress is to be made toward understanding institutional drug use such as is found with regard to qat.