Publications

Clofibric acid (p-chlorophenoxyisobutyric acid) is metabolized in vivo to a thioester-linked glutathione conjugate, S-(p-chlorophenoxyisobutyryl)glutathione (CA-SG). The formation of this metabolite is presumed to occur via transacylation reactions between glutathione (GSH) and reactive acyl-linked metabolite(s) of the drug. The present study examines the chemical reactivity of clofibryl-S-acyl-CoA (CA-SCoA), an acyl-CoA thioester intermediary metabolite of clofibric acid, with GSH to form the CA-SG in vitro. Incubations of CA-SCoA (1 mM) with GSH (5 mM) were carried out at pH 7.5 and 37 degrees C, with analysis of the formed reaction products by isocratic reverse-phase high-performance liquid chromatography (HPLC). Results showed a time-dependent and linear formation of CA-SG up to 4 h (50 microM CA-SG formed/h), and after a 1-day incubation, the reaction mixture contained 0.7 mM CA-SG. The identity of CA-SG was confirmed by analysis of HPLC-purified material by tandem mass spectrometry. The rate of CA-SG formation was found to be increased 3-fold in incubations containing rat liver glutathione S-transferases (4 mg/ml). Analysis of the chemical stability of CA-SCoA in buffer at 37 degrees C and varying pH showed the derivative to be stable under mildly acidic and basic aqueous conditions but to hydrolyze at pH values greater than 10 after a 1-day incubation (t(1/2) = approximately 1 day at pH 10.5). Results from these studies show that CA-SCoA is a reactive thioester derivative of clofibric acid and is able to acylate GSH and other thiol-containing nucleophiles in vitro and, therefore, may be able to acylate protein thiols in vivo, which could contribute to the toxic side effects of the drug.

How frequently should urine samples be collected and analyzed to accurately measure drug use in clinical trials of cocaine abuse treatments? Previous research suggests that analyzing one of three weekly urine toxicology samples in an opiate-related trial may be sufficient. To empirically address this question in the field of cocaine research, we examined the weekly variation in the cocaine metabolite benzoylecgonine (BE) concentration between pairs of weekly urine samples from a clinical trial of a treatment for cocaine dependence. Twice weekly urine samples from 71 subjects collected over eleven weeks were assayed for quantitative BE levels. Agreement between pairs of samples was estimated for both quantitative and qualitative measures of BE. Results indicated substantial intra-week variation with correlations never exceeding .50 and approximately 20% disagreement among samples using cutoff values in place of quantitative levels. Both samples, however, supported similar conclusions about group-level behavior.

BACKGROUND

Agitation occurs in up to 70% of demented patients. Haloperidol has been used for decades to control agitation in dementia, but its effectiveness remains unclear. Previous meta-analyses examined only English language publications or compared haloperidol with other drugs rather than with placebo. To study the effectiveness of haloperidol a more widely based review was performed.

OBJECTIVES

To determine whether evidence supported the use of haloperidol in agitated dementia.

SEARCH STRATEGY

The CDCIG Specialized Register which contains references from medical databases (MEDLINE, EMBASE, PsycInfo and CINAHL) as well as from many trials databases was searched on 26 July 2000 to identify reports of randomised controlled trials on haloperidol treatment of agitation in dementia.

SELECTION CRITERIA

Randomized, placebo-controlled trials, with concealed allocation, where subjects' dementia and agitation were assessed.

DATA COLLECTION AND ANALYSIS

1. Two reviewers extracted data from included trials 2. Data were pooled where possible, and analysed using appropriate statistical methods 3. Odds ratios of average differences were calculated 4. Only 'intention to treat' data were included 5. Analysis included haloperidol treated patients, compared with placebo

MAIN RESULTS

The five included trials led to the following results: 1. There was no significant improvement in agitation among haloperidol treated patients, compared with controls. 2. Aggression decreased among patients with agitated dementia treated with haloperidol; other aspects of agitation were not affected significantly in treated patients, compared with controls. 3. Although two studies showed increased dropouts due to adverse effects among haloperidol patients, there was no significant difference in dropout rates, comparing all haloperidol treated patients with controls. 4. The data were insufficient to examine response to treatment in relation to length of treatment, degree of dementia, age or sex of patients, and cause of dementia.

REVIEWER'S CONCLUSIONS

1. Evidence suggests that haloperidol was useful in the control of aggression, but was associated with increased side effects; there was no evidence to support the routine use of this drug for other manifestations of agitated dementia. 3. Similar dropout rates among haloperidol and placebo treated patients suggested that poorly controlled symptoms, or other factors, may be important in causing treatment discontinuation. 4. Variations in degree of dementia, dosage and length of haloperidol treatment, and in ways of assessing response to treatment suggested caution in the interpretation of reported effects of haloperidol in the management of agitated dementia. 4. The present study confirmed that haloperidol should not be used routinely to treat patients with agitated dementia. Treatment of agitated dementia with haloperidol should be individualized and patients should be monitored for side effects of therapy.

Recent associations between oral health and systemic disease have led to renewed interest in the mouth and its contribution to health outcomes. Many pathways for this relationship have been postulated, among them the potential mediating role of nutrition. The link between various nutrients and systemic disease has been established, but relatively little work has been done in relating oral conditions with nutrition. We searched MEDLINE, from 1966 to July, 2001, to identify articles relating specific oral measures to nutrition outcomes. We included original articles written in English with a sample size greater than 30 that used objective oral health measures. We reviewed a total of 56 articles. Only a small proportion of these studies were methodologically sound. Although many studies were small and cross-sectional, the literature suggests that tooth loss affects dietary quality and nutrient intake in a manner that may increase the risk for several systemic diseases. The impact of tooth loss on diet may be only partially compensated for by prostheses. To date, there is little information relating periodontal disease and oral pain and nutrition. A few studies suggest poorer nutrition among individuals with xerostomia and altered taste. Further, impaired dentition may contribute to weight change, depending on age and other population characteristics. There is a paucity of well-designed studies addressing oral health and nutrition. Before we can acquire a better understanding of how nutrition and oral health interrelate, however, more studies will be required to confirm these associations-preferably longitudinal studies with larger sample sizes and better control of important confounders.

Aortic valve sclerosis (AVS) is associated with myocardial infarction and mortality. Since it is not cost effective to test all patients with AVS for coronary artery disease (CAD), the identification of high-risk patients is important. We developed a morphologic classification system for AVS by transesophageal echocardiography and correlated the subtypes of AVS with the presence of cardiovascular disease. AVS in general was not associated with CAD. However, among patients with mixed nodular and diffuse AVS, the prevalence of CAD and previous coronary artery bypass graft surgery were higher than among those without this mixed type (p = 0.02 and 0.008, respectively). We concluded that the finding of mixed nodular and diffuse AVS identifies patients at increased risk for CAD. Thus, the echocardiographic assessment of AVS morphology is of clinical relevance.

PURPOSE

The purpose of this work was to describe the radiographic and CT findings in patients with respiratory bronchiolitis-associated interstitial lung disease (RB-ILD) and to correlate them with clinical, physiologic, and pathologic features.

METHOD

RB-ILD was proved pathologically in all 21 patients. Sixteen (76%) patients were current smokers, and five (24%) patients were ex-smokers. The mean cigarette consumption was 38.7 pack-years. Chest radiographs and CT scans were semiquantitatively analyzed and correlated with clinical findings, physiologic measures, and a pathologic score of disease extent.

RESULTS

The major radiographic findings were bronchial wall thickening in 16 patients (76%) and ground-glass opacity in 12 patients (57%). The predominant initial CT findings were central bronchial wall thickening (proximal to subsegmental bronchi) in 19 patients (90%), peripheral bronchial wall thickening (distal to subsegmental bronchi) in 18 patients (86%), centrilobular nodules in 15 patients (71%), and ground-glass opacity in 14 patients (67%), None of these CT findings had a significant zonal predominance. Other findings were upper lung predominant centrilobular emphysema (57%) and patchy areas of hypoattenuation (38%) with a lower lung predominance. Radiologic findings were similar in both current and ex-smokers. The amount of ground-glass opacity correlated inversely with arterial oxygen saturation ( r = -0.67, p = 0.04), and the areas of hypoattenuation correlated with alveolar-arterial oxygen gradient ( r = 0.56, p = 0.04). The extent of centrilobular nodules correlated with the extent of macrophages in respiratory bronchioles ( r = 0.53, p = 0.03) and with chronic inflammation of respiratory bronchioles ( r = 0.57, p = 0.02). The extent of ground-glass opacity correlated with the amount of macrophage accumulation in the alveoli and alveolar ducts ( r = 0.56, p < 0.01 and r = 0.54, p = 0.04, respectively). At follow-up CT after steroid treatment and smoking cessation, in nine patients, the extent of bronchial wall thickening, centrilobular nodules, and ground-glass opacity had decreased, but the areas of hypoattenuation had increased (p < 0.05).

CONCLUSION

The CT findings of RB-ILD are centrilobular nodules, ground-glass opacity, and air trapping. These radiologic features, in patients with a history of heavy cigarette smoking, may differentiate RB-ILD from other interstitial lung diseases.