GR 38032F (Ondansetron), a selective 5HT3 receptor antagonist,slows colonic transit in healthy man

The newly recognized class of 5-hydroxytryptamine receptors (5HT₃) may be involved in the induction of nausea, since their pharmacological antagonists are effective against emesis induced by chemotherapy. 5HT₃ receptors are present on enteric neurons, and 5HT₃ blockers may produce mild constipation; we thus hypothesized that 5HT₃ receptors would modulate colonic motility. To determine if GR 38032F, a selective 5HT₃ antagonist known to have antiemetic effects, influences colonic transit in health, a randomized, double-blind, placebo-controlled crossover study was performed. Using a radiopaque marker technique, colonic transit was quantified in 39 healthy volunteers (19 men, 20 nonpregnant women) 18–70 years of age. On a standard 25-g fiber diet, 16 mg of GR 38032F was given orally thrice daily. Gastrointestinal peptides (peptide YY, human pancreatic polypeptide, neurotensin, motilin, gastrin-cholecystokinin, substance P) were also measured in plasma fasting and postprandially. Mean total colonic transit time on placebo was 27.8 hr, while on GR 38032F it was 39.1 hr (P<0.0005). Transit times through the left colon (P<0.0005) and rectosigmoid (P<0.05) were prolonged by the drug, but right colonic transit was not significantly altered. Transit times did not correlate with age or gender, but subjects with shorter transit times were significantly more affected than were those with longer transit times. The peak release of peptide YY was minimally decreased following GR 38032F (P<0.01), but the peak and integrated postprandial responses of human pancreatic polypeptide, neurotensin, motilin, gastrin-cholecystokinin, and substance P were not significantly altered by the drug. We conclude that 5HT₃ receptors may be involved in the regulation of colonic transit in healthy man.Supported in part by a grant from Glaxo Group Research, Ltd., and the Mayo Digestive Disease Center (grant DK34988, National Institutes of Health, Bethesda, Maryland).Presented, in part, at the American Motility Socicty in October 1988, and published as an abstract inGastroenterology 95:891, 1988.     

Detection of ischemic myocardium in vivo through the chest wall by quantitative ultrasonic tissue characterization

Quantitative analysis of ultrasound offers a potentially valuable method for noninvasive differentiation of specific types of cardiac disease and for assessment of their severity. Clinical application necessitates quantitative measurement of the ultrasonic properties of myocardium through the chest wall. This study was designed to determine whether such measurements could be made noninvasively with the aid of conventional M mode echocardiographic guidance and to characterize the quantitative effects of intervening tissue (chest wall) on the ultrasonic signals backscattered by ischemic and normal myocardium. Frequency-dependent ultrasonic backscatter (2 to 7 MHz) from normal myocardium was measured in dogs in vivo through the closed chest with the use of M mode guidance and with the chest open, directly from the myocardium. Closed-chest and open-chest measurements were repeated after ligation of the left anterior descending coronary artery in the same animals. Closed-chest data were compensated by correcting for the average value for the slope of the attenuation-frequency function of chest wall, which was determined from measurements obtained by analysis on excised tissue. Compensated closed-chest measurements correlated with measurements obtained from the epicardial surface of the heart. The differentiation of normal from ischemic myocardium with both the closed- and open-chest measurements was consistent (p < 0.005). The successful differentiation of normal from ischemic myocardium by determination of quantitative backscatter through the intervening chest wall supports the concept that tissue characterization by quantitative analysis of backscattered ultrasound is a potentially useful, clinically applicable approach to noninvasive detection and differentiation of intrinsic properties of normal and diseased myocardium.     

Diagnosis of sulfonamide hypersensitivity reactions by in-vitro "rechallenge" with hydroxylamine metabolites

STUDY OBJECTIVE: To determine whether differences in in-vitro detoxification of sulfonamide-reactive metabolites can be detected among the lymphocytes from controls, patients with sulfonamide hypersensitivity reactions, and patients with nonhypersensitivity reactions to the sulfonamide agents. DESIGN: In-vitro toxicity assay on lymphocytes. SETTING: Clinics for adverse drug reactions in an adult and pediatric tertiary care center. PATIENTS: Peripheral blood lymphocytes were obtained from 46 normal volunteers and 76 patients referred to the clinic for assessment of adverse drug reactions to sulfonamide agents. Thirty-one patients had clinical histories consistent with a diagnosis of hypersensitivity reaction, whereas 45 patients had clinical histories felt to be inconsistent with a diagnosis of hypersensitivity reaction. INTERVENTIONS: Lymphocytes were assayed with tetrazolium to determine toxicity from the hydroxylamine of sulfamethoxazole. MEASUREMENTS AND MAIN RESULTS: The lymphocytes from patients with a history of hypersensitivity reactions showed markedly increased toxicity across a tenfold-concentration toxicity-concentration curve compared with those from controls and patients with a history of nonhypersensitivity reactions. These differences were highly significant (P less than 0.01). No difference was found between the toxicity shown by the lymphocytes from controls and that shown by the lymphocytes from patients with a history of nonhypersensitivity reactions. CONCLUSIONS: Metabolic differences in the production and detoxification of reactive metabolites of sulfonamide agents are important determinants of hypersensitivity reactions to these agents. These results suggest that the hydroxylamine derivative of sulfamethoxazole may be a reactive metabolite mediating these reactions. Sulfonamide hydroxylamines are useful in the diagnosis and study of the pathogenesis of hypersensitivity reactions to sulfonamide agents.     

ras and c-myc protein expression in colorectal carcinoma

This study was performed to determine the correlation of tumor ras and c-myc oncogene expression with clinical and prognostic variables in patients prone to develop colorectal cancer. One hundred eighteen patients with colorectal cancer were studied; mean age was 40 years. Fifty-three were young patients (age 40 or less), 49 had ulcerative colitis, and 16 had multiple polyposis coli. Immunoperoxidase stains of paraffin-embedded cancer sections were performed for the c-myc and ras proteins. ras staining was found to correlate with Dukes stage and prognosis. Patients with tumors negative for ras protein stain had an actuarial five-year survival of 61 percent versus 44 percent for those tumors with a positive stain (P less than 0.05). This correlation was not seen with the c-myc stain. Positive ras oncogene stain appears to be a useful indicator of advanced stage and poor prognosis in colorectal cancer occurring in cancer-prone patients.     

Quality of life in bridge-to-transplant patients with chronic heart failure after implantation of an axial flow ventricular assist device

Research suggests that ventricular assist devices improve quality of life for congestive heart failure patients awaiting heart transplantation. Axial flow ventricular assist devices like the Jarvik 2000 (Jarvik Heart, Inc., New York, NY) represent the newest type of ventricular assist device technology, but their effects on quality of life are not well understood. Therefore, the authors administered the Minnesota Living with Heart Failure Questionnaire to patients who had the Jarvik 2000 implanted as a bridge to heart transplantation. Patients completed the Minnesota Living with Heart Failure Questionnaire immediately before device implantation, 1 month after implantation, immediately before heart transplantation, and 1 month after transplantation. One month after implantation of the device, the nine patients who completed the study showed significant improvements in physical (p<0.008), emotional (p<0.02), and overall (p<0.008) quality of life. These improvements were maintained until the device was explanted. The authors conclude that implantation of the Jarvik 2000 ventricular assist device can substantially improve quality of life for patients awaiting heart transplantation.     

Alternative scoring of the Cutaneous Assessment Tool in juvenile dermatomyositis: results using abbreviated formats

OBJECTIVE: The Cutaneous Assessment Tool (CAT) is a comprehensive, semiquantitative tool for the assessment of skin disease in juvenile dermatomyositis (DM). The goal of this study was to determine whether alternative scoring methods would shorten the CAT without compromising its measurement characteristics. METHODS: A total of 113 children with juvenile DM were assessed at baseline; 94 were assessed again 7-9 months later. Interrater reliability, internal consistency, construct validity, and responsiveness were obtained using the original scoring method and 2 alternative methods: the maximum and binary scoring methods. RESULTS: Spearman's correlations of the maximum and binary methods with the original were both 0.98 (P < 0.0001) for the CAT activity score, and 0.96 and 0.98, respectively (P < 0.0001), for the CAT damage score. Values obtained for interrater reliability, internal consistency, construct validity, and responsiveness were similar for all 3 scoring methods. Although there was a trend toward the maximum method having higher interrater reliability and the binary method having higher responsiveness, the confidence intervals were overlapping and no statistically significant differences were observed. Correlation coefficients for the 3 scoring methods with other measures of myositis disease activity and damage were very similar. CONCLUSION: The maximum and binary methods of scoring the CAT have measurement characteristics similar to the original method. Adoption of one of these abbreviated scoring methods should increase its acceptability to clinicians and researchers.     

Relationship of high density lipoprotein cholesterol with total and free testosterone and sex hormone binding globulin

A cross-sectional study was performed to see if the previously described association between high density lipoprotein (HDL) cholesterol and plasma total testosterone concentration reflected a relationship with free testosterone or with sex hormone binding globulin (SHBG). In 295 employed middle-aged men, measurements were made of total testosterone and SHBG in serum and of testosterone in saliva, and also of plasma total and HDL cholesterol, plasma triglycerides and other factors which might influence HDL cholesterol levels such as body mass index, alcohol and smoking habits and thyroid hormone levels. In a multiple regression analysis using the GLIM package programme total testosterone concentrations had a persistent positive association with HDL cholesterol (t = 3.5, P less than 0.001) - this association was independent of SHBG (which had a negative association with HDL: t = -1.8, P less than 0.07. The association of HDL cholesterol with testosterone was independent of and stronger than the association of HDL cholesterol with body mass index, alcohol intake and cigarette smoking. Salivary testosterone (a measure of the circulating free hormone) also had a positive independent association with HDL cholesterol. The relationship between HDL cholesterol and testosterone thus appears to reflect an association with circulating hormone levels rather than with the hormone binding globulin.     

Alpha-1 antitrypsin deficiency: A conformational disease associated with lung and liver manifestations

Summary Alpha-1 antitrypsin (A1AT) is a serine anti-protease produced chiefly by the liver. A1AT deficiency is a genetic disorder characterized by serum levels of less than 11 μmol/L and is associated with liver and lung manifestations. The liver disease, which occurs in up to 15% of A1AT-deficient individuals, is a result of toxic gain-of-function mutations in the A1AT gene, which cause the A1AT protein to fold aberrantly and accumulate in the endoplasmic reticulum of hepatocytes. The lung disease is associated with loss-of-function, specifically decreased anti-protease protection on the airway epithelial surface. The so-called ‘Z’ mutation in A1AT deficiency encodes a glutamic acid-to-lysine substitution at position 342 in A1AT and is the most common A1AT allele associated with disease. Here we review the current understanding of the molecular pathogenesis of A1AT deficiency and the best clinical management protocols. Competing interests: None declared References to electronic databases: Alpha 1-antitrypsin deficiency: +107400. C.M. Greene and S.D.W. Miller contributed equally to the work.     

Cardiovascular risk markers in hypothalamic amenorrhoea

OBJECTIVE: To determine whether women with oestrogen deficiency due to hypothalamic amenorrhoea (HA) would demonstrate a lipid and lipoprotein pattern similar to that seen in menopause with higher total cholesterol (TC), LDL, triglyceride and Lp(a) and lower HDL levels than women with regular menstrual cycles. DESIGN: Cross-sectional. PATIENTS: Fifty subjects: 21 women with HA and 30 eumenorrhoeic controls (NL) matched for age, BMI and fat-free mass. MEASUREMENTS: Lipid and lipoprotein levels. RESULTS: There was a significant difference in Lp(a) levels in the HA group between women with >19% fat intake and those <19% fat intake (352+/-231 vs. 116+/-62 mg/l, P = 0.006). Percent fat intake was the most significant determinant of Lp(a) levels in HA, accounting for 51% of the variation in Lp(a) levels. Mean HDL levels were higher in the women with HA compared with the controls (1.3+/- 0.3 vs. 1.1+/-0.2 mmol/l, P = 0.002). There was no significant difference between the groups in TC [4.4+/-0.9 (HA) vs. 4.1+/-0.8 mmol/l (NL), P>0.05], LDL [2.8+/-0.6 (HA) vs. 2.7+/-0.7 mmol/l (NL), P>0.05], triglycerides [1.8+/-0.5 (HA) vs. 1.7+/-0.5 mmol/l (NL), P>0.05] or Lp(a) [234+/-199 (HA) vs. 247+/-222 (NL) mg/l, P>0.05] levels. CONCLUSION: Reduced Lp(a) levels were associated with low dietary fat in women with HA. Moreover, in contrast to menopausal oestrogen deficiency, young women with HA and oestrogen deficiency have increased levels of HDL and no increases in TC, LDL and triglycerides. These data suggest that the negative effects of oestrogen deficiency on cardiovascular risk factors may be modified in women with hypothalamic amenorrhoea.     

NADPH oxidase activity and function are profoundly greater in cerebral versus systemic arteries

Recent studies suggest that the superoxide generating enzyme NADPH oxidase may play a functional role in regulating cerebral vascular tone. We tested whether the activity, function, and expression of NADPH oxidase differs between rat cerebral and systemic arteries. Superoxide production by basilar (BA), middle cerebral (MCA), carotid (CA), renal (RA), and mesenteric (MA) arteries and aorta (AO) was measured using lucigenin-enhanced chemiluminescence. Superoxide production from NADPH oxidase was localized and semiquantified using dihydroethidium. Vascular functional responses were assessed in a myograph or organ bath. Vascular Nox4 protein expression was measured using Western blotting. Superoxide production (basal or in response to NADPH or angiotensin II) in the intracranial arteries, BA, and MCA was 10- to 100-fold greater than in AO, CA, RA, or MA. Similar results were found using either intact vessels or arterial homogenates, and were associated with 10-fold greater expression of Nox4 in the BA versus AO, CA, and MA. Superoxide production was attenuated by the NADPH oxidase inhibitors, diphenyleneiodonium, apocynin, and gp91ds-tat. NADPH and H2O2 were strong relaxing stimuli in the BA, where the H2O2 scavenger catalase, as well as apocynin, attenuated these relaxations and also augmented contractions to angiotensin II. NADPH oxidase activity is markedly higher in intracranial versus systemic arteries, in association with higher Nox4 expression. In cerebral arteries, endogenous H2O2 derived from NADPH oxidase activation appears to cause relaxation and is able to offset angiotensin II-induced constriction. These data are consistent with the concept that NADPH oxidase-derived reactive oxygen species modulate cerebral vascular tone under physiological conditions.