Maintained intentional weight loss reduces cardiovascular outcomes: results from the Sibutramine Cardiovascular OUTcomes (SCOUT) trial.

AIM: The Sibutramine Cardiovascular OUTcomes trial showed that sibutramine produced greater mean weight loss than placebo but increased cardiovascular morbidity but not mortality. The relationship between 12-month weight loss and subsequent cardiovascular outcomes is explored. METHODS: Overweight/obese subjects (N = 10 744), ≥55 years with cardiovascular disease and/or type 2 diabetes mellitus, received sibutramine plus weight management during a 6-week Lead-in Period before randomization to continue sibutramine (N = 4906) or to receive placebo (N = 4898). The primary endpoint was the time from randomization to first occurrence of a primary outcome event (non-fatal myocardial infarction, non-fatal stroke, resuscitated cardiac arrest or cardiovascular death). RESULTS: For the total population, mean weight change during Lead-in Period (sibutramine) was -2.54 kg. Post-randomization, mean total weight change to Month 12 was -4.18 kg (sibutramine) or -1.87 kg (placebo). Degree of weight loss during Lead-in Period or through Month 12 was associated with a progressive reduction in risk for the total population in primary outcome events and cardiovascular mortality over the 5-year assessment. Although more events occurred in the randomized sibutramine group, on an average, a modest weight loss of approximately 3 kg achieved in the Lead-in Period appeared to offset this increased event rate. Moderate weight loss (3-10 kg) reduced cardiovascular deaths in those with severe, moderate or mild cardiovascular disease. CONCLUSIONS: Modest weight loss over short-term (6 weeks) and longer-term (6-12 months) periods is associated with reduction in subsequent cardiovascular mortality for the following 4-5 years even in those with pre-existing cardiovascular disease. While the sibutramine group experienced more primary outcome events than the placebo group, greater weight loss reduced overall risk of these occurring in both groups.

Prediction of response to sibutramine therapy in obese non-diabetic and diabetic patients.

BACKGROUND: Early weight loss is generally considered to predict long-term weight outcome in obese patients, and this is reflected in prescribing guidelines for antiobesity drugs. For example, the current prescribing guidelines for the antiobesity drug, sibutramine, indicate that if patients have not lost 2 kg (or 4 lb) in the first 4 weeks of treatment with sibutramine 10 mg, the physician should re-evaluate the therapy, which may result in increasing the dose to 15 mg or discontinuation. This regimen may deny treatment to a large group of patients who might otherwise benefit, particularly patients with type 2 diabetes who often find it more difficult to lose weight than non-diabetic obese individuals. MATERIALS: We have re-analysed pooled data from seven randomized, controlled studies of sibutramine-induced weight loss and maintenance in which patients (n = 928; 75% female) had taken sibutramine 10 or 15 mg continuously for 12 months, in order to determine the predictors of success in weight loss (defined as loss of at least 5% of initial body weight at Month 12) in both diabetic and non-diabetic patients. Sensitivity and specificity analyses were used to calculate optimal predictive values. RESULTS: In both diabetic and non-diabetic patients, weight loss of 4 kg at 3 months was identified as the optimal predictor for achieving at least 5% weight loss at 12 months. This target was associated with the best average values for sensitivity, specificity and accuracy, as well as high positive (78% vs. 84% for non-diabetics and 76% vs. 85% for diabetics, compared to existing guidelines target of 2 kg after 1 month treatment) and negative predictive values (63% vs. 71% for non-diabetics; 52% vs. 70% for diabetics). CONCLUSION: Sibutramine, in conjunction with diet and exercise, should be continued for at least 3 months (providing there are no adverse effects) to determine whether or not patients are likely to achieve a clinically valid outcome at 1 year. This highlights the need to ensure that regulatory restrictions reflect the needs of clinical practice.

Antihistamine prophylaxis permits rapid vancomycin infusion.

OBJECTIVE: To determine whether pretreatment with intravenous antihistamines attenuates the symptoms of red-man syndrome associated with rapid vancomycin administration. DESIGN: Prospective, randomized, double-blinded, placebo-controlled study of patients undergoing elective arthroplasty. SETTING: Preoperative unit in a tertiary care center. PATIENTS: Forty preoperative patients (American Society of Anesthesiologists status I-III, receiving vancomycin prophylaxis for elective prosthetic joint replacement or revision. INTERVENTIONS: Elective orthopedic patients were randomly allocated to receive intravenous antihistamines (diphenhydramine, 1 mg/kg, and cimetidine, 4 mg/kg) or placebo before rapid vancomycin infusion (1 g over 10 mins). Hemodynamic measurements, symptoms of histamine release, and plasma histamine levels were obtained in each patient during vancomycin administration. Rapid vancomycin infusion was discontinued in cases of decreases in mean blood pressure of > or =20% or intolerable itching. MEASUREMENTS AND MAIN RESULTS: Clinical symptomatology of red-man syndrome and histamine levels were assessed using Fisher's exact test or Student's t-test. Comparison of baseline and peak histamine levels for both the treated (mean +/- SD, 0.2 +/- 0.2 vs. 4.7 +/- 2.4 ng/mL; p < .0001) and placebo patients (mean +/-SD, 0.2 +/- 0.1 vs. 3.5 +/- 3.4 ng/mL; p = .0002) was statistically significant. Although there was a significant increase in plasma histamine levels during vancomycin infusion, it did not differ between the treatment groups. Only two (11%) of the treated patients developed hypotension, vs. 12 (63%) of the placebo patients (p = .002). Rash was partially attenuated. Twelve (63%) of the treated patients developed rash, compared with 19 (100%) of the placebo patients (p = .008). The rapid infusion was discontinued in two (11%) of the treated patients, compared with 11 (58%) of the placebo patients (p = .005). Four treated patients had no symptoms of histamine release. CONCLUSIONS: Pretreatment with intravenous H1 and H2 antihistamines permitted rapid vancomycin administration in 89% of treated patients. Although protection was incomplete, rash did not predict a need to stop the rapid infusion of vancomycin in our patients.

Oral antihistamines reduce the side effects from rapid vancomycin infusion.

UNLABELLED: Rapid infusion of vancomycin causes histamine-mediated side effects, hypotension, and rash, known as "red man syndrome." In this prospective, randomized, double-blind, placebo-controlled study, we examined the ability of oral antihistamines to attenuate three clinical end points: rash, hypotension, and vancomycin discontinuation, and we compared these findings with those of a similar study using IV antihistamines. Patients (ASA physical status I-III) who required vancomycin prophylaxis for elective arthroplasty received either oral antihistamines (diphenhydramine < or = 1 mg/kg and cimetidine < or = 4 mg/kg, n = 20) or placebo (n = 10) 1 h before rapid vancomycin infusion (1 g over 10 min). The vancomycin infusion was discontinued if the mean arterial blood pressure decreased by > or = 20% or if itching was intolerable for the patient. Clinically significant hypotension developed in no treated patients, compared with five (50%) patients in the placebo group (P = 0.001). Rapid infusion was stopped for one treated patient (5%) and for five (50%) patients in the placebo group (P = 0.004). Incidence (P = 0.011) and severity of rash (P = 0.015) were also reduced in treated patients. Peak histamine levels were increased but were similar for patients in both groups (mean +/- SD, 1.9+/-2.5 vs 1.6+/-2.4 ng/mL; P = 0.75). Oral antihistamines were as effective as IV antihistamines. In conclusion, oral H1 and H2 antihistamine pretreatment is a practical, safe, and inexpensive option to attenuate histamine-mediated side effects associated with rapid vancomycin infusion. IMPLICATIONS: Clinicians often must administer vancomycin faster than the 1-h recommended time, which can cause "red man syndrome" (rash, itching, hypotension). Our randomized, double-blind, placebo-controlled study showed that oral H1 and H2 antihistamine pretreatment significantly reduced the histamine-related side effects of rapid vancomycin infusion.

Tryptase levels are not increased during vancomycin-induced anaphylactoid reactions.

BACKGROUND: Anaphylaxis, mediated by immunoglobulin E, may be clinically indistinguishable but is mechanistically different than chemically mediated anaphylactoid reactions induced by drugs such as morphine, curare, and vancomycin. A test to distinguish anaphylactic from anaphylactoid reactions would clarify therapeutic and medicolegal issues. Tryptase levels identify anaphylactic reactions but have not been evaluated in vivo during anaphylactoid reactions. A prospective, randomized, double-blinded, placebo-controlled trial of antihistamine chemoprophylaxis for rapid vancomycin infusion was performed, and plasma tryptase was measured using a new immunoassay. Histamine release was established by measurement of plasma histamine and the ability of prophylactic H1 and H2 antagonists to prevent common histamine-associated side effects. Tryptase levels were compared with histamine levels and clinical symptoms. METHODS: Before elective arthroplasty, 40 patients received vancomycin infusion (1 g over 10 min) and pretreatment with either antihistamines (1 mg/kg diphenhydramine and 4 mg/kg cimetidine) or placebo. Changes in tryptase (at peak histamine and 10 min after vancomycin infusion), histamine levels, and histamine-mediated symptoms were assessed using Fisher's exact test, the Student's t test, or the paired t test, as appropriate. Logistic regression models were used to quantify the association of clinical symptoms with antihistamine treatment and serum levels. RESULTS: Plasma tryptase levels were unchanged (99% CI, -0.5 to 1.6) independent of increased histamine levels, antihistamine pretreatment, clinical symptoms, or all of these. Histamine levels >1 ng/ml were significantly associated with hypotension, moderate-to-severe rash, and stopped infusion. Antihistamine pretreatment significantly decreased the incidence and severity of the reactions. CONCLUSION: Plasma tryptase levels were not significantly elevated in confirmed anaphylactoid reactions, so they can be used to distinguish chemical from immunologic reactions.

Isolation of nephrocalcin from kidney tissue of nine vertebrate species.

Nephrocalcin (NC), a urinary calcium oxalate monohydrate (COM) crystal growth inhibitor, was purified from kidneys of nine vertebrate species including humans. All isolates were glycoproteins with high contents of aspartic and glutamic acids and small amounts of basic and aromatic amino acids. Carbohydrate contents ranged from 4 to 16 wt% among the different species, but all contained fucose, mannose, galactose, glucose, galactosamine, glucosamine, and N-acetylneuraminic acid. Although amino acid and carbohydrate compositions were similar, dissociation constants derived from calcium oxalate monohydrate inhibition varied between 10(-7) and 10(-8) M, and highest affinity could be related to highest ability of the kidney of origin to concentrate urine. Using an antibody raised against NC from human kidney tissue culture medium, we found strong immunoreactivity with two species, pigs and sheep. Thus far all vertebrate kidneys possess COM growth-inhibiting material that seems to be of glycoprotein character, and all the glycoproteins isolated so far share similar features, suggesting NC-like proteins are a well-conserved trait.

In vitro acid production from starch and sucrose in saliva.

There was a wide range in the amounts of acid given by the assorted starch foods that were tested. In descending order, the amounts of acid formed were: boiled potato (2.50 +/- 0.10), "special wheat" bread (2.24 +/- 0.68), English muffin (2.19 +/- 0.00), raw potato (2.13 +/- 0.03), yellow cake (2.02 +/- 0.08), plain wheat flour (1.83 +/- 0.03), phosphate-enriched wheat flour (1.83 +/- 0.03), bagel (1.67 +/- 0.05), soft white bread (1.39 +/- 0.05), Italian bread (1.35 +/- 0.08), and pumpernickel bread (1.26 +/- 0.03).

Negative co-operativity in glutamate dehydrogenase. Involvement of the 2-position in glutamate in the induction of conformational changes.

The 2-position substituent on substrates or substrate analogues for glutamate dehydrogenase is shown to be intimately involved in the induction of conformational changes between subunits in the hexamer by coenzyme. These conformational changes are associated with the negative co-operativity exhibited by this enzyme. 2-Oxoglutarate and L-2-hydroxyglutarate induce indications of co-operativity similar to those induced by the substrate of oxidative deamination, glutamate, in kinetic studies. Glutarate (2-position CH2) does not. A comparison of the effects of L-2-hydroxyglutarate and D-2-hydroxyglutarate or D-glutamate indicates that the 2-position substituent must be in the L-configuration for these conformational changes to be triggered. In addition, glutarate and L-glutamate in ternary enzyme-NAD(P)H-substrate complexes induce very different coenzyme fluorescence properties, showing that glutamate induces a different conformation of the enzyme-coenzyme complex from that induced by glutarate. Although glutamate and glutarate both tighten the binding of reduced coenzyme to the active site, the effect is much greater with glutamate, and the binding is described by two dissociation constants when glutamate is present. The data suggest that the two carboxy groups on the substrate are required to allow synergistic binding of coenzyme and substrate to the active site, but that interactions between the 2-position on the substrate and the enzyme trigger the conformational changes that result in subunit-subunit interactions and in the catalytic co-operativity exhibited by this enzyme.