Search

Objectives: To quantify patient preferences for endometriosis-associated pain treatments and risk tolerance in exchange for pain reduction and to explore whether preferences vary on the basis of patient characteristics., Methods: US women with a self-reported physician diagnosis of endometriosis and moderate to severe dysmenorrhea and nonmenstrual pelvic pain (NMPP) completed an online discrete choice experiment survey. Each choice question had a pair of hypothetical treatments characterized by attributes with varying levels: improvements in severe dysmenorrhea, severe NMPP, and severe dyspareunia; mode of administration; and treatment-related risks of pregnancy-related problems, bone fracture later in life, and moderate to severe hot flashes. A random-parameters logit model was used to quantify preferences and the attributes' conditional relative importance., Results: A total of 250 women (mean age 34 years) completed the survey. The conditional relative importance of attributes was 3.66 for risk of moderate to severe hot flashes among respondents with and 3.58 among respondents without experience with moderate to severe hot flashes; 1.70, 1.49, and 1.48 for improvements in dyspareunia, NMPP, and dysmenorrhea, respectively; 0.60 for risk of pregnancy-related problems; 0.53 for mode of administration; and 0.49 for bone fracture risk. Preference weights for bone fracture risk levels were not statistically significantly different. In exchange for a greater improvement in dysmenorrhea from severe to mild (vs moderate), respondents without a history of hot flashes accepted a greater increase in the risk of moderate to severe hot flashes (38%) than did respondents with this history (16%)., Conclusions: Respondents placed the greatest weight on risk of hot flashes, followed by improvements in dyspareunia, NMPP, dysmenorrhea. Bone fracture risk did not drive preferences., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

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.

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.

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.