Vaughan, Lisa E.

AbstractIntroductionAdenomyosis is a benign uterine disease where endometrial glands and stroma are found within the myometrium surrounded by an area of hypertrophic myometrium. Symptomatology includes heavy menstrual bleeding and pelvic pain. The pathogenesis of adenomyosis is not known; however, animal models have shown increased uterine concentration of prolactin as a risk factor. Prolactin acts as a smooth muscle cell mitogen. If prolactin is central to adenomyosis pathogenesis, reducing uterine prolactin could be a possible medical treatment option. In this pilot study, we aim to evaluate the effect of bromocriptine, a prolactin inhibitor, on menstrual bleeding and pain in women with adenomyosis.Material and methods23 women with diffuse adenomyosis were enrolled from a university hospital in Sweden and a tertiary care center in the USA. Nineteen patients completed 6 months of treatment with vaginal bromocriptine at a dose of 5 mg daily. Participants completed validated measures at baseline, 3 and 6 months of treatment, and at 9 months (3 months after cessation of bromocriptine). Validated measures utilized included Pictorial Blood Loss Assessment Chart (PBLAC), Aberdeen Menorrhagia Clinical Outcomes Questionnaire (AMCOQ), Visual Analog Scale for pain (VAS), McGill Pain Questionnaire (MPQ), Endometriosis Health Profile (EHP‐30), Female Sexual Function Index (FSFI) and the Fibroid Symptom Quality of Life (UFS‐QOL) symptom severity and health‐related quality of life (HRQL) subscores. Scores were compared between baseline and 9 months using the Wilcoxon signed rank test.ResultsMean age of participants was 44.8 years. About 77.8% reported PBLAC scores >250 and 68.4% reported moderate to severe pain at baseline. Compared with baseline, women had lower 9‐month scores (median [interquartile range] for all) on PBLAC (baseline 349 [292‐645] vs 9‐month 233 [149‐515], P = 0.003), VAS (5.0 [4‐8.3] vs 2.5 [0‐4.5], P < 0.001), EHP Core Pain (15.9 [9.1‐50.0] vs 3.4 [2.3‐34.1], P = 0.029), EHP Core Self‐image (41.7 [16.7‐58.3] vs 25 [0‐5], P = 0.048) and Symptom Severity Score (60 [44‐72] vs 44 [25‐56], P < 0.001) and higher HRQL scores (57 [37‐63] vs 72 [51‐85], P < 0.001) following bromocriptine treatment. Other EHP core parameters and FSFI were not significantly different.ConclusionsSignificant improvement in menstrual bleeding, pain and quality of life after vaginal bromocriptine treatment suggests a novel therapeutic agent for adenomyosis.

ABSTRACT Background Vaginal diazepam is frequently used to treat pelvic floor tension myalgia and pelvic pain despite limited knowledge of systemic absorption. Aim To determine the pharmacokinetic and adverse event profile of diazepam vaginal suppositories. Methods We used a prospective pharmacokinetic design with repeated assessments of diazepam levels. Eight healthy volunteers were administered a 10-mg compounded vaginal diazepam suppository in the outpatient gynecologic clinic. Serum samples were collected at 0, 45, 90, 120, and 180 minutes; 8, 24, and 72 hours; and 1 week following administration of a 10-mg vaginal suppository. The occurrence of adverse events was assessed using the alternate step and tandem walk tests, the Brief Confusion Assessment Method, and numerical ratings. Plasma concentrations of diazepam and active long-acting metabolites were measured. Pharmacokinetic parameters were calculated by standard noncompartmental methods. Results The mean peak diazepam concentration (Cmax) of 31.0 ng/mL was detected at a mean time (Tmax) of 3.1 hours after suppository placement. The bioavailability was found to be 70.5%, and the mean terminal elimination half-life was 82 hours. The plasma levels of temazepam and nordiazepam peaked at 0.8 ng/mL at 29 hours and 6.4 ng/mL at 132 hours, respectively. Fatigue was reported by 3 of 8 participants. Clinical Implications Serum plasma concentrations of vaginally administered diazepam are low; however the half-life is prolonged. Strengths & Limitations Strengths include use of inclusion and exclusion criteria aimed at mitigating clinical factors that could adversely impact diazepam absorption and metabolism, and the use of an ultrasensitive LC-MS/MS assay. Limitations included the lack of addressing the efficacy of vaginal diazepam in lieu of performing a pure pharmacokinetic study with healthy participants. Conclusion Vaginal administration of diazepam results in lower peak serum plasma concentration, longer time to peak concentration, and lower bioavailability than standard oral use. Providers should be aware that with diazepam’s long half-life, accumulating levels would occur with chronic daily doses, and steady-state levels would not be reached for up to 1 week. This profile would favor intermittent use to allow participation in physical therapy and intimacy.

Background and objectives Withdrawal from maintenance hemodialysis before death has become more common because of high disease and treatment burden. The study objective was to identify patient factors and examine the terminal course associated with hemodialysis withdrawal, and assess patterns of palliative care involvement before death among patients on maintenance hemodialysis. Design, setting, participants, & measurements We designed an observational cohort study of adult patients on incident hemodialysis in a midwestern United States tertiary center, from January 2001 to November 2013, with death events through to November 2015. Logistic regression models evaluated associations between patient characteristics and withdrawal status and palliative care service utilization. Results Among 1226 patients, 536 died and 262 (49% of 536) withdrew. A random sample (10%; 52 out of 536) review of Death Notification Forms revealed 73% sensitivity for withdrawal. Risk factors for withdrawal before death included older age, white race, palliative care consultation within 6 months, hospitalization within 30 days, cerebrovascular disease, and no coronary artery disease. Most withdrawal decisions were made by patients (60%) or a family member (33%; surrogates). The majority withdrew either because of acute medical complications (51%) or failure to thrive/frailty (22%). After withdrawal, median time to death was 7 days (interquartile range, 4–11). In-hospital deaths were less common in the withdrawal group (34% versus 46% nonwithdrawal, P =0.003). A third (34%; 90 out of 262) of those that withdrew received palliative care services. Palliative care consultation in the withdrawal group was associated with longer hemodialysis duration (odds ratio, 1.19 per year; 95% confidence interval, 1.10 to 1.3; P <0.001), hospitalization within 30 days of death (odds ratio, 5.78; 95% confidence interval, 2.62 to 12.73; P <0.001), and death in hospital (odds ratio, 1.92; 95% confidence interval, 1.13 to 3.27; P =0.02). Conclusions In this single-center study, the rate of hemodialysis withdrawals were twice the frequency previously described. Acute medical complications and frailty appeared to be driving factors. However, palliative care services were used in only a minority of patients.

Background Atrial fibrillation/flutter ( AF ) produces significant morbidity in women and is typically attributed to cardiac remodeling from multiple causes, particularly hypertension. Hypertensive pregnancy disorders ( HPD s) are associated with future hypertension and adverse cardiac remodeling. We evaluated whether women with AF were more likely to have experienced a HPD compared with those without. Methods and Results A nested case–control study was conducted within a cohort of 7566 women who had a live or stillbirth delivery in Olmsted County, Minnesota between 1976 and 1982. AF cases were matched (1:1) to controls based on date of birth, age at first pregnancy, and parity. AF and pregnancy history were confirmed by chart review. We identified 105 AF cases: mean age 57±8 (mean± SD ) years, (controls 56±8 years), 32±8 years (controls 31±8 years) after the first pregnancy. Cases were more likely to have obesity during childbearing years, and hypertension, diabetes mellitus, dyslipidemia, coronary disease, valvular disease, and heart failure at the time of AF diagnosis. Cases were more likely to have a history of HPD s, compared with controls: 28/105 (26.7%) cases versus 12/105 (11.4%) controls, odds ratio: 2.60 (95% confidence interval, 1.21–6.04). After adjustment for hypertension and obesity, the association was attenuated and no longer statistically significant; odds ratio (95% confidence interval, 2.12 (0.92–5.23). Conclusions Women with AF are more likely to have had a HPD , a relationship at least partially mediated by associated obesity and hypertension. Given the high morbidity of AF , studies evaluating the benefit of screening for and management of cardiovascular risk factors in women with a history of HPD should be performed.

Background and objectives Prior work has suggested a higher risk of hypertension in kidney stone formers but lacked disease validation and adjustment for potential confounders. Certain types of stone formers may also be at higher risk of hypertension. Design, setting, participants, & measurements In our study, incident symptomatic stone formers in Olmsted County from 2000 to 2011 were manually validated by chart review and age and sex matched to Olmsted County controls. We followed up patients through November 20, 2015. Hypertension was also validated by manual chart review, and the risk of hypertension in stone formers compared with controls was assessed both univariately and after adjusting for comorbidities. The risk of hypertension among different subtypes of stone formers was also evaluated. Results Among 3023 coded stone formers from 2000 to 2011, a total of 1515 were validated and matched to 1515 controls (mean age was 45 years old, and 56% were men). After excluding those with baseline hypertension (20% of stone formers and 18% of controls), 154 stone formers and 110 controls developed hypertension. Median follow-up time was 7.8 years in stone formers and 9.6 years in controls. Stone formers were found to have a higher risk of hypertension compared with controls (hazard ratio, 1.50; 95% confidence interval, 1.18 to 1.92), even after adjusting for age, sex, body mass index, serum creatinine, CKD, diabetes, gout, coronary artery disease, dyslipidemia, tobacco use, and alcohol abuse (hazard ratio, 1.58; 95% confidence interval, 1.12 to 2.21). Results were similar after excluding patients who were ever on a thiazide diuretic (hazard ratio, 1.65; 95% confidence interval, 1.16 to 2.38). Stone composition, radiographic stone burden, number of subsequent stone events, and stone removal surgeries were not associated with hypertension ( P >0.05 for all). Conclusions The risk of hypertension was higher after the first symptomatic kidney stone event. However, kidney stone severity, type, and treatment did not associate with hypertension.