Population pharmacokinetics of valproic acid concentrations in elderly nursing home residents

The objective of this study was to identify factors that affect valproic acid (VPA) apparent clearance (CL/F) in elderly nursing home residents. Inclusion criteria included residency in a nursing home for at least 2 months, aged 65 years or older, a stable dosing regimen of VPA for at least 4 weeks, VPA concentration, and complete dosing information. CL/F was analyzed by a nonlinear mixed effects model. A one-compartment model with first-order absorption and elimination was used. Both volume and absorption rate constant were fixed (14 L and 1 hr, respectively). Covariates were tested by forward inclusion and backward elimination. Interindividual variability in clearance was estimated using an exponential error model and expressed as a coefficient of variation. Residual error was estimated using a combined additive and constant coefficient of variation error model. The study consisted of 405 observations from 146 (52 men, 94 women) elderly nursing home residents. CL/F was not affected by age or weight. The population CL/F was 0.843 L/hr. CL/F was 1) 27% lower in female residents; 2) 41% greater when the resident was on concomitant metabolic inducers carbamazepine or phenytoin cotherapy; and 3) 25% greater when the syrup formulation was used. Variability in CL/F was 32.9%. Coefficient of variation and standard deviation of the residual error were 18.2% and 10.6 mg/L, respectively. The increased CL/F in patients taking VPA syrup may be the result of a decreased bioavailability (F) rather than an increased CL that could be associated with pathology requiring use of the syrup rather than an inherent property of the drug formulation. The results from this study may be useful for individualizing dose regimens in the nursing home population based on patient-specific factors.     

Efficacy and safety of standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg in primary hypertension: A randomized,double-blind,active-controlled,multicenter phase 3 trial

The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double-blind, active-controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are −19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and −11.4 ± 14.7 mm Hg (TEL/AML) (p < .0001). The achievement rates of target BP (53.8% vs. 37.8%, p = .0017) and responder rate (54.8% vs. 35.6%, p = .0001) at week 8 were significantly higher in TEL/AML/CHTD. There are no serious adverse event and no one discontinued medication due to adverse event. Among the TEL 80/AML5/CHTD25mg treatment group, patients of female or age ≥ 65 years old showed higher rate of target BP achievement than relatively young male. (61.4 vs. 46.8%, p = .042) Our study showed standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg is efficacious and safe in treatment of primary hypertension. Target BP achievement with triple therapy would be facilitated in female or old age.     

Risk of bleeding-related complications after kidney biopsy in patients with systemic lupus erythematosus

Clinical Rheumatology - Kidney biopsy is essential for the diagnosis and classification of lupus nephritis. Percutaneous biopsy has a risk of bleeding-related complications; however, data on the...     

Incidence and Risk of Venous Thromboembolism in Bisphosphonates and Selective Estrogen Receptor Modulators Treatment in Korea

BackgroundSelective estrogen receptor modulators (SERMs) were associated with an increased risk of venous thromboembolism (VTE) due to the estrogen effect. In this study, we investigated the effect of SERMs on VTE compared to bisphosphonates (BPs) using the Korean National Health Insurance claims database.MethodsThis was a retrospective cohort study. Women over 50 years old who were first prescribed BPs or SERMs for osteoporosis treatment in 2012 were included. The difference in VTE incidence between the SERMs and BP groups was compared. Both groups were followed up for VTE or PE occurrence, death, or until December 2016. The study population was analyzed by 3:1 matching according to age using a multivariate Cox model.ResultsThe hazard ratio (HR) for VTE was 0.72 (95% confidence interval [CI], 0.40–1.28) in the SERMs group compared to BP group. Older age (60–69 vs. 50–59 years: HR, 3.77; 95% CI, 2.07–6.86 and 70–79 vs. 50–59 years: HR, 5.88; 95% CI, 3.14–11.02), major osteoporotic fracture (HR, 1.77; 95% CI, 1.16- 2.70), atrial fibrillation (HR, 3.31; 95% CI, 1.35–8.11), and estrogen replacement (HR, 3.40; 95% CI, 2.01–5.73) all increased VTE risk. In subgroup analysis of the SERMs group, past hospitalization (HR, 2.24; 95% CI, 1.02–4.92), estrogen replacement (HR, 5.75; 95% CI, 2.29–14.39), and glucocorticoid replacement (HR, 2.71; 95% CI, 1.05–7.0) increased VTE risk.ConclusionSERMs did not increase the risk of VTE compared to BPs in Koreans with osteoporosis. However, old age and estrogen replacement both increased VTE risk.     

Chronic administration of udenafil, a selective phosphodiesterase type 5 inhibitor, promotes erectile function recovery in an animal model of bilateral cavernous nerve crush injury

IntroductionPreservation of the cavernous nerves (CNs) during radical prostatectomy is crucial for the patient's erectile function. Despite advances in operative technique, the majority of men report compromised erectile function postprostatectomy or complete loss of potency due to CN trauma even with nerve-sparing modifications.AimThis study was designed to investigate whether repeated dosing of udenafil, a phosphodiesterase type 5 inhibitor, helps to improve erectile function after CN injury.MethodsUsing the CN crush injury model, 8-week-old male Sprague Dawley rats were divided into the following groups; sham-operated group, bilateral CN crush injury exposed to either no udenafil (vehicle) or udenafil (5, 20 mg/kg) daily for two different durations (4 and 8 weeks, p.o.).Main Outcome MeasuresAt both time points, CN electrical stimulation was used to assess erectile function by measuring the intracavernous pressure. The expressions of hypoxia-inducible factor 1-alpha (HIF-1α), transforming growth factor-beta (TGF-β1), nerve growth factor (NGF), endothelin B receptor (ET_B), endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and sonic hedgehog homolog (SHH) in penile tissue were examined. Immunohistochemical antibody staining was performed for NGF, eNOS, nNOS, CD31, and alpha-smooth muscle actin (α-SMA). Additionally, terminal deoxynucleotidyl transferase-mediated nick-end labeling assay was performed to quantify apoptosis and the tissue slides were stained for Masson's trichrome to assess the smooth muscle/collagen ratio.ResultsUdenafil improved erectile function in a dose- and time-dependent manner with the maximum erectile function recovery achieved by 20 mg/kg udenafil at an 8-week time point. CN injury increased the expression of HIF-1α, TGF-β1, NGF, and ET_B, however, decreased the expression of eNOS, nNOS, and SHH. Udenafil significantly suppressed these alterations. The results from the histological analyses show that udenafil markedly reduces apoptosis induced by CN injury and augments the smooth muscle/collagen ratio.ConclusionsCN injury induces significantly impaired erectile function and altered gene/protein expression. Chronic administration of udenafil preserves erectile function and has a beneficial role against the pathophysiological consequences of CN injury. Lee C-H, Kim H-S, Goo M-J, Kang K-K, Ahn B-O, Kim SH, and Yang D-Y. Chronic administration of udenafil, a selective phosphodiesterase type 5 inhibitor, promotes erectile function recovery in an animal model of bilateral cavernous nerve crush injury.     

A therapeutic confirmatory study to assess the safety and efficacy of Zydena (udenafil) for the treatment of erectile dysfunction in male patients with diabetes mellitus

IntroductionPatients with diabetes mellitus (DM) are reported to experience more severe erectile dysfunction (ED) symptoms and respond less to ED treatments compared with patients with ED of other etiologies.AimThis study was undertaken to evaluate the safety and efficacy of udenafil for the treatment of ED in a larger number of patients with DM.MethodsA placebo‐controlled, randomized, double‐blind, double‐dummy, parallel‐group design multicenter study, fixed‐dose trial was conducted. The trial involved seven study sites in Korea, with 174 ED patients with DM. The subjects, treated with placebo, 100 mg, or 200 mg of udenafil for 12 weeks, were asked to complete the International Index of Erectile Function (IIEF), the Sexual Encounter Profile (SEP) diary, and the Global Assessment Question (GAQ) during the study period.Main Outcome MeasuresThe primary efficacy parameter was the change in the erectile function domain (EFD) score of IIEF from baseline. Secondary parameters were IIEF questions 3 (Q3) and Q4, SEP Q2 and Q3, rate of achieving normal erectile function (EFD ≥ 26), and the response to GAQ.ResultsCompared with the placebo, patients receiving both doses of udenafil showed statistically significant improvements in the IIEF‐EFD score, respectively. However, statistically significant difference was not observed between the udenafil 100 mg and the udenafil 200 mg groups. Similar results were observed in the comparison of Q3 and Q4 of IIEF, SEP diary, and GAQ. The percentages of subjects experiencing at least one adverse event related to the study drugs were 3.6%, 15.8%, and 22.4% for the placebo, udenafil 100 mg, and udenafil 200 mg groups, respectively. However, these events were all mild in severity. Major adverse events were flushing, headache, nausea, and conjunctival hyperemia.ConclusionUdenafil was significantly effective for the treatment of ED, demonstrating statistically significant improvement in erectile function in patients with DM. The incidence of adverse events was relatively low and well tolerated in patients with DM. Moon DG, Yang DY, Lee CH, Ahn TY, Min KS, Park K, Park CK, and Kim JJ. A therapeutic confirmatory study to assess the safety and efficacy of Zydena^® (udenafil) for the treatment of erectile dysfunction in male patients with diabetes mellitus. J Sex Med 2011;8:2048–2061.     

Apocrine poroma with sebaceous differentiation

Poromas have been classified as eccrine neoplasms, but several recent reports of poroid tumors with sebaceous, follicular, and apocrine differentiation have challenged this concept. We report a case of apocrine poroma with sebaceous differentiation. A 69-year-old man presented with an asymptomatic elevated erythematous plaque. Histopathology revealed cellular nests composed of cuboidal poroid cells and sebocytes. The nests varied in size and were entirely intraepidermally arranged in a growth pattern similar to that of hidroacanthoma simplex. Given the common embryologic origin of folliculosebaceous and apocrine units, we believe that this lesion represents an apocrine poroma with sebaceous differentiation.     

THE DISTRIBUTION OF MELANOCYTIC NAEVI IN MELANOMA PATIENTS AND CONTROL SUBJECTS

A study of 121 melanoma patients and 139 control subjects was conducted among whites to examine and compare the distribution of non-dysplastic and dysplastic naevi and other pigmented lesions in each group. Melanoma patients had a mean of 97 melanocytic naevi which were greater than 2 mm in diameter and controls had a mean of 36 such naevi, while the medians were 58 and 22 respectively (p less than 0.0001). 55% of melanoma patients and 17% of controls had at least one clinically determined dysplastic naevus, and 26% of melanoma patients and 6% of controls had at least 5 dysplastic naevi. Men were found to have more naevi on the trunk than women in both melanoma cases (p = 0.01), and controls (p = 0.005). Dysplastic naevi were most often found on the trunk and were present at this location in 51% of cases and 17% of controls. Melanoma patients and control subjects with dysplastic naevi, when compared to those without these lesions, had larger number of non-dysplastic naevi. Lentigines were more common among melanoma patients that among control subjects (p = 0.02). There were no differences in the number of non-dysplastic naevi among cases with light and dark hair and eyes, or among controls with these characteristics. There also was little variation in the number of naevi according to number of blistering sunburns.