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Background: Isavuconazole (ISA) and voriconazole (VORI) are recommended as the first-line treatment for invasive aspergillosis (IA). Despite theoretical advantages of ISA, both triazole agents have not been compared in solid organ transplant recipients., Methods: We performed a post hoc analysis of 2 retrospective multicenter cohorts of solid organ transplant recipients with invasive fungal disease (the SOTIS [Solid Organ Transplantation and ISavuconazole] and DiasperSOT [DIagnosis of ASPERgillosis in Solid Organ Transplantation] studies). We selected adult patients with proven/probable IA that were treated for ≥48 h with ISA (n = 57) or VORI (n = 77) as first-line therapy, either in monotherapy or combination regimen. The primary outcome was the rate of clinical response at 12 wk from the initiation of therapy. Secondary outcomes comprised 12-wk all-cause and IA-attributable mortality and the rates of treatment-emergent adverse events and premature treatment discontinuation., Results: Both groups were comparable in their demographics and major clinical and treatment-related variables. There were no differences in the rate of 12-wk clinical response between the ISA and VORI groups (59.6% versus 59.7%, respectively; odds ratio [OR], 0.99; 95% confidence interval [CI], 0.49-2.00). This result was confirmed after propensity score adjustment (OR, 0.81; 95% CI, 0.32-2.05) and matching (OR, 0.79; 95% CI, 0.31-2.04). All-cause and IA-attributable mortality were also similar. Patients in the ISA group were less likely to experience treatment-emergent adverse events (17.5% versus 37.7%; P = 0.011) and premature treatment discontinuation (8.8% versus 23.4%; P = 0.027)., Conclusions: Front-line treatment with ISA for posttransplant IA led to similar clinical outcomes than VORI, with better tolerability and higher treatment completion., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This study was the first to evaluate the effect of CYP3A5*3 gene polymorphisms on plasma concentration of perampanel (PER) in Chinese pediatric patients with epilepsy., Methods: We enrolled 98 patients for this investigation. Plasma PER concentrations were measured using liquid chromatography-tandem mass spectrometry. Leftover samples from standard therapeutic drug monitoring were allocated for genotyping analysis. The primary measure of efficacy was the rate of seizure reduction with PER treatment at the final checkup., Results: The plasma concentration showed a linear correlation with the daily dose taken ( r  = 0.17; P  < 0.05). The ineffective group showed a significantly lower plasma concentration of PER (490.5 ± 297.1 vs. 633.8 ± 305.5 μg/ml; P  = 0.019). For the mean concentration-to-dose (C/D) ratio, the ineffective group showed a significantly lower C/D ratio of PER (3.2 ± 1.7 vs. 3.8 ± 2.0; P  = 0.040). The CYP3A5*3 CC genotype exhibited the highest average plasma concentration of PER at 562.8 ± 293.9 ng/ml, in contrast to the CT and TT genotypes at 421.1 ± 165.6 ng/ml and 260.0 ± 36.1 ng/ml. The mean plasma PER concentration was significantly higher in the adverse events group (540.8 ± 285.6 vs. 433.0 ± 227.2 ng/ml; P  = 0.042)., Conclusion: The CYP3A5*3 gene's genetic polymorphisms influence plasma concentrations of PER in Chinese pediatric patients with epilepsy. Given that both efficacy and potential toxicity are closely tied to plasma PER levels, the CYP3A5*3 genetic genotype should be factored in when prescribing PER to patients with epilepsy., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: For Parkinson disease (PD) patients who have been diagnosed with advanced disease that can no longer be effectively controlled with optimized oral or transdermal medications, a range of device-aided therapies (DAT) are available, comprising either deep brain stimulation or infusion therapies providing continuous dopaminergic stimulation. Levodopa-entacapone-carbidopa intestinal gel (LECIG) infusion is the latest DAT for advanced PD (APD) that was approved in Romania in 2021., Study Question: What is the experience to date in real-world clinical practice in Romania regarding the efficacy and tolerability of LECIG in APD?, Study Design: A retrospective evaluation of 74 APD patients treated with LECIG at 12 specialized APD centers in Romania., Measures and Outcomes: Demographic data and various clinical parameters were recorded, including Mini Mental State Evaluation score or Montreal Cognitive Assessment Test score. Levodopa-equivalent daily dose and the administered doses of levodopa and other PD medications were evaluated at baseline and after starting LECIG treatment. The efficacy of LECIG in reducing daily hours of off time, motor fluctuations, and dyskinesias were assessed. Any percutaneous endoscopic gastrojejunostomy system or device complications after starting LECIG treatment were noted., Results: At baseline, patients were taking oral levodopa for a mean of 5.3 times per day, with a high proportion also taking concomitant add-on therapies (dopamine agonists, 86%, monoamine oxidase type-B inhibitors, 53%; catechol-O-methyltransferase inhibitors, 64%). LECIG treatment significantly reduced daily off time versus baseline from 5.7 h/d to 1.7 hours per day ( P < 0.01). Duration and severity of dyskinesias was also significantly reduced versus baseline, and improvements were observed in Hoehn and Yahr Scale scores. LECIG treatment also allowed a significant reduction in the use of concomitant oral medications., Conclusions: These findings suggest that LECIG treatment is an effective DAT option in APD that can simplify the treatment regimen., Competing Interests: J. A. Szász consultant and speaking honoraria: AbbVie, Boehringer-Ingelheim, GSK, Lundbeck, Novartis, Pfizer, Stada, Teva, and UCB. V. A. Constantin speaking honoraria: AbbVie, Bayer, UCB, Pfizer, Stada, Ewopharma, Lundbeck and Wörwag Pharma. A. O. Dulamea has served as a scientific advisor or speaker for Novartis, Merck, Roche, Sanofi Genzyme, Genesis Pharma, Krka, Gedeon Richter, Eli Lilly, Wörwag Pharma, Zentiva, Takeda, Janssen, AbbVie, and Stada. C. Tiu speaker's honoraria from Merck, Genzyme, Roche, Janssen, Novartis, Boehringer Ingelheim, and Pfizer. L. P. Dumbravă consultant and speaking honoraria: Sanofi, Roche, SC Bayer, UCB Pharma, Ipsen Pharma, Bristol Myers Squib, Pfizer, AbbVie, Stada M&D, and Vedra International. A. Ene speaker honoraria: AbbVie, Stada, Pfizer, Genesis, and Worwag. M. Lungu speaker honoraria from AbbVie, Boehringer-Ingelheim, Stada M&D, and Bayer. A. Axelerad speaker honoraria from AbbVie, Boehringer-Ingelheim, GSK, Lundbeck, Novartis, Pfizer, Stada, Teva, UCB, Wörwag Pharma, Sanofi, Krka, Gedeon Richter, Eli Lilly, Zentiva, Takeda, Janssen, Zentiva, Merck, Roche, and Ipsen Pharma. M. Simu honoraria for advisory boards and educational lectures from: AbbVie, Astra Zeneca, Biogen, Boehringer Ingelheim, Pfizer, UCB, Servier, Teva, Merck, Ever Pharma, Roche, and Novartis A. G. Danci speaker honoraria from Teva, Stada and Ipsen Pharma. Sabău Monica consultant and speaking honoraria: Bayer, AstraZeneca, Roche, AbbVie, Pfizer, Novartis, Sanofi, Johnson& Johnson, Merk, Stada, SunWave Pharma, Ewopharma, Krka, and Elly Lilly. C. Falup-Pecurariu received royalties from Elsevier and Springer Verlag honoraria from AbbVie and the International Parkinson's Disease and Movement Disorders Society, outside of the present work. Ş. Strilciuc discloses an academic grant from Pfizer Inc (Delaware, US), unrelated to this manuscript. The remaining authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Rationale: Primary myelofibrosis is a subtype of myeloproliferative neoplasm that leads to bone marrow fibrosis. Historically, the only curative option for primary myelofibrosis was allogeneic hematopoietic stem cell transplant. Ruxolitinib, a Janus kinase inhibitor, is now used for the treatment of primary myelofibrosis and polycythemia vera. It effectively improves symptoms related to splenomegaly and anemia. However, its association with the development of opportunistic infections has been observed in clinical studies and practical application., Patient Concerns: A 64-year-old female with primary myelofibrosis and chronic hepatitis B infection who received ruxolitinib treatment. She was admitted for spiking fever and altered consciousness., Diagnosis: Tuberculosis meningitis was suspected but cerebrospinal fluid can't identify any pathogens. An abdominal computed tomography scan revealed a left psoas abscess and an enlarged spleen. A computed tomography-guided pus drainage procedure was performed, showing a strong positive acid-fast stain and a positive Mycobacterium tuberculosis polymerase chain reaction result., Interventions: antituberculosis medications were administered. The patient developed a psoas muscle abscess caused by tuberculosis and multiple dermatomes of herpes zoster during antituberculosis treatment., Outcomes: The patient was ultimately discharged after 6 weeks of treatment without apparent neurological sequelae., Lessons: This case underscores the importance of clinicians evaluating latent infections and ensuring full vaccination prior to initiating ruxolitinib-related treatment for primary myelofibrosis., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale: Teriflunomide is an inhibitor of pyrimidine synthesis available as a first-line treatment for relapsing-remitting multiple sclerosis. Drug-induced liver damage is a relevant problem in clinical practice, representing a frequent cause of treatment discontinuation. This case report describes the occurrence of liver injury, with a 33.7-fold increase in the upper limit of normality of the liver enzyme alanine aminotransferase during treatment with teriflunomide 14 mg., Patient Concern: A 44-year-old woman receiving teriflunomide 14 mg for the treatment of multiple sclerosis presented symptoms suggestive of liver dysfunction 54 days after starting treatment. The patient had no history of using disease-modifying therapy, neither previous liver disease nor other comorbidities., Diagnostics: The suggested diagnosis was drug-induced liver injury, classified as hepatocellular. Other possible hepatic and autoimmune etiologies were ruled out., Interventions: Replacement of teriflunomide treatment with glatiramer acetate and follow-up of the disease., Outcomes: Signs and symptoms regressed after treatment with teriflunomide 14 mg was discontinued, with normalization of liver enzyme activity in ∼5 months. The causality assessment of the adverse drug reaction was determined by the Naranjo scaling system, resulting in probable, with a final score of 7., Conclusions: Teriflunomide-induced liver injury in patients with multiple sclerosis is a serious adverse reaction. The report of this case contributes to updating knowledge about the safety aspects of treatment with teriflunomide and planning of monitoring strategies and patient risk management., Competing Interests: The authors have no conflicts of interest to disclose.’, (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: The NLRP3 inflammasome has been implicated in the development and progression of heart failure. The aim of this study was to determine the safety of an oral inhibitor of the NLRP3 inflammasome, dapansutrile (OLT1177), in patients with heart failure and reduced ejection fraction (HFrEF). This was a phase 1B, randomized, double-blind, dose escalation, single-center, repeat dose safety and pharmacodynamics study of dapansutrile in stable patients with HFrEF (New York Heart Association Class II-III). Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into 1 of 3 sequential ascending dose cohorts (500, 1000, or 2000 mg) each including 10 patients. Subjects underwent clinical assessment, biomarker determination, transthoracic echocardiogram, and maximal cardiopulmonary exercise testing at baseline, day 14, and day 28 to ascertain changes in clinical status. Placebo cases (N = 2 per cohort) were used as a decoy to reduce bias and not for statistical comparisons. Thirty participants (20 men) were treated for 13 (12-14) days. No serious adverse events during the study were recorded. All clinical or laboratory parameters at day 14 compared with baseline suggested clinical stability without significant within-group differences in the dapansutrile-pooled group or the 3 dapansutrile cohorts. Improvements in left ventricular EF [from 31.5% (27.5-39) to 36.5% (27.5-45), P = 0.039] and in exercise time [from 570 (399.5-627) to 616 (446.5-688) seconds, P = 0.039] were seen in the dapansutrile 2000 mg cohort. Treatment with dapansutrile for 14 days was safe and well tolerated in patients with stable HFrEF., Competing Interests: B. W. Van Tassell has served as a consultant for Novartis and Serpin Pharma. A. Abbate has served as a consultant for AstraZeneca, Janssen, Kiniksa Pharmaceuticals Ltd, Merck, Novartis, Olatec, and Serpin Pharma. A. Bonaventura and A. Vecchié received a travel grant from Kiniksa Pharmaceuticals Ltd to attend the 2019 American Heart Association Scientific Sessions. S. Carbone is supported by a Career Development Award 19CDA34660318 from the American Heart Association. The remaining authors report no conflicts of interest., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Primary objective is to evaluate safety of isavuconazonium sulfate (ISA) in pediatrics below 18 years old. Exploratory endpoint includes mortality due to probable and proven invasive fungal infection (IFI) and overall morality in this population., Patients and Methods: Retrospective review of patients below 18 years receiving ISA for ≥7 days for possible, probable, or proven IFI or prophylaxis between June 2015 and March 2018. Descriptive analysis performed to calculate median, frequency, and percentages., Results: Safety analysis included 18 patients and a subgroup of 11/18 patients were assessed for efficacy. Median age 12.5 years (4 to 17 y), median weight 50.25 kg (19 to 118 kg), 50% male, 77% acute leukemias, 94% hematopoietic cell transplant recipients, 50% matched unrelated donors and 78% in remission. Elevated alanine aminotransferase 3 times baseline within 30 days of ISA occurred in 22% (4/18). No patients had elevated bilirubin or increase in serum creatinine. All-cause mortality at 90 days was 22% (4/18) and 27% (3/11) in patients with probable or proven IFI. Clinical response rates: 14-day: 45% (5/11) partial, 27% (3/11) stable; 30-day: 45% (5/11) partial, 36% (4/11) stable; 90-day: 54% (6/11) had either partial (n=3) or complete (n=3) response to ISA., Conclusions: ISA is safe in pediatric patients for the treatment of IFI. Prospective, randomized controlled trials are warranted to determine efficacy and safety of ISA in pediatric patients with hematologic malignancies and hematopoietic cell transplant.

This retrospective study investigated the efficacy and safety of letrozole for patients with polycystic ovary syndrome (PCOS).Totally, 136 cases of infertility women with PCOS were analyzed. Of those, 68 patients received letrozole, and were assigned to Letrozole group. The other 68 cases received clomiphene, and were assigned to clomiphene group. Patients in both groups were treated up to 5 treatment cycles. The primary endpoint included infant outcomes. The secondary endpoints consisted of the number of women in conception, pregnancy, pregnancy loss, and ovulation. In addition, any kinds of adverse events were also recorded.Cases in the Letrozole group did not show better outcomes neither in primary endpoint (live birth, P = .11; birth weight, P = .95; infant gender, P = .85), nor in secondary endpoints (the number of women in conception, P = .07; pregnancy, P = .12; pregnancy loss, P = .47; pregnancy loss in first trimester, P = .70; and ovulation, P = .09), compared with cases in the clomiphene group. Moreover, no adverse events differ significantly between 2 groups.This study demonstrated that the efficacy of letrozole is not superior to the clomiphene in patients with PCOS.

Purpose of Review: Preservatives are well known skin sensitizers and represent one of the main causes of contact allergy. The purpose of this article is to review the current state of contact sensitization induced by preservatives and point future alternatives for products' preservation., Recent Findings: Isothiazolinones currently are the most common preservatives responsible of contact allergy in Europe and in the United States, and although some regulatory interventions have been taken place, the current contact allergy outbreak is not yet under control. Despite the ban of methyldibromo glutaronitrile from cosmetics in Europe, sensitized patients are still diagnosed, suggesting other nonregulated sources of exposure. Sensitization rates to formaldehyde and formaldehyde-releasers are lower in Europe in comparison with the United States due to stricter regulations regarding their use. Prevalence of contact allergy to parabens has remained stable over the last decades, whereas iodopropynyl butylcarbamate is an emerging allergen with an increasing prevalence. Future alternatives for products' preservation look for a broad antimicrobial spectrum, but with a better safety profile (in terms of sensitization) than the currently available compounds., Summary: Given the high rates of sensitization reported over the last years, timely regulatory actions are urgently required for some preservatives that currently represent a concern for public health.

Breast cancer is a common cause of cancer mortality among women. Several genetic factors have been implicated in its development. Current treatment guidelines for estrogen receptor-positive breast cancer recommend that anastrozole [or any of the other two aromatase inhibitors (letrozole and exemestane)] is used as an alternative to tamoxifen or following several years of tamoxifen treatment. Nevertheless, this approach is still associated with many challenges, ranging from the recurrence of breast cancer to considerable interindividual variability in the tolerability of anastrozole, which may cause adverse effects, such as musculoskeletal symptoms, and lead to the withdrawal of many patients from treatment. Variabilities in the genes encoding the drug target (aromatase) or its metabolizing enzymes (CYP3A and UGT1A) contribute toward the interindividual variability in anastrozole's pharmacokinetics and/or pharmacodynamics. This paper reviews the role of genetic polymorphisms of CYP19A1, CYP3A4, and UGT1A4 in the responses of female hormone receptor-positive postmenopausal breast cancer patients to anastrozole. Many reviews in the literature have suggested that the study of functional polymorphisms and investigation of relevant genetic markers may provide valuable information in predicting responses to anastrozole in terms of its therapeutic and adverse effects. Nevertheless, more studies are required before the knowledge of its pharmacogenomics can be applied to the individualization of treatment to ensure that patients receive the maximum benefits. Therefore, future analyses, including but not limited to genome-wide association studies, are encouraged to address some of the gray areas in the pharmacogenomics of anastrozole therapy in postmenopausal breast cancer cases; this will help in providing guidance for future pharmacogenomics protocols when anastrozole is utilized in patients' management.

Objectives: To compare efficacy, resistance development, and safety between rilpivirine and efavirenz in treatment-naive, HIV-1-infected adults with baseline viral load 100,000 copies/ml or less in the pooled 48-week dataset of the ECHO (Efficacy Comparison in treatment-naive HIV-infected subjects Of TMC278 and EFV) and THRIVE (TMC278 against HIV, in a once-daily RegImen Vs. Efavirenz) trials., Design: Phase III, double-blind, double-dummy, randomized trials., Methods: Patients received rilpivirine 25 mg once daily (q.d.) or efavirenz 600 mg q.d. with two nucleoside/tide reverse transcriptase inhibitors [N(t)RTIs]. This analysis considers the subpopulation of 368 rilpivirine and 330 efavirenz patients with baseline viral load 100,000 copies/ml or less., Results: Significantly higher 48-week response rates (viral load <50 copies/ml, intent-to-treat-time-to-loss-of-virological response) were observed with rilpivirine vs. efavirenz [90 vs. 84%, respectively; difference 6.6% (95% confidence interval 1.6-11.5%)]. The proportion of patients experiencing virological failure (VF(res)) was 5% in each treatment group. A comparable proportion of VF(res) patients in each group developed nonnucleoside reverse transcriptase inhibitor resistance-associated mutations (RAMs) [rilpivirine: 6/16 (38%) vs. efavirenz: 5/12 (42%)]. A numerically higher proportion of rilpivirine VF(res) patients developed N(t)RTI RAMs [7/16 (44%)] vs. efavirenz [2/12 (17%)]; P = 0.2232. A significantly lower incidence for rilpivirine vs. efavirenz was observed for the following events: treatment-related grade 2-4 overall adverse events (17 vs. 30%; P <0.0001), rash (any type; 2 vs. 12%; P <0.0001), and neurological adverse events (19 vs. 40%; P <0.0001), including dizziness (10 vs. 29%; P <0.0001). There was no significant difference between groups in the total cholesterol/high-density lipoprotein cholesterol ratio., Conclusion: In treatment-naive patients with baseline viral load 100,000 copies/ml or less, rilpivirine along with two N(t)RTIs achieved a high response, with a comparable frequency of VF(res) and more favorable tolerability than efavirenz.

Background: In the week 48 primary analysis of ECHO and THRIVE, rilpivirine demonstrated noninferior efficacy and more favourable tolerability versus efavirenz in treatment-naive, HIV-1-infected adults. Pooled 96-week results are presented., Methods: Patients (N = 1368) received rilpivirine 25 mg once-daily (q.d.) or efavirenz 600 mg q.d., with two background nucleoside/nucleotide reverse transcriptase inhibitors, in two randomized, double-blind, double-dummy Phase III trials., Results: At week 96, response rate (% confirmed viral load <50 copies/ml; intent-to-treat, time-to-loss-of-virologic response) was 78% in both groups. Responses were similar for both treatments by background regimen, sex, race, and in patients with more than 95% adherence (M-MASRI) or baseline viral load 100,000 copies/ml or less. Responses were lower and virologic failure higher for rilpivirine versus efavirenz in patients with 95% or less adherence or baseline viral load more than 100,000 copies/ml. Beyond week 48, the incidence of virologic failure was comparable (3 versus 2%) between treatment groups, rilpivirine resistance-associated mutations were consistent with those observed in year 1, there were few adverse events in both groups and no new safety concerns. Over 96 weeks, discontinuations due to adverse events (4 versus 9%), treatment-related grade 2-4 adverse events (17 versus 33%), rash (4 versus 15%), dizziness (8 versus 27%) and abnormal dreams/nightmares (8 versus 13%), and grade 2-4 lipid abnormalities were lower with rilpivirine than efavirenz. Only 2 and 4% of patients in the rilpivirine and efavirenz treatment groups, respectively, reported at least possibly treatment-related grade 2-4 adverse events during the second year of treatment., Conclusions: Rilpivirine 25 mg q.d. and efavirenz 600 mg q.d. had comparable responses at week 96. Rilpivirine had more virologic failures but improved tolerability versus efavirenz. The majority of virologic failures occurred in the first 48 weeks.

Clomiphene citrate (CC) is the most commonly used oral agent for the induction of ovulation. It is a nonsteroidal selective estrogen receptor modulator that has predominant antiestrogenic action resulting in long-lasting estrogen receptor depletion. Side effects include antiestrogenic effects systemically and on the endometrium and cervical mucous. Letrozole is a potent, nonsteroidal, aromatase inhibitor, originally used for postmenopausal breast cancer therapy, at present its only registered indication. We hypothesized that letrozole could mimic the action of CC without depletion of estrogen receptors. As there is no estrogen receptor antagonism, antiestrogenic effects such as poor cervical mucus and thin endometrium are not expected with aromatase inhibitor treatment. In addition, because estrogen receptors in the brain are not depleted, normal negative feedback occurs with letrozole and generally results in monoovulation. We and others have demonstrated the success of aromatase inhibition in inducing ovulation in women with polycystic ovarian syndrome. Letrozole may be very effective for ovulation induction and pregnancy in cases of CC resistance. When used together with follicle-stimulating hormone (FSH) injections, letrozole resulted in a significant reduction in the FSH dose needed for controlled ovarian hyperstimulation. Aromatase inhibitors likely increase ovarian sensitivity to FSH, and may be useful in poor responders and in women undergoing ovarian stimulation for in vitro fertilization. The safety of letrozole in pregnancy outcome studies has been demonstrated by examination of spontaneous pregnancy loss, multiple pregnancy rates, and congenital anomalies compared with a control group of infertility patients treated with CC. In addition, new data suggest that CC may result in cardiac anomalies and other birth defects and in low birth weight babies. We believe aromatase inhibitors are acceptable alternatives to CC as first line oral agents for ovulation induction or controlled ovarian stimulation.

Objectives: To retrospectively compare radiation toxicity in patients treated with concurrent anastrozole and whole breast irradiation versus women treated sequentially with whole breast irradiation followed by hormonal suppression., Methods: The records of 249 consecutive estrogen or progesterone receptor positive breast cancer patients treated with breast-conserving surgery and postoperative whole breast irradiation were reviewed. Of total, 57 patients (the concurrent anastrozole group) received concurrent anastrozole prior to and during radiotherapy. In 126 patients (the sequential group), adjuvant hormone suppression therapy (anastrozole, other aromatase inhibitors, or tamoxifen) was administered after the completion of breast irradiation. In 66, women either concurrent tamoxifen was given with radiation or the sequence of hormonal therapy was not known. These women were excluded from the analysis., Results: The frequency of acute grade 2 radiation dermatitis (24.6% in the concurrent anastrozole group vs. 20.6% in the sequential group; P = 0.55), grade 3 radiation dermatitis (8.8% vs. 7.1%; P = 0.77) and treatment interruptions due to skin reactions (14.0% vs. 11.2%; P = 0.69) did not differ between groups. The rates of clinically detectable breast fibrosis were not different (24.2% vs. 24.7%; P = 0.97). With a median follow-up of 28 months and 30.8 months, respectively, 1 local failure occurred in the concurrent anastrozole group and 5 in the sequential group., Conclusions: Anastrozole, administered concurrently with whole breast irradiation, did not increase acute or late morbidity when compared with sequential administration of radiation and hormonal suppression therapy.

Objective: To compare the success rate and side effects of letrozole and misoprostol versus misoprostol alone for medical termination of early pregnancy., Methods: Patients requesting termination of pregnancy up to 63 days of gestation were randomized into two groups. The letrozole group received letrozole 10 mg daily for 3 days followed by 800 micrograms of vaginal misoprostol, while the placebo group received placebo for 3 days followed by the same dosage of misoprostol. The complete abortion rate and the side effects profiles of the two groups were compared. The primary outcome measure was the complete abortion rate., Results: A total of 168 women were recruited. The complete abortion rate of the letrozole group was significantly higher than that of the placebo group (86.9% compared with 72.6%, relative risk [RR] 1.20, 95% confidence interval [CI] 1.03-1.40). The complete abortion rate in gestations up to 49 days was significantly higher in the letrozole group than in the placebo group (93.3% compared with 78.7%, RR 1.19, 95% CI 1.002-1.40), while the corresponding rates for gestation between 50 and 63 days were not significantly different between the two groups. There were significantly fewer women complaining of vomiting in the letrozole group than those in the placebo group (8.3% compared with 19.0%, P=.043, RR 2.29, 95% CI 1.005-5.27)., Conclusion: The use of letrozole and misoprostol is associated with a higher complete abortion rate., Clinical Trial Registration: HKClinicalTrials.com, http://www.hkclinicaltrials.com, HKCTR-349., Level of Evidence: I.

Objective: To investigate the effects on viral load and assess dose-response relationships, pharmacokinetics, safety and tolerability of lersivirine (UK-453,061), a next-generation nonnucleoside reverse transcriptase inhibitor, in asymptomatic HIV-1-infected patients., Design: Randomized, double-blind, placebo-controlled, parallel group, multicenter phase IIa clinical study., Methods: Forty-eight HIV-1-infected patients were enrolled for the study of once-daily or twice-daily lersivirine at total daily doses ranging from 20 to 1000 mg. The primary endpoint was the change in log10 plasma HIV-1 RNA viral load from baseline to day 8. Secondary endpoints related to pharmacokinetics, safety and tolerability and potential development of viral resistance and genotyping patterns., Results: Patients treated with lersivirine achieved day 8 mean viral load reductions of 0.3, 0.8, 1.3 and 1.6 log10 after receiving 10, 30, 100 and 500 mg twice daily, respectively, and 0.9, 1.7 and 1.8 log10 after receiving 100, 500 and 750 mg once daily, respectively. Mean changes from baseline to day 8 were small in patients receiving placebo. For all dose regimens, plasma exposure increased approximately in line with lersivirine dose. Median plasma concentrations of lersivirine at steady state were above the IC90 for lersivirine at once-daily doses of at least 500 mg and twice-daily doses of at least 100 mg. The most commonly reported treatment-emergent adverse events were headache, fatigue and nausea., Conclusion: Seven-day monotherapy with lersivirine achieved mean viral load reductions up to 1.8 log10. Lersivirine was safe and well tolerated. Further studies of lersivirine in combination with other antiretroviral drugs to assess long-term durability of antiviral response, safety and tolerability are warranted.

Breast cancer survivors (BCSs) on aromatase inhibitor (AI) therapy often experience musculoskeletal symptoms (joint pain and stiffness, bone and muscle pain, and muscle weakness), and these musculoskeletal symptoms may be related to low serum levels of vitamin D. The primary purpose of this pilot exploratory study was to determine whether serum levels of 25-hydroxyvitamin D (25[OH]D) concentration were below normal (<30 ng/mL) in 29 BCSs on AI therapy and if musculoskeletal symptoms were related to these low vitamin D levels. The mean (SD) serum 25(OH)D level was 25.62 (4.93) ng/mL; 86% (n = 25) had levels below 30 ng/mL. Patients reported muscle pain in the neck and back, and there was a significant inverse correlation between pain intensity and serum 25(OH)D levels (r = -0.422; P < .05 [2 tailed]). This sample of BCSs taking AIs had below normal levels of serum 25(OH)D despite vitamin D supplements. This is one of the few studies to document a significant relationship between vitamin D levels and muscle pain in BCSs on AI therapy. Findings from this pilot study can be used to inform future studies examining musculoskeletal symptoms in BCSs on AI therapy and relationships with low serum levels of vitamin D.

Purpose: To determine whether women using anastrozole (an aromatase inhibitor, which suppresses estrogen synthesis) are likely to have retinal hemorrhages., Methods: Fundus photographs were obtained for a study comparing effects on vision and the eye of anastrozole (1 mg/d) and tamoxifen (20 mg/d) for women receiving adjuvant endocrine therapy for early-stage breast cancer. Photographs (2 eyes per subject) were evaluated for hemorrhages by an ophthalmologist masked from identifying subject information. The presence of hemorrhages was assessed for 35 anastrozole users, 38 amenorrheic tamoxifen users, and 53 amenorrheic (peri- or postmenopausal) control subjects not using any endocrine medication. The age range was 43 to 69 years; only subjects reporting normal vision and healthy eyes were recruited. Photographs from 36 tamoxifen users from a previous study also were assessed. Views of the fundus extended appreciably beyond the posterior pole for all tamoxifen and anastrozole users, and for 38 of the control subjects. Photographic assessments were compared with medical history and blood pressure data, and optical coherence tomography was used for quantifying aspects of foveal shape that might be affected by vitreoretinal traction., Results: Four anastrozole users and no contemporaneous tamoxifen users but one previously tested tamoxifen user had retinal hemorrhages, in each case within the posterior pole. Two anastrozole users had a flame hemorrhage (in the retinal nerve fiber layer), and two had a blot hemorrhage (deeper in the retina). No control subjects were observed to have hemorrhages., Conclusions: Anastrozole use appears to be associated with an increased prevalence of retinal hemorrhages. The hemorrhages may mark systemic vascular compromise resulting from estrogen depletion, and/or they may be consequences of vitreoretinal traction resulting from estrogen depletion. They may also depend on the use of medications for controlling common anastrozole-induced side effects. Prospective studies need to be conducted with larger numbers of subjects.

Objective: To evaluate the effect of anastrazole on symptomatic uterine leiomyomata., Methods: This was a prospective intervention study carried out in a university department of obstetrics and gynecology. Forty-one premenopausal women eligible for hysterectomy with 45 uterine leiomyomata were enrolled and treated with anastrazole 1 mg daily for three cycles of 28 days each. The effect of treatment was evaluated on leiomyoma and uterine volumes, endometrial thickness, gonadotrophins, estradiol and hematocrit levels, menstrual pattern, severity of leiomyoma-related symptoms, and adverse effects. The effects of leiomyoma location, size, and age of participants on tumor volume changes were evaluated., Results: Thirty-five women with 39 leiomyomata finished the study. Anastrazole resulted in a mean 55.7% reduction of leiomyoma volumes (163 mL to 72 mL, P<.001), a 29.9% reduction in total uterine volumes (278 mL to 195 mL, P<.001), and an 11.3% increase of the hematocrit levels (33.4% to 37.2%, P<.001) at the end of the treatment. Leiomyoma location had no significant effect on volume decrease. Leiomyoma volume decreased in women aged older than 40 years (P=.002), whereas no difference was found in women younger than 40. The size of large (greater than 50 mm) leiomyomata decreased significantly (P=.004). Less difference was observed in small (50 mm or less) leiomyomata (P=.031). No differences were detected in hormonal status. Anastrazole improved leiomyoma-related symptomatology and caused no serious adverse effects., Conclusion: In premenopausal women, anastrazole reduces the size of uterine leiomyomata, improves symptomatology, and is generally well tolerated., Level of Evidence: III.

Objective: To evaluate antiviral activity, pharmacokinetics, tolerability and safety of TMC278, a non-nucleoside reverse transcriptase inhibitor (NNRTI), when given as a 25, 50, 100 or 150 mg once-daily dose for 7 days to antiretroviral-naive HIV-infected subjects., Design: Randomized, double-blind, placebo-controlled, phase IIa clinical trial., Methods: Participants were 47 antiretroviral naive HIV-infected subjects. Primary outcome was the change in plasma HIV-1 RNA viral load from baseline to day 8. Secondary outcomes were evaluation of pharmacokinetics of TMC278, immunologic changes, safety and tolerability, and evolution of viral genotypic and phenotypic patterns., Results: Patients treated with TMC278 achieved a median decrease in plasma viral load from baseline of 1.199 log10 copies/ml compared with a 0.002 log10 copies/ml gain in the placebo group (P < 0.01). A significantly higher proportion of subjects in the TMC278 groups obtained a viral load decrease of > 1.0 log10 compared with the placebo group (25/36 versus 0/11) (P < 0.01). No significant dose differences were noted in either antiviral effect or safety. No genotypic changes associated with antiretroviral resistance were detected between baseline and the end of the trial. Plasma concentrations of TMC278 were above the target concentration (13.5 ng/ml) at all time points for all TMC278-treated subjects. The most common reported adverse event was headache (TMC278 14%; placebo 18%)., Conclusions: TMC278 showed antiviral activity when given as monotherapy for 7 days at all doses studied and the drug was safe and well tolerated. Trials of longer treatment duration with TMC278, in combination with other antiretroviral drugs, are underway to assess the long-term durability of antiviral response, safety and tolerability.

Fulvestrant, an estrogen receptor downregulator, is an effective and a safe endocrine option for postmenopausal women with advanced breast cancer who progress or develop recurrent disease on prior endocrine therapy. The recommended dose is 250 mg given as a single 5-mL or 2 concurrent 2.5-mL monthly intramuscular injections. Common adverse events associated with fulvestrant are hot flashes, nausea, and mild injection site reactions. Applying warm or cold compresses to the injection site can minimize injection site reactions. In randomized double-blind clinical trials, the frequency of injection site reactions for fulvestrant are no different from the comparator (anastrozole) arm. Overall, fulvestrant has a safety profile similar to aromatase inhibitors. Advantages of this agent are its effectiveness in tamoxifen-resistant tumors and the lack of agonistic property, creating a favorable side-effect profile. One limitation is that there is no evidence regarding the safety and effectiveness of fulvestrant in premenopausal women. Among endocrine therapies used to treat breast cancer, fulvestrant is unique not only in its mechanism of action but also in its mode of administration. With oral therapies, the patient fills the prescription in a pharmacy and takes the medication home. In contrast, with monthly fulvestrant intramuscular injection, the patient will have increased contact with the nurse. The increased interaction between the patient and the nurse will affect the role of nurses providing patient education and monitoring.