Fluconazole in Hypercalciuric Patients with Increased 1,25(OH)2D Levels: The Prospective, Randomized, Placebo-Controlled, Double Blind FLUCOLITH Trial.

BackgroundHypercalciuria is one of the most frequent metabolic disorders associated with nephrolithiasis and/or nephrocalcinosis possibly leading to chronic kidney disease (CKD) and bone complications in adults. Orphan diseases with different underlying primary pathophysiology share inappropriately increased 1,25(OH)2D levels and hypercalciuria, e.g., hypersensitivity to vitamin D and renal phosphate wasting. Their management is challenging, typically based on hyperhydration and dietary advice. The antifungal azoles are known to inhibit the 1α-hydroxylase and therefore decrease 1,25(OH)2D levels; they are commonly used, with well described pharmacokinetic and tolerability data. Fluconazole has been successfully reported to reduce calciuria in patients with CYP24A1 or SLC34A3 mutations, with no safety warnings. Thus, based on these case reports, we hypothesize that fluconazole is effective to decrease and normalize calciuria in patients with hypercalciuria and increased 1,25(OH)2D levels.MethodsThe FLUCOLITH trial is a prospective, interventional, randomized in parallel groups (1:1), placebo-controlled, double blind trial. A total of 60 patients (10-60years) with nephrolithiasis and/or nephrocalcinosis history, hypercalciuria (> 0.1 mmol/kg/d), increased 1,25(OH)2D levels (> 150 pmol/L) and 25-OH-D levels >20 nmol/L, will be included. Inclusions will be performed only from mid-September to the beginning of February to avoid bias due to sunlight-induced vitamin D synthesis. The primary endpoint will be the proportion of patients with normalization of 24-hour calciuria between baseline and 16 weeks, or with a relative decrease of at least 30% of 24-hour calciuria in patients who still display at W16 a 24-hour hypercalciuria. DiscussionThe current challenge is to propose an efficient treatment to patients with hypercalciuria and increased 1,25(OH)2D levels in order to prevent later complications and notably CKD that can ultimately lead to end-stage renal disease. Based on improvement of knowledge in phosphate/calcium metabolism, pathophysiology and genetics, the “off-label” use of fluconazole was recently reported to be useful in hypercalciuric patients with increased 1,25(OH)2D levels. Thus, the FLUCOLITH study is a unique opportunity to develop a new indication of a well-known and not expensive drug in orphan renal diseases, the ultimate objective being the secondary prevention of CKD worsening in these patients. Trial RegistrationClinicalTrial.gov, ID: identifier: NCT04495608. Registered on July 23rd, 2020

Imidazole-Thiosemicarbazide Derivatives as Potent Anti-Mycobacterium tuberculosis Compounds with Antibiofilm Activity

Mycobacterium tuberculosis (Mtb) is an intracellular pathogenic bacterium and the causative agent of tuberculosis. This disease is one of the most ancient and deadliest bacterial infections, as it poses major health, social and economic challenges at a global level, primarily in low- and middle-income countries. The lack of an effective vaccine, the long and expensive drug therapy, and the rapid spread of drug-resistant strains of Mtb have led to the re-emergence of tuberculosis as a global pandemic. Here, we assessed the in vitro activity of new imidazole-thiosemicarbazide derivatives (ITDs) against Mtb infection and their effects on mycobacterial biofilm formation. Cytotoxicity studies of the new compounds in cell lines and human monocyte-derived macrophages (MDMs) were performed. The anti-Mtb activity of ITDs was evaluated by determining minimal inhibitory concentrations of resazurin, time-kill curves, bacterial intracellular growth and the effect on biofilm formation. Mutation frequency and whole-genome sequencing of mutants that were resistant to ITDs were performed. The antimycobacterial potential of ITDs with the ability to penetrate Mtb-infected human macrophages and significantly inhibit the intracellular growth of tubercle bacilli and suppress Mtb biofilm formation was observed.

Pattern of albumin consumption in patients hospitalized in intensive care unit of two teaching hospitals in Iran

Aims: The goal of this study was to evaluate the consumption pattern of human albumin according to the available and reliable guidelines. Methods: This research was a descriptive-analytical study. The study sample consisted of patients admitted to the intensive care units (ICUs) of Shahid Sadoughi and Rahnemoon Yazd Teaching Hospitals. In this study, 67 patients were selected. The study was carried out over three months. During the study, the albumin request by ICUs was investigated. Along with observing albumin orders' para-clinic findings were evaluated. The specific form of albumin consumption and prescription prepared by the Hospital Steering Board of Pharmacy was completed for each patient individually. Results: In this study, 65.7% of prescribed albumin was infused for approved cases by the US food and drug administration (FDA). Administration after burn injury with 32.8% and hypoalbuminemia with 19.4% of cases were the most frequently reasonable prescribed albumin. About 34.3% of prescribed albumin (18 cases) did not have FDA-approved indications. Albumin infusion after patients edema in 14.9% of cases, nutritional support 6 % and Major surgery 6% have been the most frequently incorrect prescribed albumin. Conclusion: Based on the findings of this study, the prescription of albumin in patients admitted to ICUs of Sadoughi and Rahnemoon teaching hospitals from October to December 2015 was not completely in accordance with the guidelines. So , consulting with relevant health care professionals can be helpful to improve the proper administration of this essential and expensive drug.

Adding aprepitant to palonosetron does not decrease carboplatin-induced nausea and vomiting in patients with gynecologic cancer

Background Recently, aprepitant has been recommended in carboplatin-based regimens, but there are limited reports on the efficacy of administering aprepitant, palonosetron, and dexamethasone (DEX) in carboplatin-containing regimens. Moreover, because aprepitant is an expensive drug, confirming its effectiveness is very important from the medical cost perspective. In this study, we examined the efficacy of prophylactically administered aprepitant, palonosetron and DEX, in paclitaxel and carboplatin (TC) combination chemotherapy. Methods Patients with gynecologic cancer who were treated with paclitaxel (175 mg/m2) and carboplatin (area under the curve, AUC = 5–6) combination chemotherapy were retrospectively evaluated. The complete response (CR) rate, severity of nausea, and incidence of anorexia in the first course were compared between patients who did not receive aprepitant (control group) and those who received (aprepitant group). Results The 106 patients were divided into two groups, consisting of 52 and 54 the control and aprepitant groups, respectively, and the patient background showed no significant difference between both groups. The CR rate of the overall phase between the control and aprepitant groups was 73.1 vs. 74.1%, that in the acute phase was 98.1 vs. 100%, and in the delayed phase was 75.0 vs. 74.1%, respectively, without any significant difference. The severity of nausea and incidence of anorexia were also not significantly different between both groups. Conclusions The results of the study suggest that adding aprepitant to palonosetron and DEX does not prevent carboplatin-induced nausea and vomiting in gynecologic cancer patients. Therefore, adding aprepitant to palonosetron does not decrease carboplatin-induced nausea and vomiting in patients with gynecologic cancer.

Onasemnogene Abeparvovec-xioi: World’s most expensive and approved therapy for spinal muscular atrophy

On May 24, 2019, the U.S. Food and Drug Administration approved Onasemnogene Abeparvovec-xioi (Zolgensma), the first gene therapy approved to treat children less than two years of age with spinal muscular atrophy (SMA), the most severe form of SMA and a leading genetic cause of infant mortality. It is priced in the United States at $2.1m (£1.6m; €1.9m) the world’s most expensive drug. Children with SMA experience difficulty performing essential functions of life. Most children with this disease do not survive past early childhood due to respiratory failure. Patients with SMA now have another treatment option to minimize the progression of SMA and improve survival. This review summarized the clinical guidelines for the Onasemnogene Abeparvovec-xioi use and may be useful to healthcare professionals.

Cost Analysis and Rational Use of Anti Glaucoma Therapy in A Tertiary Hospital in Ghana

IntroductionGlaucoma is the leading cause of irreversible blindness worldwide. In Ghana, 19.4% of all blindness recorded is due to glaucoma. Reducing intraocular pressure medically (using eye drops) is the evidence-based therapeutic optionObjectives To determine the rational use and undertake cost analysis of anti-glaucoma drugs among patients attending clinic at the Lions International Eye Centre, Korle bu Teaching Hospital (LIEC).MethodsIn this cross sectional study, we reviewed all prescriptions presented to the pharmacy unit from 01/12/015 to 31/03/2016. The dispensed drops were classified and all anti-glaucoma drugs were identified. This was followed by cost analysis.ResultsA total of 588 prescriptions were captured, 27.3% (161/588) contained an anti-glaucoma medication. The mean number of anti-glaucoma medications was1.71 of which 52.7% was prescribed to females.Prostaglandin analogues were the most prescribed (37% (102/276)), followed by beta blockers (25.4% (70/276)), carbonic anhydrase group of medicines (16.3% (45/276)), combined beta blockers (11.2% (31/276)), alpha agonists (8.7% (24/276)) and miotics (1.4% (4/276)). The median (IQR) average cost of anti-glaucoma therapy per prescription per month was GHC 65.00 (GHC38.5-GHC140). Azopt (Brimonidine) was the most expensive with daily treatment cost of GHC 5.8 (about US$ 1.45), whilst the least expensive drug with a daily treatment cost of GHC 0.14 (about US$ 0.035) was timolol eye drops. ConclusionsProstaglandins analogues remain the most preferred treatment for managing glaucoma at the Korle-Bu Eye Centre in Ghana but are also the most costly. This may adversely affect treatment among the poor since prostaglandins are currently not reimbursed.

Virtual Screening of Potential Anticancer Drugs based on Microbial Products

The development of microbial products for cancer treatment has been in the spotlight in recent years. In order to accelerate the lengthy and expensive drug development process, in silico screening tools are systematically employed, especially during the initial discovery phase. Moreover, considering the steadily increasing number of molecules approved by authorities for commercial use, there is a demand for faster methods to repurpose such drugs. Here we present a review on virtual screening web tools, publicly available databases of molecular targets and libraries of ligands, with the aim to facilitate the discovery of potential anticancer drugs based on microbial products. We provide an entry-level step-by-step description of the workflow for virtual screening of microbial metabolites with known protein targets, as well as two practical examples using freely available web tools. The first case presents a virtual screening study of drugs developed from microbial products using Caver Web, a web tool that performs docking along a tunnel. The second case comprises a comparative analysis between a healthy isocitrate dehydrogenase 1, a mutant that results in cancer, using the recently developed web tool PredictSNPOnco. In summary, this review provides the basic and essential background information necessary for virtual screening experiments, which may accelerate the discovery of novel anticancer drugs.

Cost containment by peer prior authorization program for second line treatment in patients with retinal disease

Background High and increasing drug prices have prompted the establishment of a broad range of cost-containment treatment policies in health systems globally. In 2012, the supplemental insurance program of a large Israeli health maintenance organization (Clalit Health Services) introduced a prior authorization process for second-line use of ranibizumab in patients with retinal disease for whom treatment with bevacizumab proved to be ineffective. A Clalit steering committee established authorization criteria based on cost and periodically updated clinical considerations, while a team of ophthalmic specialists evaluated their colleagues’ individual patient subsidization requests, based on the funding criteria. The objectives of this study were to detail this unique authorization process and study its effectiveness in limiting unwarranted spending, while allowing for a smooth transition to a second-line more expensive drug when needed. Methods A retrospective cohort study including all applications for a first or ongoing treatment with ranibizumab, for one or both eyes, received during March 1, 2012 - December 31, 2015. The key parameters examined were percentages of requests from patients treated by first line treatment bevacizumab, requests approved, reapplications, and results. Requests studied include reapplications and requests for treatment continuation. Results During the study period, Clalit affiliated ophthalmologists’ submitted 16,778 funding applications for intravitreal ranibizumab treatment on behalf of 5642 patients who applied for approximately three applications. An efficient sentinel effect was achieved, resulting in only 31% of patients treated with bevacizumab applying for treatment, while maintaining extremely high accessibility to second line treatment with almost 95% of requests being approved. Conclusions The data presented shows a low request rate for funding with a high approval rate, proving this peer reviewed report-based authorization process successfully achieved a sentinel effect while controlling cost. We suggest this innovative model be considered in similar decisions processes.

Ensuring access to medicines at a fair price? Innovative contracting experiences in France

Issue Innovative contracting models are developed to ease price-setting negotiations in case an extremely expensive drug has not proven sufficient efficiency in clinical trials. As disruptive HIV treatments are expected in the near future, French patient organizations evaluated the ability of these innovative contracts to ensure accessible medicines at a fair price. Description Performance-based schemes condition prices paid by the State to the efficiency of the medicine observed through real-world data. In France, thirteen performance-based contracts have been concluded between 2008 and 2015. They are presented as a triple solution: innovative treatments are available to patients, manufacturers access markets, and states ensure healthcare within limited budgets. Establishing the added value of these models implies determining if they allow rapid access to treatments with substantial savings for payers, while ensuring rigorous price and cost transparency. Results Performance-based contracts indeed ensure patient access to treatments, but other mechanisms (such as temporary use authorizations) already serve this purpose. Regarding expenditure reduction however, these schemes have not proven their worth. The Court of Auditors' evaluation showed they do not generate substantial savings, as final prices correspond to those that would have applied with the European price guarantee. Lastly, as contracts are protected by business secrecy, the public cannot access neither to actual prices negotiated by payers, nor the amount of public investment that have been used for the research and development of the drug. Lessons The derogatory nature of performance contracts invites us to consider them on a case-by-case basis if ensuring access to a specific innovation is necessary. These contracts are certainly innovative, but they cannot be presented as technologies providing access at a fair price. Finally, their contractual and derogatory nature raises serious transparency issues. Key messages Performance-based contracts should be considered as alternatives to existing administrative channels provided that they lead to substantial savings and are drawn up in full transparency. Patient organizations need to assess innovative schemes such as performance-based contracting to ensure access to treatments without undermining historical struggles for fair and transparent pricing.