Effective Daily Dose Research Articles

Drug-resistant epilepsy: Current concepts, pathogenesis, risk factors, outcomes of surgical treatment

Despite the wide choice of antiepileptic drugs (AEDs), a third of patients remain resistant to the effects of modern AEDs. Drug-resistant epilepsy (DRE) is characterized by the inability to control seizures in a patient when using at least two adequate AED regimens at an effective daily dose as monotherapy or in combination. In this case, the mechanisms responsible for drug resistance are mainly either increased excretion of AEDs by transporters from epileptogenic tissue (the multidrug transporter hypothesis) or a decrease in the sensitivity of drug receptors in epileptogenic brain tissue. It is assumed that there are other mechanisms, but they remain understudied. A number of factors are associated with the risk of DRE developing in patients with diagnosed epilepsy, including genetic, iatrogenic, brain malformations, and others. Patients with DRE have a higher probability of developing psychopathological disorders (depression, anxiety, psychosis), the proportion of which is significantly higher than in the general population. They have a 10-fold increased risk of death due to injury, cognitive decline, and sudden unexpected death in epilepsy (SUDEP). The priority treatment method for DRE is surgery. Early identification of DRE is critical for identifying potential treatment alternatives and determining whether a patient is a surgical candidate. Analysis of data from clinical and instrumental research of operated patients with DRE in the early and late postoperative period will allow us to identify factors of unfavorable outcome and to increase the effectiveness of treatment for this category of patients.The aim was to study and to summarize literature data on the pathogenesis and risk factors of drug resistance to antiepileptic drugs in patients with epilepsy, justifying the need for timely identification of drug resistance and referral of patients with drugresistant epilepsy to specialized centers for possible surgical treatment.

Dietary Supplements for Erectile Dysfunction: Analysis of Marketed Products, Systematic Review, Meta-Analysis and Rational Use.

The use of nutraceutical products to enhance male sexual performance has a long history, especially with regard to the treatment of erectile dysfunction (ED). Alternative treatments for ED are becoming increasingly popular, with growing interest from consumers, as well as increased revenue for manufacturers. Dietary supplements (DSs), which are a mixture of active ingredients, are mainly sold online. In randomized controlled trials, the molecules contained in DSs have demonstrated varying degrees of effectiveness, or even have no evidence to support their use. However, none of the studies carried out provided sufficient evidence to consider these products a first-line therapy. Therefore, the combination of the various active ingredients, especially in relation to the daily dose, leaves doubts about the real effectiveness. In order to evaluate the potential efficacy of DS formulations, we analyzed the products marketed in Italy using a scoring approach. A systematic review of the literature was performed to evaluate the effect of DS and to detect the active ingredients able to improve erectile function-called effective ingredients (EIs)-and their minimal effective daily dose (mED). A metanalysis identified some nutraceuticals, such as Panax ginseng, Tribulus terrestris and L-arginine, that are able to improve male sexual function. Based on the scoring system, 2 (8%) supplements matched with the cluster of higher expected efficacy, 3 (12%) with the lower efficacy cluster and 20 (80%) matched with the criterion of no expected efficacy. DSs marketed in Italy are usually blends of many substances that are frequently employed at a negligible dose or without any evidence.

Study on the daily dose and serum concentration of clozapine in psychiatric patients and possible influencing factors of serum concentration

BackgroundClozapine is the most effective drug for treatment-resistant schizophrenia, and the dosage and concentration of clozapine in the treatment of mental illness vary greatly in different populations and are affected by many factors.MethodsThe serum clozapine concentration of 3734 psychiatric patients was detected, and data on daily dose, sex, age and other medical records were collected for statistical analysis.ResultsThe mean daily dose, mean serum concentration and mean C/D (concentration/dose) ratio of clozapine were 191.02 ± 113.47 mg/day, 326.15 ± 235.66 ng/mL and 1.94 ± 1.25 ng/mL per mg/day, respectively. There was difference in daily dose between sexes, and females had higher daily dose (p <0.01), higher serum clozapine concentrations (p < 0.01) and higher C/D ratios (p < 0.01). There were significant differences in daily dose (p < 0.001), serum drug concentration (p < 0.001) and C/D ratio (p < 0.001) among different age groups. The daily dose decreased with age (p for trend < 0.001), and the C/D ratio increased with age (p for trend < 0.001). Inpatients and outpatients had no difference in daily dose, but inpatients had higher serum concentration (p < 0.001) and C/D ratio (p < 0.001). There was no difference in daily dose among different occupations, but there were significant differences in serum concentration (p < 0.001) and C/D ratio (p < 0.001), and unemployed patients may have higher serum concentration and C/D ratio. Duration of disease, comorbidity, marital status, and psychotic type may influence the daily dose and serum concentration.ConclusionsThe effective daily dose and serum concentration of clozapine in the study area may be lower than recommended levels, and women have higher serum concentrations and slower metabolic rates. With increasing age, the daily dose decreases, and the metabolic rate slows. Inpatient status and occupation of patients may influence the serum concentration and metabolic rate of clozapine.

ANTIVIRAL ACTIVITY OF A BIOLOGICALLY ACTIVE ADDITIVE BASED ON THE EXTRACT OF ASPEN BARK IN RELATION TO THE SARS-COV-2 IN EXPERIMENTS IN VIVO

Purpose of the research. Study of antiviral activity, determination of a safe and effective dose of a dietary supplement based on aspen bark extract against the SARS-CoV-2 virus in a Syrian hamster model. Material and methods. The object of the study was a biologically active food supplement based on an extract of aspen bark (Populus tremula L.), containing a concentrated aqueous extract of aspen bark and dihydroquercetin. We used a strain of coronavirus homologous to the early strain of hu-man SARS-CoV-2, Wuhan-Hu-1, obtained from the State Collection of Viral Infections and Rickettsiosis of the FBRI SRC VB «Vector» of Rospotrebnadzor. The study of antiviral activity was carried out on Syrian hamsters (Mesocricetus auratus) obtained from the nursery of laboratory animals of the FBRI SRC VB «Vector» of Rospotrebnadzor, according to the following parameters: the amount of virus RNA (viral load) and the infectious titer of the virus in the tissues of the lungs and nasal cavity. Results. It was established that under the indicated conditions of therapy, an effective safe daily dose of the drug based on aspen bark extract is a dose of 2000 mg/kg – on the fourth day after infection, virus replication on the nasal mucosa of infected animals significantly decreased by 3 times and the infectious titer of the virus – by 43 times. With an increase in the daily dose to 4000 mg / kg, signs of a toxic effect were observed. The min-imum therapeutic daily dosage of the drug in the early period after infection with respect to SARS-CoV-2 was determined - at a daily dose of 250 mg/kg, the drug significantly reduced the viral load in the tissues of the nasal cavity by 6.6 times and the infectious titer by 12.5 times. Conclusions. As a result of in vivo studies, it has been shown that a biologically active food supplement based on aspen bark extract has antiviral ac-tivity against the SARS-CoV-2 virus.

Functional Ingredients for specialized Foods: Issues to be Addressed

Review was carried out using the RSCI, Google Scholar, Pubmed, and ReserchGate databases. When biologically active substances (BAS) are used as functional ingredients in the composition of specialized food products (SPP) of dietary therapeutic and dietary preventive nutrition, the problems of choosing their dose arise. There are epidemiological data on the level of consumption of BAS with food, an associative relationship between the level of consumption of biologically active substances and the risk of diseases, as well as the results of assessing clinical efficacy are described. The content of BAS is regulated by regulatory documents that establish an adequate and upper permissible level of consumption as part of the SPP.The purpose of the review is to assess the level of dietary intake of curcumin, carotenoids, β-glucans, and taurine, and to compare the doses allowed for use as part of the SPP with doses that provide a clinical effect. An analysis of literature data showed that the consumption of taurine with a normaldiet is 50–400 mg, curcumin – 10–1500 mg, β-carotene – 0.8–10 mg, lycopene – 5–10.5 mg, lutein – 1–3 mg, zeaxanthin – 0.1–0.6 mg, cereal β-glucans – 0.7–2.8 g, mushroom β-glucans – 0.9–1.8 g. With the exception of β-glucans, especially cereals, these values do not exceed the current upper allowable consumption level as part of the SPP. The results of clinical trials have shown that effective daily doses for lutein are 15 mg, taurine are 1.5–3 g, curcumin are 300–1600 mg, cereal β-glucans are 3–8 g, mushroom and yeast β-glucans are about 1 g. These data indicate the need to increase the amount of BAS as part of the SPP of dietary therapeutic nutrition to clinically justified values. At the same time, the given data indicate the expediency of differentiating the SPP, depending on the doses of BAS, into 2 categories: SPP for preventive and SPP for therapeutic action. SPP for dietary preventive nutrition is necessary to compensate the insufficient intake of essential micronutrients and achieve an adequate level of consumption of BAS, which will reduce the risk of alimentary-dependent diseases. In order to provide a clinical effect in pathological conditions, dietary therapeutic SPP should contain higher doses of biologically active substances that exceed the adequate intake level, but do not reach the upper safe intake level.

Prediction of in vivo prenatal chlorpyrifos exposure leading to developmental neurotoxicity in humans based on in vitro toxicity data by quantitative in vitro-in vivo extrapolation.

Introduction: Epidemiological studies in children suggested that in utero exposure to chlorpyrifos (CPF), an organophosphate insecticide, may cause developmental neurotoxicity (DNT). We applied quantitative in vitro-in vivo extrapolation (QIVIVE) based on in vitro concentration and non-choline esterase-dependent effects data combined with Benchmark dose (BMD) modelling to predict oral maternal CPF exposure during pregnancy leading to fetal brain effect concentration. By comparing the results with data from epidemiological studies, we evaluated the contribution of the in vitro endpoints to the mode of action (MoA) for CPF-induced DNT. Methods: A maternal-fetal PBK model built in PK-Sim® was used to perform QIVIVE predicting CPF concentrations in a pregnant women population at 15weeks of gestation from cell lysate concentrations obtained in human induced pluripotent stem cell-derived neural stem cells undergoing differentiation towards neurons and glia exposed to CPF for 14days. The in vitro concentration and effect data were used to perform BMD modelling. Results: The upper BMD was converted into maternal doses which ranged from 3.21 to 271mg/kg bw/day. Maternal CPF blood levels from epidemiological studies reporting DNT findings in their children were used to estimate oral CPF exposure during pregnancy using the PBK model. It ranged from 0.11 to 140μg/kg bw/day. Discussion: The effective daily intake doses predicted from the in vitro model were several orders of magnitude higher than exposures estimated from epidemiological studies to induce developmental non-cholinergic neurotoxic responses, which were captured by the analyzed in vitro test battery. These were also higher than the in vivo LOEC for cholinergic effects. Therefore, the quantitative predictive value of the investigated non-choline esterase-dependent effects, although possibly relevant for other chemicals, may not adequately represent potential key events in the MoA for CPF-associated DNT.

Comparison of 300 mg versus 600 mg daily maintenance doses of aspirin treatment after desensitization in N-ERD: A three-year multicentre experience

Background: Aspirin treatment after desensitization (ATAD) is effective in preventing nasal polyps recurrence as well as respiratory symptoms in patients with nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory diseases (N-ERD). However, there is no consensus on effective daily maintenance doses in ATAD. Therefore, we aimed to compare the effects of two different maintenance doses of aspirin on clinical outcomes for 1-3 years of ATAD. Methods: This was a retrospective, multicenter study that involved four tertiary centers. The maintenance doses of daily aspirin were 300 mg in one center and 600 mg in the remaining three. The data of patients who were on ATAD for 1-3 years were included. Study outcomes (nasal surgeries, sinusitis, asthma attacks, hospitalization, oral corticosteroid use, and medication uses) were assessed in a standardized way and recorded from case files. Results: The study initially included 125 subjects, 38 and 87 were receiving 300 and 600 mg daily aspirin for ATAD, respectively. Number of nasal polyp surgeries decreased after 1 -3 years compared with before ATAD in both groups (group 1, baseline: 0.44 ± 0.07 versus first year: 0.08 ± 0.05; p < 0.001 and baseline: 0.44 ± 0.07 versus 3rd year: 0.01 ± 0.01; p < 0.001; and group 2, baseline 0.42 ± 0.03 versus first year: 0.02 ± 0.02; p < 0.001 and baseline: 0.42 ± 0.03 versus 3rd year: 0.07 ± 0.03; p < 0.001). Conclusion: Given the comparable effects of 300 mg and 600 mg aspirin daily as maintenance treatment of ATAD on both asthma and sinonasal outcomes in N-ERD, our results suggest using 300 mg of aspirin daily in ATAD owing to its better safety profile.

Ganirelix and the prevention of premature luteinizing hormone surges

Ganirelix is a gonadotropin-releasing hormone (GnRH) antagonist with high antagonistic activity that blocks the GnRH receptor by competitive binding. A daily dose of 0.25 mg of ganirelix was sel5ected after a phase II study because it was the minimal, effective daily dose to prevent premature luteinizing hormone surges and this dose yielded the highest ongoing pregnancy rate per started cycle. After subcutaneous administration, ganirelix is rapidly absorbed, reaching peak levels within 1-2 hours (tmax), and has a high absolute bioavailability (>90%). Prospective, comparative studies have demonstrated the advantages of GnRH antagonists over long GnRH agonist treatment in assisted reproduction, including the immediate reversibility of drug effects, a requirement for less follicle-stimulating hormone, a shortened duration of stimulation, a reduced incidence of ovarian hyperstimulation syndrome, and reduced patient burden. Combined analyses concluded that in the general invitro fertilization population, there is a trend for a slightly lower ongoing pregnancy rate and a lower risk of ovarian hyperstimulation syndrome that is largely eliminated when considering triggering with GnRH agonist instead of human chorionic gonadotropin. Regardless of all the research, it is still not fully elucidated why the long GnRH agonist protocol has a trend for higher pregnancy rates after fresh transfer of the same number of good-quality embryos.

Selection of an effective dose of autologous probiotics for patients in the rehabilitation period

It is known that the presence of microorganisms with probiotic properties protects the body from pathogenic bacteria. The classification of symbiotic microorganisms living in the human gastrointestinal tract is constantly changing. Probiotics do not form colonies in the intestine, therefore, to obtain a long-term positive effect, the concentrations of probiotic strains in the intestine should reach a level of at least 10⁸ CFU/ml and remain so for a long time. The biotechnology of designing probiotic drugs is based on the isolation of probiotic strains of microbes from the intestines of a healthy individual. This is the basis for a new promising direction in practical medicine — the preparation of autoprobiotics used for the treatment and prevention of various diseases. The recommended effective daily dose of probiotic should be 10⁸–10⁹ CFU, but the dose may vary depending on the probiotic strain and the pharmaceutical form. The preservation of the viability of bacteria in the required amount until the end of the drug shelf life is also crucial for its effective use. It is assumed that auto-strains of probiotics in identical doses will be effective as well.

Effect of daily dosing with tiotropium against methacholine induced bronchoconstriction in asthmatics

IntroductionLoss of bronchoprotection against direct and indirect acting stimuli following regular use of inhaled beta2-agonists occurs with both short and long-acting formulations. Comparatively little is known about the development of tolerance following regular use of inhaled muscarinic receptor antagonists. Two investigations with the short-acting muscarinic receptor antagonist ipratropium bromide have reported no tolerance after regular use against inhaled methacholine. To our knowledge, there are no data regarding loss of bronchoprotection following regular use of long-acting muscarinic receptor antagonist. We therefore looked at the effect of daily dosing with tiotropium on methacholine induced bronchoconstriction in a population of mild asthmatics. MethodsWe performed a randomized, double-blind, placebo-controlled cross-over study comparing tiotropium Respimat® 5 μg to placebo in adult asthmatics. Each treatment arm began with baseline methacholine challenge followed immediately by treatment administration. One hour later a post treatment methacholine challenge was performed. Participants dosed daily (two puffs) at home for the next six days and returned to the lab on Day 8 for a final dose of treatment 1 h prior to methacholine challenge. ResultsThe average doubling dose increase in methacholine PD20 following a single dose of tiotropium was 3.9 doubling doses whereas that following placebo was 0.93 (p = 0.003). After regular use, methacholine PD20 was further increased to 6.4 doubling doses following tiotropium whereas that following placebo decreased by 0.57 doubling doses (p < 0.001). ConclusionLAMA are indicated for use as add-on monotherapy or in triple therapy combination for poorly controlled asthma. It may be reassuring to know therefore, that regular use does not result in loss of bronchoprotection like that which occurs with beta2-agonist bronchodilators.

Outcomes of prednisone-tapering regimens for cardiac sarcoidosis: A retrospective analysis demonstrating a benefit of infliximab

BackgroundThe optimal treatment strategy for cardiac sarcoidosis has not been standardized. We examined the effectiveness of three prednisone-tapering treatment regimens for cardiac sarcoidosis. MethodsWe retrospectively reviewed prednisone-tapering treatment regimens for cardiac sarcoidosis that contained prednisone alone (P), prednisone plus methotrexate (P-M), and prednisone plus infliximab containing regimens (P–I). We defined the success of each regimen as the ability to lower the daily prednisone dose to 7.5 mg or less for 6 or more months without developing an adverse cardiac event. We also examined the lowest effective daily prednisone dose achieved without developing an adverse cardiac event. ResultsWe identified 61 treatment regimens in 33 cardiac sarcoidosis patients that were analyzed. The success rate of prednisone-tapering regimens was significantly different P: 8/30, 27%; P-M: 3/23, 13%; P–I: 6/8, 75%., p = 0.04. The lowest effective daily prednisone dose for the regimens was also significantly different: P: 14.1 ± 10.1 mg; P-M: 16.9 ± 9.4 mg; infliximab: 7.8 ± 4.9 mg, (p = 0.03); by both measures the success was greatest with the P–I regimen. ConclusionsFor the treatment of cardiac sarcoidosis, prednisone-tapering regimens containing infliximab are superior to those containing prednisone alone or prednisone plus methotrexate in terms of reaching 7.5 mg/day of prednisone for more than 6 months and achieving the lowest effective prednisone.

Tenofovir, Lamivudine, and Dolutegravir Among Rural Adolescents in Zimbabwe: A Cautionary Tale.

Tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD) as a safe and more effective single daily dose regimen is rolling out in Africa for people living with HIV. Although access to viral load (VL) testing is improving, patients may still be transitioned to TLD with virological failure and potential drug resistance. We reviewed annual VL test results of 390 children and adolescents who had enrolled in a community-based antiretroviral therapy program in rural Zimbabwe between 2018 and 2019. VL testing was done by the near point of care simplified amplification-based assays (Diagnostics for the Real World, Sunnyvale, CA, USA) at Chidamoyo Christian Hospital and rate of virological suppression (VS) on TLD (VL <1,000 copies/mL) was assessed. Overall, 184 children and adolescents on TLD were enrolled in this study. The median [interquartile range (IQR)] age was 15 (11-19) years, above half of the participants were female (57%). Before switching to TLD, rate of VS was 76% (139/184). After a median (IQR) duration of 6.9 (5.5-9.1) months on TLD, VS was observed in 95% (174/184) of the participants. Of the 10 participants with VL ≥1,000 copies/mL on TLD, 90% (9/10) were failing on their previous regimens, 6 of 9 (67%) having been on boosted protease inhibitor-based regimens. A high rate (95%) of VS was observed among children and adolescents on TLD in rural Zimbabwe. TLD may address the problems of virological failure and emergence of resistance in Africa. However, longer follow-up might be needed to ascertain sustained VS in this vulnerable population. Randomized Control Trial NCT03986099.

Therapeutic effects of dietary antioxidative supplements on the management of type 2 diabetes and its complications; umbrella review of observational/trials meta-analysis studies.

Controversial data on the effects of vitamins (V) and nutrients on the management of type 2 diabetes mellitus (T2DM) is available. Thus, it is aimed to clarify the role of vitamins and nutrients through an umbrella review regarding the available observational/ trials meta-analyses. All meta-analyses of observational and clinical trials conducted on the impact of vitamins and nutrients in T2DM published until 5th June 2021 in PubMed or Web of Sciences were included in this review. Also, the meta-analysis on children, pregnant women, type 1 DM, or in vivo/in vitro studies was excluded. Search results were reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) flowchart. The overall of 93 papers (99 studies) consisting of 75 trials and 24 observational studies were included. Most studies were conducted on the effect of VD and alpha-lipoic acid (ALA) in both genders. Consumption of VD or its analogous; 20IU/d to 450,000IU/once for 3weeks to 7years showed to have a positive effect on the parameters of glucose hemostasis. Moreover, an inverse association was observed between VD level and T2DM risk. Daily consumption of 1200mg VC for at least 12weeks improved lipid profile and glucose hemostasis parameters. Furthermore, VB and medications for diabetic polyneuropathy (DPN) increased nerve conduction velocity. Vitamins K and E were showen to not have significant impact on T2DM. ALA had a beneficial effect on DPN symptoms after 2-4weeks of intake of at least 300mg/d. T2DM risk was reduced by doubling ALA intake. The effective daily doses of chromium, zinc and coenzyme Q10 on lipid profile and glucose hemostasis parameters were > 200mg, < 25mg, and < 200mg, respectively. This umbrella review suggests that dietary vitamins and nutrients can result in protective impacts the complications associated with T2DM. However, due to discrepancies between the results of the trials and observational studies is essential to conduct long-term high-qualified studies to prove the beneficial therapeutic effects of the vitamins and nutrients on T2DM and its complications.

A Single-Dose Weight-Based Challenge Predicts the Minimally Effective Daily Dose of Prednisone in Hypereosinophilic Syndrome

A Single-Dose Weight-Based Challenge Predicts the Minimally Effective Daily Dose of Prednisone in Hypereosinophilic Syndrome

Prevention of Gallstones After Bariatric Surgery using Ursodeoxycholic Acid: A Narrative Review of Literatures.

Obesity by itself is a factor in the development of gallstone disease, and periods of weight loss after bariatric surgery further increase the risk of gallstone formation. In patients with obesity, hypersecretion of cholesterol may increase the risk of gallstone formation, which is approximately five-fold higher than that in the general population. The incidence of gallstone formation after bariatric surgery is 10-38% and often associated with a proportional increase in the risk of developing biliary complications. Routine postoperative administration of ursodeoxycholic acid (UDCA) is recommended to prevent gallstone formation. Several randomized trials have indicated that UDCA can effectively prevent gallstones and reduce the risk of cholecystectomy after bariatric procedures. The effective daily dose of UDCA in each study ranged from 500 to 1,200 mg, and it may be considered at least during the period of rapid weight loss (first 3-6 months postoperatively) to decrease the incidence of symptomatic gallstones.

Dietary Supplements for Female Infertility: A Critical Review of Their Composition.

Infertility is the condition of about 15% of couples that cannot get a conception after one year of unprotected sexual intercourse. In females, the reduced reproductive capacity underlies the most varied causes. Dietary supplements (DS) might be used to improve the pregnancy rate and a wide range of DS are proposed today to support female fertility. Although many authors demonstrated the positive effect of some of these products, the real efficacy of this approach is still debated. In order to evaluate the potential efficacy of DS for female infertility, we analysed the products marketed in Italy, using an original approach. A review of literature was performed to evaluate the effect of nutraceuticals on various female reproductive outcomes and to detect the minimal effective daily dose (mED) able to improve at least one of these. Thereafter, we conceived a formula to classify the expected efficacy of each DS. Each DS was scored and included into three classes of expected efficacy: higher, lower, and none. Ten out of 24 supplements (41.7%) resulted in the higher and 8 (34.3%) in the lower efficacy group, the remaining 6 DS (25.0%) were expected to have no efficacy. DS marketed in Italy are usually blends of many substances that are frequently employed at a negligible dose or without any evidence of efficacy. These findings raise serious doubt about the potential effectiveness of most commercial DS for female infertility.

PH-dependent Release Matrix Oral Formulation of Prussian Blue to Improve its Efficacy as an Internal Decorporation Agent.

Prussian Blue (PB) is available as conventional release dosage form "Radiogardase" with effective daily dose of 3-10 g (very high). The target site is the duodenum, where it inhibits the enterohepatic circulation of Cs & Tl ions, enhancing their fecal excretion. To enhance efficacy, target release, reduce the dose and side effects, oral pH-dependent matrix formulation of PB based on in-situ gelation of sodium alginate along with calcium salts was formulated and evaluated. Different combinations of matrix granules were formulated and optimized. The optimized one was compressed using Polyvinylpyrrolidone K30 (Pvp K30) in different batches and optimized. Langmuir adsorption isotherm was used to assess in-vitro binding efficacy of formulation to thallium using atomic absorption spectroscopy. The proof of concept i.e., drug release in the duodenum was studied through pharmacoscintigraphy using radiolabeled formulation in rabbits. The optimized granules showed no drug release in an acidic medium for 2 h whereas complete empty of the basket in a basic medium within 30-60 minutes. The matrix tablet formulation with Pvp K30 (10% w/w) was optimized with desired hardness and optimum in-vitro release profile. The release data fitted to various linear kinetic models, Hixson-Crowell r2 (0.9906) best fit, confirmed the erosion-based release mechanism. The maximum binding capacity (MBC) was found significantly higher (89.60 mg Tl/g formulation) than that of PB API (65.90 mg Tl /g PB API). Pharmacoscintigraphic images confirmed intact formulation in the stomach up to 2h and burst release in intestine thereafter. The results exemplify oral pH-dependent PB matrix formulation which achieved desirable target release at the duodenum and in-vitro binding efficacy towards Tl ion was appreciable.

A PRACTICAL APPROACH TO SWITCH FROM A MULTIPLE PILL THERAPEUTIC STRATEGY TO A POLYPILL-BASED STRATEGY FOR SECONDARY PREVENTION IN PATIENTS WITH HYPERTENSION

Objective: The recommendation in hypertension is to initiate treatment with a combination of two blood pressure-lowering drugs in a single pill regardless of the cardiovascular (CV) risk, to add a statin in patients with established CV disease (CVD) or at moderate or high risk, and to add as well an antiplatelet agent only among those with established CVD. Some clinical guidelines nowadays endorse the polypill approach to increase the efficiency of the pharmacological treatment and decrease CV morbidity and mortality. The CNIC polypill is the only CV polypill marketed in Europe and the only approved by the EMEA for the secondary prevention of CVD. This polypill contains aspirin, ramipril, and atorvastatin. We aimed at helping clinicians to start treatment with the CNIC polypill switching from any other statin to atorvastatin, and from any angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) to ramipril. Design and method: We looked for available data and recommendations to build tables of equivalent effective daily doses of two of the polypill components (ramipril and atorvastatin), and we developed a treatment algorithm based on expert opinion. Results: We provide the approximate equivalent effective daily doses of other ACEIs and ARBs with ramipril and of other statins according to atorvastatin's potency. Moreover, to guide clinicians in the management of patients for secondary prevention of CVD, we provide a treatment algorithm and detail the indications and different available preparations to start treatment with the CV polypill in patients with high BP and prior CVD, and how to associate other BP-lowering drugs or lipid-lowering drugs if need be. Finally, we give advice on how to switch and adapt the treatment of patients already on fixed-dose combinations of antihypertensive medications to initiate the CV polypill regimen. Conclusions: The multiple doses of the individual components of the CNIC polypill versions allow for increased flexibility in prescribing and use it to start treatment in patients with high BP and prior CVD, and probably also in the particular scenario of hypertensive patients at high CVD risk without previous CV event and no significant risk of major bleeding.

Dual-trajectories of opioid and gabapentinoid use and risk of subsequent drug overdose among Medicare beneficiaries in the United States: a retrospective cohort study.

Little is known about opioid and gabapentinoid (OPI-GABA) use duration and dose patterns' associations with adverse outcome risks. We examined associations between OPI-GABA dose and duration trajectories and subsequent drug overdose. Retrospective cohort study. US Medicare. Using a 5% sample (2011-16), we identified 71 005 fee-for-service Medicare beneficiaries with fibromyalgia, low back pain, neuropathy and/or osteoarthritis initiating OPIs and/or GABAs [mean age±standard deviation (SD)=65.5±14.5years, female=68.1%, white=76.8%]. Group-based multi-trajectory models identified distinct OPI-GABA use patterns during the year of OPI and/or GABA initiation, based on weekly average standardized daily dose (i.e. OPIs=morphine milligram equivalent, GABAs=minimum effective daily dose). We estimated models with three to 12 trajectories and selected the best model based on Bayesian information criterion (BIC) and Nagin's criteria. We estimated risk of time to first drug overdose diagnosis within 12months following the index year, adjusting for socio-demographic and health factors using inverse probability of treatment weighted multivariable Cox proportional hazards models. We identified 10 distinct trajectories (BIC=-1 176 954; OPI-only=3, GABA-only=3, OPI-GABA=4). Compared with OPI-only early discontinuers (40.6% of the cohort), 1-year drug overdose risk varied by trajectory group: consistent low-dose OPI-only users [16.6%; hazard ratio (HR)=1.47, 95% confidence interval (CI)=1.19-1.82], consistent high-dose OPI-only users (1.8%; HR=4.57, 95% CI=2.99-6.98), GABA-only early discontinuers (12.5%; HR=1.39, 95% CI=1.09-1.77), consistent low-dose GABA-only users (11.0%; HR=1.44, 95% CI=1.12-1.85), consistent high-dose GABA-only users (3.1%; HR=1.43, 95% CI=0.94-2.17), early discontinuation of OPIs and consistent low-dose GABA users (6.9%; HR=1.24, 95% CI=0.90-1.69), consistent low-dose OPI-GABA users (3.4%; HR=2.49, 95% CI=1.76-3.52), consistent low-dose OPI and high-dose GABA users (3.2%; HR=2.46, 95% CI=1.71-3.53) and consistent high-dose OPI and moderate-dose GABA users (0.9%; HR=7.22, 95% CI=4.46-11.69). Risk of drug overdose varied substantially among US Medicare beneficiaries on different use trajectories of opioids and gabapentinoids. High-dose opioid-only users and all consistent opioid and gabapentinoid users (regardless of doses) had more than double the risk of subsequent drug overdose compared with opioid-only early discontinuers.

Dietary Supplements for Male Infertility: A Critical Evaluation of Their Composition.

Dietary supplements (DS) represent a possible approach to improve sperm parameters and male fertility. A wide range of DS containing different nutrients is now available. Although many authors demonstrated benefits from some nutrients in the improvement of sperm parameters, their real effectiveness is still under debate. The aim of this study was to critically review the composition of DS using the Italian market as a sample. Active ingredients and their minimal effective daily dose (mED) on sperm parameters were identified through a literature search. Thereafter, we created a formula to classify the expected efficacy of each DS. Considering active ingredients, their concentration and the recommended daily dose, DS were scored into three classes of expected efficacy: higher, lower and none. Twenty-one DS were identified. Most of them had a large number of ingredients, frequently at doses below mED or with undemonstrated efficacy. Zinc was the most common ingredient of DS (70% of products), followed by selenium, arginine, coenzyme Q and folic acid. By applying our scoring system, 9.5% of DS fell in a higher class, 71.4% in a lower class and 19.1% in the class with no expected efficacy. DS marketed in Italy for male infertility frequently includes effective ingredients but also a large number of substances at insufficient doses or with no reported efficacy. Manufacturers and physicians should better consider the scientific evidence on effective ingredients and their doses before formulating and prescribing these products.