De-simplifying single-tablet antiretroviral treatments for cost savings in France: From the patient perspectives to a 6-month follow-up on generics.

In developed countries, most people living with HIV/AIDS are treated with costly brand single-tablet regimens. Given the economic impact, French guidelines recommend using generic antiretroviral therapy when possible to decrease antiretroviral therapy costs. We aimed to study HIV-infected patients' acceptability to switch from a brand single-tablet regimens [abacavir/lamivudine/dolutegravir (Triumeq®) or emtricitabine/tenofovir disoproxil fumarate/rilpivirine (Eviplera®)] to a treatment comprising of two pills: one is a fixed-dose generic combination of 2 Nucleoside Analogs and the second tablet is the third antiretroviral. This study was a prospective observational study in a French hospital. During their follow-up, patients on stable single-tablet regimens were made aware of the possible cost-saving. They were questioned about their willingness and barriers accepting the substitution. Participants chose between the two regimens, either to remain on single-tablet regimens or switch to the de-simplified regimen. Six months later, a second survey was given to the patient who chose to de-simplify and HIV viral load was controlled. The study included 98 patients: 60 receiving emtricitabine/tenofovir disoproxil fumarate/rilpivirine (Eviplera®) and 38 on abacavir/lamivudine/dolutegravir (Triumeq®). Forty-five patients accepted the de-simplified treatment, 37 refused and 16 were undecided and followed the decision offered by their physician. The main reason for unwillingness to switch is the number of pills (77.3%). In multivariate model analysis, male patients (p = 0.001) who have taken antiretroviral therapy for over 20 years (p = 0.04) and who retrieve their treatment in their community hospital (p = 0.03) are more likely to accept the switch. Fifty-one patients accepted to replace their single-tablet regimens and six months later, the majority was satisfied; only four returned to single-tablet regimens because of suspected side effects. Half of the people living with HIV/AIDS in our cohort accepted to switch from brand single-tablet regimens to a two-tablet regimen containing generic drugs within a process that emphasizes health expenditure savings.

Real-world adherence and persistence for newly-prescribed HIV treatment: single versus multiple tablet regimen comparison among US medicaid beneficiaries.

BACKGROUND: Once-daily, single-tablet regimens (STRs) have been associated with improved patient outcomes compared to multi-tablet regimens (MTRs). This study evaluated real world adherence and persistence of HIV antiretroviral therapy (ART), comparing STRs and MTRs. METHODS: Adult Medicaid beneficiaries (aged ≥ 18 years) initiating ART with ≥ 2 ART claims during the identification period (January 1, 2015-December 31, 2016) and continuous health plan enrollment for a 12-month baseline period were included. For STRs, the first ART claim date was defined as the index date; for MTRs, the prescription fill claim date for the last drug in the regimen was defined as the index date, and prescription fills were required to occur within a 5-day window. Adherence was assessed in 30-day intervals over a 6-month period, with adherence defined as having less than a 5-day gap between fills. Persistence was evaluated as median number of days on therapy and percent persistence at 12 months. Cox Proportional Hazard models were used to evaluate risk of discontinuation, controlling for baseline and clinical characteristics. RESULTS: A total of 1,744 (STR = 1290; MTR = 454) and 2409 (STR = 1782; MTR = 627) patients newly prescribed ART had available data concerning adherence and persistence, respectively. Average age ranged 40-42 years. The patient population was predominantly male. Adherence assessments showed 22.7% of STR initiators were adherent to their index regimens over a 6-month period compared to 11.7% of MTR initiators. Unadjusted persistence analysis showed 36.3% of STR initiators discontinued first-line therapy compared to 48.8% for MTR initiators over the 2-year study period. Controlling for baseline demographic and clinical characteristics, MTR initiators had a higher risk of treatment discontinuation (hazard ratio [HR] = 1.6, p < 0.0001). Among STRs, compared to the referent elvitegravir(EVG)/cobicistat(COBI)/emtricitabine(FTC)/tenofovir alafenamide(TAF), risk of discontinuation was higher for efavirenz(EFV)/FTC/tenofovir disoproxil fumarate(TDF) (HR = 3.6, p < 0.0001), EVG/COBI/FTC/TDF (HR = 2.8, p < 0.0001), and abacavir (ABC)/lamivudine (3TC)/dolutegravir (DTG) (HR = 1.8, p = 0.004). Among backbones, FTC/TAF was associated with lower risk of discontinuation than FTC/TDF (HR = 4.4, p < 0.0001) and ABC/3TC (HR = 2.2, p < 0.0001). CONCLUSIONS: Among patients newly prescribed ART, STR initiators were significantly less likely to discontinue therapy and had greater adherence and persistence compared to MTR initiators. Regimens containing FTC/TAF as a backbone had higher persistence than those consisting of other backbones.

Comparative health risk assessment of realgar and NiuHuangJieDu tablets based on tissue arsenic levels after multiple oral administration to rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Realgar (As2S2), a mineral traditional Chinese medicine (TCM), is proved to have great therapeutic effects in clinic and has been widely used in China for hundreds of years. As one of the most popular realgar-containing TCMs, NiuHuangJieDu Tablets (NHJDT) is used as OTC (over-the-counter) drug in daily life for fever relieving, detoxicating, as well as cure of sore throat and gingival swelling. However, the safety of realgar and its-containing TCMs still remains unclear. AIM OF THE STUDY: This study was to investigate the accumulation of arsenic in rat body and evaluate the safety of realgar-containing TCMs in vivo. MATERIALS AND METHODS: The health risk of arsenic was evaluated in rats by tissue distribution and histopathology, as well as arsenic speciation in plasma after multiple oral gavage of low and high doses of realgar and NiuHuangJieDu Tablets (NHJDT), respectively. Total arsenic and arsenic speciation were determined by hydride generation-atomic fluorescence spectrometry (HG-AFS) and high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS), respectively. RESULTS: Arsenic accumulated in rat tissues especially in heart, liver, spleen, lung, kidney, uterus and ovary. Dimethylarsenic acid (DMA) was detected as the predominant species in rat plasma after dosing. In comparison of realgar, NHJDT with co-existing components significantly alleviated tissues injury, and reduced arsenic concentration in rat tissues and plasma. CONCLUSIONS: NHJDT with co-existing components combination was relatively safer than realgar, but the accumulation of arsenic was still significant after long-term medication. Therefore, great attentions should be paid to realgar-containing TCMs to avoid toxicity from arsenic accumulation. Moreover, the dose regimen of realgar-containing TCMs should be designed rationally for clinical application. These results may provide useful references for the application of realgar-containing TCMs and might be helpful for the understanding of TCM compound compatibility.

Partição de Comprimidos Antineoplásicos Utilizados no Tratamento de Leucemias Agudas em Crianças e Adolescentes / Splitting of Antineoplastic Tablets Used in Acute Leukemias Treatment in Children and Adolescents / Partición de Comprimidos Antineoplásicos Empleados en el Tratamiento de Leucemias Agudas en Niños y Adolescentes

Introdução: A manipulação de antineoplásicos para ajuste de dose, como partição de comprimidos, é comum no tratamento de leucemias agudas de crianças e adolescentes. Objetivo: Identificar a frequência e descrever a prática da partição domiciliar de comprimidos antineoplásicos utilizados no tratamento oral de crianças e adolescentes com leucemias agudas na fase de manutenção. Método: Trata-se de um estudo transversal descritivo, realizado em um hospital pertencente à rede de saúde pública do Distrito Federal com assistência especializada em pediatria. Foram incluídos no estudo crianças e adolescentes entre 1 e 18 anos, diagnosticados com leucemias agudas e em fase de manutenção do tratamento no período de estudo. Foi aplicado um questionário semiestruturado ao responsável principal pela administração dos medicamentos quimioterápicos via oral, podendo ser o cuidador ou a própria criança/adolescente. Foram coletadas variáveis sociodemográficas dos pacientes e cuidadores e variáveis sobre a prática de partição de medicamentos antineoplásicos no domicílio. Resultados: Todos os 48 entrevistados no período do estudo relataram ter partido comprimidos antineoplásicos ao longo do tratamento de leucemias agudas, sendo estes mercaptopurina (n=45 [93,75%]) e tioguanina (n=3 [6,25%]). Conclusão: A partição de comprimidos antineoplásicos foi uma prática unânime em virtude da necessidade referida de ajuste de dose individual para o tratamento de leucemias agudas de crianças e adolescentes, considerando a indisponibilidade de formulações adequadas. Os resultados reforçam a necessidade de a partição ser uniformizada e realizada de maneira a minimizar os riscos e a garantir a segurança para as crianças e adolescentes e seus cuidadores.

Introduction: Antineoplastic drug manipulation for dose adjustment, such as tablet splitting, is standard in acute leukemia treatment for children and adolescents. Objective: To identify the frequency and describe the practice of household splitting of antineoplastic tablet for oral treatment of children and adolescents with acute leukemias in the maintenance phase. Method: Cross-sectional descriptive study performed in a public health system hospital from Distrito Federal (Brazil) with specialized pediatric assistance. Children and teenagers between 1 and 18 years old, diagnosed with acute leukemia and in treatment maintenance phase during the study period were included. A semi-structured questionnaire was applied to the main responsible for administering oral chemotherapy drugs, which could be the caregiver or the child/adolescent themselves. Sociodemographic variables of patients and caregivers and variables on the practice of splitting antineoplastic drugs at home were collected. Results: All 48 interviewees in the study period reported having split antineoplastic tablets during the treatment for acute leukemias, such as mercaptopurine (n = 45 [93.75%]) and thioguanine (n = 3 [6.25%]). Conclusion: The splitting of antineoplastic tablets was a unanimous practice due to the reported need to adjust the individual dose for acute leukemia treatment in children and adolescents, considering the unavailability of adequate formulations. The results reinforce the need for splitting to be standardized and performed in a way that minimizes risks and ensures safety for patients and their caregivers

Introducción: La manipulación de fármacos antineoplásicos para el ajuste de dosis, como las particiones de comprimidos, es frecuente en el tratamiento de las leucemias agudas en niños y jóvenes. Objetivo: Identificar la frecuencia y describir la práctica de la división domiciliaria de medicamentos antineoplásicos utilizados en el tratamiento oral de niños y adolescentes con leucemias agudas en la fase de mantenimiento. Método: Se trata de un estudio transversal descriptivo realizado en un hospital de la red de salud pública del Distrito Federal (Brasil) con asistencia especializada en pediatría. El estudio incluyó a niños y jóvenes de entre 1 y 18 años de edad diagnosticados con leucemia aguda y en fase de mantenimiento del tratamiento en el período del estudio. Se aplicó un cuestionario semiestructurado a la persona principal responsable de la administración de fármacos quimioterapéuticos por vía oral, que puede ser el cuidador o el propio niño/joven. Fueron colectadas variables sociodemográficas de los pacientes y cuidadores y variables sobre la práctica de la división de los medicamentos antineoplásicos en domicílios. Resultados: Los 48 entrevistados en el período de estudio informaron haber roto las pastillas antineoplásicas durante el tratamiento de la leucemia aguda, siendo éstas mercaptopurina (n=45 [93,75%]) y tioguanina (n=3 [6,25%]). Conclusión: La partición de comprimidos antineoplásicos fue una práctica unánime debido a la necesidad mencionada de ajustar la dosis individual para el tratamiento de las leucemias agudas de niños y adolescentes, considerando la falta de formulaciones apropiadas. Los resultados refuerzan la necesidad de estandarizar y realizar la partición para minimizar los riesgos y garantizar la seguridad de los niños, jóvenes y sus cuidadores.

Does splitting a tablet obtain the accurate dose?: A systematic review protocol.

BACKGROUND: Physical manipulation of the manufactured dose form is a common practice, with almost a quarter of all drugs administered in primary care having their dose altered. Splitting a tablet can be advantageous as it facilitates swallowing, allows for dose flexibility and provides cost reductions. However, there are concerns these physical changes can lead to inaccurate portions resulting in significant variations from the prescribed dose. Thus, the review described in this protocol aims to summarise the literature assessing the effect of tablet splitting on dose accuracy. METHODS: Relevant studies will be identified through electronic searches in databases including EMBASE, MEDLINE, CINAHL, and the Cochrane Library, from the beginning of databases until January 2020. Studies investigating any drug, where the tablet was split, will be potentially eligible. Two reviewers will independently screen studies and extract data using standardised forms. Data extracted will include general study information, characteristics of the study, intervention characteristics and outcomes. Primary outcome is to assess dose accuracy of a split tablet measured by drug content or weight variability. Assessment of risk of bias will be dependent upon study design. If deemed feasible, meta-analysis will be performed. RESULTS: The study described within this protocol will provide a synthesis of current evidence assessing the effect of tablet splitting on dose accuracy. CONCLUSION: The conclusion of our study will provide evidence to judge whether splitting a tablet results in an accurate half dose. ETHICS AND DISSEMINATION: Ethics approval was not required for this study. The results of the systematic review described will be published in a peer-reviewed journal. REGISTRATION DETAILS: PROSPERO CRD42018106252.

Health risk assessment of arsenic in Realgar and NiuHuangJieDu Tablets based on pharmacokinetic study.

NiuHuangJieDu Tablets (NHJDT), a popular realgar (As4S4) containing patented traditional Chinese medicine (TCM), is widely used in the treatment of acute tonsillitis, pharyngitis, periodontitis and mouth ulcer. However, arsenic is considered as one of the most toxic elements, leading to growing concerns about the quality and safety of realgar-containing TCMs recently. In this study, health risk assessment of arsenic in realgar and NHJDT was conducted through oral administration of both substances to rats with single and multiple doses, respectively. The total blood arsenic concentration was used as the health risk indicator and determined by hydride generation-atomic fluorescence spectrometry after modified Kjeldahl digestion, and then applied to the pharmacokinetic study. For single oral dose study in rats, the low, medium, and high doses of realgar and NHJDT were set equivalent to 1, 5 and 20 times the human therapeutic dose (1.3 mg realgar/kg), respectively. Multiple doses were given at low and high dose levels every 12 h for seven consecutive days, respectively. Significant differences in the total blood arsenic pharmacokinetic profiles were observed between the corresponding realgar and NHJDT groups. These results indicated that NHJDT significantly reduced the total blood arsenic exposure present in realgar, and the detoxification mechanism might be attributed to herb-herb interactions in NHJDT. However, the accumulation of blood total arsenic was significant due to the long elimination half-life and high accumulation index in both realgar and NHJDT groups. Therefore, the potential health risk of arsenic caused by the administration of realgar-containing TCMs should be taken into account for excessive or long-term medication. Precautions should be taken for the clinical application of realgar-containing TCMs.

Assessment of Clinical Practices for Crushing Medication in Geriatric Units.

OBJECTIVES: To assess the modification of the form of medication and evaluate staff observance of good clinical practices. DESIGN: One-day assessment of clinical practices. SETTING: 17 geriatrics units in the 3 Teaching Hospitals of Paris-Sud (APHP), France. PARTICIPANTS: Elderly in-patients with difficulties swallowing capsules and tablets. MEASUREMENTS: Assessment of target-patient prescriptions and direct observation of nurses' medical rounds. RESULTS: 155/526 in-patients (29.5%) were unable to swallow tablets or capsules: 98 (40.3%) in long-term care, 46 patients (23.8%) in the rehabilitation unit and 11 (12.2%) in the acute care unit (p = .005). In thirty-nine (27.3%) of the 143 prescriptions studied all tablets were safe to crush and all capsules were safe to open. In 104 cases, at least one medication could not be safely modified, including 26 cases (18.2%) in which none of the prescribed drugs were safe to crush or open. In 48.2% of the 110 medications that were crushed, crushing was forbidden, and presented a potential threat in 12.7% of cases or a reduced efficacy in 8.2% of cases. Crushing methods were rarely appropriate: no specific protective equipment was used (81.8%), crushing equipment was shared between patients without cleaning (95.1%), medications were spilled or lost (69.9%). The method of administration was appropriate (water, jellified water) in 25% of the cases, questionable (soup, coffee, compote, juice, cream) in 55% of the cases and unacceptable (laxative) in 21% of the cases. CONCLUSION: Management of drug prescriptions in patients with swallowing difficulties is not optimal, and may even have iatrogenic effects. In this study, 12.7% of the modifications of the drug form could have been harmful. Doctors, pharmacists and nurses need to reevaluate their practices.

Population Pharmacokinetics of Posaconazole Tablets and Monte Carlo Simulations To Determine whether All Patients Should Receive the Same Dose.

Posaconazole is extensively used for prophylaxis for invasive fungal infections. The gastro-resistant tablet formulation has allowed the bioavailability issues encountered with the oral suspension to be overcome. However, overexposure is now frequent. This study aimed to (i) describe the pharmacokinetics of posaconazole tablets in a real-life cohort of patients with hematological malignancies and (ii) perform Monte Carlo simulations to assess the possibility that the daily dose can be reduced while keeping a sufficient exposure. Forty-nine consecutive inpatients were prospectively included in the study. Posaconazole trough concentrations (TC) were measured once a week, and biological and demographic data were collected. The concentrations were analyzed by compartmental modeling, and Monte Carlo simulations were performed using estimated parameters to assess the rate of attainment of the target TC after dose reduction. The pharmacokinetics of posaconazole were well described using a one-compartment model with first-order absorption and elimination. The values of the parameters (interindividual variabilities) were as follows: the absorption constant (ka ) was 0.588 h-1 (fixed), the volume of distribution (V/F) was 420 liters (28.2%), and clearance (CL/F) was 7.3 liters/h (24.2%) with 31.9% interoccasion variability. Forty-nine percent of the simulated patients had TC at steady state of ≥1.5 µg/ml and maintained a TC above 1 µg/ml after a reduction of the dose to 200 mg daily. A third of these patients eligible for a dose reduction had TC of ≥1.5 µg/ml as soon as 48 h of treatment. Though posaconazole tablets were less impacted by bioavailability issues than the oral suspension, the pharmacokinetics of posaconazole tablets remain highly variable. Simulations showed that approximately half of the patients would benefit from a reduction of the dose from 300 mg to 200 mg while keeping the TC above the minimal recommended target of 0.7 µg/ml, resulting in a 33% savings in the cost of this very expensive drug.

First Successful Pre-Distribution of Stable Iodine Tablets Under Japan's New Policy After the Fukushima Daiichi Nuclear Accident.

Stable iodine tablets are effective in reducing internal exposure to radioactive iodine, which poses a risk for thyroid cancer and other conditions. After the Fukushima Daiichi nuclear power plant accident, the Japanese government shifted its policy on stable iodine tablet distribution from "after-the-fact" to "before-the-fact" and instructed local governments to pre-distribute stable iodine tablets to residents living within a 5-km radius of nuclear facilities. The nation's first pre-distribution of stable iodine tablets was carried out in June and July of 2014 in Kagoshima Prefecture. Health surveys were conducted so that the medication would not be handed out to people with the possibility of side effects. Of the 4715 inhabitants in the area, 132 were found to require a physician's judgment, mostly to exclude risks of side effects. This was considered important to prevent the misuse of the tablets in the event of a disaster. The importance of collective and individualized risk communication between physicians and inhabitants at the community health level was apparent through this study. Involvement of physicians through the regional Sendai City Medical Association was an important component of the pre-distribution. Physicians of the Sendai City Medical Association were successfully educated by using the Guidebook on Distributing and Administering Stable Iodine Tablets prepared by the Japan Medical Association and Japan Medical Association Research Institute with the collaboration of the National Institute of Radiological Sciences and the Japanese government. Thus, the physicians managed to make decisions on the dispensing of stable iodine tablets according to the health conditions of the inhabitants. All physicians nationwide should be provided continuing medical education on stable iodine tablets. (Disaster Med Public Health Preparedness. 2017;11:365-369).

Switch from unboosted protease inhibitor to a single-tablet regimen containing rilpivirine improves cholesterol and triglycerides.

This study aimed to evaluate the efficacy, tolerability and potential savings of combined antiretroviral therapy (cART) simplification from an unboosted protease inhibitor (PI) regimen with atazanavir or fosamprenavir to a single-tablet regimen (STR) based on rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) among HIV-1-infected patients with HIV-1 RNA <50 copies/mL. This was a retrospective, multicentre, open-label, 12-week trial. Plasma HIV-1-RNA levels, CD4+ cell counts, cholesterol, triglycerides, bilirubin, glycaemia, creatinine and physical examination were performed at baseline and at scheduled follow-up. All patient costs were calculated and were estimated for 52 weeks of therapy. Fifty-one patients were enrolled [28 male (54.9%)]. At baseline, 30 patients (58.8%) were treated with FTC/TDF, 20 (39.2%) with abacavir/lamivudine and 1 (2.0%) with lamivudine/zidovudine. Thirty-three patients (64.7%) received atazanavir. All patients maintained HIV-RNA <50 copies/mL; the median CD4+ cell count remained stable. Mean triglycerides decreased from 124 mg/dL (range, 39-625) at enrolment to 108.7 mg/dL (range, 39-561) at study end (P = 0.25). At baseline, mean cholesterol was 172.8 ± 38.1 mg/dL and decreased to 161.9 ± 38.6 mg/dL (P = 0.038); likewise, median total bilirubin decreased from 1.07 mg/dL (range, 0.2-4.7) to 0.6 mg/dL (range, 0.13-3.1) (P <0.001). cART-related annual cost reduction with a STR was €3155.47 per patient (-24%). Non-cART patient management expenses were €402.68 vs. €299.10 for atazanavir or fosamprenavir and STR regimens, respectively. Switching to RPV/FTC/TDF from an unboosted PI in virologically suppressed HIV-infected patients is safe and is associated with a reduction in triglycerides, cholesterol and cART-related costs.

Use of biorelevant media for assessment of a poorly soluble weakly basic drug in the form of liquisolid compacts: in vitro and in vivo study.

The purpose of this work is to use biorelevant media to evaluate the robustness of a poorly water soluble weakly basic drug to variations along the gastrointestinal tract (GIT) after incorporation in liquisolid compacts and to assess the success of these models in predicting the in vivo performance. Liquisolid tablets were prepared using mosapride citrate as a model drug. A factorial design experiment was used to study the effect of three factors, namely: drug concentration at two levels (5% and 10%), carriers at three levels (avicel, mannitol and lactose) and powder excipients ratio (R) of the coating material at two levels (25 and 30). The in vitro dissolution media utilized were 0.1 N HCl, hypoacidic stomach model and a transfer model simulating the transfer from the stomach to the intestine. All compacts released above 95% of drug after 10 min in 0.1 N HCl. In the hypoacidic model, the compacts with R 30 were superior compared to R 25, where they released >90% of drug after 10 min compared to 80% for R 25. After the transfer of the optimum compacts from Simulated gastric fluid fast (SGFfast) to fasted state simulated intestinal fluid, slight turbidity appeared after 30 min, and the amount of drug dissolved slightly decreased from 96.91% to 90.59%. However, after the transfer from SGFfast to fed state simulated intestinal fluid, no turbidity or precipitation occurred throughout time of the test (60 min). In vivo pharmacokinetic study in human volunteers proved the success of the in vitro models with enhancement of the oral bioavailability (121.20%) compared to the commercial product.

QbD-based carbopol transgel formulation: characterization, pharmacokinetic assessment and therapeutic efficacy in diabetes.

In order to develop transdermal drug delivery system that facilitates the skin permeation of Pioglitazone (PZ) encapsulated in carbopol-based transgel system (proniosomes/niosome). The developed formulations were optimized using quality by design (QbD) approach and particle size, percentage entrapment and transdermal flux were determined. It was found to be more efficient delivery carriers with high encapsulation and enhanced flux value demonstrated that the permeation of PZ through skin was significantly increased with developed formulation. The transdermal enhancement from proniosome was 3.16 times higher than that of PZ from control formulation (ethanol buffer formulation, 3:7), which was further confirmed by confocal laser scanning microscopy. In vivo pharmacokinetic study of carbopol transgel showed a significant increase in bioavailability (2.26 times) compared with tablet formulation. It also showed better antidiabetic activity in comparison to marketed tablet, so our results suggest that carbopol-based transgel are an efficient carrier for delivery of pioglitazone through skin.

Development and Efficacy Assessment of an Enteric Coated Porous Tablet Loaded With F4 Fimbriae for Oral Vaccination of Piglets against F4+ Escherichia coli Infections.

Enterotoxigenic Escherichia coli (ETEC) infection is one of the major causes contributing to the development of diarrhoea and mortality in new born, suckling and newly weaned piglets. To date, no preventive/treatment strategy showed promising results, which could be due to the lack of potent vaccines, and/or due to the development of resistance of ETEC to antibiotics. Therefore, in the present investigation, a novel porous sodium alginate (SA) tablet formulation loaded with F4 fimbriae antigen was developed and tested for efficacy against ETEC infections in piglet models. Precompression parameters of the powder mixes and post compression parameters of tablets have been evaluated and results were found to be satisfactory. Loading of F4 fimbrial antigens into the tablets was achieved by inducing pores in the tablets via the sublimation of camphor followed by incubation with purified F4 fimbriae. The loaded tablets have been coated with Eudragit L100 to protect the F4 fimbriae from (a) highly acidic gastric environment; (b) proteolytic cleavage by pepsin; and (c) to promote subsequent release in the intestine. Evaluation of developed F4 fimbrial tablets in a Pig model demonstrated induction of mucosal immunity, and a significant reduction of F4+ E. coli in faeces. Therefore, F4 fimbriae loaded porous tablets could be a novel oral vaccination candidate to induce mucosal and systemic immunity against ETEC infections.

Cost-effectiveness of extended-release methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder sub-optimally treated with immediate release methylphenidate.

BACKGROUND: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common psychiatric disorder in children and adolescents. Immediate-release methylphenidate (IR-MPH) is the medical treatment of first choice. The necessity to use several IR-MPH tablets per day and associated potential social stigma at school often leads to reduced compliance, sub-optimal treatment, and therefore economic loss. Replacement of IR-MPH with a single-dose extended release (ER-MPH) formulation may improve drug response and economic efficiency. OBJECTIVE: To evaluate the cost-effectiveness from a societal perspective of a switch from IR-MPH to ER-MPH in patients who are sub-optimally treated. METHODS: A daily Markov-cycle model covering a time-span of 10 years was developed including four different health states: (1) optimal response, (2) sub-optimal response, (3) discontinued treatment, and (4) natural remission. ER-MPH options included methylphenidate osmotic release oral system (MPH-OROS) and Equasym XL/Medikinet CR. Both direct costs and indirect costs were included in the analysis, and effects were expressed as quality-adjusted life years (QALYs). Univariate, multivariate as well as probabilistic sensitivity analysis were conducted and the main outcomes were incremental cost-effectiveness ratios. RESULTS: Switching sub-optimally treated patients from IR-MPH to MPH-OROS or Equasym XL/Medikinet CR led to per-patient cost-savings of €4200 and €5400, respectively, over a 10-year treatment span. Sensitivity analysis with plausible variations of input parameters resulted in cost-savings in the vast majority of estimations. CONCLUSIONS: This study lends economic support to switching patients with ADHD with suboptimal response to short-acting IR-MPH to long-acting ER-MPH regimens.

Challenges and emerging solutions in the development of compressed orally disintegrating tablets.

INTRODUCTION: Orally disintegrating tablets (ODTs) provide several advantages over conventional tablets such as suitability for patients with swallowing difficulties and faster onset of action. The manufacture of ODTs by compression/tableting offers a practical and cost-effective strategy over the freeze drying (lyophilisation) method. Nonetheless, the FDA recommends a disintegration time of 30 s and a maximum weight of 500 mg for a tablet to be labelled as an ODT. These requirements, alongside other desirable product properties, have created a number of challenges for the formulator to overcome while developing compressed ODTs. AREAS COVERED: The review discusses the main challenges of ODT manufacturing process and the emerging solutions featured at early drug development stages. The research specifically describes the methods reported for taste masking/assessment and solubilisation of unpalatable and poorly soluble drugs, respectively. Furthermore, this review highlights the techniques used for developing modified-release ODTs, an emerging area in the field. In addition, it also discusses the poor flowability and segregation problems of directly compressed powders. Moreover, the review describes the tests reported in the literature for ODT disintegration time assessment since a universal technique is still non-existent. EXPERT OPINION: The approaches used to overcome the manufacturing challenges often have a bearing on the price of the end product. However, despite the technical and regulatory challenges, ODTs can offer many advantages over the conventional dosage forms if accompanied by suitable adjuvant technologies and in vitro analytical tools.

Solid oral forms availability in children: a cost saving investigation.

AIM: To assess the suitability and potential cost savings, from both the hospital and community perspective, of prescribed oral liquid medicine substitution with acceptable solid forms for children over 2 years. METHOD: Oral liquid medicines dispensed from a paediatric hospital (UK) in 1 week were assessed by screening for existence of the solid form alternative and evaluating the acceptability of the available solid form, firstly related to the prescribed dose and secondly to acceptable size depending on the child's age. Costs were calculated based on providing treatment for 28 days or prescribed duration for short term treatments. RESULTS: Over 90% (440/476) of liquid formulations were available as a marketed solid form. Considering dosage acceptability (maximum of 10% deviation from prescribed dosage or 0% for narrow therapeutic range drugs, maximum tablet divisions into quarters) 80% of liquids could be substituted with a solid form. The main limitation for liquid substitution would be solid form size. However, two-thirds of prescribed liquids could have been substituted with a suitable solid form for dosage and size, with estimated savings being of £5K and £8K in 1 week, respectively based on hospital and community costs, corresponding to a projected annual saving of £238K and £410K (single institution). CONCLUSION: Whilst not all children over 2 years will be able to swallow tablets, drug cost savings if oral liquid formulations were substituted with suitable solid dosage forms would be considerable. Given the numerous advantages of solid forms compared with liquids, this study may provide a theoretical basis for investing in supporting children to swallow tablets/capsules.

The practice and clinical implications of tablet splitting in international health.

OBJECTIVE: Tablet splitting is frequently performed to facilitate correct dosing, but the practice and implications in low-income settings have rarely been discussed. METHODS: We selected eight drugs, with narrow therapeutic indices or critical dosages, frequently divided in the Lao PDR (Laos). These were split, by common techniques used in Laos, by four nurses and four laypersons. The mean percentage deviation from the theoretical expected weight and weight loss of divided tablets/capsules were recorded. RESULTS: Five of eight study drugs failed, on splitting, to meet European Pharmacopoeia recommendations for tablet weight deviation from the expected weight of tablet/capsule halves with 10% deviating by more than 25%. There was a significant difference in splitting accuracy between nurses and laypersons (P = 0.027). Coated and unscored tablets were less accurately split than uncoated (P = 0.03 and 0.0019 for each half) and scored (0.0001 for both halves) tablets. CONCLUSION: These findings have potential clinical implications on treatment outcome and the development of antimicrobial resistance. Investment by drug companies in a wider range of dosage units, particularly for narrow therapeutic index and critical dosage medicines, is strongly recommended.

"Take your pill": the role and fantasy of pills in modern medicine.

The pharmaceutical industry has undergone a vast expansion in the 20th and 21st centuries. This article explores the central role now played by pills in clinical practice, but also in the public imagination. First, this article analyzes four properties that, together, account for many of the promises and perils associated with pills: They are ingestible, potent, reproducible, and miniaturized. This allows them to serve as ideal consumer items for widespread distribution and sale and also as model technological "devices" capable of downloading into the body healing chemicals. As such, they seem to promise a disburdening solution to many of life's ills. In our cultural fantasy, often shared by physician and patient alike, pills can be used not only to treat and prevent disease but also raise energy, lose weight, lessen pain, lift mood, cope with stress, and enhance sexual and athletic performance. This article also explores many adverse effects not only of pills themselves but of this exaggerated cultural fantasy of the pill. It tends to distract us from other, more holistic understandings of the locus of disease and healing. It even fosters misunderstandings of the ways in which pills themselves work, which is to assist bodily processes, and the mind's "meaning response." The intent here is not to demonize all pills-many have great therapeutic potential-but to learn how to better choose and use them wisely. We propose that this process be assisted through recontextualizing the pill as a multidimensional gift. Taken in such a way, with appropriate gratitude and discernment, we may ingest fewer pills, but with greater efficacy.

Development of a low-dose fast-dissolving tablet formulation of Newcastle disease vaccine for low-cost backyard poultry immunisation.

The immunisation of backyard poultry is critical for maintaining healthy flocks to provide nutrition and income for low-resource farmers worldwide. A vaccine presentation for flocks of less than 50 birds could make it more affordable and accessible, increasing uptake and impact. Fast-dissolving tablets (FDT) of Newcastle disease virus (NDV) vaccine were produced by freeze drying the LaSota NDV strain combined with excipients into tablets containing a small number of doses and packaged in polymer blister sheets. The NDV-FDT vaccine maintained virus stability for more than six months at 4°C, based on plaque assay and egg infectivity dose data. Stability was further confirmed in a challenge study, where the tablet vaccine elicited a strong immune response and provided 100 per cent protection to vaccinated chickens infected with a virulent strain of NDV. The vaccine tablet can be diluted in water (no needle or syringe required) and administered either in drinking water or with a dropper via an intraocular and/or intransal route. Results indicate that FDTs containing a small number of doses are a feasible presentation for backyard poultry farmers. The compact packaging of the FDTs will also provide cost savings in storing and distributing the vaccine in the cold chain.

Design and evaluation of an economic taste-masked dispersible tablet of pyridostigmine bromide, a highly soluble drug with an extremely bitter taste.

Pyridostigmine bromide (PTB) is a highly soluble and extremely bitter drug. Here, an economic complexation technology combined with direct tablet compression method has been developed to meet the requirements of a patient friendly dosage known as taste-masked dispersible tablets loaded PTB (TPDPTs): (1) TPDPTs should have optimal disintegration and good physical resistance (hardness); (2) a low-cost, simple but practical preparation method suitable for industrial production is preferred from a cost perspective. Physicochemical properties of the inclusion complex of PTB with beta-cyclodextrin were investigated by Fourier transformed infrared spectroscopy, differential scanning calorimetry and UV spectroscopy. An orthogonal design was chosen to properly formulate TPDPTs. All volunteers regarded acceptable bitterness of TPDPTs. The properties including disintegration time, weight variation, friability, hardness, dispersible uniformity and drug content of TPDPTs were evaluated. The dissolution profile of TPDPTs in distilled water exhibited a fast rate. Pharmacokinetic results demonstrated that TPDPTs and the commercial tablets were bioequivalent.