Drug Substitution Research Articles

What drug to buy? generic brand substitution in base of the pyramid markets: Evidence from Ghana

Prescription brand substitution also known as generic substitution (GS)is a worldwide phenomenon. In the pharmaceutical industry, growth of the generic drug market implies growth in the number and types of substitutes for ethical (innovator) pharmaceutical products. This threat is relevant mainly due to the comparatively lower prices of these substitutes. Ultimately, prescription brand substitution renders the various marketing efforts and investments of the affected pharmaceutical companies fruitless. The efforts in the literature have focused more on cost as the reason but there seems to be more reasons than cost in developing countries like Ghana. The study examined the marketing-related impacts of prescription brand substitution at community pharmacies in Ghana. Utilizing the ideas of Porter’s five competitive forces model, specifically the threat of substitute products and services, the study which is cross-sectional, deductive and descriptive survey in nature, used a mix of cluster sampling and purposive sampling to arrive at a final sample size of 50 pharmacies and 9 pharmaceutical companies,. Data collected were analysed using simple linear regression and descriptive statistics. Weak but statistically significant relationship between frequency of pharmacy calls and nature of drug substitution was observed. Also, prescription brand substitution is prevalent at community pharmacies in Ghana, and that ethical companies are the most affected. Pharmacy front line staff and patients played contributory roles in this phenomenon. It is recommended that Ethical pharmaceutical companies should acknowledge, plan and act in order to minimize the competitive effects of prescription brand substitution

Resource utilization associated with the management of potential interactions between direct-acting antivirals for chronic hepatitis C treatment and cardiovascular and central nervous system drugs

Objective: Patients with chronic Hepatitis C Virus Infection (HCV) present high rates of comorbidity and polypharmacy. We aimed to assess the additional actions and resource utilization required for the management of potential drug-drug interactions (pDDIs) in HCV patients showing cardiovascular (CVS) and central nervous system (CNS) comorbidities, treated with sofosbuvir/velpatasvir (SOF/VEL) compared to glecaprevir/pibrentasvir (GLE/PIB) in routine clinical practice in Spain. Methods: The most prevalent CVS and CNS drugs in HCV patients were identified from real-world published data. The pDDIs between SOF/VEL, GLE/PIB and comedications, and their management recommendations were identified on the University of Liverpool Hepatitis Drug Interaction Group website. An expert panel defined real-world management of pDDIs, and a consensus was reached on actions required on the concomitant drug and resource utilization. Results: Additional actions are required in 89% of the CVS drugs when co-administered with GLE/PIB, while 39% were required with SOF/VEL (dose adjustment: 39% vs 17%; drug suspension: 28% vs 11%; drug substitution: 22% vs 11%; drug restart after DAA treatment: 33% vs 22%); additional visits and/or tests are needed in 50% and 22%, respectively. Regarding CNS drugs, 71% required additional actions when co-administered with GLE/PIB, while 14% require them with SOF/VEL (dose adjustment: 57% vs 0%; drug substitution: 14% vs 14%); additional visits and/or tests are needed in 71% and 14%, respectively. Conclusion: In routine clinical practice, fewer actions and less resource utilization are needed to manage pDDIs with SOF/VEL than with GLE/PIB, when treating HCV patients with CVS and CNS comorbidities. Keywords: chronic hepatitis C; drug-drug interactions; pangenotypic direct acting antivirals; resource utilization; comorbidity.

Evaluation of Drug Interactions in Patients Treated with DAAs for Hepatitis C Therapy with Comorbidities and Cardiovascular Issues—A Delphi Consensus Project

Orally administered direct-acting antivirals (DAAs) have dramatically changed the possibility of curing HCV (hepatitis C virus) infection, with the two principal HCV regimens based on the combination of glecaprevir + pibrentasvir (GLE-PIB) and sofosbuvir + velpatasvir (SOF-VEL). A combination of drugs containing NS3/4A protease inhibitors, as well as the fact that almost all HCV patients can be treated at present, may expose patients to a higher rate of drug-drug interactions (DDIs). The hepatitis C treatment recommendations from the EASL (European Association for the Study of the Liver) state that, prior to starting treatment with a DAA, a detailed drug history should be taken; yet, the decision on managing the potential DDIs is not always clear. For this reason, a group of Italian cardiologists and hepatologists promoted a survey among colleagues to assess the controversial issues when treating patients with chronic hepatitis C taking concomitant cardiovascular drugs, aiming to reach a consensus on the best practice to apply when treating a patient with chronic hepatitis C who is taking concomitant drugs for cardiovascular diseases. Two consecutive questionnaires were proposed between June and July 2022 to a qualitative Expert Panel (EP) of 14 gastroenterologists, infectologists, hepatologists, and internists, with statistical analyses performed on 100% of the responses for both questionnaires. Agreement among experts was assessed following the Delphi method as developed by the RAND Corporation. The interviewed experts consider DDIs a critical clinical problem to be evaluated in HCV patients. Therefore, dose changes, drug substitution, and discontinuation of concomitant cardiovascular drugs should be discouraged, even if planned for a relatively short period. Since oral DAAs have different DDIs profiles, hepatologists should prefer the antiviral DAA combination presenting the lowest instance of potential interactions.

The sound stimulation method and EEG change analysis for development of digital therapeutics that can stimulate the nervous system: Cortical activation and drug substitution potential.

The purpose of this study is to propose a treatment method and the effect on the nervous system of digital therapeutics, which is a new treatment method to replace surgery and drug prescription for the treatment and prevention of diseases. The 20 subjects who participated in the experiment, including men and women, had an average age of 26 ± 2.40 years. The proposed treatment method used three types of sound stimulation and air or bone conduction sound transmission methods to induce total of 6-time EEG electroencephalogram(EEG) changes. EEG was measured with 200 sampling rate each in the P4, Cz, F8 and T7 channel located in the parietal, central, frontal and temporal lobes, respectively, according to the 10/10 system. A total of 2min of data were created by extracting EEG signals with less noise from the measured data and the extracted data were applied with a 1-40 Hz Butterworth filter and a 50 Hz notch filter with a quality factor of 30. After that, EEG are subdivided into delta (0.5-4Hz), theta (4-8Hz), alpha (8-13 Hz), beta (13-30 Hz), and gamma (30-45 Hz) bands. Finally, EEG changes in response to sound stimuli were analyzed using power spectral density and T-test validation in the frequency band. When a sound stimulus of less than 1 KHz was stimulated by air conduction, brainstem activation was induced and the reticular activation system was activated. In addition, a great potential for replacing drugs was confirmed by inducing changes in the nervous system similar to drugs used for sedation. These results will be able to expand the concept of digital therapeutics, and it is expected that it will be developed as a safer treatment method that can replace surgery and drugs.

Disentangling Medicinal and Recreational cannabis Use Among People Living with HIV: An Ecological Momentary Assessment Study.

This study examined the feasibility of using ecological momentary assessment (EMA) to disentangle medicinal cannabis use (MCU) from recreational cannabis use (RCU) among people living HIV (PLWH). Over a 14-day period, PLWH (N = 29) who engaged in both MCU and RCU completed a smartphone-based survey before and after every cannabis use event assessing general motivation for cannabis use (MCU-only, RCU-only, or mixed MCU/RCU), cannabis use behavior, and several antecedents and outcomes of cannabis use. A total of 739 pre-cannabis surveys were completed; 590 (80%) of the prompted post-cannabis surveys were completed. Motives for cannabis use were reported as MCU-only on 24%, RCU-only on 30%, and mixed MCU/RCU on 46% of pre-cannabis surveys. Mixed effects models examined within-person differences across MCU-only, RCU-only, and mixed MCU/RCU events. Results showed that relative to RCU-only events, MCU-only events were more likely to involve symptom management and drug substitution motives, physical and sleep-related symptoms, solitary cannabis use, and use of cannabis oils and sprays; MCU-only events were less likely to involve relaxation, happiness, and wellness motives, cannabis flower use, and positive cannabis consequences. Differences between mixed MCU/RCU and RCU-only events were similar, except that mixed MCU/RCU events were additionally associated with stress reduction motives and symptoms of anxiety and depression. Findings support the feasibility of partially disentangling MCU and RCU behavior among PLWH who engage in concurrent MCU and RCU. This study highlights the need for more EMA studies isolating MCU from RCU to inform ongoing changes to cannabis policies.

Minimising the Toxicities of First Line Hodgkin Lymphoma Treatment in the Modern Era.

Striking advances in the treatment of Hodgkin lymphoma over the last 30 years have culminated in high rates of disease-free survival in younger patients with early and advanced stage disease. In this review we focus on strategies that have evolved over recent years to reduce short and long-term toxicities of treatment. These strategies include the selection of first-line chemotherapy, the stratification of patients based on initial response and subsequent adaptation of treatment, the addition of novel agents (e.g., brentuximab vedotin), the removal of specific drugs (e.g., bleomycin), the use of drug substitution, and the removal of consolidation radiotherapy based on interim and end of treatment PET assessment. While these strategies have successfully reduced toxicity of Hodgkin lymphoma therapy, the cornerstone of treatment continues to be combination chemotherapy and radiotherapy with significant short- and long-term side effects. To further reduce toxicity while maintaining or improving efficacy, we shall need to incorporate novel agents into our first-line treatment algorithms, and several such potentially practice-changing trials are underway.

First line antiretroviral treatment failure and its association with drug substitution and sex among children in Ethiopia: systematic review and meta-analysis

Antiretroviral Treatment (ART) has significantly decreased HIV-related morbidity and mortality among children despite the issue of drug resistance and subsequent treatment failure appearing as a challenge. Different studies have been conducted in Ethiopia regarding the prevalence of first-line ART failure among children but the magnitudes of these studies were inconsistent and had great variability. This review aimed to estimate the pooled prevalence of first line ART failure among children and its association with drug substitution and sex of children among first-line ART users in Ethiopia. The review was conducted using both published and unpublished studies until September 2020 in Ethiopia. MEDLINE, PubMed, Hinari, Web of Science, Google Scholar, Africa journal online (AJOL), Open gray literature, and online repository articles were searched. The quality of individual studies was assessed by Joanna Briggs Institute's (JBI) critical appraisal checklist. The statistical analysis was done by STATA-14 software and a random effect model was used. Heterogeneity was assessed using forest plot Cochrane Q–test and I-squared statistic. Publication bias was checked by using a funnel plot and Egger’s and Begg’s statistical tests. The interpretation was made by an odds ratio and with their respective 95% confidence intervals. The heterogeneity rate was 90% and Begg’s and Egger’s for publication bias were insignificant with p-values of 0.89 and 0.11 respectively. The pooled prevalence of pediatric first line ART failure in Ethiopia was 14.98% (95% CI 11.74, 18.21). Subgroup analysis showed that the highest failure rate was virological (9.13%). Female children had 1.4 times more risk of first-line ART failure (OR = 1.42; 95% CI 1.08, 1.85). First-line ART failure among children in Ethiopia is considerably high. Being female increases the likelihood of facing first line ART failure. More attention should be given to female children.

Predictors of unsuppressed viral load among adults on follow up of antiretroviral therapy at selected public and private health facilities of Adama town: unmached case-control study

BackgroundDespite the scale up of antiretroviral therapy (ART), unsuppressed viral load among population taking ART in private and public health facilities is still a public health concern increasing the risk of treatment failure. Studies comprehensively assessing significant predictors of non-suppressed viral load among patients on follow up of AR in public and private health facilities are limited. The objective of the study was to identify predictors of unsuppressed viral load among adult patients taking antiretroviral therapy at selected public and private health facilities of Adama town, East shewa zone, Ethiopia.MethodsAn unmatched case-control study was conducted from April 15 /2021 to May 20/2021. A total sample size of 347 patients consisting 116 cases and 231 controls was selected from electronic database among patients who started ART from September 2015 to August 2020. Data were collected using checklist from patient medical records and analyzed by SPSS. The association of dependent and independent variables was determined using multivariate analysis with 95% confidence interval and P - value in logistic regression model to identify independent predictors.ResultFrom the total 347 participants, 140 (40.3%) of them were males and 207 (59.7%) were females. In multivariate logistic regression, CD4 count < 100 [(AOR:1.22, 95% CI: 1.4-7.3)], CD4 100-200[(AOR: 2.58 95% CI: 1.06-8.28)], Fair Adherence [(AOR: 2.44, 95% CI: 1.67-4.82)], poor adherence [(AOR: 1.11, 95% CI: 1.7-6.73)], History of Cotrimoxazole Therapy (CPT) use and not used [(AOR: 2.60, 95% CI: 1.23-5.48)] and History of drug substitution [(AOR:. 361, 95% CI: .145-.897)] were independent predictors of unsuppressed viral load with the p-value less than 0.05.Conclusion and commendationIn this study, Baseline CD4, adherence, History of CPT used and history of drug substitution was predictors of unsuppressed viral load. Monitoring immunological response through scheduled CD4 tests is essential to maintain immunity of the patients preventing diseases progression. Intensive adherence support and counseling should conclusively be provided through effective implementation of ART programs by providers would enhance viral suppression ensuring the quality of care and treatment.

An illicit drug early warning system in Victoria, Australia: The role of forensic toxicology in clinical casework

In response to the evolving threat of illicit substance use in Australia, public health bodies and advisory committees have called for an enhanced public health response including greater visibility related to community illicit drug use, particularly novel psychoactive substances (NPS). Victorian state government agencies recommended the development of a state-wide illicit drug early warning system (EWS), utilising data-sharing collaborations between emergency physicians, forensic laboratories, researchers, and health services. Current monitoring modalities utilised in Australia, such as surveys, wastewater monitoring and coronial investigations, lack the specificity and/or responsiveness required for an effective EWS. Clinical toxicity observed in patients presenting to emergency departments (EDs) following exposure to an illicit drug provides an objective and timely measure of harm. Although illicit drug EWS exist in other jurisdictions, not all utilise high-quality forensic analysis and instead rely on patient-reported exposure. However, there is evidence demonstrating poor correlation between reported exposure and forensic analytical findings. The Emerging Drugs Network of Australia Victoria (EDNAV) was therefore created to provide a clinical registry collecting high-quality clinical and analytical data from Emergency Department (ED) illicit drug presentations, combined with a multi-disciplinary expert team to analyse registry data and provide intelligence to a state illicit drug EWS. The EDNAV is a Human Research Ethics Committee (HREC) approved project created in conjunction with a pilot project utilising data from wastewater analysis, syringe residue analysis and ED illicit drug presentations to provide health authorities with intelligence on community drug use. Patients 16 years of age or older presenting to one of eleven EDNAV project EDs with reported or suspected illicit drug related toxicity requiring a venipuncture as part of their standard clinical care are eligible for registry inclusion. Blood samples from cases are transferred weekly to the Victorian Institute of Forensic Medicine (VIFM) Toxicology Department. Overnight liquid chromatography-tandem mass spectrometry (LC-MS/MS) screens for 327 common pharmaceuticals and illicit substances (including ∼80 NPS), followed by a secondary NPS specific screen targeting 268 NPS. The NPS specific screen is actively updated based on emerging drug intelligence and literature reports. The HREC approved waiver of patient consent to include deidentified clinical and analytical data into a purpose built secure on-line (REDCap platform) registry. Forensic and clinical toxicologists/emergency physicians produce intelligence reports based on EDNAV registry data, which are provided to department of health policy officers to identify triggers and/or threats that lead to interventions designed to reduce community harm. There were 700 ED illicit drug presentations included in the EDNAV registry during the period September 2020–February 2022 (71% male, median age 33 years). Eighty-seven percent of patients arrived in ED via ambulance. Overall clinical acuity was high with 22% Australasian triage category 1 (require immediate treatment), and 62% category 2 (require treatment within 10 minutes), while 47% of patients were classified as having moderate, and 41% severe clinical toxicity. In additional to traditional illicit substances, novel substance detections included illicit benzodiazepines ( n = 10), cathinones ( n = 9), synthetic cannabinoid receptor agonists ( n = 6), and opioids ( n = 3). Forensic analyses revealed that in over 90% of cases there were different and/or additional drugs detected in comparison to the reported exposure, suggesting significant drug adulteration, drug substitution or under-reporting and highlighting the potential limitations of illicit drug EWS that do not utilise high-quality forensic analysis. Three public health alerts have been released in Victoria as the result of EDNAV registry intelligence, involving detections of N-ethylpentylone, 25B-NBOH, and paramethoxymethamphetamine. The EDNAV registry project has highlighted the critical role of a high-quality forensic analytical service in an illicit drug EWS in the state of Victoria.

Bioequivalence, Drugs with Narrow Therapeutic Index and The Phenomenon of Biocreep: A Critical Analysis of the System for Generic Substitution.

The prescription of generic drugs represents one of the main cost-containment strategies of health systems, aimed at reducing pharmaceutical expenditure. In this context, most regulatory authorities encourage or obligate dispensing generic drugs because they are far less expensive than their brand-name alternatives. However, drug substitution can be critical in particular situations, such as the use of drugs with a narrow therapeutic index (NTI). Moreover, generics cannot automatically be considered bioequivalent with each other due to the biocreep phenomenon. In Italy, the regulatory authority has established the Transparency Lists which include the medications that will be automatically substituted for brand-name drugs, except in exceptional cases. This is a useful tool to guide prescribers and guarantee pharmaceutical sustainability, but it does not consider the biocreep phenomenon.

Nanosponges for Drug Delivery and Cancer Therapy: Recent Advances.

Nanosponges with three-dimensional (3D) porous structures, narrow size distribution, and high entrapment efficiency are widely engineered for cancer therapy and drug delivery purposes. They protect the molecular agents from degradation and help to improve the solubility of lipophilic therapeutic agents/drugs with targeted delivery options in addition to being magnetized to attain suitable magnetic features. Nanosponge-based delivery systems have been applied for cancer therapy with high specificity, biocompatibility, degradability, and prolonged release behavior. In this context, the drug loading within nanosponges is influenced by the crystallization degree. Notably, 3D printing technologies can be applied for the development of novel nanosponge-based systems for biomedical applications. The impacts of polymers, cross-linkers, type of drugs, temperature, loading and mechanism of drug release, fabrication methods, and substitution degree ought to be analytically evaluated. Eco-friendly techniques for the manufacturing of nanosponges still need to be uncovered in addition to the existing methods, such as solvent techniques, ultrasound-assisted preparation, melting strategies, and emulsion solvent diffusion methods. Herein, the recent advancements associated with the drug delivery and cancer therapy potential of nanosponges (chiefly, cyclodextrin-based, DNAzyme, and ethylcellulose nanosponges) are deliberated, focusing on the important challenges and future perspectives.

Pharmacist-led medication reconciliation on admission to an acute psychiatric hospital unit.

Background:Therapy management in patients suffering from mental health disorders is complex and the risks derived from changes or interruptions of treatment should not be ignored. Medication reconciliation in psychiatry may reduce medication errors and promote patient safety during transitions of care.Objective:To identify the influence of complementary information sources in the construction of the best possible medication history, and to ascertain the potential clinical impact of discrepancies identified in a medication reconciliation service.Methods:An observational study was conducted in an acute mental hospital unit, with a further validation in an internal medicine unit. Adult patients taking at least one medicine admitted in the unit were included. Patients/caregivers were interviewed upon admission and the information gathered was compared with hospital medical and shared electronic medical records. Once the best possible medication history was gathered, therapeutic information was reconciled against the prescription on admission to identify discrepancies. Potential clinical impact of medication errors was classified using the International Safety Classification.Results:During the study period, 148 patients were admitted, 50.7% females, mean age 54.6 years (SD=16.3). Collaboration of a caregiver was a needed in 74% of the interviews. In total, 1,147 drugs were considered to obtain patients’ best possible medication history. After reconciliation, 560 clinically sound intentional discrepancies were identified and 359 discrepancies required further clarification from prescribers: 84.12% “drug omission”, 5.57% “drug substitution”, 6.96% “dose change”, and 3.34% “dosage frequency change”. Potential clinical impact of these medication discrepancies was classified as: 95 mild, 100 moderate, and 29 severe medication errors.Conclusion:About 1 in three intentional discrepancies observed in a pharmacists-led medication reconciliation service required further clarification from prescribers, being 80% of them unintentional discrepancies. Results highlight the importance of the caregiver as source of information for the psychiatric patient, the relevance of analyzing shared electronic health records until 6 months before, and the need to use hospital medical records efficiently. Additionally, 29 discrepancies were classified as errors with potentially severe clinical impact. A medication reconciliation service is concluded to be feasible and necessary in a mental health unit.

HIV drug resistance in various body compartments.

HIV drug resistance testing using blood plasma or dried blood spots forms part of international guidelines. However, as the clinical utility of assessing drug resistance in other body compartments is less well established, we review this for blood cells and samples from other body compartments. Although clinical benefit is not clear, drug resistance testing in blood cells is often performed when patients with suppressed plasma viral loads require a treatment substitution. In patients with HIV neurocognitive disease, cerebral spinal fluid (CSF) drug resistance is rarely discordant with plasma but has nevertheless been used to guide antiretroviral drug substitutions. Cases with HIV drug resistance in genital fluids have been documented but this does not appear to indicate transmission risk when blood plasma viral loads are suppressed. Drug-resistant variants, which may be selected in tissues under conditions of variable adherence and drug penetration, appear to disseminate quickly, and become detectable in blood. This may explain why drug resistance discordance between plasma and these compartments is rarely found. Partial compartmentalization of HIV populations is well established for the CSF and the genital tract but other than blood plasma, evidence is lacking to support drug resistance testing in body compartments.

Methyl ester and aromatic ether modification of mitragynine for generation of mitragynine-specific polyclonal antibodies

Mitragynine is an alkaloid from Mitragyna speciosa Korth. (kratom), a native tropical plant in Southeast Asia. It could render psychotropic effects and is often misused in substitution for commercial drugs. In recent years, the consumption of kratom has grown rapidly and has led some countries to ban its use. The misuse of kratom can be detected and monitored through the determination of mitragynine from biological samples of the users. Therefore, the development of a rapid and effective detection method is needed. In this study, polyclonal antibodies were produced using mitragynine coupled to a carrier protein (cationic bovine serum albumin, cBSA) as an immunogen, which was prepared with coupling agents (i.e., N, N- dicyclohexylcarbodiimide, DCC and N-hydroxysuccinimide, NHS). It was conjugated to different mitragynine structure, 16-COOCH3 (methyl ester) and 9-OCH3 (aromatic ether). 2,4,6-Trinitrobenzenesulfonic acid (TNBS) method showed that 45 and 46 amino groups were bound to C22-MG-cBSA and C9-MG-cBSA, respectively. Fourier-transform infrared spectroscopy (FTIR) spectral changes at C22- and C9-hydroxymitragynine indicated reduction and demethylation process. In UV–Vis spectra, conjugated mitragynine to cBSA and OVA were displayed at a spectral region at 240–300 nm. For the antibody titre, the C22-MG-cBSA anti-serum showed a significantly higher titre than the C9-MG-cBSA at 1/128000 and 1/32000 dilutions, respectively. The detection range of the developed competitive indirect ELISA (CI-ELISA) was 0.01 to 10.00 μg/mL (R2 = 0.9964). The assay exhibited a limit of detection (LOD) and limit of quantification (LOQ) at 0.041 and 0.124 μg/mL, respectively. The antibody produced is a high-value biorecognition molecule that can be further used in developing immuno-based detection methods such as immunosensors and immunochromatographic lateral flow assays. This will benefit the task force or forensic agencies for toxicological screening with high speed and efficiency.

Efficacy of a Standardized Premedication and Therapeutic Drug Monitoring Protocol for Pegaspargase to Prevent Hypersensitivity Reactions.

The purpose of this study was to evaluate the efficacy of a standardized premedication and therapeutic drug monitoring (TDM) protocol to prevent hypersensitivity reactions from pegaspargase infusions. Pegaspargase is an essential therapeutic agent used for the treatment of acute lymphoblastic leukemia (ALL) in pediatric patients. This study was a retrospective cohort study conducted at Wolfson Children's Hospital, Jacksonville, Florida, and included pediatric ALL patients 0 to 21 years old. Patients were excluded if they had not received the appropriate premedication after protocol implementation or had received premedication before protocol implementation. Patients were separated into 2 groups: those who received premedication before pegaspargase infusion and those who did not. The primary endpoint was the incidence of documented hypersensitivity reactions. Observational data endpoints included incidence of silent inactivation and cost savings from reducing complicated drug substitutions. A total of 38 patients (50 doses in no premedication group; 80 doses in premedication group) were evaluated. There was not a significant reduction in the incidence of hypersensitivity reactions for patients receiving premedication and TDM (5.3% vs 6.4%, p = 1.0). A trend towards patients reacting earlier with more severe reactions in the post-implementation group was observed. There were no incidences of silent inactivation. Observational cost analysis predicts potential drug cost savings of $106,550.45. A standardized premedication protocol did not reduce the incidence of hypersensitivity reactions. Premedication to prevent hypersensitivity reactions may provide a potential drug cost savings. Further investigation is warranted to assess the efficacy of a standardized premedication and TDM protocol to prevent hypersensitivity reactions.

The unified medical prescription as a tool to promote generic prescription: A cross-sectional study addressing physicians’ perception in Lebanon

INTRODUCTION: The unified medical prescription was implemented as a policy to decrease the overall health expenditures and increase the use of generic drugs. The main objective of this study was to evaluate the perception of Lebanese physicians towards the unified medical Prescription and its impact on the overall generic prescription. Additionally, an overview was assessed concerning the type of drugs that physicians tend more to accept to be substituted to generic alternatives. METHODS: A cross-sectional descriptive study was conducted in Lebanon over a period of three months targeting physicians in their private clinics or in various hospitals using a survey as an instrument. RESULTS: Our findings demonstrated that more than the half of respondents (56.6%) believed that the unified medical prescription preserves the exclusivity for physicians to choose the medication while only 39.5% of physicians think that the unified medical prescription encouraged generic prescription and almost 42% admitted that the unified medical prescription lowers the medical cost for the patient. DISCUSSION: Despite that this new medical form of prescription is a high achievement for the Lebanese Ministry Of Public Health, this last should make essential actions: coordinating the generic drug substitution policy and monitoring its implementation over time and achievement of goals; establishing appropriate pricing system and medicines prices and controlling the interactions between physicians, pharmacists, and pharmaceutical industries; ensure their full commitment; and update the national list of substitutable generic drugs. CONCLUSION: The main objective of the unified medical prescription is to decrease the pharmaceutical expenditure and to provide access to medications for patients with lower socio-economic status. Lebanese physicians reported that this tool did not achieve its goal yet but have an impact on lowering the medical cost for patients and promoting generic prescription.

Clinical Outcome and Medical Cost of Originator and Generic Antihypertensive Drugs: A Population-Based Study in Yinzhou, China.

Background: The substitution of generic drugs can effectively alleviate the rapid growth of drug costs; however, the clinical effectiveness and medical costs of originator products and generics were barely studied in China. Objectives: To compare the effectiveness of antihypertensive drugs and hypertension-related medical costs between originator and generic initiators in Yinzhou, China. Methods: We conducted a population-based retrospective cohort study using the Chinese Electronic Health Records Research in Yinzhou (CHERRY), from July 1, 2011, to December 31, 2018. Hypertension patients initiating with originator products were compared with patients initiating with generic counterparts. We used 1:1 propensity score matching to pair the two groups based on sociodemographic, clinical, and health service utilization variables. Cox proportional regression was adopted to compare the rate of hospitalization for hypertension-related cardiovascular disease between matched originator and generic initiators. Wilcoxon matched-pairs signed-rank test was used to compare annual hypertension-related medical costs. Results: Matched pairs (10,535) of patients were included in the comparative study of originator products and generics, corresponding to seven antihypertensive drugs including amlodipine, felodipine, nifedipine, irbesartan, losartan, valsartan, and metoprolol. The average age of patients included in the analysis was around 60 years (originator vs. generics initiators: from 59.0 vs. 59.1 years in losartan to 62.9 vs. 63.6 years in nifedipine). Higher hospitalization rates among originator initiators were observed for three calcium channel blockers (hazard ratio[95% CI]: amlodipine, 3.18[1.43, 7.11]; felodipine, 3.60[1.63, 7.98]; and nifedipine, 3.86[1.26, 11.81]; respectively). The remaining four out of seven drugs of the clinical endpoint estimates showed comparable outcomes between originator products and generics (hazard ratio[95% CI]: irbesartan, 1.19[0.50, 2.84]; losartan, 1.84[0.84, 4.07]; valsartan, 2.04[0.72, 5.78]; and metoprolol, 1.25[0.56, 2.80]; respectively). Higher median annual hypertension-related medical costs were observed in originator initiators (all p < 0.001), except for metoprolol (p = 0.646). Conclusion: We observed comparable or even better clinical outcomes and less medical cost associated with the use of antihypertensive generics compared to originator counterparts. This could help increase patient and provider confidence in the efficacy of generic medicines to manage hypertension diseases.

Pharmaceutical pricing dynamics in an internal reference pricing system: evidence from changing drugs' reimbursements.

Reference pricing systems for prescription drugs are usually implemented with the aim of curbing public expenditure with pharmaceuticals, induce drug substitution from branded to generic drugs, and enhance competition. In these systems, patients co-pay the difference between the drug's pharmacy retail price and the health system reimbursement level. Relying on a detailed product-level panel dataset of prescription drugs sold in Portuguese retail pharmacies, from 2016 to 2019, we evaluate pharmaceutical firms' pricing decisions for branded and generic drugs, as well as consumers' reaction to price changes. In particular, we exploit the variation induced by a policy change, which decreased reference prices for 36% of the drug groups in our sample. Results from difference-in-differences analyses show that, despite the reference price decrease, affected firms increased their prices-particularly for off-patent branded products. Such reaction from firms resulted in an increase in the co-payment paid by patients. Such price effects caused a 17% decline on branded drugs' consumption, with significant heterogeneity across therapeutics. Estimates suggest that NHS reimbursement savings were mainly achieved through higher co-payments paid by patients. Additionally, pharmaceutical firms' reaction to the reference price decrease was contrary to what was expected, suggesting underlying competitive dynamics which should be considered prior to policy changes.

An All-Oral 6-Month Regimen for Multidrug-Resistant Tuberculosis: A Multicenter, Randomized Controlled Clinical Trial (the NExT Study).

Rationale: Improving treatment outcomes while reducing drug toxicity and shortening the treatment duration to ∼6 months remains an aspirational goal for the treatment of multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB). Objectives: To conduct a multicenter randomized controlled trial in adults with MDR/RR-TB (i.e., without resistance to fluoroquinolones or aminoglycosides). Methods: Participants were randomly assigned (1:1 ratio) to a ∼6-month all-oral regimen that included levofloxacin, bedaquiline, and linezolid, or the standard-of-care (SOC) ⩾9-month World Health Organization (WHO)-approved injectable-based regimen. The primary endpoint was a favorable WHO-defined treatment outcome (which mandates that prespecified drug substitution is counted as an unfavorable outcome) 24 months after treatment initiation. The trial was stopped prematurely when bedaquiline-based therapy became the standard of care in South Africa. Measurements and Main Results: In total, 93 of 111 randomized participants (44 in the comparator arm and 49 in the interventional arm) were included in the modified intention-to-treat analysis; 51 (55%) were HIV coinfected (median CD4 count, 158 cells/ml). Participants in the intervention arm were 2.2 times more likely to experience a favorable 24-month outcome than participants in the SOC arm (51% [25 of 49] vs. 22.7% [10 of 44]; risk ratio, 2.2 [1.2-4.1]; P = 0.006). Toxicity-related drug substitution occurred more frequently in the SOC arm (65.9% [29 of 44] vs. 34.7% [17 of 49]; P = 0.001)], 82.8% (24 of 29) owing to kanamycin (mainly hearing loss; replaced by bedaquiline) in the SOC arm, and 64.7% (11 of 17) owing to linezolid (mainly anemia) in the interventional arm. Adverse event-related treatment discontinuation in the safety population was more common in the SOC arm (56.4% [31 of 55] vs. 32.1% [17 of 56]; P = 0.007). However, grade 3 adverse events were more common in the interventional arm (55.4% [31 of 56] vs. 32.7 [18 of 55]; P = 0.022). Culture conversion was significantly better in the intervention arm (hazard ratio, 2.6 [1.4-4.9]; P = 0.003) after censoring those with bedaquiline replacement in the SOC arm (and this pattern remained consistent after censoring for drug replacement in both arms; P = 0.01). Conclusions: Compared with traditional injectable-containing regimens, an all-oral 6-month levofloxacin, bedaquiline, and linezolid-containing MDR/RR-TB regimen was associated with a significantly improved 24-month WHO-defined treatment outcome (predominantly owing to toxicity-related drug substitution). However, drug toxicity occurred frequently in both arms. These findings inform strategies to develop future regimens for MDR/RR-TB.Clinical trial registered with www.clinicaltrials.gov (NCT02454205).

Modelling trends of CD4 counts for patients on antiretroviral therapy (ART): a comprehensive health care clinic in Nairobi, Kenya

BackgroundIn resource-limited settings, changes in CD4 counts constitute an important component in patient monitoring and evaluation of treatment response as these patients do not have access to routine viral load testing. In this study, we quantified trends on CD4 counts in patients on highly active antiretroviral therapy (HAART) in a comprehensive health care clinic in Kenya between 2011 and 2017. We evaluated the rate of change in CD4 cell count in response to antiretroviral treatment. We further assessed factors that influenced time to treatment change focusing on baseline characteristics of the patients and different initial drug regimens used. This was a retrospective study involving 432 naïve HIV patients that had at least two CD4 count measurements for the period. The relationship between CD4 cell count and time was modeled using a semi parametric mixed effects model while the Cox proportional hazards model was used to assess factors associated with the first regimen change.ResultsMajority of the patients were females and the average CD4 count at start of treatment was 362.1 cell/mm^3. The CD4 count measurements increased nonlinearly over time and these trends were similar regardless of the treatment regimen administered to the patients. The change of logarithm CD4 cell count rises fast for in the first 450 days of antiretroviral initiation. The average time to first regimen change was 2142 days. Tenoforvir (TDF) based regimens had a lower drug substitution(aHR 0.2682, 95% CI:0.08263- 0.8706) compared to Zidovudine(AZT).ConclusionThe backbone used was found to be associated with regimen changes among the patients with fewer switches being observed, with the use of TDF when compared to AZT. There was however no significant difference between TDF and AZT in terms of the rate of change in logarithm CD4 count over time.