[Wholesale distribution and delivery of plant-based medicinal products through the pharmaceutical system of Burkina Faso]. / Distribution en gros et délivrance des médicaments à base de plantes à travers le circuit pharmaceutique du Burkina Faso.

OBJECTIVE: In order to improve the contribution of medicines from traditional pharmacopoeia to health care, African countries like Burkina Faso have adopted for several years, policies and regulations organizing their distribution. This study aims to analyze the situation of the wholesale and retail sale of herbal medicines imported by the official pharmaceutical facilities. METHOD: This is a retrospective study involving all 18 drug wholesalers and 115 pharmacies in the city of Ouagadougou (Burkina Faso). It consisted of a collection of sales data of herbal medicines from 2013 to 2016 and interviews of the pharmacists responsible for the facilities surveyed. RESULTS: All the pharmacies surveyed obtain their supplies from national wholesalers, but eleven of them do so directly from manufacturers or non-wholesalers. Only 40% (44/111) of herbal medicines distributed by wholesalers and pharmacies had valid marketing authorizations. Also, although the average growth rates of annual sales by wholesalers and private pharmacies, respectively 23.67% and 11.94%, are significant, the turnover generated from their sale remains low. CONCLUSION: Supporting local producers with appropriate funding and adequate promotion of herbal medicines is still needed to boost the share of the national herbal medicines market.

Association between gifts from pharmaceutical companies to French general practitioners and their drug prescribing patterns in 2016: retrospective study using the French Transparency in Healthcare and National Health Data System databases.

OBJECTIVE: To evaluate the association between gifts from pharmaceutical companies to French general practitioners (GPs) and their drug prescribing patterns. DESIGN: Retrospective study using data from two French databases (National Health Data System, managed by the French National Health Insurance system, and Transparency in Healthcare). SETTING: Primary care, France. PARTICIPANTS: 41 257 GPs who in 2016 worked exclusively in the private sector and had at least five registered patients. The GPs were divided into six groups according to the monetary value of the received gifts reported by pharmaceutical, medical device, and other health related companies in the Transparency in Healthcare database. MAIN OUTCOME MEASURES: The main outcome measures were the amount reimbursed by the French National Health Insurance for drug prescriptions per visit (to the practice or at home) and 11 drug prescription efficiency indicators used by the National Health Insurance to calculate the performance related financial incentives of the doctors. Doctor and patient characteristics were used as adjustment variables. The significance threshold was 0.001 for statistical analyses. RESULTS: The amount reimbursed by the National Health Insurance for drug prescriptions per visit was lower in the GP group with no gifts reported in the Transparency in Healthcare database in 2016 and since its launch in 2013 (no gift group) compared with the GP groups with at least one gift in 2016 (-€5.33 (99.9% confidence interval -€6.99 to -€3.66) compared with the GP group with gifts valued at €1000 or more reported in 2016) (P<0.001). The no gift group also more frequently prescribed generic antibiotics (2.17%, 1.47% to 2.88% compared with the ≥€1000 group), antihypertensives (4.24%, 3.72% to 4.77% compared with the ≥€1000 group), and statins (12.14%, 11.03% to 13.26% compared with the ≥€1000 group) than GPs with at least one gift between 2013 and 2016 (P<0.001). The no gift group also prescribed fewer benzodiazepines for more than 12 weeks (-0.68%, -1.13% to -0.23% compared with the €240-€999 group) and vasodilators (-0.15%, -0.28% to -0.03% compared with the ≥€1000 group) than GPs with gifts valued at €240 or more reported in 2016, and more angiotensin converting enzyme (ACE) inhibitors compared with all ACE and sartan prescriptions (1.67%, 0.62% to 2.71%) compared with GPs with gifts valued at €1000 or more reported in 2016 (P<0.001). Differences were not significant for the prescription of aspirin and generic antidepressants and generic proton pump inhibitors. CONCLUSION: The findings suggest that French GPs who do not receive gifts from pharmaceutical companies have better drug prescription efficiency indicators and less costly drug prescriptions than GPs who receive gifts. This observational study is susceptible to residual confounding and therefore no causal relation can be concluded. TRIAL REGISTRATION: OSF register OSF.IO/8M3QR.

Are We Opening the Door to a New Era of Medicinal Chemistry or Being Collapsed to a Chemical Singularity?

The paradigm of "drug-like-ness" dramatically altered the behavior of the medicinal chemistry community for a long time. In recent years, scientists have empirically found a significant increase in key properties of drugs that have moved structures closer to the periphery or the outside of the rule-of-five "cage". Herein, we show that for the past decade, the number of molecules claimed in patent records by major pharmaceutical companies has dramatically decreased, which may lead to a "chemical singularity". New compounds containing fragments with increased 3D complexity are generally larger, slightly more lipophilic, and more polar. A core difference between this study and recently published papers is that we consider the nature and quality of sp3-rich frameworks rather than sp3 count. We introduce the original descriptor MCE-18, which stands for medicinal chemistry evolution, 2018, and this measure can effectively score molecules by novelty in terms of their cumulative sp3 complexity.

Safety pharmacology investigations on the nervous system: An industry survey.

The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system ('CNS') drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1000 employees). Oncology (67%) and neurology/psychiatry (66%) were the most frequent target indications pursued by companies followed by inflammation (48%), cardiovascular (43%), metabolic (39%), infectious (37%), orphan (32%) and respiratory (29%) diseases. Seizures (67% of participants), gait abnormalities (67%), tremors (65%), emesis (56%), sedation (52%) and salivation (47%) were the most commonly encountered CNS issues in pre-clinical drug development while headache (65%), emesis/nausea (60%), fatigue (51%) and dizziness (49%) were the most frequent issues encountered in Phase I clinical trials. 54% of respondents reported that a standard battery of tests applied to screen drug candidates was the approach most commonly used to address non-clinical CNS safety testing. A minority (14% of all participants) reported using electroencephalography (EEG) screening prior to animal inclusion on toxicology studies. The most frequent group size was n=8 for functional observation battery (FOB), polysomnography and seizure liability studies. FOB evaluations were conducted in a dedicated room (78%) by blinded personnel (66%) with control for circadian cycle (55%) effects (e.g., dosing at a standardized time; balancing time of day across treatment groups). The rat was reported as the most common species used for seizure liability, nerve conduction and drug-abuse liability testing.

An analysis of the attrition of drug candidates from four major pharmaceutical companies.

The pharmaceutical industry remains under huge pressure to address the high attrition rates in drug development. Attempts to reduce the number of efficacy- and safety-related failures by analysing possible links to the physicochemical properties of small-molecule drug candidates have been inconclusive because of the limited size of data sets from individual companies. Here, we describe the compilation and analysis of combined data on the attrition of drug candidates from AstraZeneca, Eli Lilly and Company, GlaxoSmithKline and Pfizer. The analysis reaffirms that control of physicochemical properties during compound optimization is beneficial in identifying compounds of candidate drug quality and indicates for the first time a link between the physicochemical properties of compounds and clinical failure due to safety issues. The results also suggest that further control of physicochemical properties is unlikely to have a significant effect on attrition rates and that additional work is required to address safety-related failures. Further cross-company collaborations will be crucial to future progress in this area.

Renal studies in safety pharmacology and toxicology: A survey conducted in the top 15 pharmaceutical companies.

INTRODUCTION: With the recent development of more sensitive biomarkers to assess kidney injury preclinically, a survey was designed i) to investigate what strategies are used to investigate renal toxicity in both ICH S7A compliant Safety Pharmacology (SP) studies after a single dose of a compound and within repeat-dose toxicity studies by large pharmaceutical companies today; ii) to understand whether renal SP studies have impact or utility in drug development and/or if it may be more appropriate to assess renal effects after multiple doses of compounds; iii) to ascertain how much mechanistic work is performed by the top 15 largest pharmaceutical companies (as determined by R&D revenue size); iv) to gain an insight into the impact of the validation of DIKI biomarkers and their introduction in the safety evaluation paradigm; and v) to understand the impact of renal/urinary safety study data on progression of projects. METHODS: Two short anonymous surveys were submitted to SP leaders of the top 15 pharmaceutical companies, as defined by 2012 R&D portfolio size. Fourteen multiple choice questions were designed to explore the strategies used to investigate renal effects in both ICH S7A compliant SP studies and within toxicology studies. RESULTS: A 67% and 60% response rate was obtained in the first and second surveys, respectively. Nine out of ten respondent companies conduct renal excretory measurements (eg. urine analysis) in toxicology studies whereas only five out of ten conduct specific renal SP studies; and all of those 5 also conduct the renal excretory measurements in toxicology studies. These companies measure and/or calculate a variety of parameters as part of these studies, and also on a case by case basis include regulatory qualified and non-qualified DIKI biomarkers. Finally, only one company has used renal/urinary functional data alone to stop a project, whereas the majority of respondents combine renal data with other target organ assessments to form an integrated decision-making set. CONCLUSION: These short surveys highlighted areas of similarity: a) urinary measurements are most commonly taken on repeat-dose toxicity studies, and b) renal SP studies are less often utilised. The two major differences are a) lack of consistent use of DIKI biomarkers in urinary safety studies and b) the way large pharmaceutical companies assess renal function. Finally, suggestions were made to improve the safety assessment methods for determining the safety of compounds with potential renal liability.

Preclinical pharmacokinetic/pharmacodynamic modeling and simulation in the pharmaceutical industry: an IQ consortium survey examining the current landscape.

The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with ~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally, ~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner.

Reducing attrition in drug development: smart loading preclinical safety assessment.

Entry into the crucial preclinical good laboratory practice (GLP) stage of toxicology testing triggers significant R&D investment yet >20% of AstraZeneca's potential new medicines have been stopped for safety reasons in this GLP phase alone. How could we avoid at least some of these costly failures? An analysis of historical toxicities that caused stopping ('stopping toxicities') showed that >50% were attributable to target organ toxicities emerging within 2 weeks of repeat dosing or to acute cardiovascular risks. By frontloading 2-week repeat-dose toxicity studies and a comprehensive assessment of cardiovascular safety, we anticipate a potential 50% reduction in attrition in the GLP phase. This will reduce animal use overall, save significant R&D costs and improve drug pipeline quality.

Food-pharma convergence in medical nutrition- best of both worlds?

At present, industries within the health and life science sector are moving towards one another resulting in new industries such as the medical nutrition industry. Medical nutrition products are specific nutritional compositions for intervention in disease progression and symptom alleviation. Industry convergence, described as the blurring of boundaries between industries, plays a crucial role in the shaping of new markets and industries. Assuming that the medical nutrition industry has emerged from the convergence between the food and pharma industries, it is crucial to research how and which distinct industry domains have contributed to establish this relatively new industry. The first two stages of industry convergence (knowledge diffusion and consolidation) are measured by means of patent analysis. First, the extent of knowledge diffusion within the medical nutrition industry is graphed in a patent citation interrelations network. Subsequently the consolidation based on technological convergence is determined by means of patent co-classification. Furthermore, the medical nutrition core domain and technology interrelations are measured by means of a cross impact analysis. This study proves that the medical nutrition industry is a result of food and pharma convergence. It is therefore crucial for medical nutrition companies to effectively monitor technological developments within as well as across industry boundaries. This study further reveals that although the medical nutrition industry's core technology domain is food, technological development is mainly driven by pharmaceutical/pharmacological technologies Additionally, the results indicate that the industry has surpassed the knowledge diffusion stage of convergence, and is currently in the consolidation phase of industry convergence. Nevertheless, while the medical nutrition can be classified as an industry in an advanced phase of convergence, one cannot predict that the pharma and food industry segments will completely converge or whether the medical industry will become an individual successful industry.

Immunogenicity of mAbs in non-human primates during nonclinical safety assessment.

The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug-antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies.

[Some worries about Dendrobium officinale industry].

In recent years, with the continuous development of the industry of Dendrobium officinale, the technological alliance on CEEUSRO has been established. However, many problems also exposed with the rapid expansion of the industry, such as weak basic research, single species of the product, lack of in-depth studies and difficult to guarantee the quality. Industrial foam was gradually formed. To guard against the D. officinale becoming another "Puer Tea" , the authors believe that the key to sustainable development of the industry is enterprises and research institutes should strengthen basic research, speed up development of application of integrated innovations, government should strengthen guidance, regulate the operation of the market, then protect the quality of D. officinale in the market.

In search of preclinical robustness.

Systematic engagement of statisticians in preclinical research could help address the weaknesses that are undermining the likelihood of subsequent success in drug discovery and development.

La homeopatía como propuesta válida para la atención primaria de salud / Homeopathy as a valid proposal for primary health care

Se plantea un análisis de la pertenencia histórica del empleo de la homeopatía, con valiosos datos que aparecen desde el siglo XIX en Cuba. Actualmente es una terapéutica de elección, tanto en países desarrollados como en vías de desarrollo, se estima que millones de personas son atendidas cada año con productos homeopáticos que además tienen muy bajos reportes de reacciones adversas. A partir de interrogantes tales como: ¿puede la homeopatía superar sus debilidades e impactar en la comunidad científica?; ¿existe certidumbre dentro de la ciencia que apoye la utilidad de la homeopatía para el médico de atención primaria de salud?; ¿conseguirá la homeopatía convertirse en herramienta terapéutica en la atención primaria de salud? Se pretende aclarar la validez de esta disciplina clínica para el médico de la familia, en su labor comunitaria, ya que es el único especialista que atiende integralmente a la familia con un enfoque clínico-epidemiológico. La homeopatía le ofrece la posibilidad de tratar al niño desde que es recién nacido, a la embarazada, al adulto y a los ancianos, tanto en sus enfermedades crónicas, como en las agudas e incluso en epidemias; además, puede contribuir a que mejore la calidad de vida de estos pacientes(AU)

We propose an analysis of historical association of using homeopathy with valuable data that appears from the nineteenth century in Cuba. Today it is a therapeutic choice in both developed and developing countries, it is estimated that millions of people are treated each year with homeopathic products, which also have very low adverse reaction reports. From such questions as: Can homeopathy overcome their weaknesses and impact in the scientific community? Is there certainty in science that supports the usefulness of homeopathy for the primary health care? Will homeopathy become a therapeutic tool in primary health care? It seeks to clarify the validity of this clinical discipline for the family physician in his/her community work, since it is the only specialist, who fully assists the family with a clinical and epidemiological approach. Homeopathy offers the possibility to treat children including the newly born, pregnant women, adults and the elderly, in their chronic and acute diseases, as well as in epidemics. It can also contribute to improve the quality of life for these patients(AU)

La homeopatía como propuesta válida para la atención primaria de salud / Homeopathy as a valid proposal for primary health care

Se plantea un análisis de la pertenencia histórica del empleo de la homeopatía, con valiosos datos que aparecen desde el siglo XIX en Cuba. Actualmente es una terapéutica de elección, tanto en países desarrollados como en vías de desarrollo, se estima que millones de personas son atendidas cada año con productos homeopáticos que además tienen muy bajos reportes de reacciones adversas. A partir de interrogantes tales como: ¿puede la homeopatía superar sus debilidades e impactar en la comunidad científica?; ¿existe certidumbre dentro de la ciencia que apoye la utilidad de la homeopatía para el médico de atención primaria de salud?; ¿conseguirá la homeopatía convertirse en herramienta terapéutica en la atención primaria de salud? Se pretende aclarar la validez de esta disciplina clínica para el médico de la familia, en su labor comunitaria, ya que es el único especialista que atiende integralmente a la familia con un enfoque clínico-epidemiológico. La homeopatía le ofrece la posibilidad de tratar al niño desde que es recién nacido, a la embarazada, al adulto y a los ancianos, tanto en sus enfermedades crónicas, como en las agudas e incluso en epidemias; además, puede contribuir a que mejore la calidad de vida de estos pacientes

We propose an analysis of historical association of using homeopathy with valuable data that appears from the nineteenth century in Cuba. Today it is a therapeutic choice in both developed and developing countries, it is estimated that millions of people are treated each year with homeopathic products, which also have very low adverse reaction reports. From such questions as: Can homeopathy overcome their weaknesses and impact in the scientific community? Is there certainty in science that supports the usefulness of homeopathy for the primary health care? Will homeopathy become a therapeutic tool in primary health care? It seeks to clarify the validity of this clinical discipline for the family physician in his/her community work, since it is the only specialist, who fully assists the family with a clinical and epidemiological approach. Homeopathy offers the possibility to treat children including the newly born, pregnant women, adults and the elderly, in their chronic and acute diseases, as well as in epidemics. It can also contribute to improve the quality of life for these patients

Availability and use of essential medicines in China: manufacturing, supply, and prescribing in Shandong and Gansu provinces.

BACKGROUND: The current health care reform in China launched in 2009 tackles the problem of access to appropriate medicines for its 1.3 billion people by focusing on providing essential medicines to all. To provide evidence for the reform process, we investigated the manufacturing, purchasing, and prescribing of essential medicines in two provinces. METHODS: We conducted surveys in 2007 of all manufacturers (n = 253) and of 59 purposively selected retail and 63 hospital pharmacies in Shandong and Gansu provinces to assess production and supply of products on the 2004 National Essential Medicines List (NEML), as well as factors underlying decision making about production and supply. We also reviewed prescriptions (n = 5456) in health facilities to calculate standard indicators of appropriate medicines use. RESULTS: Overall, manufacturers in Shandong and Gansu produced only 62% and 50%, respectively, of the essential medicines they were licensed to produce. Of a randomly selected 10% of NEML products, retail pharmacies stocked up to 60% of Western products. Median availability in hospital pharmacies ranged from 19% to 69%. Manufacturer and retail pharmacy managers based decisions on medicines production and stocking on economic considerations, while hospital pharmacy managers cited clinical need. Between 64% and 86% of prescriptions contained an essential medicine. However, overprescribing of antibiotics (34%-77% of prescriptions) and injectables (22%-61%) for adult non-infectious outpatient consultations was common. CONCLUSIONS: We found that manufacturers, retail pharmacies, and hospital pharmacies paid limited attention to China's 2004 NEML in their decisions to manufacture, purchase, and stock essential medicines. We also found that prescribing of essential medicines was frequently inappropriate. These results should inform strategies to improve affordable access to essential medicines under the current health care reform.

The impact of drug vintage on patient survival: a patient-level analysis using Quebec's provincial health plan data.

OBJECTIVES: There is some debate about the value received for the money spent on prescription drugs. Some argue that most drug spending is on "me-too" drugs--drugs that provide only marginal health gains. Others suggest that the opposite is true--new drugs offer good value for money and are well worth the cost. To provide evidence on this issue, we evaluated the impact of drug innovation on the longevity of Canadians. METHODS: We analyzed patient-level claims data from Quebec's provincial health plan. We selected elderly patients with continuous health coverage dispensed at least one drug prescription in each year of the study period, 1997 to 2006. Drug vintage was defined as the active ingredient's earliest marketed date. We estimated the impact of drug vintage on patient survival using a time-varying Cox proportional hazards model that controlled for year indicator variables, patient age, sex, region of residence, low income status, medical services use, concomitant drug use, and comorbidities. RESULTS: Of the 102,743 subjects in the study population, 14,154 (14%) died during the study period. Mean patient age was 68 years; 59% were women. Our survival models indicated that the use of newer medications was associated with a statistically significant mortality risk reduction (hazard ratio: 0.522; 95% confidence interval: 0.476 to 0.572, P < 0.0001), relative to older medications. Other covariates associated with an increased risk of mortality included age, sex (male), low guaranteed income supplement status, hospitalization, and number of comorbidities. CONCLUSION: This analysis showed that recent drug innovation has had a significant beneficial impact on the longevity of elderly patients.

The identification of benefit in medical intervention: an overview and suggestions for process.

Benefit and risk assessments are not only important to regulatory authorities but also important to the providers, patients, pharmaceutical industry, and payers. In order for patients and providers to continue to have access to new innovative medicines, which have some level of inherent risk, it is critical to have a systematic and balanced focus on understanding the safety risks and benefits to the patient during drug development, at the time of approval and postmarketing. There has been a significant amount of activity around efforts to improve the ability to assess risks in the postmarketing environment. However, there is no widely accepted, systematic approach or process for the ongoing evaluation of benefit. This article introduces 4 critical components in the process of identifying and assessing benefit with a goal of providing a framework that is transparent, comprehensive, applicable to various perspectives, and simple to communicate and implement. We propose the development of a catalog applied to a particular disease to identify the optimal data sources and methods to address the interests of a given perspective. Two key resources will need to be developed to support the catalog development: (1) a summary of benefit measures and preferences by disease and from various perspectives and (2) an investment in a simple visual communication mechanism with minimal statistical language. As the emphasis is on transparency, relevance, applicability, and communication, this approach to assessing benefit should maximize the impact of these data to all stakeholders and decision makers.

Effects of the introduction of in vitro assays on the use of experimental animals in pharmacological research.

The introduction of in vitro assays in pharmacological research has led to a reduction in the number of experimental animals used. But what has been the degree of this reduction, and when did it really start? This report describes the events in a medium-sized pharmaceutical company. Analysis of data collected over the last 12 years shows a five-fold reduction in the number of experimental animals used per compound synthesised. Compounds from compound libraries (large collections of randomly-synthesised molecules) that are being assessed for potential bioactivity in 'high-throughput screening' were not included in this analysis. Over the years, the (average) degree of discomfort for the animals in the experiments did not vary much; with variation generally observed from 1.5 to 2.0 (on a scale from 1-6). There was a peak in the discomfort score of experimental mice in 1997, which could be explained by the initiation of arthritis models that were subsequently refined, resulting in a lower degree of suffering. It might be concluded that the introduction of in vitro assays has indeed brought about a significant reduction in the number of experimental animals required to select a good compound (i.e. one that could progress to the preclinical toxicology phase). However, this development appears to have been neutralised by the low survival rate of new chemical entities in clinical studies, leading to a lower number of compounds per annum that actually reach the market place. Put in this 'productivity perspective', the number of experimental animals required to select a marketable drug has not much changed in the last decade.