Nonclinical safety assessment of epigenetic modulatory drugs: Current status and industry perspective.

Pharmaceutic products designed to perturb the function of epigenetic modulators have been approved by regulatory authorities for treatment of advanced cancer. While the predominant effort in epigenetic drug development continues to be in oncology, non-oncology indications are also garnering interest. A survey of pharmaceutical companies was conducted to assess the interest and concerns for developing small molecule direct epigenetic effectors (EEs) as medicines. Survey themes addressed (1) general levels of interest and activity with EEs as therapeutic agents, (2) potential safety concerns, and (3) possible future efforts to develop targeted strategies for nonclinical safety assessment of EEs. Thirteen companies contributed data to the survey. Overall, the survey data indicate the consensus opinion that existing ICH guidelines are effective and appropriate for nonclinical safety assessment activities with EEs. Attention in the framework of study design should, on a case by case basis, be considered for delayed or latent toxicities, carcinogenicity, reproductive toxicity, and the theoretical potential for transgenerational effects. While current guidelines have been appropriate for the nonclinical safety assessments of epigenetic targets, broader experience with a wide range of epigenetic targets will provide information to assess the potential need for new or revised risk assessment strategies for EE drugs.

Role of Health Technology Assessment in Drug Policies: Korea.

South Korea is the first Asian country to mandate the submission of pharmacoeconomic data for reimbursement decision making. For a new drug to be listed, it must demonstrate its value in terms of comparative effectiveness and cost effectiveness. The Health Insurance Review and Assessment Service (HIRA) judges the submitted drug's value and decides whether its coverage is appropriate on the basis of the recommendation of the Pharmaceutical Benefit Coverage Assessment Committee. Once the drug has been accepted by HIRA, the National Health Insurance Service and the sponsoring company negotiate the price and expected sales volume. Even if HIRA acknowledges the value of the drug, it cannot be listed if the negotiation fails. In the off-patent market, generic and original branded drugs are treated equally in terms of pricing. Once generics enter the market, both drug prices should be lowered to 53.55% or less of the on-patent price. Since the current system was implemented, concerns have been raised about a decline in the accessibility of new drugs, especially for high-priced drugs used to treat serious diseases. In 2013, several measures had been introduced aimed at improving the accessibility of these drugs. A risk-sharing scheme and an increase in the maximum acceptable cost-effectiveness ratio were subsequently initiated. Although these schemes have been successful in improving access to high-priced drugs, they are often criticized for reducing transparency in pricing. Finding a balance between accessibility and efficiency is still a challenge in Korea.

Drug Policy in Greece.

OBJECTIVES: To provide a detailed overview of the recent reforms in pharmaceutical pricing and reimbursement processes as well as in other important areas of the pharmaceutical policy in Greece. METHODS: Information was collected via a structured questionnaire. The study used publicly available resources, such as publications, relevant legislation, and statistical data, while health experts were also consulted. RESULTS: Recent pharmaceutical reforms included significant price cuts, increased co-payments and some provisions for vulnerable groups, rebates/clawbacks, mandatory electronic prescribing and prescription by international nonproprietary name, generics substitution, prescription limits and detailed auditing, centralized procurement, as well as changes in the pricing and reimbursement processes, with the introduction of positive and negative lists and an internal price referencing system. Price lists are compiled by the National Organization for Medicines and are issued by the Ministry of Health (MoH). An advisory pricing committee comprising representatives of stakeholder groups was abolished in early 2018. Nevertheless, under the new provisions, a health technology assessment body for the economic evaluation of reimbursed drugs is to be established for the first time in Greece. The committee is to be staffed by experts appointed by a ministerial decision of the MoH. The specific features of the process are yet to be determined. CONCLUSIONS: The pricing and reimbursement decision-making processes are centralized under the competence of the MoH. Despite the good intentions of the reformers, there are still some aspects of transparency, equity, and long-term sustainability that remain under question in Greece.

US Adult Illicit Cannabis Use, Cannabis Use Disorder, and Medical Marijuana Laws: 1991-1992 to 2012-2013.

Importance: Over the last 25 years, illicit cannabis use and cannabis use disorders have increased among US adults, and 28 states have passed medical marijuana laws (MML). Little is known about MML and adult illicit cannabis use or cannabis use disorders considered over time. Objective: To present national data on state MML and degree of change in the prevalence of cannabis use and disorders. Design, Participants, and Setting: Differences in the degree of change between those living in MML states and other states were examined using 3 cross-sectional US adult surveys: the National Longitudinal Alcohol Epidemiologic Survey (NLAES; 1991-1992), the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; 2001-2002), and the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III; 2012-2013). Early-MML states passed MML between NLAES and NESARC ("earlier period"). Late-MML states passed MML between NESARC and NESARC-III ("later period"). Main Outcomes and Measures: Past-year illicit cannabis use and DSM-IV cannabis use disorder. Results: Overall, from 1991-1992 to 2012-2013, illicit cannabis use increased significantly more in states that passed MML than in other states (1.4-percentage point more; SE, 0.5; P = .004), as did cannabis use disorders (0.7-percentage point more; SE, 0.3; P = .03). In the earlier period, illicit cannabis use and disorders decreased similarly in non-MML states and in California (where prevalence was much higher to start with). In contrast, in remaining early-MML states, the prevalence of use and disorders increased. Remaining early-MML and non-MML states differed significantly for use (by 2.5 percentage points; SE, 0.9; P = .004) and disorder (1.1 percentage points; SE, 0.5; P = .02). In the later period, illicit use increased by the following percentage points: never-MML states, 3.5 (SE, 0.5); California, 5.3 (SE, 1.0); Colorado, 7.0 (SE, 1.6); other early-MML states, 2.6 (SE, 0.9); and late-MML states, 5.1 (SE, 0.8). Compared with never-MML states, increases in use were significantly greater in late-MML states (1.6-percentage point more; SE, 0.6; P = .01), California (1.8-percentage point more; SE, 0.9; P = .04), and Colorado (3.5-percentage point more; SE, 1.5; P = .03). Increases in cannabis use disorder, which was less prevalent, were smaller but followed similar patterns descriptively, with change greater than never-MML states in California (1.0-percentage point more; SE, 0.5; P = .06) and Colorado (1.6-percentage point more; SE, 0.8; P = .04). Conclusions and Relevance: Medical marijuana laws appear to have contributed to increased prevalence of illicit cannabis use and cannabis use disorders. State-specific policy changes may also have played a role. While medical marijuana may help some, cannabis-related health consequences associated with changes in state marijuana laws should receive consideration by health care professionals and the public.

Aportaciones de la reducción de riesgos y daños en un contexto de regulación / No disponible

Esta revisión trata sobre los beneficios de la regulación respecto a la prohibición, la guerra a las drogas, sus costes y consecuencias negativas no previstas, la ley de seguridad ciudadana, la nueva política de drogas, la regulación del mercado de cannabis, las asociaciones cannábicas y sus buenas prácticas para la prevención de riesgos. Se concluye que en el ámbito de las drogas es necesaria la regulación responsable y la información veraz

This review discusses the benefits of regulation regarding prohibition, the war on drugs, their costs and unintended negative consequences, the Spanish law of public safety, the new drug policy, market regulation of cannabis, cannabis associations and best practices for risk prevention. We conclude that in the field of drugs responsible regulation and accurate information is needed

Cannabis: acciones desde la salud pública / No disponible

Se sistematizan las acciones a efectuar desde la salud pública en el consumo de cannabis. Previamente se resumen los conocimientos sobre el cannabis y las cuestiones que plantea; la situación internacional actual y las tendencias del consumo; los efectos en la salud; el marco legal actual y las implicaciones en salud pública; los clubes sociales de cannabis y su marco normativo en Cataluña. Las conclusiones son que el cannabis es la droga ilegal más consumida en el mundo y su uso comporta riesgos para la salud; debe desincentivarse el consumo de cannabis, de la misma manera que el del tabaco; existe una proliferación de asociaciones y sus clubes sociales de cannabis; debe informarse sobre los riesgos y consecuencias que el consumo de alcohol, tabaco, cannabis y otras drogas puede generar en la salud física y/o mental de los consumidores y/o potenciales consumidores; hay acuerdo en la necesidad de disminuir el impacto en la salud del consumo de esta sustancia en población vulnerable: menores, jóvenes y personas con trastornos mentales, entre otros; existe interés en separar el consumo de cannabis del de otras drogas; han de establecerse ejes de actuación que partan de las intervenciones preventivas de reducción de daños, que han demostrado ser efectivas en los últimos veinte años; los cambios normativos destinados a regular el consumo de cannabis deben insertarse en el marco de la legislación vigente; hay que estar atentos a los procesos de cambio en las políticas sobre drogas a nivel mundial; los cambios legislativos y normativos destinados a regular el consumo de cannabis y el resto de sustancias deben hacerse bajo la perspectiva de la Salud Pública y de los Derechos Humanos

Public health actions to face cannabis use are systematized. This paper includes current knowledge on cannabis and the issues raised; the current international situation and substance use trends; effects of cannabis on health; the legal framework and the public health implications; and social clubs of cannabis and regulatory framework in Catalonia. The conclusions are: cannabis is the most commonly used illicit drug in the world and cannabis use carries health risks; it should be discouraged cannabis use as tobacco use is discouraged; there is a proliferation of associations and social clubs of cannabis; people should be informed about the risks and consequences of using alcohol, tobacco, cannabis and other drugs; cannabis and substances of abuse can cause physical and mental harm on actual and potential users; there is agreement on the need to reduce the impact of cannabis use on health in vulnerable population: children, youth and people with mental disorders, among others; there is interest in separate the cannabis from other drugs market; preventive and harm/risk reduction interventions, proven effective in the past twenty years, have to be implemented; low changes designed to regulate cannabis have to be introduced in the existing legislation; we must be attentive to the processes of change in drug policies worldwide; and legislative changes to regulate the use of cannabis and other substances should be done under the perspective of public health and human rights

U.S. Policy Responses to Calls for the Medical Use of Cannabis.

This paper discusses the evolution of U.S. policy responses to calls to allow patients to use cannabis for medical purposes. It first summarizes the research evidence on the safety and efficacy of cannabinoids for various medical uses. It then outlines the challenges in developing new pharmaceutical cannabinoids that are safe, effective, and acceptable to patients. It briefly describes the strengths and limitations of the different ways in which U.S. states have allowed patients to use cannabis for medical purposes. These include allowing access for research trials only, allowing medical necessity as a defense against prosecution, and allowing commercial medical dispensaries to provide cannabis to approved patients. It argues that liberal definitions of indications for medical cannabis use and the commercialization of medical cannabis supply in California have produced the de facto legalization of recreational cannabis use.

Medicamentos y productos homeopáticos: cada cosa en su lugar / Homeopathic medications and products: Everything in its place

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Dietary supplements for athletes: emerging trends and recurring themes.

Dietary supplements are widely used at all levels of sport. Changes in patterns of supplement use are taking place against a background of changes in the regulatory framework that governs the manufacture and distribution of supplements in the major markets. Market regulation is complicated by the increasing popularity of Internet sales. The need for quality control of products to ensure they contain the listed ingredients in the stated amount and to ensure the absence of potentially harmful substances is recognized. This latter category includes compounds prohibited under anti-doping regulations. Several certification programmes now provide testing facilities for manufacturers of both raw ingredients and end products to ensure the absence of prohibited substances. Athletes should carry out a cost-benefit analysis for any supplement they propose to use. For most supplements, the evidence is weak, or even completely absent. A few supplements, including caffeine, creatine, and bicarbonate, are supported by a strong research base. Difficulties arise when new evidence appears to support novel supplements: in recent years, ß-alanine has become popular, and the use of nitrate and arginine is growing. Athletes seldom wait until there is convincing evidence of efficacy or of safety, but caution is necessary to minimize risk.

Enfermedades crónicas de alta prevalencia en una población asistida por la Seguridad Social / Highly prevalent chronic diseases in a population with Social Security coverage

Objetivo: Una de las prioridades sanitarias de las políticas europeas es la obtención de información sobre enfermedades crónicas y de alta prevalencia; ésta se encuentra limitada por la calidad de los datos disponibles. El objetivo del estudio fue describir el comportamiento de las enfermedades crónicas más prevalentes a través de bases de datos de gestión administrativa. Método: Estudio transversal retrospectivo sobre medicamentos fabricados industrialmente, dispensados y financiados total o parcialmente con fondos públicos por el Servicio de Salud deCastilla-La Mancha, a través de farmacias. El estudio se realizó durante 2003 y 2004 en el área de salud de Albacete y en él se aplicó la metodología recomendada por la Organización Mundial de la Salud para los estudios de utilización de medicamentos. El valor de la dosis diaria definida permitió conocer el número que contenía cada envase y el utilizado por 1.000 usuarios y por día, variable cuantitativa asimilable al concepto de tasa poblacional. Mediante la variable cualitativa, principio activo identificado por su código ATC, se agruparon medicamentos por indicación principal y se relacionaron con la variable cuantitativa. Resultados: La mayor prevalencia se observó en la hipertensión (27,3%: 24,2-36,7), las alteraciones del metabolismo lipídico (7,4%: 5,9-10,7) y la diabetes (6,8%: 5,9-9,7); se constató un incremento en todos los casos (del 8,9, el 27,5 y el 9,2%, respectivamente). Ambas situaciones destacan en los distritos dela sierra. Conclusiones: Es posible conocer cuál es la situación de las enfermedades crónicas de alta prevalencia, con bases de datos de gestión, mediante estudios de utilización de medicamentos. Su aplicación a ámbitos y periodos diferentes requiere la adopción de criterios metodológicos similares (AU)

Objective: One of the sanitary priorities in Europe is the obtaining of information about the high prevalence and chronic diseases, which is limited by the quality of the available information. The aim of the present study was to describe the behavior of the most prevalent chronic diseases using databases of administrative management. Method: We performed a retrospective, cross-sectional study of drugs made industrially, dispensation and financed, whole or partially with public funds, by the Health Service of Castilla-La Mancha, through pharmacies. The study was conducted between the years 2003 and 2004 in the health area of Albacete; in the study the methodology recommended by the World Health Organization WHO for conducting drug utilization studies was applied. The value of the defined daily dose allowed knowing the number contained in each package and the number of them used per thousand users and per day, quantitative assimilable variability to the population rate concept. Through the qualitative variable, active drug substance identified by ATC code, drugs with the same composition and principal indication were grouped, and they were related to the quantitative variable. Results: The greater prevalence was seen in hypertension(27.3%: 24.2-36.7), lipid metabolism alterations (7.4%: 5.9-10.7) and diabetes (6.8%: 5.9-9.7); an increase was established in all the cases (of 8.9%, of 27.5% and of 9.2%, respectively). Both situations stand out in the districts of the mountain range. Conclusions: It is possible to know the status of chronic diseases and high prevalence, with management databases, by means of studies of medication use. Its application to different areas and periods requires the adoption of similar methodological criteria (AU)

The role of patient advocacy organisations in neuromuscular disease R&D--The case of the Dutch neuromuscular disease association VSN.

This article investigates to what extent patient advocacy organisations play a role in influencing R&D and policymaking for rare neuromuscular diseases. The Dutch neuromuscular disease organisation VSN is studied in depth. A brief history of the VSN is sketched along with the international embedding of the organisation. Then, a more general perspective is provided on the reasons and extent of the involvement of patient organisations (and especially the VSN) in innovation processes. Lastly, internal mechanisms are presented that can best be applied by these organisations. The VSN adheres to a rare, long-term vision on drug innovation that requires long-term planning and policy and vision creation and steering the direction of science and technology. At the same time, other actors like scientific organisations and science policymakers and managers can benefit from these lessons to learn how to deal with patients and patient organisations in the future.

Drug treatment or alleviating the negative consequences of imprisonment? A critical view of prison-based drug treatment in Denmark.

BACKGROUND: The availability of prison-based drug treatment has increased markedly throughout Europe over the last 15 years in terms of both volume and programme diversity. However, prison drug treatment faces problems and challenges because of the tension between ideologies of rehabilitation and punishment. METHODS: This article reports on a study of four cannabis treatment programmes and four psychosocial drug treatment programmes in four Danish prisons during 2007. The data include the transcripts of 22 semi-structured qualitative interviews with counsellors and prison employees, prison statistics, and information about Danish laws and regulations. RESULTS: These treatment programmes reflect the 'treatment guarantee' in Danish prisons. However, they are simultaneously embedded in a new policy of zero tolerance and intensified disciplinary sanctions. This ambivalence is reflected in the experiences of treatment counsellors: reluctantly, they feel associated with the prison institution in the eyes of the prisoners; they experience severe opposition from prison officers; and the official goals of the programmes, such as making clients drug free and preparing them for a life without crime, are replaced by more pragmatic aims such as alleviating the pain of imprisonment felt by programme clients. CONCLUSION: The article concludes that at a time when prison-based drug treatment is growing, it is crucial that we thoroughly research and critically discuss its content and the restrictions facing such treatment programmes. One way of doing this is through research with counsellors involved in delivering drug treatment services. By so doing, the programmes can become more pragmatic and focused, and alternatives to prison-based drug treatment can be seriously considered.

Pharmacogenetics of osteoporosis: future perspectives.

Drug response is known to be highly variable among treated patients and affected by many factors, such as age, sex, ethnicity, concomitant diseases, and pharmacological therapy. However, sequence variants in the human genome are now considered an important cause of differences in drug responses. Pharmacogenetics, which is the utilization of individual genetic data to predict the outcome of drug treatment with respect to both beneficial and adverse effects, represents an emerging field of genetics with the potential to become useful for the identification of the most effective drug and the most beneficial dose for a given individual. On the basis of these considerations and thanks to recent advances in genetics and molecular biology, pharmacogenetics is becoming a flowering field in both basic and clinical research. Nevertheless, to date the opportunity to apply pharmacogenetic approaches to drug response and the possibility to use genetic screenings to tailor decisions about pharmacological treatments have limited applications. And this is even truer in the field of osteoporosis, in which pharmacogenetic studies are in their infancy. In this paper we review the most recent data on pharmacogenetics of osteoporosis, highlighting the presentations at the Second International Meeting on Pharmacogenetics of Osteoarticular Disorders held in Florence in April 2008.

Hepatotoxicidad inducida por el uso de hierbas y medicamentos para perder peso / Hepatotoxicity induced by herbs and medicines used to induce weight loss

En los últimos años ha aparecido un considerable númerode publicaciones en la literatura médica sobre la hepatotoxicidadasociada a productos herbarios a los que se ha atribuidoun efecto adelgazante. La expresión clínica de hepatotoxicidadha oscilado entre cuadros de hepatitis autolimitada,indistinguibles de los causados por los virus de la hepatitis,hasta formas de hepatitis fulminante que han causadomuerte o han requerido un trasplante hepático. Estos productos,que se venden como productos dietéticos o suplementosdietéticos, no pasan los controles de seguridad a quese somete a los fármacos antes de su comercialización, por loque la prevención de sus efectos tóxicos exige un mejor conocimientodel público para que evite su empleo, ya que susbeneficios nunca han sido comprobados, y una actuación decididade los médicos para que contribuyan a disuadir de suempleo a sus pacientes. Una regulación estricta de la autorizaciónde la comercialización de todos estos productos, denominadosnaturales, es muy necesaria para minimizar losdaños que pueden causar

In the last few years, a considerable number of reports havebeen published on hepatotoxicity associated with herbalproducts attributed with weight-reducing properties. Clinicalexpression of hepatotoxicity has ranged from symptomsof self-limiting hepatitis, indistinguishable from those causedby the hepatitis viruses, to forms of fulminant hepatitiscausing death or requiring liver transplantation.These products, which are sold as dietary products or supplements,do not undergo the safety tests required of drugsbefore their release on to the market. To prevent the toxiceffects of herbal products, the general public should bemade aware of their harmful effects and – since the benefitsof these products have not been demonstrated – avoid theiruse, while physicians should strongly discourage patientsfrom taking these products. Authorization of the commercializationof all these “natural” products should be strictlyregulated to minimize the harm they can cause

Complementary and alternative medical therapies.

PURPOSE OF REVIEW: Complementary and alternative medical therapies include herbs, acupuncture, and mind-body therapies. This review highlights the findings of recently published studies of complementary and alternative medical therapies and epilepsy, and provides an update of the US Food and Drug Administration's role in regulating herbal products. RECENT FINDINGS: Complementary and alternative medical therapies are often tried by patients with epilepsy, frequently without physician knowledge. Many modalities have been evaluated in patients with epilepsy, though methodological issues preclude any firm conclusions of efficacy or safety. Some herbal medicines have been shown experimentally to have mechanisms of action relevant to epilepsy and promising actions in animal models. SUMMARY: There is currently a paucity of credible evidence to support the use of complementary and alternative medical therapies in patients with epilepsy. Herbal medicines traditionally used for epilepsy and compounds isolated from them, as well as other herbal medicines and their constituent compounds that have been shown experimentally to have mechanisms of action relevant to epilepsy, should undergo further preclinical evaluation with a view towards clinical development under the new US Food and Drug Administration guidelines. Additional studies of other, nonherbal complementary and alternative medical therapies are also warranted based on anecdotal observations or pilot studies that suggest a favorable risk-benefit ratio.

What is being done to address the new drug epidemic?

As osteopathic physicians care for patients with complaints of pain, they commonly prescribe controlled substances. The use of these agents presents special challenges for providers, patients, and communities. The US Drug Enforcement Administration (DEA) has provided testimony to the US Congress in regard to the growing problem of diversion and misuse of such medications. Joseph T. Rannazzisi, the deputy assistant administrator in the Office of Diversion Control, appeared before the House Government Reform Committee's Subcommittee on Criminal Justice, Drug Policy, and Human Resources on July 26, 2006.

Uso racional del medicamento y eficacia terapéutica / Adequate use of drugs and therapeutic efficacy

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