Systematic Review of the Impact of Protease Inhibitor-Based Combination Antiretroviral Therapy on Renal Transplant Outcomes in Recipients Living with HIV Infection.

Advances in Human Immunodeficiency Virus (HIV) treatment including combination antiretroviral therapy (cART) have transformed HIV into a chronic condition. Kidney diseases cause morbidity and mortality in patients living with HIV (PLWH), though cART has permitted kidney transplants with acceptable post-transplant graft and patient survival. Risk of allograft rejection remains high, which may be related to interactions between cART, specifically protease inhibitors (PI), and immunosuppressants prescribed post-transplant. This systematic review evaluates renal transplant outcomes in PLWH treated with PI- vs. non-PI-based cART. A search strategy was generated with terms related to renal transplant, HIV, and cART and run on PubMed, Embase, Scopus, and Cochrane. Studies were evaluated using PRISMA guidelines on Covidence by two reviewers, then evaluated for bias. Of 803 studies, 9 were included. Included papers were prospective or retrospective cohort studies or chart reviews of adult patients. Outcome measures included acute graft rejection, graft survival, and patient survival. One study had significant results demonstrating that PI-based therapy was correlated with increased graft rejection rates. Two studies demonstrated significant graft survival benefit to non-PI-based therapy while one demonstrated significant benefit to PI-based therapy. Two studies found significant patient survival benefit to non-PI-based therapy. For each outcome measure, remaining data suggested improved outcomes with non-PI-based therapies without achieving statistical significance. The results demonstrate superior outcomes in PLWH taking non-PI-based cART, though the paucity of significant results suggests that PLWH who require PI-based cART for virological control may continue their regimen safely post-kidney transplant.

Long-term safety and efficacy of the anti-tissue factor pathway inhibitor marstacimab in participants with severe haemophilia: Phase II study results.

Marstacimab, an investigational human monoclonal antibody targeting tissue factor pathway inhibitor, demonstrated safety and efficacy in preventing bleeding episodes in patients with haemophilia. This multicentre, open-label study investigated safety, tolerability, and efficacy of long-term weekly prophylactic marstacimab treatment in participants with severe haemophilia A and B, with or without inhibitors. Adult participants were enrolled from a previous phase Ib/II study or de novo and assigned to one of two subcutaneous (SC) marstacimab doses: once-weekly 300 mg or a 300-mg loading dose followed by once-weekly 150-mg doses, for up to 365 days. Study end-points included safety assessments and annualised bleeding rates (ABRs). Of 20 enrolled participants, 18 completed the study. Overall, 70% of participants had treatment-emergent adverse events, including injection site reactions, injection site haematoma, and haemarthrosis. No treatment-related serious adverse events or thrombotic events occurred. Across all dose cohorts, mean and median on-study ABRs ranged from 0 to 3.6 and 0 to 2.5 bleeding episodes/participant/year respectively, demonstrating comparable efficacy to that observed in the short-term parent study. No treatment-induced anti-drug antibodies were detected. Once-weekly SC marstacimab prophylaxis was well tolerated, with an acceptable safety profile, and maintained long-term efficacy up to 365 days. (Clinicaltrials.gov identifier, NCT03363321).

Recently approved treatment options for patients with metastatic triple-negative and HER2-neu-positive breast cancer.

Breast cancer (BC) is the most common cancer affecting women worldwide. In 2021, the estimated number of new breast cancer cases was 281 550 and about 43 500 women died from metastatic breast cancer (mBC). For women aged 20-59 years, mBC remains the leading cause of cancer death and is, therefore, an important public health concern. Only 5% of women initially present with metastatic disease. Approximately 20% of patients presenting with local or locoregional disease progress to mBC despite adjuvant therapy. Inspite of all the medicosurgical advancements, the overall prognosis for patients diagnosed with mBC remains poor, with median overall survival of approximately 31 months, although this varies based on tumor biology. In recent years, there has been significant progress in developing immunotargeted therapies such as antihuman epidermal growth factor receptor 2 (anti-HER2) or check point inhibitors that confirmed to have dramatically improve the prognosis of mBC, a historically unfavorable disease subset. Even with the major progress that has been made in understanding the biology of BC, challenges such as resistance frequency to therapies, unknown efficacy, concerns for safety of drug combination and toxicities still remain high. Therefore, a new targeted and more selective treatment approaches are the need of the hour. In this review, we aim to outline the most recently approved medications in treatment of Her2-positive and triple-negative breast cancers.

Representative analysis of elderly subjects in clinical trials of prostate cancer drugs / 中华老年医学杂志

Objective:To analyze whether the sample of elderly subjects in clinical trials of prostate cancer drugs is representative.Methods:From the level of trial design, the age distribution of subjects in clinical trials of prostate cancer drugs for elderly patients from January 2019 to December 2021 was inquired on the platform of drug clinical trial registration and information disclosure.From the actual enrollment level, the prostate cancer drug clinical trials initiated and completed by a hospital from January 2010 to June 2022 were collected.The age information of subjects in all centers was collected for multicenter trials with a summary report, and the age data of subjects in the center was collected for trials without a summary report or single-center trials.The average age of prostate cancer onset and the incidence of prostate cancer in different age groups were compared with the Chinese Cancer Registry System, so as to compare whether the two were consistent.Results:Most of the trials(72.1%、44/61)did not set upper age limit at the protocol design level.Phase Ⅲ and phase Ⅳ trials did not set an upper age limit for enrolled subjects in the protocol.From the actual enrollment level, a total of 19 studies were included in this study, with 1 402 subjects, and the average age of subjects was 67.1±8.6 years old, which was significantly different from the average age of prostate cancer in China and Beijing(all P<0.001). The age group with the largest number of participants was 60-64 years old(34.2%、479/1 402). The population aged ≥75 years was the least(21.5%, 301/1 402), which was different from the high incidence age group of prostate cancer in China in 2017(421.77/100 000). Conclusions:Clinical trials of prostate cancer drugs are designed to cover all age groups of elderly patients, but the actual sample representation of the enrolled elderly subjects is insufficient.Under the premise of protecting the safety of subjects, the trial population who are matched for the average age of prostate cancer onset and the incidence of prostate cancer in age groups, should be gradually increased.

Access to innovation through the national early access program and clinical trials for patients with malignant melanoma.

BACKGROUND: The arrival of immunotherapies and targeted therapies challenged the authorities to make them available as soon as possible. France has effective tools, such as clinical trials (CTs) and a national early access program (temporary authorizations for use [ATUs] and temporary recommendations for use [RTUs]), allowing the use of innovative drugs, whether or not they have been authorized or used off-label, for cases that have reached a therapeutic impasse. METHODS: The methodology involved real-time data collection from ATUs, RTUs (between September 1, 2009 and September 1, 2019), and CT authorizations (from December 1, 2017 to September 1, 2019) that were filed and reviewed by the French National Agency for Medicines for metastatic melanoma (MM). RESULTS: In total, 45 CTs were authorized for MM (51% early phase trials and 44% phase 2 and 3 trials), mainly for the metastatic line (86%) and with an industrial sponsor (73%). Immunotherapies and targeted therapies (63% and 24%, respectively) mostly were used in combination. Three RTUs were authorized for the adjuvant treatment of MM, whereas 13 drugs were available through nominal ATUs (nATUs), of which 5 were awarded a cohort ATU (cATU). This enabled the treatment of 6538 patients (28% through nATUs and 72% through cATUs). All of these drugs were granted marketing authorization and were included in the reimbursement list. CONCLUSIONS: Thanks to CTs and the national early access program, patients in France have been able to benefit from innovative MM treatments. LAY SUMMARY: Several tools allow the use of innovative drugs in France, even if they are not yet authorized or used off-label. From December 1, 2017 to September 1, 2019, 45 clinical trials have been authorized for metastatic melanoma, mostly using immunotherapy (63%) and targeted therapy (24%) at an early phase (51%). Since 2010, the national early access program has treated 6538 patients, including 28% under nominative temporary authorizations for use and 72% under cohort temporary authorizations for use. Fourteen drugs are available through nominative temporary authorizations for use, and 5 are available through cohort temporary authorizations for use, and all of these drugs were granted marketing authorization.

Investigator Responsibilities in Clinical Research.

Background: Clinical trials are an integral part of translating new basic science research into therapeutics. It is crucial for those who run clinical trials to realize the gravity of their responsibilities as principal investigators. Methods: This review focuses on the relevant investigator responsibilities under the Code of Federal Regulations Title 21, the contents of Form 1572, FDA inspections, and methods to improve compliance. Results: While responsibility for day-to-day study activities can be delegated to outside entities and to study staff, a clinical principal investigator who has signed US Food and Drug Administration (FDA) Form 1572 is held responsible for noncompliance and misconduct by anyone working on the study. Depending on the infraction, consequences can range from a publicly posted warning letter by the FDA to criminal prosecution and fines or imprisonment. Conclusion: Investigators are not only responsible for producing high-quality, meaningful, scientific research, but they are also responsible for maintaining public trust. If the principal investigator acts with integrity and provides training and oversight of employees, FDA inquiries should go smoothly. Following good clinical practice standards for clinical research will result in quality data collection and facilitate the analysis and publication process.

Experimental study of the inhibition effect of CXCL12/CXCR4 in malignant pleural mesothelioma.

Previous studies have demonstrated that CXCL12/CXCR4 axis is closely related to tumors such as malignant pleural mesothelioma (MPM). This research was conducted in order to detect whether CXCL12/CXCR4 inhibitors could restrain MPM and have a synergistic effect with chemotherapy, also to investigate the relationship of CXCL12/CXCR4 with other gene expressions in MPM. Forty mice were injected MPM cells and randomly divided into four groups: the PBS (control group), AMD3100 (CXCR4-CXCL12 antagonist), pemetrexed and AMD3100 plus pemetrexed. The mice were treated respectively for duration of 3 weeks. The size, bioluminescence and weight of tumors were measured. The differences between gene expressions in each group were analyzed. The tumor weights of each treatment group were lower than that of the control group (p<0.05). The bioluminescence of the tumor of the AMD3100 treatment group and the AMD3100 plus pemetrexed treatment group were lower than that of the control group (p<0.05), and AMD3100 was shown to have synergistic effects with pemetrexed (p<0.05). Among the 2.5 billion genes, several hundreds of genes expressed differently between groups. Results show that AMD3100 and pemetrexed can inhibit the growth of MPM in vivo, also that there is a better result if both are used together. Our findings suggest that CXCL12/CXCR4 axis affects a certain amount of gene expression in MPM.

Clinical trials tracking nonalcoholic fatty liver disease: Drug classification / 临床肝胆病杂志

At present, there are still no effective drugs launched for the treatment of nonalcoholic fatty liver disease (NAFLD), and many drugs are being evaluated in clinical trials. These drugs have different mechanisms of action in treatment, such as improvement of glycolipid metabolism, anti-inflammation, anti-fibrosis, and improvement of intestinal microbiota. This article elaborates on the research and development of drugs from the following aspects: inflammatory response and immune activation, lipid metabolism and insulin resistance, lipotoxicity, oxidative stress, cell apoptosis and necrosis, collagen formation and degradation, and proliferation of intestinal microbiota.

Declaración de la Academia Chilena de Medicina sobre el Título V de la Ley 20. 850 (Ley Ricarte Soto) y su proyecto de reglamento "De los ensayos clínicos de productos farmacéuticos y elementos de uso médico" / Declaration of the Chilean Academy of Medicine of Law 20. 850 "On clinical trials of pharmaceutical products and medical devices" and of the bylaw that will regulate its application

In Chile, high cost treatments required by selected medical conditions are financed by the State, according to Law 20.850. A bylaw under discussion by the Senate regulates clinical trials, posing complex issues that will endanger local interest in front-line research: 1) The exclusive and mandatory control bestowed to the Institute of Public Health during all stages of the trials and also the surveillance of institutions performing clinical trials, overriding their Clinical Research Review Boards; 2) The 10 year period during which any adverse event is assumed to have been caused by the medication or devise evaluated by the trial, unless the contrary is proven in a judicial process; 3) Individuals submitted to the trials are entitled to free post trial access to the treatment received during the study, financed by the trial supporting entities and as long as the drug or devise is considered to be useful. While agreeing with the need to have a National Registry of Clinical Trials, we predict that the mentioned critical issues in the bylaw will lead to difficulties and unnecessary judicial processes, thus limiting clinicians’ interest in performing research. We propose to modify the bylaw, excluding responsibilities on events associated with the natural evolution of the medical condition, with patients’ ageing or with comorbidities and clinical events considered unpredictable when the protocol was accepted. We recommend that the free post trial access should be a joint decision involving the patient and the attending physician, taking in consideration that the volunteer has been exposed to risks and burdens, or when discontinuation of treatment entails a vital risk until the treatment under study has been approved and becomes available in the national market.

En Chile los tratamientos de alto costo requeridos por seleccionadas condiciones médicas son financiados por el Estado, de acuerdo a la Ley 20.85, que se hizo efectiva en noviembre de 2015. Un reglamento de esta ley -actualmente en discusión por el Senado- incluye la regulación de los ensayos clínicos y plantea importantes aspectos que van a poner en riesgo la realización de investigaciones clínicas avanzadas: 1) El control exclusivo y mandatorio otorgado al Instituto de Salud Pública durante todas las etapas de los ensayos y la vigilancia de las instituciones que los realizan, que sobrepasa las atribuciones de los Comités de Ética Científica Institucionales; 2) El período de hasta 10 años después de la aparición de cualquier efecto adverso, durante el cual se asume causado por el medicamento o dispositivo evaluado en el ensayo, mientras no se demuestre lo contrario en un proceso judicial; 3) Los participantes de los estudios tienen derecho a continuar con el tratamiento recibido durante el estudio una vez terminado este, financiado por las entidades que patrocinan los estudios y mientras el fármaco o dispositivo se consideren útil. Estamos de acuerdo con la necesidad de contar con un Registro Nacional de Ensayos Clínicos. Sin embargo, predecimos que los aspectos críticos del reglamento causarán dificultades y procesos judiciales innecesarios, lo que limitará el interés de los clínicos en realizar investigación. Proponemos que el reglamento debe modificarse a fin de excluir responsabilidades sobre eventos asociados con la evolución natural de la condición clínica, el envejecimiento del paciente, comorbilidades y eventos clínicos no predecibles cuando se aceptó el estudio. Recomendamos que el acceso gratuito posterior al estudio debe constituir una decisión conjunta del paciente y su médico tratante, considerando los riesgos y la carga a que se expuso el paciente, o al riesgo vital secundario a la suspensión del tratamiento del estudio mientras no esté disponible en el mercado nacional.

Declaración de la Academia Chilena de Medicina sobre el Título V de la Ley 20. 850 (Ley Ricarte Soto) y su proyecto de reglamento “De los ensayos clínicos de productos farmacéuticos y elementos de uso médico” / Declaration of the Chilean Academy of Medicine of Law 20. 850 On clinical trials of pharmaceutical products and medical devices” and of the bylaw that will regulate its application

In Chile, high cost treatments required by selected medical conditions are financed by the State, according to Law 20.850. A bylaw under discussion by the Senate regulates clinical trials, posing complex issues that will endanger local interest in front-line research: 1. The exclusive and mandatory control bestowed to the Institute of Public Health during all stages of the trials and also the surveillance of institutions performing clinical trials, overriding their Clinical Research Review Boards; 2.The 10 year period during which any adverse event is assumed to have been caused by the medication or devise evaluated by the trial, unless the contrary is proven in a judicial process; 3. Individuals submitted to the trials are entitled to free post trial access to the treatment received during the study, financed by the trial supporting entities and as long as the drug or devise is considered to be useful. While agreeing with the need to have a National Registry of Clinical Trials, we predict that the mentioned critical issues in the bylaw will lead to difficulties and unnecessary judicial processes, thus limiting clinicians’ interest in performing research. We propose to modify the bylaw, excluding responsibilities on events associated with the natural evolution of the medical condition, with patients’ ageing or with comorbidities and clinical events considered unpredictable when the protocol was accepted. We recommend that the free post trial access should be a joint decision involving the patient and the attending physician, taking in consideration that the volunteer has been exposed to risks and burdens, or when discontinuation of treatment entails a vital risk until the treatment under study has been approved and becomes available in the national market.

Does aspirin use reduce the risk for cancer?

Recently, studies have reported that aspirin has chemopreventive properties. In this study, we used the Taiwan NHI database, which covers a population of 23 million (99.99%) Taiwanese from 2001 to 2011. This was a case-control study which identified 601,733 patients using ICD-9-CM codes who were diagnosed with cancer. Each case with 4 eligible controls was matched for age, sex, and index date and adjusted for confounding factors. The observed overall cancer risk (adjusted OR (AOR), 0.95; 95% CI 0.94 to 0.96) reduced with aspirin use, specifically, colorectal (AOR, 0.97; 95% CI 0.94 to 0.99) and digestive system (AOR, 0.96; 95% CI 0.94 to 0.98) cancers. Findings from the Asian population would contribute to the discussion on aspirin's safety profile.

Effects of curcumin in experimental diabetic nephropathy.

Diabetic nephropathy (DN) is currently well established as the most common cause of end-stage renal disease in most parts of the world. Notwithstanding the expanding basic and clinical research in this field, the pathogenesis remains far from clear and hence the treatment of DN remains suboptimal. There is a critical need for the development of newer therapeutic strategies including alternative and complementary therapies. One of the natural products that was extensively studied in cancer and other chronic disease states such as diabetes is curcumin, an active ingredient in turmeric, a spice extensively used in India. In this manuscript, we present a critical review of the experimental and clinical evidence that supports the use of curcumin and its analogs in DN as well as the various proposed mechanisms for its biological actions in health and disease states.

Investigational New Drug applications: a 1-year pilot study on rates and reasons for clinical hold.

BACKGROUND: The Food and Drug Administration (FDA)'s Center for Drug Evaluation and Research (CDER) receives about 1500 initial Investigational New Drug applications (INDs) per year. In the first 30 days after initial IND submission, FDA conducts a review to determine whether the proposed investigation is safe to proceed, and if not, the IND may be placed on clinical hold. METHODS: A retrospective study of rates and reasons for clinical hold for all initial INDs submitted to CDER in fiscal year (FY) 2013 was performed. INDs were assessed for reasons that led to clinical hold, included chemistry, manufacturing and controls (CMC), animal toxicology or clinical issues. INDs were further categorized by commercial versus research sponsorship, and rare versus common disease indications. All INDs placed on hold were reassessed by whether they remained on hold within the first year following hold imposition. RESULTS: CDER received 1410 initial INDs in FY 2013, of which 125 (8.9%) were placed on hold during the first 30 days after initial submission. Of the INDs placed on hold, more than half became active within the first year after first imposition of hold. CMC reasons were most commonly cited, followed by clinical, then toxicology reasons. There were no substantive differences in rates and reasons for hold between INDs for rare or common disease indications, or between commercial or research INDs. CONCLUSIONS: The vast majority of initial INDs moved forward within 30 days after submission, and for those applications placed on hold, most became active within 1 year. The findings also suggest that many holds for new drug product programs can be avoided by following the available guidelines for investigational product development.

Desarrollo de nuevos medicamentos: oportunidades y beneficios para el Perú / Development of new drugs: opportunities and benefits for Peru

El desarrollo de drogas innovadoras permite la obtención de nuevos medicamentos para así prevenir y tratar mejor las enfermedades, ello mejora la calidad de vida y la hace más productiva; por tanto, la misión de la investigación farmacéutica es desarrollar drogas seguras y eficaces. Los ensayos clínicos permiten evaluar los perfiles de seguridad y eficacia de nuevos medicamentos, dispositivos médicos y pruebas diagnósticas. La investigación y el desarrollo de nuevas drogas es un proceso largo y costoso en donde por cada 5000 a 10 000 nuevos compuestos que ingresan a las pruebas preclínicas, solo uno es aprobado. En la actualidad, el desarrollo de drogas muestra un crecimiento de 7,6% con respecto al 2011. Según ClinicalTrials.gov, el 5% de los ensayos se implementan en Latinoamérica, en donde, Perú ocupa el quinto lugar, con un descenso de estudios aprobados desde el año 2009. De otro lado, según el Reporte Global de Competitividad del Foro Económico Mundial, Perú ocupa el puesto 61 con retos principalmente en el funcionamiento de sus instituciones públicas, inversión en I&D y capacidad tecnológica. La complejidad de la I&D de medicamentos explica la búsqueda de locaciones competitivas para el desarrollo de estudios clínicos. La Investigación Clínica es una industria humanizada por su plataforma ética enunciada en las guías de buenas prácticas clínicas, y que exige de nuestro país desarrollar un valor diferenciador que contribuya con el desarrollo de conocimiento y su competitividad.

The development of innovative drugs allows coming up with new medicines to prevent and better treat illnesses. This improves people´s quality of life and makes it more productive. Therefore, the mission of pharmaceutical research is to develop safe and effective drugs. Clinical trials allow the evaluation of the safety and efficacy profiles of new medicines, medical devices and diagnostic tests. Research and development (R&D) of new drugs is a long and costly process, where out of every 5000 to 10000 new components that enter preclinical testing, only one is approved. Compared to 2011, drug development has increased by 7.6%. According to ClinicalTrials.gov, 5% of the trials take place in Latin America, and Peru is in the fifth position. On the other hand, according to the Global Competitiveness Report issued by the World Economic Forum, Peru ranks 61st, its biggest challenges being the functioning of its public institutions, investment in R&D and technological capacity. The complexity of drug R&D results in a search for competitive places to develop clinical trials. Clinical Research is a humanized industry due to its ethical platform, stated in the guidelines of good clinical practices. This industry demands our country to develop a differentiating value that contributes to the development of knowledge and its competitiveness.

Fornecimento de medicamento investigacional após o fim da pesquisa clínica: revisão da literatura e das diretrizes nacionais e internacionais / Provision of investigational drug after clinical research: review of literature, national and international guidelines

A continuidade do tratamento com os medicamentos investigacionais após a conclusão de uma pesquisa clínica vem sendo discutida desde o final dos anos 1980, inicialmente em associação a estudos na área da Síndrome de Imunodeficiência Adquirida e, particularmente, em países em desenvolvimento, onde a vulnerabilidade dos participantes de pesquisa é maior. Diretrizes nacionais e internacionais fazem referência ao tema do acesso pós-pesquisa; entretanto, a complexidade do assunto não é facilmente endereçada e usualmente demanda discussões adicionais e específicas. A decisão sobre o fornecimento do medicamento após a pesquisa deve passar, no mínimo, por avaliações de eficácia e segurança, considerando tratar-se de um medicamento ainda experimental. Cada pesquisa deve ter avaliação própria, levando-se em consideração a doença em questão, assim como a população do estudo e suas necessidades. Desta forma, a natureza da obrigação pós-pesquisa não pode ser considerada a mesma em todas as situações e contextos, mas deve-se assegurar que a relação criada entre pesquisadores e pacientes durante uma pesquisa clínica seja sempre terminada com responsabilidade e respeito.

The post-trial access to investigational drugs has been the object of discussion since the late 1980s at least, initially linked to trials carried out in acquired immunodeficiency syndrome and, particularly, in developing countries, where the concern with patient vulnerability is more important. National and international guidelines do mention the subject; however, the complexity of the issue is not easily addressed and usually requires additional and specific discussions. The decision on providing the investigational drug after the trial shall rest on at least two dimensions: efficacy and safety assessments, as the new drug is still on the experimental phase. Each clinical trial shall have its own assessment, taking into account the disease being studied, as well as the study population and their specific needs. Therefore, the nature of post-trial obligations cannot be considered the same in all situations and contexts; nevertheless, it should be assured that the relationship developed between investigators and patients during the study must be always terminated with respect and responsibility.

Levosimendan na insuficiência cardíaca descompensada: revisão sistemática e metanálise / Levosimendan in acute decompensated heart failure: systematic review and meta-analysis

FUNDAMENTO: A insuficiência cardíaca descompensada (ICD) é uma condição bastante prevalente e com alta mortalidade. O levosimendan está entre as novas drogas que têm sido testadas para o seu manejo. OBJETIVO: Realizar uma revisão sistemática da literatura e uma metanálise da redução de morbimortalidade associada ao levosimendan no tratamento da ICD. MÉTODOS: Foi feita uma pesquisa bibliográfica no Medline buscando todos os ensaios clínicos randomizados (ECRs) que avaliassem o uso do levosimendan na ICD. Os desfechos de interesse foram: morte por todas as causas, tempo de internação hospitalar e reinternação hospitalar por ICD. Todos os ECRs com desfechos de interesse foram incluídos. Critérios de qualidade metodológica, como cegamento e sigilo da lista de alocação, foram avaliados em análise de sensibilidade. O cálculo principal foi feito com efeitos randômicos. RESULTADOS: Dos 179 artigos identificados, 48 eram ECRs, sendo 19 com desfechos clínicos de interesse. Na comparação com placebo (7 ensaios clínicos, 1.652 pacientes), o risco relativo (RR) para morte total foi de 0,87 (intervalo de confiança [IC] 95 por cento: 0,65 - 1,18). Na comparação com dobutamina (10 ensaios clínicos, 2.067 pacientes), o RR foi de 0,87 (IC 95 por cento: 0,75 - 1,02). Três estudos tinham dados sobre tempo de internação, onde o levosimendan mostrou diminuição de 2,27 e 2,30 dias em relação ao placebo e a dobutamina, respectivamente (p < 0,05 para ambos). Nenhum artigo apresentou isoladamente dados sobre reinternação. CONCLUSÃO: As evidências disponíveis até o momento não mostram benefício em termos de mortalidade associada ao levosimendan, que apresentou benefício de pequena magnitude apenas no tempo de internação.

BACKGROUND: Congestive heart failure (CHF) is a rather prevalent condition with a high mortality rate. Levosimendan is one among the new drugs that have been tested for its management. OBJECTIVE: To undertake a systematic review and meta-analysis of the morbidity and mortality reduction associated with levosimendan in the treatment of CHF. METHODS: A bibliographic search was conducted in the Medline database for all randomized controlled trials (RCTs) that assessed the use of levosimendan in CHF. The outcomes were death from all causes, length of hospital stay, and hospital readmission for CHF. All RCTs with outcomes of interest were included. Methodological quality criteria, such as blinding and confidentiality of the list of allocation, were evaluated in sensitivity analysis. The main calculation was done with random effects. RESULTS: Of the 179 articles identified, 48 were RCTs, 19 of them with outcomes of interest. In the comparison with placebo (7 trials, 1,652 patients), the relative risk (RR) for overall death was 0.87 (95 percent confidence interval [CI]: 0.65 to 1.18). In comparison with dobutamine (10 trials, 2,067 patients), the RR was 0.87 (95 percent CI: 0.75-1.02). Three studies had data on length of stay, in which levosimendan showed a decrease of 2.27 and 2.30 days compared to placebo and dobutamine, respectively (p < 0.05 for both). No article presented data on readmission alone. CONCLUSION: The evidence available so far has shown no benefit in terms of mortality in association with the use of levosimendan, which only showed a small benefit in the time of hospitalization.

O uso de drogas ainda experimentais em assistência: extensão de pesquisa, uso compassivo e acesso expandido / Therapeutic uses of investigational drugs: research extension, compassionate use, and expanded access

O presente artigo descreve os aspectos metodológicos, regulatórios e éticos das diferentes formas de acesso a drogas ainda experimentais em situações assistenciais - extensão de pesquisa, uso compassivo e acesso expandido. Em todo o mundo, essa modalidade de assistência tem como principais desafios o estabelecimento de critérios mínimos de qualificação tanto dos pesquisadores quanto das instituições para que possam realizar projetos envolvendo novas drogas em suas diferentes fases, a capacitação dos membros dos comitês de avaliação de projetos quanto aos aspectos metodológicos, regulatórios e éticos envolvidos na pesquisa de novas drogas, a explicitação das relações entre pesquisadores e patrocinadores e entre pesquisadores e participantes da pesquisa e a oposição quanto à recente proposta de possibilitar aos fabricantes de medicamentos a cobrança pelas drogas utilizadas em projetos de pesquisa.

This article describes the methodological, regulatory, and ethical aspects of the different therapeutic uses of investigational drugs-research extension, compassionate use, and expanded access. Worldwide, the principle challenges of this kind of treatment are: setting minimum quality standards for researchers, as well as institutions, so that projects can include drugs at various stages of development; training of evaluation and assessment committees on the methodological, regulatory, and ethical aspects of new drug research; clearly outlining the relationship between researchers and funding organizations and between researchers and study participants; and understanding the opposition to the recent proposal to enable drug manufacturers to charge for drugs used in research studies.

Investigation on utilization situation of antipyretic pharmaceutical products containing PPA by visiting some pharmacies in the area of Hanoi

A survey on PPA-containing products consumption was conducted in 10 pharmacies located in Hanoi from February to May 2002. It revealed that there were 20 such products available in the market(of them, 16 were domestic). The PPA content as base form in a single dose of all these preparations was not exceeded 25mg. During the studied period, out of 250 people buying medication for cough and cold, 74 people (29.6% bought PPA-containing products with the most purchased ones were Decolgen forte and Rhumenol. Many patients with cough and cold consumed relatively high amount of PPA, not being aware of its adverse effects and contraindications