Host-modifying drugs against COVID-19: some successes,but not yet the breakthrough

After reviewing antiviral drugs (Brüssow Environmental Microbiology 2021) the present review summarizes the results of clinical trials with host-modifying drugs in COVID-19 patients. Clinical benefits were observed with different immunomodulators. The variable outcomes of trials with the interleukin 6 receptor inhibitor tocilizumab demonstrated that treatment benefits might only be present in specific subgroups of patients or in specific infection stages. A meta-analysis of trials with the interleukin 1 receptor antagonist anakinra showed a survival benefit only in patients with hyperinflammation. The Janus kinase inhibitor baricitinib is an anti-inflammatory treatment that showed a clinical benefit in hospitalized patients who do not yet need supplementary oxygen. In contrast, the corticosteroid dexamethasone showed mortality reducing effects that were limited to patients on ventilation or in need of supplementary oxygen. Therapeutic dose of anticoagulation met the criteria for inferiority in severe cases, but showed a small survival benefit in non-severe COVID-19 patients. Large trials with colchicine showed a small or no survival benefit. Azithromycin, an antibiotic with immunomodulatory activity, showed no effects in numerous clinical trials. The trials showed a clear need for new drugs instead of repurposed drugs and drugs that specifically target the SARS-CoV-2 virus or the pathology developing in COVID-19 patients.     

Current trends in the cardiovascular clinical trial arena (I)

The existence of effective therapies for most cardiovascular disease states, coupled with increased requirements that potential benefits of new drugs be evaluated on clinical rather than surrogate endpoints, makes it increasingly difficult to substantiate any incremental improvements in efficacy that these new drugs might offer. Compounding the problem is the highly controversial issue of comparing new agents with placebos rather than active pharmaceuticals in drug efficacy trials. Despite the recent consensus that placebos may be used ethically in well-defined, justifiable circumstances, the problem persists, in part because of increased scrutiny by ethics committees but also because of considerable lingering disagreement regarding the propriety and scientific value of placebo-controlled trials (and trials of antihypertensive drugs in particular).The disagreement also substantially affects the most viable alternative to placebo-controlled trials: actively controlled equivalence/noninferiority trials. To a great extent, this situation was prompted by numerous previous trials of this type that were marked by fundamental methodological flaws and consequent false claims, inconsistencies, and potential harm to patients.As the development and use of generic drugs continue to escalate, along with concurrent pressure to control medical costs by substituting less-expensive therapies for established ones, any claim that a new drug, intervention, or therapy is "equivalent" to another should not be accepted without close scrutiny. Adherence to proper methods in conducting studies of equivalence will help investigators to avoid false claims and inconsistencies. These matters will be addressed in the third article of this three-part series.     

Advances in the clinical development of antiepileptic drugs

In this paper we describe advances in the clinical development of antiepileptic drugs as a function of the Antiepileptic Drug Development Program of the National Institute of Neurological and Communicative Disorders and Stroke. This program encompasses both the preclinical and clinical elements of drug development through the Anticonvulsant Screening Project, the Toxicology Project, and the support of controlled clinical trials of potential new drugs that emerge from these projects and promise to be more effective and less toxic than those currently available for the treatment of epilepsy.     

Indian pharma enters the global arena

Although known as a major supplier of generic drugs, India has begun to forge new alliances with big US and European pharma companies. Such collaborations are helping to shepherd Indian drug companies into a new era of innovative drug discovery, but regulations governing patents, drug approvals, and clinical trials are still in the process of being updated.     

Imidazoles in the treatment of ocular mycoses

The use of a new class of broad spectrum antifungal drugs i.e. imidazoles and in particular ketoconazole in treatment of severe affections of the eye such as mycoses is described. The clinical trials included 40 patients with various forms of mycosis: mycotic canaliculitis (6 patients), mycotic blepharitis (4 patients), mycotic conjunctivitis (7 patients), keratomycosis (17 patients) and mycotic endophthalmitis (6 patients). Ketoconazole was used in the form of tablets and instillations. The combined treatment included nonsteroid antiinflammatory drugs and antibacterial agents. The clinical trials showed that ketoconazole had pronounced antifungal activity and was rather efficient in treatment of ocular mycoses. Its broad spectrum and low toxicity were recorded.     

The quest for surrogate markers of angiogenesis: a paradigm for translational research in tumor angiogenesis and anti-angiogenesis trials

Inhibition of tumor angiogenesis suppresses tumor growth and metastatic spreading in many experimental models, suggesting that anti-angiogenic drugs may be used to treat human cancer. During the past decade more than eighty molecules that showed anti-angiogenic activity in preclinical studies were tested in clinical cancer trials, but most of them failed to demonstrate any measurable anti-tumor activity and none have been approved for clinical use. Recent results stemming from trials with anti-VEGF antibodies, used alone or in combination with chemotherapy, suggest that systemic anti-angiogenic therapy may indeed have a measurable impact on cancer progression and patient survival. From the clinical studies it became nevertheless clear that the classical endpoints used in anti-cancer trials do not bring sufficient discriminative power to monitor the effects of anti-angiogenic drugs. It is therefore necessary to identify and validate molecular, cellular and functional surrogate markers of angiogenesis to monitor activity and efficacy of anti-angiogenic drugs in patients. Availability of such markers will be instrumental to re-evaluate the role of tumor angiogenesis in human cancer, to identify new molecular targets and drugs, and to improve planning, monitoring and interpretation of future studies. Future anti-angiogenesis trials integrating biological endpoints and surrogate markers or angiogenesis will require close collaboration between clinical investigators and laboratory-based researchers.     

Observation versus intervention in the evaluation of drugs: the story of hormone replacement therapy

Hormone replacement therapy, which was approved for menopausal symptoms, offers an opportunity to compare clinical trials and observational studies when evaluating the risks and benefits of drugs. The differences between randomized and observational evidence relate mainly to the risks of coronary heart diseases and dementia, higher or not elevated in users in trials, and decreased in observational studies. The most likely explanation for these discrepancies is bad accounting for confounders, in particular, time-dependent confounders in classical multivariate analyses and use of prevalent user design. Marginal structural models and new user design should help to diminish strongly indication bias in future observational studies aiming at the evaluation of the risks and benefits of drugs.     

Early-phase clinical trials of anti-HIV Drugs——understanding and discussion

Innovative anti-HIV drugs developed by local sponsors in China have come into the stage of early-phase clinical trials. How to systemically design the clinical trials of innovative anti-HIV drugs still remains a challenge for them. This article references the literature and the experience of reviewers, to introduce general considerations concerning early-phase clinical trials of innovative anti-HIV drugs.     

Finding a chink in the armor: Update,limitations, and challenges toward successful antivirals against flaviviruses

Flaviviruses have caused large epidemics and ongoing outbreaks for centuries. They are now distributed in every continent infecting up to millions of people annually and may emerge to cause future epidemics. Some of the viruses from this group cause severe illnesses ranging from hemorrhagic to neurological manifestations. Despite decades of research, there are currently no approved antiviral drugs against flaviviruses, urging for new strategies and antiviral targets. In recent years, integrated omics data-based drug repurposing paired with novel drug validation methodologies and appropriate animal models has substantially aided in the discovery of new antiviral medicines. Here, we aim to review the latest progress in the development of both new and repurposed (i) direct-acting antivirals; (ii) host-targeting antivirals; and (iii) multitarget antivirals against flaviviruses, which have been evaluated both in vitro and in vivo, with an emphasis on their targets and mechanisms. The search yielded 37 compounds that have been evaluated for their efficacy against flaviviruses in animal models; 20 of them are repurposed drugs, and the majority of them exhibit broad-spectrum antiviral activity. The review also highlighted the major limitations and challenges faced in the current in vitro and in vivo evaluations that hamper the development of successful antiviral drugs for flaviviruses. We provided an analysis of what can be learned from some of the approved antiviral drugs as well as drugs that failed clinical trials. Potent in vitro and in vivo antiviral efficacy alone does not warrant successful antiviral drugs; current gaps in studies need to be addressed to improve efficacy and safety in clinical trials.     

药物基因组学在新药临床试验及个体化用药中的应用

药物安全性和有效性评价是药物临床试验和个体化用药的核心,也是药物基因组学研究的主要内容。药物基因组学研究贯穿于药物 研发、上市评价和临床应用整个过程, 根据药物代谢酶、转运体、受体相关基因多态性对用药者进行分层分析,评价与药物体内的处置过程、 安全性、有效性个体差异的相关性。综述药物基因组学在新药临床试验、个体化用药中的应用研究新进展。     

人类非洲锥虫病的治疗研究进展

人类非洲锥虫病是一种被忽视的热带寄生虫病,威胁着撒哈拉以南非洲人民的生命健康。目前临床使用的治疗药物有四种,这些药物副作用多,用药困难并产生了一定的耐药性,因此有必要开发安全有效且利于服用的药物。目前有三类候选药物相继进入临床实验阶段,在不久的将来可能会进入临床应用。另外,还有许多正在研究的治疗药物,包括天然产物、磷酸二酯酶抑制剂、蛋白酶抑制剂、拓扑异构酶抑制剂、亮氨酰t RNA合成酶抑制剂、微管蛋白抑制剂以及一些靶点尚不明确却有很好的锥虫抑制活性的化合物。其中,壳二孢呋喃酮选择性较好,喹啉-3-羧酸类衍生物毒性低,5-硝基-2-呋喃酰胺类化合物对硝呋莫司耐受的锥虫仍有活性。这些研究无疑都为新型抗锥虫药物的出现提供了可能,相信在不久的将来越来越多的药物会在临床使用。     

On-line control of atracurium induced muscle relaxation

We described recently a microcomputer system capable of controlling muscle relaxation during surgical procedures; the system was tested and evaluated in 42 clinical trials involving the use of the muscle relaxant, d-tubucurarine. The advent of new non-depolarizing neuromuscular blocking drugs with significant clinical advantages makes it essential that any automatic control system for muscle relaxation can also be used with such drugs, and benefit from their improved properties. This paper describes a series of 22 clinical trials in which our controller was used successfully to control muscle relaxation using atracurium. We also investigated an alternative control strategy, taking advantage of the rapid elimination of atracurium from the body.     

A surplus of positive trials: weighing biases and reconsidering equipoise

In this issue, Fries and Krishnan raise provocative new ideas to explain the surfeit of positive industry sponsored trials evaluating new drugs. They suggest that these trials were designed after so much preliminary work that they were bound to be positive (design bias) and that this violates clinical equipoise, which they characterize as an antiquated concept that should be replaced by a focus on subject autonomy in decision making and expected value for all treatments in a trial. We contend that publication bias, more than design bias, could account for the remarkably high prevalence of positive presented trials. Furthermore, even if all new drugs were efficacious, given the likelihood of type 2 errors, not all trials would be positive. We also suggest that clinical equipoise is a nuanced concept dependent on the existence of controversy about the relative value of two treatments being compared. If there were no controversy, then trials would be both unnecessary and unethical. The proposed idea of positive expected value is intriguing, but in the real world such clearly determinable values do not exist. Neither is it clear how investigators and sponsors, who are invested in the success of a proposed therapy, would (or whether they should) develop such a formula.     

2016 年 10 月美国和欧盟新批准药物概述

2016 年 10 月,美国和欧盟共批准 10 个新药,包括新分子实体、新有效成分、新生物制品、新增适应证及新剂型药物。对全球 首次获得批准的新分子实体、新有效成分、新生物制品进行分析,重点介绍这些药物的临床研究结果和研发历史进程。     

2015年10月美国、欧盟和日本新批准药物概

2015 年 10 月,美国、欧盟共批准 25 个新药,包括新分子实体、新有效成分、新生物制品、新增适应证及新剂型药物。对全球首 次获得批准的新分子实体、新有效成分、新生物制品进行分析,重点介绍这些药物的临床研究结果和研发历史进程。     

Recent advances in novel heterocyclic scaffolds for the treatment of drug-resistant malaria

Malaria is a major public health problem all over the world, particularly in tropical and subtropical countries due to the development of resistance and most deadly infection is caused by Plasmodium falciparum. There is a direct need for the discovery of new drugs with unique structures and mechanism of action to treat sensitive and drug-resistant strains of various plasmodia for radical cure of this disease. Traditional compounds such as quinine and related derivatives represent a major source for the development of new drugs. This review presents recent modifications of 4-aminoquinoline and 8-aminoquinolone rings as leads to novel active molecules which are under clinical trials. The review also encompasses the other heterocyclic compounds emerged as potential antimalarial agents with promising results such as acridinediones and acridinone analogues, pyridines and quinolones as antimalarials. Miscellaneous heterocyclics such as tetroxane derivatives, indole derivatives, imidazolopiperazine derivatives, biscationic choline-based compounds and polymer-linked combined antimalarial drugs are also discussed. At last brief introduction to heterocyclics in natural products is also reviewed. Most of them have been under clinical trials and found to be promising in the treatment of drug-resistant strains of Plasmodium and others can be explored for the same purpose.     

2017 年 1 月美国和欧盟新批准药物概述

2017 年 1 月,美国和欧盟共批准 20 个新药,包括新分子实体、新有效成分、新生物制品、新增适应证及新剂型药物。对全球 首次获得批准的新分子实体、新有效成分、新生物制品进行分析,重点介绍这些药物的临床研究结果和研发历史进程。     

Modeling and predicting clinical efficacy for drugs targeting the tumor milieu

Disappointing results from most late-stage clinical trials of cancer therapeutics indicate a need for improved and more-predictive animal tumor models. This insufficiency of models, combined with the advent of a class of drugs that target the tumor microenvironment rather than the tumor cell, presents new challenges for designing and interpreting preclinical efficacy studies. A comparison of the clinical efficacy of anti-angiogenic drugs with their corresponding preclinical studies over the past two decades offers many lessons that can inform and improve the design of experiments in existing mouse models. In addition, technological and logistical advances in mouse models of human cancer over the past five years have the potential to increase the clinical translatability of animal studies.     

Clinical trials with antiviral drugs against COVID-19: some progress and many shattered hopes

Vaccines and drugs are the cornerstones in the fight against the SARS-CoV-2 pandemic. While vaccines were a success story, the development of antiviral drugs against SARS-CoV-2 turned out to be difficult. For an accelerated use of antivirals in the clinic, most SARS-CoV-2 antivirals represented repurposed drugs. The present article summarizes the outcomes of clinical trials with antiviral drugs in COVID-19 patients. Many antiviral drugs failed to demonstrate beneficial effects or showed mixed results. One reason for the low success rate of clinical trials was shortcomings of antiviral tests in cell culture systems and another reason was the abundance of ill-coordinated and underpowered clinical trials. However, large pragmatic clinical trials particularly of the British RECOVERY trial series demonstrated that even under emergency situation drug trials can be conducted in a timely way such that the therapy of COVID-19 patients can be based on evidence basis instead on expert opinion or even worse on political pressure.     

基于控制模型的药物动力学静注问题的研究

在新药临床的研究中,以静脉注射方式给药时,药物进入全身循环快速分布到体内的各个组织,通过将机体作为单室模型对血药浓度进行控制,可以从血药浓度的变化得到组织药物水平的状态、本文针对药物动力学的特点,利用控制模型,给出了对其稳定性分析的方法．