[Problems and thoughts in clinical safety evaluation of traditional Chinese medicine].

Amid the modernization and internationalization of traditional Chinese medicine(TCM), the safety of TCM has attracted much attention. At the moment, the government, scientific research teams, and pharmaceutical enterprises have made great efforts to explore methods and techniques for clinical safety evaluation of TCM. Although considerable achievements have been made, there are still many problems, such as the non-standard terms of adverse reactions of TCM, unclear evaluation indicators, unreasonable judgment methods, lack of evaluation models, out-of-date evaluation standards, and unsound reporting systems. Therefore, it is urgent to further deepen the research mode and method of clinical safety evaluation of TCM. Based on the current national requirements for the life-cycle management of drugs, this study focused on the problems in the five dimensions of clinical safety evaluation of TCM, including normative terms, evaluation modes, judgment methods, evaluation standards, and reporting systems, and proposed suggestions on the development of a life-cycle clinical safety evaluation method that conformed to the characteristics of TCM, hoping to provide a reference for future research.

Assessing Transporter-Mediated Natural Product-Drug Interactions Via In vitro-In Vivo Extrapolation: Clinical Evaluation With a Probe Cocktail.

The botanical natural product goldenseal can precipitate clinical drug interactions by inhibiting cytochrome P450 (CYP) 3A and CYP2D6. Besides P-glycoprotein, effects of goldenseal on other clinically relevant transporters remain unknown. Established transporter-expressing cell systems were used to determine the inhibitory effects of a goldenseal extract, standardized to the major alkaloid berberine, on transporter activity. Using recommended basic models, the extract was predicted to inhibit the efflux transporter BCRP and uptake transporters OATP1B1/3. Using a cocktail approach, effects of the goldenseal product on BCRP, OATP1B1/3, OATs, OCTs, MATEs, and CYP3A were next evaluated in 16 healthy volunteers. As expected, goldenseal increased the area under the plasma concentration-time curve (AUC0-inf ) of midazolam (CYP3A; positive control), with a geometric mean ratio (GMR) (90% confidence interval (CI)) of 1.43 (1.35-1.53). However, goldenseal had no effects on the pharmacokinetics of rosuvastatin (BCRP and OATP1B1/3) and furosemide (OAT1/3); decreased metformin (OCT1/2, MATE1/2-K) AUC0-inf (GMR, 0.77 (0.71-0.83)); and had no effect on metformin half-life and renal clearance. Results indicated that goldenseal altered intestinal permeability, transport, and/or other processes involved in metformin absorption, which may have unfavorable effects on glucose control. Inconsistencies between model predictions and pharmacokinetic outcomes prompt further refinement of current basic models to include differential transporter expression in relevant organs and intestinal degradation/metabolism of the precipitant(s). Such refinement should improve in vitro-in vivo prediction accuracy, contributing to a standard approach for studying transporter-mediated natural product-drug interactions.

The traditional use of southern African medicinal plants in the treatment of viral respiratory diseases: A review of the ethnobotany and scientific evaluations.

ETHNOPHARMACOLOGICAL RELEVANCE: Viral respiratory infections are amongst the most common infections globally, with most of the world's population contracting at least one infection annually. Numerous plant species are used in traditional southern African healing systems to treat these diseases and to alleviate the symptoms. Despite this, the therapeutic potential of these plants against viral respiratory diseases remains poorly explored. AIM OF THE STUDY: The aim of this study was to document the southern African plant species used in traditional medicine to treat viral respiratory infections. We also examined the extent of scientific evaluations of southern African plant species against the respiratory-infective viruses, with the aim of stimulating interest in this area and focusing on future studies. MATERIALS AND METHODS: We undertook an extensive review of ethnobotanical books, reviews and primary scientific studies to identify southern African plants which are used in traditional southern African medicine to treat viral respiratory diseases. This information was used to identify gaps in the current research that require further study. RESULTS: Two hundred and fifty-seven southern African plant species were identified as traditional therapies for viral respiratory diseases. Surprisingly, only one of those species (as well as twenty-one other species not recorded for these purposes) has been evaluated for the ability to block respiratory virus production. Furthermore, most of these studies screened against a single viral strain and none of those studies examined the mechanism of action of the plant preparations. CONCLUSIONS: Despite well documented records of the use of southern African plants to treat respiratory viral diseases, the field is poorly explored. Nearly all of the plant species used in traditional healing systems to treat these diseases are yet to be tested. Substantial further work is required to verify the efficacy of these traditional medicines.

The traditional use of southern African medicinal plants for the treatment of bacterial respiratory diseases: A review of the ethnobotany and scientific evaluations.

ETHNOPHARMACOLOGICAL RELEVANCE: Multiple plant species were used traditionally in southern Africa to treat bacterial respiratory diseases. This review summarises this usage and highlights plant species that are yet to be verified for these activities. AIM OF THE STUDY: This manuscript reviews the traditional usage of southern African plant species to treat bacterial respiratory diseases with the aim of highlighting gaps in the literature and focusing future studies. MATERIALS AND METHODS: An extensive review of ethnobotanical books, reviews and primary scientific studies was undertaken to identify southern African plants which are used in traditional southern African medicine to treat bacterial respiratory diseases. We also searched for southern African plants whose inhibitory activity against bacterial respiratory pathogens has been conmfirmed, to highlight gaps in the literature and focus future studies. RESULTS: One hundred and eighty-seven southern African plant species are recorded as traditional therapies for bacterial respiratory infections. Scientific evaluations of 178 plant species were recorded, although only 42 of these were selected for screening on the basis of their ethnobotanical uses. Therefore, the potential of 146 species used teraditionally to treat bacterial respiratory diseases are yet to be verified. CONCLUSIONS: The inhibitory properties of southern African medicinal plants against bacterial respiratory pathogens is relatively poorly explored and the antibacterial activity of most plant species remains to be verified.

Bioengineering tools to speed up the discovery and preclinical testing of vaccines for SARS-CoV-2 and therapeutic agents for COVID-19.

This review provides an update for the international research community on the cell modeling tools that could accelerate the understanding of SARS-CoV-2 infection mechanisms and could thus speed up the development of vaccines and therapeutic agents against COVID-19. Many bioengineering groups are actively developing frontier tools that are capable of providing realistic three-dimensional (3D) models for biological research, including cell culture scaffolds, microfluidic chambers for the culture of tissue equivalents and organoids, and implantable windows for intravital imaging. Here, we review the most innovative study models based on these bioengineering tools in the context of virology and vaccinology. To make it easier for scientists working on SARS-CoV-2 to identify and apply specific tools, we discuss how they could accelerate the discovery and preclinical development of antiviral drugs and vaccines, compared to conventional models.

Pharmaceutical evaluation of Graphirine syrup formulated from some common indigenous herbs of Pakistan.

Since ancient times humans have relied on traditional medicine and herbal formulation for the cure of various diseases and disorders. Globally, interest in use of herbal medicine has increased; as drawbacks of modern medicine and have started getting more prominent. Most of the traditional system of medicine; all in their formulations depends on plants. Traditional herbal cough products have considered to be mild, nontoxic, non-sedative and even harmless. As Syrup is commonly taken for the relief of cough; we aimed to formulate a cough syrup (Graphirine) from some common indigenous herbs; Adhatoda vasica, Piper longum and Rosa Damasena and evaluate its physicochemical parameters along with the changes in accelerated stability testing. Preformulation studies, i.e. moisture content, ash, water and ethanol extractive values of all three herbs were defined. Physicochemical factors, quantitative spectral measurement, FTIR spectrum for identification of compounds; along with accelerated stability and possible microbial fungal growth; were also checked for the formulated syrup. Each and every parameter complied with the specifications.

Evaluation of anti-inflammatory and wound healing potential of tannins isolated from leaf callus cultures of Achyranthes aspera and Ocimum basilicum.

Herbal medicines are important in treatment of inflammation as they are safe and nontoxic. Tannins are important bioactive compounds used as anti-inflammatory agents and possess wound healing potential. Anti-inflammatory activity of tannins extracted from seedling leaf tissue and callus culture extracts of Achyranthes aspera L. and Ocimum basilicum L. were determined using Carrageenan induced paw edema model. Wound healing potential of tannins from callus cultures of leaf explants of both plants were evaluated using four models in rabbits i.e. excision, incision, dead space and burn wound. Group I acted as control, Group II treated with Povidone iodine as standard drug. Groups III and IV were experimental groups treated with creams which consisted of tannins of callus cultures of leaf; cream A (A. aspera) and cream O (O. basilicum). The results of anti-inflammatory activity of callus cultures of leaf explants were comparable with standard drug Indomethacin. Seedling leaf tissue and callus culture extracts of A. aspera and O. basilicum plant showed decrease in paw edema thickness, size and maximum percentage inhibition of paw edema respectively. Among four wound models burn wound showed the best wound contraction by Cream O. Hydroxyproline content and tensile strength of dead space and incision wounds exhibited good result also respectively. Cream O exhibited best results as compared to cream A. Histopathological examination showed that cream O showed faster rate of fibroblast and collagen formation as compared to cream A. The results showed that condensed tannins of callus cultures of leaf of A. aspera exhibited the best anti-inflammatory activity while tannins from callus cultures O. basilicum showed the best results for wound healing. These findings may enable use of both plants for formulation of new phytomedicine.

In vitro and in vivo characterization of pharmaceutical nanocarriers used for drug delivery.

Nanotechnology has emerged strongly in most of the field of sciences at a tiny scale. At this size, atoms and molecules work differently and present a diversity of amazing and appealing applications. Pharmaceutical nanocarriers comprise nanoparticles, nanospheres, nanocapsules, nanoemulsion, nanoliposomes and nanoniosomes. The major objectives in designing nanocarriers are to manage particle size, surface properties as well as drug release in order to fulfil specific objectives. Hence, characterizations of nanocarriers are very critical to control their desired in vitro and in vivo behaviour. Nanocarriers are characterized by their size, morphology and surface charge, using highly advanced microscopic techniques as scanning electron microscopy, transmission electron microscopy and atomic force microscopy. Surface morphology and size are measured by electron microscopy while dynamic light scattering and photon-correlation spectroscopy are used to determine the particle size and size distribution. Colloidal stability is ascertained through zeta potential which is an indirect measure of the surface charge and differential scanning calorimetry is used to characterize particles and drug interaction. Further, binding and internalization of targeted carriers to the specific cells could be determined by cell uptake study. Biodistribution study of targeted nanocarriers is carried out and intracellular uptake and subcellular localization of the nanocarrier could be confirmed using confocal microscopy. This review covers all the aforementioned aspect related to in vitro and in vivo characterization of pharmaceutical nanocarriers.

Japan-Specific Key Regulatory Aspects for Development of New Biopharmaceutical Drug Products.

Japan represents the third largest pharmaceutical market in the world. Developing a new biopharmaceutical drug product for the Japanese market is a top business priority for global pharmaceutical companies while aligning with ethical drivers to treat more patients in need. Understanding Japan-specific key regulatory requirements is essential to achieve successful approvals. Understanding the full context of Japan-specific regulatory requirements/expectations is challenging to global pharmaceutical companies due to differences in language and culture. This article summarizes key Japan-specific regulatory aspects/requirements/expectations applicable to new drug development, approval, and postapproval phases. Formulation excipients should meet Japan compendial requirements with respect to the type of excipient, excipient grade, and excipient concentration. Preclinical safety assessments needed to support clinical phases I, II, and III development are summarized. Japanese regulatory authorities have taken appropriate steps to consider foreign clinical data, thereby enabling accelerated drug development and approval in Japan. Other important topics summarized in this article include: Japan new drug application-specific bracketing strategies for critical and noncritical aspects of the manufacturing process, regulatory requirements related to stability studies, release specifications and testing methods, standard processes involved in pre and postapproval inspections, management of postapproval changes, and Japan regulatory authority's consultation services available to global pharmaceutical companies.

Evaluating the abuse potential of psychedelic drugs as part of the safety pharmacology assessment for medical use in humans.

Psychedelics comprise drugs come from various pharmacological classes including 5-HT2A agonists, indirect 5-HT agonists, e.g., MDMA, NMDA antagonists and κ-opioid receptor agonists. There is resurgence in developing psychedelics to treat psychiatric disorders with high unmet clinical need. Many, but not all, psychedelics are schedule 1 controlled drugs (CDs), i.e., no approved medical use. For existing psychedelics in development, regulatory approval will require a move from schedule 1 to a CD schedule for drugs with medical use, i.e., schedules 2-5. Although abuse of the psychedelics is well documented, a systematic preclinical and clinical evaluation of the risks they pose in a medical-use setting does not exist. We describe the non-clinical tests required for a regulatory evaluation of abuse/dependence risks, i.e., drug-discrimination, intravenous self-administration and physical dependence liability. A synopsis of the existing data for the various types of psychedelics is provided and we describe our findings with psychedelic drugs in these models. FDA recently issued its guidance on abuse/dependence evaluation of drug-candidates (CDER/FDA, 2017). We critically review the guidance, discuss the impact this document will have on non-clinical abuse/dependence testing, and offer advice on how non-clinical abuse/dependence experiments can be designed to meet not only the expectations of FDA, but also other regulatory agencies. Finally, we offer views on how these non-clinical tests can be refined to provide more meaningful information to aid the assessment of the risks posed by CNS drug-candidates for abuse and physical dependence. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

The safety assessment of herbals with a new and ethical approach.

The increasing use of plant medicines (herbals) in Europe needs a shared methodology to determine the toxicity and the daily exposure level to these drugs. For this reason, the European regulatory agencies have undertaken a study that could meet popular uses and toxicological research in different countries of the Union. Here we list some examples of the most used herbal drug classes and we propose a decision-making process based on their characteristics, their content in active principles and on the basis of the present scientific pharmacological and toxicological literature. The proposed decision tree actually makes easier for the assessor to quickly and accurately evaluate the accredited indexes for risk and toxicity assessment based on the preclinical literature data and using the correct classification that some of them may have because they are already present in medicinal products or used as food.

Vedolizumab en Enfermedad de Crohn; Informe de evaluación GENESIS-SEFH / Vedolizumab in Crohn Disease genesis-sefh drug evaluation report

No disponible

[Overview of traditional Chinese medicine quality evaluation method based on overall research].

The establishment of quality evaluation of traditional Chinese medicine system that not only accords with Chinese medicine function characteristics but also is recognized as international medical circles, is an arduous task in urgent need of solving the current modernization of traditional Chinese medicine in the process of internationalization. It is difficult to evaluate atraditional Chinese medicine by detection of single active components in traditional Chinesemedicinewiththe western medicine quality controlmethod due to the overall effects of traditional Chinese drugs, the components of the overall diversity, targets, and the complexity of the interaction between components of unpredictable make the Long-term since, domestic and foreign scholars continue to explore and put forward a series of quality evaluation of traditional Chinese medicine to promote the development of traditional Chinese medicine. This article summarized the related academic ideas and developments to, providea new thought and perspective for the quality control of traditional Chinese medicine.

[Controllability pyramid: an integrated control system of quality for traditional Chinese medicines].

Quality control is one of the key scientific tissues in the modernization of traditional Chinese medicines (TCM). In order to overcome the deficiencies of assessment indexes, including little systematization and quantification, as well as loose association with clinical efficacy and dosage, a new integrated method named controllability pyramid ( CP) is first proposed in this paper. In addition, some study cases are used to explain how this model is constructed. We hope the establishment of CP could promote the clinical-orien- ted integrated innovation research of TCM, and provide control strategy and technology examples for improving the quality of Chinese medicines and clinical efficacy.

[Methodology for systematic analysis of in vivo efficacy material base of traditional Chinese medicine--Chinmedomics].

The efficacy material base of traditional Chinese medicines (TCMs) is those constituents absorbed in blood and show the efficacy of TCMs after oral administration of a TCM formula. In TCM, formula consisted of more than one herbal drug is the clinical medication form which corresponding to TCM syndrome. The efficacy material base of TCMs had to be found in the condition of compatibility and efficacy of TCM formula. Therefore we take the biological characters of TCM syndrome as a research starting point, taking formula as object, through the integration of serum pharmacochemistry of TCM methods and metabolomics technologies, establish a system research methodology of the efficacy material basis in vivo--Chinmedomics. The use of metabolomics technology is used to fully understand nature biology on syndromes or disease, identify biomarkers for disease to bridging disease animal model, establishing the biological evaluation system of traditional Chinese medicine. On the basis of the validity of the premise, the use of serum pharmacochemistry of TCM to analysis in vivo directly substance after oral prescription and dynamic law, combined with changes law of the endogenous disease biomarkers (pharmacodynamic markers of TCM), Though establishing two variable correlation analysis method between Chinese chemical compositions in serum exogenous and endogenous biomarkers, to extract TCM compositions highly correlated with the endogenous marker as potential basis for traditional Chinese medicines, and to biological validation to determine the efficacy material basis of TCM.

[Study on methodology for evaluating clinical efficacy of traditional Tibetan medicine].

The evaluation on clinical efficacy of traditional Tibetan medicine (TTM) is an important scientific subject during the development of TTM. Firstly, the authors introduced the current situations and problems in evaluation on clinical efficacy of traditional Tibetan medicine both at home and abroad in this study. Secondly, they compared the similarities and differences between TTM and traditional Chinese medicine (TCM) in evaluation on clinical efficacy, define their differences in details but not in nature, and proposed that TTM could selectively learn TCM's experiences in clinical research and build a specific methodology system for evaluation on clinical efficacy according to its own characteristics. Thirdly, they discussed the methodological challenges in evaluation on clinical efficacy of TTM, including the pending clinical research guidelines and disease diagnosis standards according to its own characteristics. Finally, they propound some suggestions for promoting the evaluation on clinical efficacy of TTM, including the comprehensive application of multiple research methods, overall research-based evaluation on efficacy of TTM complex intervention and selection of accepted and objective outcome indexes for efficacy evaluation.

The use of adjunctive traditional Chinese medicine therapy and survival outcome in patients with head and neck cancer: a nationwide population-based cohort study.

BACKGROUND: Traditional Chinese medicine (TCM) is widely used in the treatment of patients with several types of cancer. However, no large-scale clinical studies have evaluated whether TCM is associated with better survival in patients with head and neck cancer (HNC). METHODS: The Taiwan National Health Insurance Research Database was used to conduct a retrospective cohort study of patients with HNC between 2001 and 2011. The patients with HNC were separated into TCM users and non-users, and Cox regression models were applied to determine the association between the use of TCM and survival outcome. RESULTS: The TCM and comparison cohorts comprised data for 2966 and 2670 patients, respectively. The mean age was 51.3 years in the TCM cohort and 51.7 years in the comparison cohort. Multivariate analysis demonstrated that the use of TCM was significantly associated with lower risk of all-cause mortality by 32% (adjusted hazard ratio, 0.68; 95% confidence interval, 0.62-0.75). Patients with longer TCM use had a lower mortality rate (P for trend < 0.001). CONCLUSIONS: Our study showed that adjunctive therapy with TCM is associated with higher survival outcome. However, some limitations exist, such as the lack of information of cancer stage. In addition, causality cannot be assessed with this retrospective study. A randomized controlled trial to test the effect of adjunctive TCM therapy in HNC patients is needed.