Pharmacological Actions, Molecular Mechanisms, Pharmacokinetic Progressions, and Clinical Applications of Hydroxysafflor Yellow A in Antidiabetic Research.

Hydroxysafflor yellow A (HSYA), a nutraceutical compound derived from safflower (Carthamus tinctorius), has been shown as an effective therapeutic agent in cardiovascular diseases, cancer, and diabetes. Our previous study showed that the effect of HSYA on high-glucose-induced podocyte injury is related to its anti-inflammatory activities via macrophage polarization. Based on the information provided on PubMed, Scopus and Wanfang database, we currently aim to provide an updated overview of the role of HSYA in antidiabetic research from the following points: pharmacological actions, molecular mechanisms, pharmacokinetic progressions, and clinical applications. The pharmacokinetic research of HSYA has laid foundations for the clinical applications of HSYA injection in diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy. The application of HSYA as an antidiabetic oral medicament has been investigated based on its recent oral delivery system research. In vivo and in vitro pharmacological research indicated that the antidiabetic activities of HSYA were based mainly on its antioxidant and anti-inflammatory mechanisms via JNK/c-jun pathway, NOX4 pathway, and macrophage differentiation. Further anti-inflammatory exploration related to NF-κB signaling, MAPK pathway, and PI3K/Akt/mTOR pathway might deserve attention in the future. The anti-inflammatory activities of HSYA related to diabetes and diabetic complications will be a highlight in our following research.

Cannabinoid Formulations and Delivery Systems: Current and Future Options to Treat Pain.

The field of Cannabis sativa L. research for medical purposes has been rapidly advancing in recent decades and a growing body of evidence suggests that phytocannabinoids are beneficial for a range of conditions. At the same time impressing development has been observed for formulations and delivery systems expanding the potential use of cannabinoids as an effective medical therapy. The objective of this review is to present the most recent results from pharmaceutical companies and research groups investigating methods to improve cannabinoid bioavailability and to clearly establish its therapeutic efficacy, dose ranges, safety and also improve the patient compliance. Particular focus is the application of cannabinoids in pain treatment, describing the principal cannabinoids employed, the most promising delivery systems for each administration routes and updating the clinical evaluations. To offer the reader a wider view, this review discusses the formulation starting from galenic preparation up to nanotechnology approaches, showing advantages, limits, requirements needed. Furthermore, the most recent clinical data and meta-analysis for cannabinoids used in different pain management are summarized, evaluating their real effectiveness, in order also to spare opioids and improve patients' quality of life. Promising evidence for pain treatments and for other important pathologies are also reviewed as likely future directions for cannabinoids formulations.

Pathogenesis of Keratinocyte Carcinomas and the Therapeutic Potential of Medicinal Plants and Phytochemicals.

Keratinocyte carcinoma (KC) is a form of skin cancer that develops in keratinocytes, which are the predominant cells present in the epidermis layer of the skin. Keratinocyte carcinoma comprises two sub-types, namely basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). This review provides a holistic literature assessment of the origin, diagnosis methods, contributing factors, and current topical treatments of KC. Additionally, it explores the increase in KC cases that occurred globally over the past ten years. One of the principal concepts highlighted in this article is the adverse effects linked to conventional treatment methods of KC and how novel treatment strategies that combine phytochemistry and transdermal drug delivery systems offer an alternative approach for treatment. However, more in vitro and in vivo studies are required to fully assess the efficacy, mechanism of action, and safety profile of these phytochemical based transdermal chemotherapeutics.

Vitamin C in the Treatment of COVID-19.

Vitamin C is an essential nutrient that serves as antioxidant and plays a major role as co-factor and modulator of various pathways of the immune system. Its therapeutic effect during infections has been a matter of debate, with conflicting results in studies of respiratory infections and in critically ill patients. This comprehensive review aimed to summarize the current evidence regarding the use of vitamin C in the prevention or treatment of patients with SARS-CoV2 infection, based on available publications between January 2020 and February 2021. Overall, 21 publications were included in this review, consisting of case-reports and case-series, observational studies, and some clinical trials. In many of the publications, data were incomplete, and in most clinical trials the results are still pending. No studies regarding prevention of COVID-19 with vitamin C supplementation were found. Although some clinical observations reported improved medical condition of patients with COVID-19 treated with vitamin C, available data from controlled studies are scarce and inconclusive. Based on the theoretical background presented in this article, and some preliminary encouraging studies, the role of vitamin C in the treatment of patients with SARS-CoV-2 infection should be further investigated.

Egg nutritional modulation with amino acids improved performance in zebrafish larvae.

New and more efficient methods to sustainably intensify Aquaculture production are essential to attain the seafood demand for direct human consumption in the near future. Nutrition has been identified as one strategy of early exposure that might affect animal early development and later phenotype. This strategy may have positive consequences in the modulation of fish digestive physiology, which will correlate with higher performance outputs. Thus, improving fish digestive efficiency will lead to higher productivity and lower biogenic emission from aquaculture facilities, minimising the impact on the environment while increasing the biological efficiency. An innovative in ovo nutritional modulation technique based on low-frequency ultrasounds was used to enhance the transport of amino acids across the embryo membranes. An early stimulus with either arginine or glutamine, both involved in gut maturation, was applied in zebrafish (Danio rerio) embryos at 3.5 hours post-fertilization (hpf). At 22 days post-fertilization (dpf), growth performance, digestive enzyme activities and gut microbiota composition were analysed to evaluate the larval nutrition-induced metabolic plasticity and the effects on fish digestive efficiency. Results showed that fish survival was not affected either by the sonophoresis technique or amino acid supplementation. Final dry weight at 22 dpf was statistically higher in larvae from glutamine treatment when compared to the control even with lower trypsin activity, suggesting a higher nutrient digestion capacity, due to a slightly modulation of gut microbiota. Higher arginine supplementation levels should be tested as strategy to enhance growth at later developmental stages. In conclusion, this study demonstrated the efficiency of sonophoresis technique for in ovo nutritional modulation and suggests that in ovo glutamine supplementation might promote growth at later developmental stage through a positive microbiota modulation.

Cannabis and Migraine: It's Complicated.

PURPOSE OF REVIEW: The use of cannabis for the treatment of migraine has become an area of interest with the legalization of medical cannabis in the USA. Understanding the mechanisms of cannabinoids, available studies, and best clinical recommendations is crucial for headache providers to best serve patients. RECENT FINDINGS: Patients utilizing medical cannabis for migraine have reported improvement in migraine profile and common comorbidities. Reduction in prescription medication is also common, especially opioids. Side effects exist, with the majority being mild. Not enough data is available for specific dose recommendations, but THC and CBD appear to mediate these observed effects. The purpose of this article is twofold: review the limited research surrounding cannabis for migraine disease and reflect on clinical management experiences to provide recommendations that best capture the potential use of cannabis for migraine.

Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders.

The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD displays an interesting pharmacological profile without the potential for becoming a drug of abuse, unlike THC. In this review, we focused on the anxiolytic, antidepressant, and antipsychotic effects of CBD found in animal and human studies. In rodents, results suggest that the effects of CBD depend on the dose, the strain, the administration time course (acute vs. chronic), and the route of administration. In addition, certain key targets have been related with these CBD pharmacological actions, including cannabinoid receptors (CB1r and CB2r), 5-HT1A receptor and neurogenesis factors. Preliminary clinical trials also support the efficacy of CBD as an anxiolytic, antipsychotic, and antidepressant, and more importantly, a positive risk-benefit profile. These promising results support the development of large-scale studies to further evaluate CBD as a potential new drug for the treatment of these psychiatric disorders.

Use of cannabidiol (CBD) for the treatment of chronic pain.

Chronic pain can be recurrent or constant pain that lasts for longer than 3 months and can result in disability, suffering, and a physical disturbance. Related to the complex nature of chronic pain, treatments have a pharmacological and non-pharmacological approach. Due to the opioid epidemic, alternative therapies have been introduced, and components of the plant Cannabis Sativa, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have gained recent interest as a choice of treatment. The exact mechanism for CBD is currently unknown, but unlike the CBD's psychoactive counterpart, THC, the side effects of CBD itself have been shown to be overall much more benign. The current pharmaceutical products for the treatment of chronic pain are known as nabiximols, and they contain a ratio of THC combined with CBD, which has been promising. This review focuses on the treatment efficacy of CBD, THC: CBD-based treatments for chronic pain and adverse events with each.

Bioavailability Based on the Gut Microbiota: a New Perspective.

The substantial discrepancy between the strong effects of functional foods and various drugs, especially traditional Chinese medicines (TCMs), and the poor bioavailability of these substances remains a perplexing problem. Understanding the gut microbiota, which acts as an effective bioreactor in the human intestinal tract, provides an opportunity for the redefinition of bioavailability. Here, we discuss four different pathways associated with the role of the gut microbiota in the transformation of parent compounds to beneficial or detrimental small molecules, which can enter the body's circulatory system and be available to target cells, tissues, and organs. We further describe and propose effective strategies for improving bioavailability and alleviating side effects with the help of the gut microbiota. This review also broadens our perspectives for the discovery of new medicinal components.

Optimization of an Experimental Vaccine To Prevent Escherichia coli Urinary Tract Infection.

Urinary tract infections (UTI) affect half of all women at least once during their lifetime. The rise in the numbers of extended-spectrum beta-lactamase-producing strains and the potential for carbapenem resistance within uropathogenic Escherichia coli (UPEC), the most common causative agent of UTI, create an urgent need for vaccine development. Intranasal immunization of mice with UPEC outer membrane iron receptors FyuA, Hma, IreA, and IutA, conjugated to cholera toxin, provides protection in the bladder or kidneys under conditions of challenge with UPEC strain CFT073 or strain 536. On the basis of these data, we sought to optimize the vaccination route (intramuscular, intranasal, or subcutaneous) in combination with adjuvants suitable for human use, including aluminum hydroxide gel (alum), monophosphoryl lipid A (MPLA), unmethylated CpG synthetic oligodeoxynucleotides (CpG), polyinosinic:polycytidylic acid (polyIC), and mutated heat-labile E. coli enterotoxin (dmLT). Mice intranasally vaccinated with dmLT-IutA and dmLT-Hma displayed significant reductions in bladder colonization (86-fold and 32-fold, respectively), with 40% to 42% of mice having no detectable CFU. Intranasal vaccination of mice with CpG-IutA and polyIC-IutA significantly reduced kidney colonization (131-fold) and urine CFU (22-fold), respectively. dmLT generated the most consistently robust antibody response in intranasally immunized mice, while MPLA and alum produced greater concentrations of antigen-specific serum IgG with intramuscular immunization. On the basis of these results, we conclude that intranasal administration of Hma or IutA formulated with dmLT adjuvant provides the greatest protection from UPEC UTI. This report advances our progress toward a vaccine against uncomplicated UTI, which will significantly improve the quality of life for women burdened by recurrent UTI and enable better antibiotic stewardship.IMPORTANCE Urinary tract infections (UTI) are among the most common bacterial infection in humans, affecting half of all women at least once during their lifetimes. The rise in antibiotic resistance and health care costs emphasizes the need to develop a vaccine against the most common UTI pathogen, Escherichia coli Vaccinating mice intranasally with a detoxified heat-labile enterotoxin and two surface-exposed receptors, Hma or IutA, significantly reduced bacterial burden in the bladder. This work highlights progress in the development of a UTI vaccine formulated with adjuvants suitable for human use and antigens that encode outer membrane iron receptors required for infection in the iron-limited urinary tract.

Efficacy of Vitamin D3 Buccal Spray Supplementation Compared to Other Delivery Methods: A Systematic Review of Superiority Randomized Controlled Trials.

(1) Background: Vitamin D deficiency is an important public health concern and supplementation is common for this deficiency. Many different modes of delivering supplementation have been proposed in order to enhance absorption and utilization. The present review compared the efficacy of vitamin D3 buccal spray against other forms of supplementation delivery. (2) Methods: The protocol was registered at PROSPERO (CRD42019136146). Medline/PubMed, CENTRAL and clinicaltrials.gov were searched from their inception until September 2019, for randomized controlled trials (RCTs) that compare vitamin D3 delivery via sublingual spray against other delivery methods. Eligible RCTs involved humans, of any age and health status, published in any language that evaluated changes in plasma 25(OH)D concentrations. Three reviewers independently extracted data, assessed risk of bias (RoB) and the quality of the trials. (3) Results: Out of 9759 RCTs, four matched the predefined criteria. Intervention duration ranged from 30 days to 3 months whereas vitamin D3 dosage ranged between 800 and 3000 IU/day. One RCT advocated for the superiority of buccal spray in increasing plasma 25(OH)D concentrations, although several limitations were recorded in that trial. The rest failed to report differences in post-intervention 25(OH)D concentrations between delivery methods. Considerable clinical heterogeneity was observed due to study design, intervention duration and dosage, assays and labs used to perform the assays, population age and health status, not allowing for synthesis of the results. (4) Conclusions: Based on the available evidence, delivery of vitamin D3 via buccal spray does not appear superior to the other modes of delivery. Future RCTs avoiding the existing methodological shortcomings are warranted.

Tetrahydrocannabinol and Cannabidiol Use in an Outpatient Palliative Medicine Population.

BACKGROUND: Palliative medicine physicians are challenged by lack of guidance regarding effectiveness and dosing of cannabis products in the setting of their emerging popularity. OBJECTIVE: The aim of this study was to describe early patterns of tetrahydrocannabinol (THC) and cannabidiol (CBD) use in Florida following passage of the state's first medical marijuana law. We describe here the perceived benefits, side effects, and beliefs expressed by patients in a single outpatient academic palliative medicine practice. METHODS: A cross-sectional survey was performed of a sequential convenience sample of patients who presented to an outpatient academic palliative medicine clinic over a 3-month period. RESULTS: In all, 24% (14/58) of respondents reported THC use, with half using THC on a daily basis. Patients reported improvements in pain, appetite, and nausea. In all, 71% (10/14) began using THC after the diagnosis of their chronic illness, and the most common form of usage was vaping. In all, 24% (14/58) of patients reported CBD use. Patients reported improvements in pain, and the most common form of usage was topical application. None of the patients had used CBD prior to the onset of their chronic illness. In all, 21% (3/14) of THC users and 21% (3/14) of CBD users thought that their substance was helping to cure their illness. Individual reported side effects in both groups were minimal. CONCLUSIONS: Approximately a quarter of outpatient palliative care patients use THC or CBD, often on a daily basis. Palliative care providers should be aware of the frequency, diverse usage, and beliefs behind cannabis product use in this patient population.

Using Therapeutic Drug Monitoring and Pharmacovigilance to Overcome Some of the Challenges of Developing Medicinal Cannabis from Botanical Origins.

PURPOSE: Plants belonging to the genus Cannabis have been domesticated and used by humans for millennia. Thought to have originated from central Asia, cannabis has been harnessed for its nutritional, therapeutic, and psychoactive properties, and as a source of fiber (Office of Medicinal Cannabis. Analytical Monograph Cannabis Flos. Den Haag, The Netherlands: Office of Medicinal Cannabis; 2014). Human use of cannabis is not novel; however, its medicalization offers a new pharmacotherapeutic frontier. METHODS: The authors recently reported a systematic review of the contaminants of cannabis (National Academies of Sciences Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. Washington, DC; 2017). This article draws on the research limitations identified by that review and examines a collection of the relevant literature to provide an appreciation of the current evidence base. RESULTS: The review explores the current status of cannabis in medical use, the drug development aspects that apply when taking a plant through to pill development, and the roles that therapeutic drug monitoring and pharmacovigilance have to guide practice until the drug development information on medicinal cannabis preparations is complete. CONCLUSIONS: A surge of public and clinical interest in the possible therapeutic applications of constituent cannabinoids has potentiated global legislative and policy reform. However, our understanding of its properties, optimized use, and harmful effects remains incomplete (Therapeutic Goods Administration. Guidance for the use of medicinal cannabis in Australia In: Department of Health Department, editor. Woden ACT Australian Government 2017; Dryburgh LM, Bolan NS, Grof CP, Galettis P, Schneider J, Lucas CJ, et al. Cannabis contaminants: sources, distribution, human toxicity and pharmacologic effects. Brit J Clin Pharm. 2018;84(11):2468-2476). In particular, a comprehensive appreciation of its toxicity profile is lacking.

Leading RNA Interference Therapeutics Part 1: Silencing Hereditary Transthyretin Amyloidosis, with a Focus on Patisiran.

In 2018, patisiran was the first-ever RNA interference (RNAi)-based drug approved by the US Food and Drug Administration. Now pharmacology textbooks may include a new drug class that results in the effect first described by Fire and Mello 2 decades ago: post-transcriptional gene silencing by a small-interfering RNA (siRNA). Patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) present with mutations in the transthyretin (TTR) gene that lead to the formation of amyloid deposits in peripheral nerves and heart. The disease may also affect the eye and central nervous system. The formulation of patisiran comprises the RNAi drug encapsulated into a nanoparticle especially developed to deliver the anti-TTR siRNA into the main TTR producer: the liver. Hepatic cells contain apolipoprotein E receptors that recognize ApoE proteins opsonized in the lipid carrier and internalize the drug by endocytosis. Lipid vesicles are disrupted in the cell cytoplasm, and siRNAs are free to trigger the RNAi-based TTR gene silencing. The silencing process involves the binding of siRNA guide strand to 3'-untranslated region sequence of both mutant and wild-type TTR messenger RNA, which culminates in the TTR mRNA cleavage by the RNA-induced silencing complex (RISC) as the first biochemical drug effect. Patisiran 0.3 mg/kg is administered intravenously every 3 weeks. Patients require premedication with anti-inflammatory drugs and antagonists of histamine H1 and H2 receptors to prevent infusion-related reactions and may require vitamin A supplementation. Following patisiran treatment, TTR knockdown remained stable for at least 2 years. Adverse effects were mild to moderate with unchanged hematological, renal, or hepatic parameters. No drug-related severe adverse effects occurred in a 24-month follow-up phase II open-label extension study. At the recommended dosage of patisiran, Cmax and AUC values (mean ± standard deviation) were 7.15 ± 2.14 µg/mL and 184 ± 159 µg·h/mL, respectively. The drug showed stability in circulation with > 95% encapsulated in lipid particles. Metabolization occurred by ribonuclease enzymes, with less than 1% excreted unchanged in the urine. Patisiran ameliorated neuropathy impairment according to the modified Neuropathy Impairment Score + 7 analysis of the phase III study. The Norfolk Quality of Life-Diabetic Neuropathy score and gait speed improved in 51% of the patisiran-treated group in 18 months. Additionally, the modified body mass index showed positive outcomes. Altogether, the data across phase I-III clinical trials points to patisiran as an effective and safe drug for the treatment of hATTR amyloidosis. It is hoped that real-world data from a larger number of patients treated with patisiran will confirm the effectiveness of this first-approved siRNA-based drug.

Effects of abomasal infusion of essential fatty acids and conjugated linoleic acid on performance and fatty acid, antioxidative, and inflammatory status in dairy cows.

The objective of this study was to test the effects of essential fatty acids (EFA), particularly α-linolenic acid, and conjugated linoleic acid (CLA) supplementation on fatty acid (FA) composition, performance, and systemic and hepatic antioxidative and inflammatory responses in dairy cows. Four cows (126 ± 4 d in milk) were investigated in a 4 × 4 Latin square and were abomasally infused with 1 of the following for 6 wk: (1) coconut oil (control treatment, CTRL; 38.3 g/d; providing saturated FA), (2) linseed and safflower oil (EFA treatment; 39.1 and 1.6 g/d, respectively; providing mainly α-linolenic acid), (3) Lutalin (BASF, Ludwigshafen, Germany; CLA treatment; cis-9,trans-11 and trans-10,cis-12 CLA, 4.6 g/d each), (4) or EFA+CLA. The initial dosage was doubled every 2 wk, resulting in 3 dosages (dosage 1, 2, and 3). Cows were fed a corn silage-based total mixed ration with a high n-6/n-3 FA ratio. Dry matter intake and milk yield were recorded daily, and milk composition was measured weekly. The FA compositions of milk fat and blood plasma were analyzed at wk 0, 2, 4, and 6. The plasma concentration and hepatic mRNA abundance of parameters linked to the antioxidative and inflammatory response were analyzed at wk 0 and 6 of each treatment period. Infused FA increased in blood plasma and milk of the respective treatment groups in a dose-dependent manner. The n-6/n-3 FA ratio in milk fat was higher in CTRL and CLA than in EFA and EFA+CLA. The sum of FA

Medical cannabis for inflammatory bowel disease: real-life experience of mode of consumption and assessment of side-effects.

OBJECTIVE: Use of medical cannabis for improving symptoms of inflammatory bowel disease is increasing. However, reports on long-term outcomes are lacking. This prospective, observational study assessed the effects of licensed cannabis use among patients with inflammatory bowel disease. METHODS: Dose and mode of consumption, adverse events, use of other medications, and long-term effects were evaluated among 127 patients with inflammatory bowel disease using legalized medical cannabis. Blood count, albumin, and C-reactive protein were assessed before, 1 month, and at least 1 year after medical cannabis therapy was initiated. Questionnaires on disease activity, patient function, and signs of addiction were completed by patients and by a significant family member to assess its effects. RESULTS: The average dose used was 31 ± 15 g/month. The average Harvey-Bradshaw index improved from 14 ± 6.7 to 7 ± 4.7 (P < 0.001) during a median follow-up of 44 months (interquartile range, 24-56 months). There was a slight, but statistically significant, average weight gain of 2 kg within 1 year of cannabis use. The need for other medications was significantly reduced. Employment among patients increased from 65 to 74% (P < 0.05). We conclude that the majority of inflammatory bowel disease patients using cannabis are satisfied with a dose of 30 g/month. We did not observe negative effects of cannabis use on the patients' social or occupational status. CONCLUSIONS: Cannabis use by inflammatory bowel disease patients can induce clinical improvement and is associated with reduced use of medication and slight weight gain. Most patients respond well to a dose of 30 g/month, or 21 mg Δ9-tetra- hydrocannabinol (THC) and 170 mg Cannabidiol (CBD) per day.

Role of kaempferol to increase bioavailability and pharmacokinetics of nifedipine in rats.

Herein, the purpose of this study is to evaluate the effects of kaempferol on bioavailability and pharmacokinetics of nifedipine and its metabolite dehydronifedipine in rats. The experimental design is based on with or without kaempferol in the oral and intravenous administration of nifedipine in rats. Moreover, the pharmacokinetic parameters including nifedipine and dehydronifedipine were evaluated in rats.The in vitro studies ofkaempferol were investigated on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity. Kaempferol reduced a 50% inhibitory concentration (IC50) of 8.6 µmol·L-1 on CYP3A4 enzyme activity. Moreover, kaempferol clearly improved the cell internalization of rhodamine-123 in MCF-7/ADR cells overexpressing P-gp. Depending on increased concentrations of kaempferol, the areas under the plasma concentration-time curve (AUC0-∞) and the peak concentration (Cmax) of nifedipine were increased after oral and intravenous administration. Moreover, the absolute bioavailability (AB) and relative bioavailability (RB) of nifedipine in the presence of kaempferol was significantly higher than those of the control group after oral and intravenous administration. Improvement of bioavailability of nifedipine by kaempferol may be mainly because of the inhibition of the P-gp-mediated efflux transporter in the small intestine and CYP3A4-mediated metabolism in the small intestine or liver, or both.

An update on the animal studies conducted for biosimilar approvals - Regulatory requirement vs actual scenario.

Nonclinical animal studies are considered as an integral part of biosimilar development program to demonstrate similarity and safety. We have compiled, reviewed and summarized animal studies conducted for European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA) submission from 2006 till December 2018. The commonest animal studies conducted included repeat-dose toxicity study along with toxicokinetic, local tolerance and immunogenicity assessments, while the least common included primary pharmacodynamic, pharmacokinetic, safety pharmacology and single-dose toxicity studies. Animal studies were designed based on pharmacology of the drug, disease condition and innovator studies. Studies mostly used EU-sourced reference products as a comparator. For biosimilars approved both in the US and European Union (EU), similar data packages were submitted to these regions. Despite the regulatory guidelines allowing waiver of animal studies based on analytical data, animal studies have been conducted for almost all the approved biosimilars in the US and EU. There is an increasing need to re-assess the relevance of animal studies to support regulatory approval of biosimilars. Stepwise assessment for biosimilarity and conducting animal studies only if required at the right instance based on residual uncertainties may assist in optimizing animal study requirement for biosimilar development.

The Effect of Vitamin C (Ascorbic Acid) in the Treatment of Patients with Cancer: A Systematic Review.

Many cancer patients on intensive chemotherapy lack vitamin C. Vitamin C stimulates the production and activation of immune cells, so perhaps supplementation could be used to improve the immunity in those patients. This review assesses the effectiveness and safety of vitamin C administration in cancer. The PubMed and EMBASE databases were searched and all study designs except for phase I studies, and case reports were included in this review. A total of 19 trials were included. In only 4 trials randomization was used to determine if patients received vitamin C or a placebo. The result of this review does not prove that there is a clinically relevant positive effect of vitamin C supplementation in cancer patients in general on the overall survival, clinical status, quality of life (QOL) and performance status (PS), since the quality of the studies published is low. Interventions and patient groups are very diverse, hence an effect in some patient groups is possible. There seems to be a better effect with intravenous than oral administration. Nevertheless, treatment with vitamin C is safe with minimal side effects. Thereby, we think it is safe to examine the effects of vitamin C on specific groups of patients in a randomized controlled setting.

Cancer Chemoprevention: Preclinical In Vivo Alternate Dosing Strategies to Reduce Drug Toxicities.

Cancer chemopreventive agents inhibit the formation of precursor lesions and/or the progression of these lesions to late stage disease. This approach to disease control has the potential to reduce the physical and financial costs of cancer in society. Several drugs that have been approved by the FDA for other diseases and have been extensively evaluated for their safety and pharmacokinetic/pharmacodynamic characteristics have the potential to be repurposed for use as cancer chemopreventive agents. These agents often mechanistically inhibit signaling molecules that play key roles in the carcinogenic process. The safety profile of agents is a primary concern when considering the administration of drugs for chemoprevention, as the drugs will be given chronically to high-risk, asymptomatic individuals. To decrease drug toxicity while retaining efficacy, several approaches are currently being explored. In this short review, we describe studies that use preclinical in vivo models to assess efficacy of alternative drug dosing strategies and routes of drug administration on chemopreventive drug efficacy. In vivo drug dosing strategies that reduce toxicity while retaining efficacy will pave the way for future cancer prevention clinical trials.