Human Pharmaceutical Products Research Articles

Redox mechanisms of environmental toxicants on male reproductive function.

Humans and wildlife, including domesticated animals, are exposed to a myriad of environmental contaminants that are derived from various human activities, including agricultural, household, cosmetic, pharmaceutical, and industrial products. Excessive exposure to pesticides, heavy metals, and phthalates consequently causes the overproduction of reactive oxygen species. The equilibrium between reactive oxygen species and the antioxidant system is preserved to maintain cellular redox homeostasis. Mitochondria play a key role in cellular function and cell survival. Mitochondria are vulnerable to damage that can be provoked by environmental exposures. Once the mitochondrial metabolism is damaged, it interferes with energy metabolism and eventually causes the overproduction of free radicals. Furthermore, it also perceives inflammation signals to generate an inflammatory response, which is involved in pathophysiological mechanisms. A depleted antioxidant system provokes oxidative stress that triggers inflammation and regulates epigenetic function and apoptotic events. Apart from that, these chemicals influence steroidogenesis, deteriorate sperm quality, and damage male reproductive organs. It is strongly believed that redox signaling molecules are the key regulators that mediate reproductive toxicity. This review article aims to spotlight the redox toxicology of environmental chemicals on male reproduction function and its fertility prognosis. Furthermore, we shed light on the influence of redox signaling and metabolism in modulating the response of environmental toxins to reproductive function. Additionally, we emphasize the supporting evidence from diverse cellular and animal studies.

Reverse phase, ion exchange, HILIC and mix-mode chromatography for the determination of metformin and evogliptin in human plasma and pharmaceutical formulations

Separation and quantification of highly polar metformin (MTF) alone or in combination with dipeptidyl peptidase-4 inhibitors, such as evogliptin (EVG), sitagliptin, saxagliptin, vildagliptin, linagliptin and teneligliptin, specifically from human plasma and pharmaceutical products is still difficult in mostly preferred ODS based RP-HPLC techniques. Since, owing to weak retention of MTF in ODS, it elutes together with the biological fluid components and drug excipients. Therefore, in this study, alternative to ODS based RP-HPLC, comparatively less known analytical techniques like strong cation exchange chromatography (SCX-3), hydrophilic interaction liquid chromatography (HILIC) and mix-mode chromatography (MMC) were comprehensively evaluated for their potentials and limitations in simultaneous quantification of newly approved EVG and MTF combination (Valera-M). In results, prolonged application of SCX-3, exhibits irreproducible and irreversible retention of MTF and EVG. While in HILIC with Cyano column, excessive acetonitrile as eluent developed the precipitation of MTF and column back pressure. Comparatively, the Acclaimed® mix-mode HILIC-1, demonstrated much promising and reproducible results for MTF and EVG separation and importantly, it can be used either reverse phase or HILIC mode. Considering the overall benefits of Acclaimed® mix-mode HILIC-1, it was used in estimation of MTF and EVG from human plasma and pharmaceutical formulations.

Proposal for regulatory risk mitigation measures for human pharmaceutical residues in the environment

Environmental risks of human pharmaceutical products should be made transparent and mitigated as far as possible. We propose to apply a risk mitigation scheme to the marketing authorisation of human medicinal products which is pragmatic and tailored, and thus will not increase the burden to regulators and industry too much. This scheme takes into account increasing knowledge and accuracy of the environmental risk estimates, applying preliminary risk mitigation when risks are determined based on model estimates, and definitive, more strict and far-reaching risk mitigation when risks are based on actual measured environmental concentrations. Risk mitigation measures should be designed to be effective, proportional, easy to implement, and in line with current (other) legislation, as well as not being a burden to the patient/health care professionals. Furthermore, individual risk mitigation measures are proposed for products showing environmental risks, while general risk mitigation measures can be applied to all products to reduce the overall burden of pharmaceuticals in the environment. In order to effectively mitigate risk, linking marketing authorisation legislation to environmental legislation is essential.

Inspectional approaches for the oversight of human and animal pharmaceutical products (FDA)

Inspectional approaches for the oversight of human and animal pharmaceutical products (FDA)

The risks of marine micro/nano-plastics on seafood safety and human health.

A considerable mass of plastics has been released into the marine environment annually through different human activities, including industrial, agriculture, medical, pharmaceutical and daily care products. These materials are decomposed into smaller particles such as microplastic (MP) and nanoplastic (NP). Hence, these particles can be transported and distributed in coastal and aquatic areas and are ingested by the majority of marine biotas, including seafood products, thus causing the contamination of the different parts of aquatic ecosystems. In fact, seafood involves a wide diversity of edible marine organisms, such as fish, crustaceans, molluscs, and echinoderms, which can ingest the micro/nanoplastics particles, and then transmit them to humans through dietary consumption. Consequently, these pollutants can cause several toxic and adverse impacts on human health and the marine ecosystem. Therefore, this chapter provides information on the potential risks of marine micro/nanoplastics on seafood safety and human health.

Au-PEDOT/rGO nanocomposites functionalized graphene electrochemical transistor for ultra-sensitive detection of acetaminophen in human urine

A novel graphene electrochemical transistor (GECT) sensor based on Au-poly(3,4-ethylenedioxythiophene)/reduced graphene oxide (Au-PEDOT/rGO) nanocomposites functionalized the gate electrode and monolayer graphene as channel was proposed and constructed for the ultra-sensitive detection of acetaminophen (AP). Au-PEDOT/rGO nanocomposites were synthesized by a simple one-pot method to modify the gate electrode of GECT. With the high catalytic activity of Au nanoparticles, the good conductivity and stability of PEDOT, the large specific surface area and abundant adhesion sites of rGO, the sensitivity and stability of the device for AP detection could be effectively improved. The sensing mechanism of the device was that the electrochemical reactions of the AP on the surface of gate electrode causes the effective gate voltage on the GECT to change, thereby adjusting the carrier concentration and current of the graphene channel. Combined with the excellent catalytic properties of Au-PEDOT/rGO nanocomposites and the high carrier mobility of the graphene channel, the resulting device has remarkable sensing performance for AP, with a detection limit as low as 1 nM and a linear range from 1 nM to 8 mM. In addition, the device has good anti-interference ability and accuracy in the detection of AP in urine samples and tablets, which proved that it could be used to determine AP in human non-invasive and pharmaceutical products. The GECT sensor based on Au-PEDOT/rGO provides an efficient, sensitive and cost-effective sensing platform for AP detection, and is expected to realize in vitro diagnosis of diseases.

Influence of hollow sphere surface heterogeneity and geometry of N-doped carbon on sensitive monitoring of acetaminophen in human fluids and pharmaceutical products

A sensitive and selective acetaminophen sensor assay was designed based on N-HCCS. The surface morphology, and composition of open hollow conjugated spheres of N-HCCS resulted in facile AC diffusion/loading and electrocatalytic oxidation.

Operationalization of the One Health approach in two rural municipalities of Niger

Abstract Despite multiple efforts made by its government to improve public health, Niger still regularly faces numerous disasters including epidemics. Between 2017 and 2019, a consortium was established between Doctors of the World and Veterinarians Without Borders to implement a “One Health” project. This approach aims to reduce the populations' vulnerabilities to health risks related to environmental disasters and improve the health system's resilience at several levels. By promoting interdisciplinary between human, veterinary and environmental health issues, it aims to tackle emerging diseases with pandemic risk. The project was implemented in 2 municipalities: Sakoira and Ingall. For the first time, a program focused on preventing health and environmental risks rather than responding to a crisis. An external evaluation based on 278 interviews identified 5 project's achievements: (1) the increase in availability and accessibility of human and veterinary pharmaceutical products which improved vaccination coverage and medicalization while lowering treatment and prevention costs; (2) the mobilization and coordination of human and animal health professionals, national authorities and municipalities; (3) the strengthening of joint epidemiological surveillance through professional and community actors in order to reduce the response time to epidemics and disasters; (4) the strengthening of communities' understanding of health risks and how to prevent them; (5) the capacity building of professionals regarding the One Health approach at national, regional and local level. Coordination between human and animal health professionals has made possible the design and implementation of joint actions. These actions have enabled to: build capacity for 43 health providers, 116 community health workers and 41 livestock auxiliaries, vaccinate, de-worm and treat 24311 small and 7590 large ruminants, give primary health care to 4190 people, sensitize 2268 people on human and animal health. Key messages The project is innovative as it focuses on preventing epidemic risks instead of responding to crisis. Collaboration between human and animal health actors is the main success factor of the project.

Selective Detection of Folic Acid Using 3D Polymeric Structures of 3-Carboxylic Polypyrrole.

The detection of folic acid in biological samples or pharmaceutical products is of great importance due to its implications in the biological functions of the human body, along with the development and growth of the fetus. The deficiency of folic acid can be reversed by the intake of different pharmaceutical formulations or alimentary products fortified with this molecule. The elaboration of sensing platforms represents a continuous work in progress, a task in which the use of conductive polymers modified with different functionalities represents one of the outcoming strategies. The possibility of manipulating their morphology with the use of templates or surfactants represents another advantage. A sensing platform based on carboxylic functionalized polypyrrole was synthesized via the electrochemical approach in the presence of a polymeric surfactant on a graphite-based surface. The sensor was able to detect the folic acid from 2.5 μM to 200 μM with a calculated limited of detection of 0.8 μM. It was employed for the detection of the analyte from commercial human serum and pharmaceutical products with excellent recovery rates. The results were double checked using an optimized spectrophotometric procedure that confirmed furthermore the performances of the sensor related to real samples assessment.

Limitations of Animal Studies for Predicting Toxicity in Clinical Trials: Is it Time to Rethink Our Current Approach?

SummaryAnimal testing is used in pharmaceutical and industrial research to predict human toxicity, and yet analysis suggests that animal models are poor predictors of drug safety in humans. The cost of animal research is high—in dollars, delays in drug approval, and in the loss of potentially beneficial drugs for human use. Human subjects have been harmed in the clinical testing of drugs that were deemed safe by animal studies. Increasingly, investigators are questioning the scientific merit of animal research. This review discusses issues in using animals to predict human toxicity in pharmaceutical development. Part 1 focuses on scientific concerns over the validity of animal research. Part 2 will discuss alternatives to animal research and their validation and use in production of human pharmaceuticals.

Selective sensor for simultaneous determination of mesalazine and folic acid using chitosan coated carbon nanotubes functionalized with amino groups

First analytical method was developed for simultaneous determination of aminosalycilate drug mesalazine (5-ASA) and folic acid (FA) used as a supplement in treatment of inflammatory bowel diseases. Various types of functionalized multi-walled carbon nanotubes embedded in different kinds of polymer matrix were evaluated to design selective and sensitive electrochemical sensor for this purpose. Carbon nanotubes functionalized with amino groups and chitosan as biopolymer modifier exhibited an excellent electroanalytical performance due to strong adsorptive ability of ionized analytes and subtle electronic properties followed by well-separated oxidation peaks towards 5-ASA and FA at potential of 0.33 and 0.81 V, respectively. After 60 s preconcentration at deposited nanocomposite layer, the voltammetric response had linear relationship with 5-ASA concentration in the range of 1.25 × 10−7–8.0 × 10−6 M, while FA gave a good linear correlation in a broad range from 1.25 × 10−8 to 1.25 × 10−6 M. Applicability of proposed nanosensor for rapid and precise measurements of 5-ASA and FA in human serum samples and pharmaceutical products was demonstrated.

Application of diethylene glycol monoethyl ether in solubilization of poorly water-soluble drugs

Diethylene glycol monoethyl ether (DEGEE) is produced via the O-alkylation of ethanol with two ethylene oxide units, followed by distillation. It has a long history of safe use in food and personal-care products, and is used as an effective strong solubilizer in oral, topical, transdermal, and injectable human and veterinary pharmaceutical products. It has been used as a pharmaceutical solvent for many years under the trade name transcutol. DEGEE, a hydroalcoholic solvent, is gaining interest as a penetration/permeation enhancer, solubilizer, and surfactant for drug delivery systems. The physicochemical properties of DEGEE, the solubility data for drugs in DEGEE or DEGEE-water mixtures, and the applications of DEGEE in the solubilization of poorly water-soluble drugs are summarized in this review. DEGEE is a promising excipient as a solubilizer for many pharmaceutical products with enhanced drug absorption via oral, parenteral, and topical administration, as well as cosmetic products.

PharmCycle: a holistic approach to reduce the contamination of the aquatic environment with antibiotics by developing sustainable antibiotics, improving the environmental risk assessment of antibiotics, and reducing the discharges of antibiotics in the wastewater outlet

BackgroundThe overall aim of the interdisciplinary research project “PharmCycle” is to reduce the contamination of the aquatic environment with antibiotics by developing sustainable antibiotics, improving the environmental risk assessment of antibiotics, and reducing the discharges of antibiotics in the wastewater outlet. An overview of the holistic approach and first results are given.ResultsThe first step is to design sustainable antibiotics, which are effective against target organisms but, after their use, are less toxic, and are rapidly and completely degradable. To develop sustainable antibiotics, two different approaches (subprojects) are applied within PharmCycle: First, a re-design of the existing antibiotics with chemical and in silico methods (“Benign by Design”). Second, sustainable peptide-based antibiotics are produced with biotechnological methods. In the second step, the environmental risk assessment for antibiotics in the framework of the authorization process and for monitoring purposes is improved. There is a lack of data for the environmental risk assessment of antibiotics on the European market. With more transparency of these data, the environmental risk assessment for active substances and for the class of antibiotics can be improved. The aim is to increase the data availability by applying the Aarhus convention and by providing legal access to environmental information. Beside other shortages in the environmental risk assessment required by the European legislation, the effects of antibiotics directly applied in marine aquacultures are not assessed by marine prokaryotic test systems. Therefore, a marine cyanobacteria test was developed, which is more sensitive to selected priority antibiotics than the marine eukaryotic algae test (DIN EN ISO 10253) required by the European Medicines Agency. Marine cyanobacteria are of high importance for the nitrogen cycle and primary production. Moreover, they seem to play an important role with respect to climate change. To reduce the emission of antibiotics used as human pharmaceutical products to the aquatic environment, the third step focusses on the main pathway, the wastewater. Investigations to improve the wastewater treatment of priority antibiotics and sustainable antibiotics are conducted by a combination of methods: activated sludge units, activated carbon adsorption, and membrane filtration systems.ConclusionsWith the aim of improving the environmental risk assessment of antibiotics and to reduce the emission of antibiotics to the aquatic environment, an interdisciplinary approach is applied which includes the analysis of the German, European, and international law and the development of new legal instruments.

Magnetic nanoparticles embedded with graphene quantum dots and multiwalled carbon nanotubes as a sensing platform for electrochemical detection of progesterone

Results of this paper related to fabrication of a simple, reproducible, stable and sensitive electrochemical sensing platform of progesterone (P4) based on graphene quantum dots (GQDs) nanocomposite. GQDs, Fe3O4 nanoparticles and functionalized multi–walled carbon nanotubes (f–MWCNTs) modified glassy carbon electrode (Fe3O4@GQD/f–MWCNTs/GCE) were constructed and the electrocatalytic properties of the modified electrode toward the oxidation of P4 were analyzed. GQDs with the size of about 15nm were prepared by a facile and low expense bottom–up method by carbonization of citric acid and dispersing the carbonized products into alkaline solution. The characterization of the sensor was studied by transmission electron microscopy (TEM), X–ray diffraction (XRD), UV–vis spectroscopy, Fourier transform infrared spectroscopy (FT–IR) and voltammetry techniques. Electrochemical studies suggested that as–prepared sensor revealed some advantages in terms of high effective surface area, more reactive sites and excellent electrochemical catalytic activity toward the oxidation of P4. After optimization of analytical conditions, the peak currents for P4 were found to vary linearly with its concentrations in the wide range of 0.01–0.5 and 0.5–3.0μM. The estimated detection limit and sensitivity of the electrode were 2.18nM and 16.84μAμM−1, respectively. This sensor exhibited excellent stability, selectivity, sensitivity and reproducibility and could be successfully applied for determination of P4 in human serum samples and pharmaceutical products with excellent recoveries and without the interferences of coexisting substances.

Analytical characterization of cyclodextrins: History, official methods and recommended new techniques

The main goal of this review is to provide a comprehensive overview on the methods used for analysis of cyclodextrins (CDs) and CD-derivatives. The paper intends to act as a guide for the readers in looking around the classical and modern instrumental analytical methods suitable for identification, characterization and determination of CDs themselves, CDs in finished products or even in biological samples.At present, in the European and United States Pharmacopoeias, the three parent CDs and two synthetic derivatives, namely the (2-hydroxypropyl)-beta-CD and sulfobutylether-beta-CD Na salt are official. Besides these modified CDs, two other derivatives are approved as excipients in human pharmaceutical products: the (2-hydroxypropyl)-gamma-CD and the randomly methylated-beta-CD.Although most of the official analysis methods in the pharmacopoeias have been well used for decades, new aspects of the functional excipient CD characterization suggest a need to revisit compendial methods.Comparison of strengths and weaknesses of current official methods with new improved techniques intends to help analysts to decide on changing traditional analytical methods with improved new ones. This review also deals with the analytical aspects of the first single isomer CD derivative approved as a drug active (Sugammadex/Bridion®) as well as analytical considerations of using CDs themselves as active pharmaceutical ingredients.Stability-indicating instrumental methods suitable to adequately follow chemical- and enzymatic degradation of CDs will also be discussed. Challenges in the determination of CDs in different biological matrices will be illustrated on real pharmaco- and toxicokinetic studies of CD-enabled drug formulations.

Toxicological evaluation of sediment samples spiked with human pharmaceutical products: Energy status and neuroendocrine effects in marine polychaetes Hediste diversicolor

There is a lack of studies about the ecotoxicology of pharmaceutical products on marine environment. To predict possible adverse effects of pharmaceutical products on benthic biota, polychaetes Hediste diversicolor were exposed for 14-days to pharmaceutical-spiked sediments under laboratory conditions. Carbamazepine (CBZ), ibuprofen (IBP) and propranolol (PRO) at concentrations of 500ngg−1, 50ngg−1, 5ngg−1, 0.5ngg−1 and 0.05ngg−1, fluoxetine (FX) and 17α-ethynylestradiol (EE2) at concentrations of 100ngg−1, 10ngg−1, 1ngg−1, 0.1ngg−1 and 0.01ngg−1, including environmental concentrations (underlined), were spiked in marine sediment samples. After the exposure, cellular energy status (total lipids content – TLP; and mitochondrial electron transport activity – MET), metabolism of monoamines (monoamine oxidase activity – MAO) and inflammation properties (cyclooxygenase activity – COX) were observed in polychaetes. CBZ increased TLP content and MET activity, and decreased MAO activity in polychaetes. IBP did not interfere on the TLP level, but on the MET and MAO activities (environmental concentrations). FX did not cause changes in the energy status. Therefore, environmental concentration diminished MAO activity. EE2 did not affect the energy status, however, MAO activity was significantly lower in polychaetes exposed to environmental concentration. PRO increased TLP level in polychaetes, but not MET activity. MAO activity was significantly lower for polychaetes exposed to environmental concentration. Except FX, all pharmaceuticals showed anti-inflammatory properties confirmed by the decrease of COX activity. Pharmaceutical products affected H. diversicolor physiology and health. As a benthic top predator, adverse effects on sea-worms can potentially culminate in ecosystem perturbations.

Improving environmental risk assessment of human pharmaceuticals.

This paper presents 10 recommendations for improving the European Medicines Agency's guidance for environmental risk assessment of human pharmaceutical products. The recommendations are based on up-to-date, available science in combination with experiences from other chemical frameworks such as the REACH-legislation for industrial chemicals. The recommendations concern: expanding the scope of the current guideline; requirements to assess the risk for development of antibiotic resistance; jointly performed assessments; refinement of the test proposal; mixture toxicity assessments on active pharmaceutical ingredients with similar modes of action; use of all available ecotoxicity studies; mandatory reviews; increased transparency; inclusion of emission data from production; and a risk management option. We believe that implementation of our recommendations would strengthen the protection of the environment and be beneficial to society. Legislation and guidance documents need to be updated at regular intervals in order to incorporate new knowledge from the scientific community. This is particularly important for regulatory documents concerning pharmaceuticals in the environment since this is a research field that has been growing substantially in the last decades.

Pharmaceuticals in the environment: scientific evidence of risks and its regulation.

During the past two decades scientists, regulatory agencies and the European Commission have acknowledged pharmaceuticals to be an emerging environmental problem. In parallel, a regulatory framework for environmental risk assessment (ERA) of pharmaceutical products has been developed. Since the regulatory guidelines came into force the German Federal Agency (UBA) has been evaluating ERAs for human and veterinary pharmaceutical products before they are marketed. The results show that approximately 10% of pharmaceutical products are of note regarding their potential environmental risk. For human medicinal products, hormones, antibiotics, analgesics, antidepressants and antineoplastics indicated an environmental risk. For veterinary products, hormones, antibiotics and parasiticides were most often discussed as being environmentally relevant. These results are in good correlation with the results within the open scientific literature of prioritization approaches for pharmaceuticals in the environment. UBA results revealed that prospective approaches, such as ERA of pharmaceuticals, play an important role in minimizing problems caused by pharmaceuticals in the environment. However, the regulatory ERA framework could be improved by (i) inclusion of the environment in the risk-benefit analysis for human pharmaceuticals, (ii) improvement of risk management options, (iii) generation of data on existing pharmaceuticals, and (iv) improving the availability of ERA data. In addition, more general and integrative steps of regulation, legislation and research have been developed and are presented in this article. In order to minimize the quantity of pharmaceuticals in the environment these should aim to (i) improve the existing legislation for pharmaceuticals, (ii) prioritize pharmaceuticals in the environment and (iii) improve the availability and collection of pharmaceutical data.

Human pharmaceutical products in the environment – The “problem” in perspective

Concerns about the potential for significant environmental impact from residues of human pharmaceuticals emerged at the beginning of the 21st century. Since then there has been an exponential rise in the number of publications and conferences on this “problem”. However, this intense focus on human pharmaceuticals is misplaced. Pharmaceuticals do not consist of a coherent group of substances with similar chemical, structural, biological or toxicological properties. Pharmaceuticals are only identifiable from their use: in other words substances can be divided into two classes, those that are used as pharmaceuticals and those for which a possible pharmaceutical use has not yet been discovered. For example, nitro-glycerine, Warfarin and dimethyl fumarate, initially sold respectively as an explosive, a rodenticide and a mould inhibitor have subsequently all been used as pharmaceuticals.As analytical science advances, an increasing range of environmental contaminants, including pharmaceuticals, is being identified at sub μgL−1 concentrations. Although, human and environmental exposure to these contaminants will be low, all of them need to be subjected to risk assessment on a case by case basis. Many of these substances, including human pharmaceuticals, may have little, if any, impact on human health or the environment, however for some substances there may be a significant risk and in these cases appropriate action should be taken. However considering all human pharmaceuticals as a special case, isolated from the wider range of emerging contaminants, is scientifically unjustifiable and diverts resources away from the consideration of other substances that may be of considerably more significance.

Draft Genome Sequence of Probiotic Strain Lactobacillus rhamnosus R0011

Lactobacillus rhamnosus R0011 is a commercially available probiotic that is widely used in human dietary supplements and pharmaceutical products. We prepared a draft genome sequence consisting of 10 contigs totaling 2,900,620 bases and a G+C content of 46.7% for this strain.