Concept and utility of population pharmacokinetic and pharmacokinetic/pharmacodynamic models in drug development and clinical practice

Due to frequent clinical trial failures and consequently fewer new drug approvals, the need for improvement in drug development has, to a certain extent, been met using model-based drug development. Pharmacometrics is a part of pharmacology that quantifies drug behaviour, treatment response and disease progression based on different models (pharmacokinetic - PK, pharmacodynamic - PD, PK/PD models, etc.) and simulations. Regulatory bodies (European Medicines Agency, Food and Drug Administration) encourage the use of modelling and simulations to facilitate decision-making throughout all drug development phases. Moreover, the identification of factors that contribute to variability provides a basis for dose individualisation in routine clinical practice. This review summarises current knowledge regarding the application of pharmacometrics in drug development and clinical practice with emphasis on the population modelling approach.

Assessment of hot-melt coating methods for multiparticulate substrates: Mortar-coating vs. pan-coating

Hot-melt coating (HMC) is an alternative, solvent-free coating method generally used to modify substrate release rate and/or mask its unpleasant taste. The aim of this study was to assess two HMC methods (pan-coating and mortar-coating) by assaying functional properties of the coated material. The selected substrates included highly soluble sodium chloride (model substance) and caffeine (bitter drug), and the coating agent was glycerol distearate without/with the addition of liquid paraffin. Experiments with sodium chloride revealed that pan-coating yielded particles of more regular shape, while mortar-coating yielded samples of more uniform coating layer. The flowability of the coated material depended on the particle size. Sustained sodium chloride release was achieved for all mortar-coated and some pan-coated samples. The analysis of the results indicated mortar-coating as a preferable HMC method for caffeine coating. The resulting caffeine yield in the coated samples was high (99%), the material showed satisfactory mechanical properties and drug release from the coated particles was sustained. Overall, the obtained results suggest that both pan-and mortar-coating can be used to sustain the release of drugs with unpleasant taste, but mortar-coating can be considered as a more simple and practical method that can be potentially used in compounding pharmacies.

Photocontrollable PROTAC molecules: Structure and mechanism of action

Traditional drug discovery strategies are usually focused on occupancy of binding sites that directly affect functions of proteins. Hence, proteins that lack such binding sites are generally considered pharmacologically intractable. Modulators of protein activity, especially inhibitors, must be applied in appropriate dosage regimens that often lead to high systemic drug exposures in order to maintain sufficient protein inhibition in vivo. Consequently, there is a risk of undesirable off-target drug binding and side effects. Recently, PROteolysis TArgeting Chimera (PROTAC) technology has emerged as a new pharmacological modality that exploits PROTAC molecules for induced protein degradation. PROTAC molecule is a heterobifunctional structure consisting of a ligand that binds a protein of interest (POI), a ligand for recruiting an E3 ubiquitin ligase (an enzyme involved in the POI ubiquitination) and a linker that connects these two. After POI-PROTAC-E3 ubiquitin ligase ternary complex formation, the POI undergoes ubiquitination (an enzymatic post-translational modification in which ubiquitin is attached to the POI) and degradation. By merging the principles of photopharmacology and PROTAC technology, photocontrollable PROTACs for spatiotemporal control of induced protein degradation have recently emerged. The main advantage of photocontrollable over conventional PROTACs is the possible prevention of off-target toxicity thanks to local photoactivation.

On Frankincense (Olibanum, Boswellia spp., Burseraceae)

Boswellia species (Burseraceae) are trees or shrubs whose area of distribution covers the wide geographic area between North Africa and India. After incision, their bark produces oleogum resin known as frankincense (Olibanum). In traditional medicine, frankincense is often used for medical treatment of arthritis, asthma, ulcerative colitis, coughs, sores, and wound healing. Various frankincense preparations are marketed almost exclusively as dietary supplements. Indian frankincense, or Olibanum indicum, is official in the European Pharmacopoeia. The major components of frankincense are boswellic acids, among which the most important and abundant is 3-O-acetyl-11-keto-b-boswellic acid (AKBA). AKBA is a 5-lipoxygenase inhibitor with anti-inflammatory and anti-arthritic effects. Besides, frankincense contains essential oil, whose composition greatly depends on the biological source, as well as arabinogalactans and glycoproteins. In small clinical trials, certain benefits of various frankincense preparations have been demonstrated in cases of ulcerative colitis, bronchial asthma, mild symptoms of irritable bowel syndrome, and various disorders of osteo-muscular system. However, for collagenous colitis and Crohn's disease remission maintenance, the evidence is ambiguous or negative. AKBA-containing extract was found advantageous in patients with osteoarthritis, and to some extent with rheumatoid arthritis. Almost all the trials had serious flaws in experimental design, such as insufficient sample size and/or incomplete reporting of data. For any clinical recommendation of frankincense preparations, larger and better-designed studies are needed.

Engineering cocrystals of Paliperidone with enhanced solubility and dissolution characteristics

In the present study, co-crystals (CCs) of Paliperidone (PPD) with coformers like benzoic acid (BA) and P-amino benzoic acid (PABA) were synthesized and characterized to improve the physicochemical properties and dissolution rate. CCs were prepared by the solvent evaporation (SE) technique and were compared with the products formed by neat grinding (NG) and liquid assisted grinding (LAG) in their enhancement of solubility. The formation of CCs was confirmed by the IR spectroscopy, powder X-ray diffraction and thermal analysis methods. The saturation solubility studies indicate that the aqueous solubility of PPD-BA and PPD-PABA CCs was significantly improved to 1.343±0.162mg/ml and 1.964±0.452mg/ml, respectively, in comparison with the PPD solubility of 0.473mg/ml. This increase in solubility is 2.83-and 3.09-fold, respectively. PPD exhibited a poor dissolution of 37.8% in 60min, while the dissolution of the CCs improved tremendously to 96.07% and 89.65% in 60min. CCs of PPD with BA and PABA present a novel approach to overcome the solubility challenges of poorly water-soluble drug PPD.

Testicular dysgenesis syndrome and phthalate exposure: A review of literature

Endocrine disruptors are chemicals that interfere with the body's endocrine system and cause adverse effects in biological systems. Phthalates are a group of man-made chemicals which are mainly used as plasticizers and classified as endocrine disruptors. They are also used in cosmetic and personal care products as color or smell fixators. Moreover, phthalates are present in inks, adhesives, sealants, automobile parts, tools, toys, carpets, medical tubing and blood storage bags, and food packages. Pathological condition known as "testicular dysgenesis syndrome" (TDS) or "phthalate syndrome" is usually linked to phthalate exposure and is coined to describe the rise in alterations in reproductive health in men, such as reduced semen quality (decrease in sperm counts, sperm motility and increase in abnormal sperms), hypospadias, cryptorchidism, reduced anogenital distance and early-life testicular cancer. Phthalates are suggested to cause direct effect on gonadal and non-gonadal tissues, impair the differentiation and morphogenesis of seminiferous tubules and accessory sex organs and testicular cells (both Sertoli and Leydig cells), alter estradiol and/or testosterone levels, decrease insulin-like 3 (INSL3) peptide production, impair spermatogenesis and lead to epigenetic alterations, all of which may lead to TDS. This review will mainly focus on phthalates as causes of TDS and their mechanisms of action.

Endocrine-disrupting activity of mancozeb

The objective of the present study was to review the existing data on the mechanisms involved in the endocrine disrupting activity of mancozeb (MCZ) in its main targets, including thyroid and gonads, as well as other endocrine tissues that may be potentially affected by MCZ. MCZ exposure was shown to interfere with thyroid functioning through impairment of thyroid hormone synthesis due to inhibition of sodium-iodine symporter (NIS) and thyroid peroxidase (TPO) activity, as well as thyroglobulin expression. Direct thyrotoxic effect may also contribute to thyroid pathology upon MCZ exposure. Gonadal effects of MCZ involve inhibition of sex steroid synthesis due to inhibition of P450scc (CYP11A1), as well as 3b-HSD and 17b-HSD. In parallel with altered hormone synthesis, MCZ was shown to down-regulate androgen and estrogen receptor signaling. Taken together, these gonad-specific effects result in development of both male and female reproductive dysfunction. In parallel with clearly estimated targets for MCZ endocrine disturbing activity, namely thyroid and gonads, other endocrine tissues may be also involved. Specifically, the fungicide was shown to affect cortisol synthesis that may be mediated by modulation of CYP11B1 activity. Moreover, MCZ exposure was shown to interfere with PPARg signaling, being a key regulator of adipogenesis. The existing data also propose that endocrine-disrupting effects of MCZ exposure may be mediated by modulation of hypothalamus-pituitary-target axis. It is proposed that MCZ neurotoxicity may at least partially affect central mechanisms of endocrine system functioning. However, further studies are required to unravel the mechanisms of MCZ endocrine disrupting activity and overall toxicity.

Developmental toxicity of endocrine-disrupting chemicals: Challenges and future directions

Maternal exposure to a mixture of various endocrine disruptors (EDCs) may have a substantial impact on postnatal health of her offspring(s) and increase the risk for health disorders and diseases in adulthood. Research efforts to better understand the health risk associated with endocrine disruptor exposures in early life have increased in recent decades. This paper provides a short overview of the current challenges that researchers continue to face in selecting appropriate epidemiologic methods and study designs to identify endocrine disruptors and evaluate their adverse health effects during this critical developmental window. Major challenges involve the selection of a representative biomarker that reflects the foetal internal dose of the biologically active chemical or its metabolite(s) that may be associated with adverse health effects with regard to variable level and duration of exposure and the latency between exposure and disorder/disease manifestation. Future studies should pay more attention to identifying factors that contribute to interindividual variability in susceptibility to various EDCs and other toxicants.

Endocrine disruption by PFAS: A major concern associated with legacy and replacement substances

Perand poly-fluorinated alkyl substances (PFAS) have been used for decades in a great variety of processes and products by virtue of their exceptional properties, versatility and chemical stability. Nevertheless, it is increasingly recognized that these substances can represent a serious hazard to human health and living organisms due to their persistence, long-range transport potential and tendency to accumulate in biota. For this reason, some efforts have been made across the EU to identify alternative molecules, with a shorter carbon chain and theoretically safer profile, that might replace the previous generation of legacy PFAS. Unfortunately, this strategy has not been entirely successful and serious concerns are still posed by PFAS in different human populations. Among others, an emerging aspect is represented by the adverse effects that both legacy and alternative PFAS can exert on the human endocrine system, with respect to vulnerable target subpopulations. In this review we will briefly summarize PFAS properties, uses and environmental fate, focusing on their effects on human reproductive capacity and fertility, body weight control and obesity as well as thyroid function.

A review of botanical characteristics, chemical composition, pharmacological activity and use of parsley

Parsley is a biennial aromatic plant from the Apiaceae family, which is characterized by an unbranched root, pinnately divided leaves, umbels and schizocarp. It contains essential oil in all parts, with phenylpropane and terpene compounds as main components. It is rich in flavonoids and other polyphenolic compounds, containing furanocoumarins, carotenoids, polyacetylenes, and its leaves are a source of vitamins and minerals. The chemical composition of parsley depends on a number of factors, so it differs not only in different parts and varieties of the plant but also in different samples of the same parts of one variety. The most important parsley compounds are myristicin, apiol, 1-allyl-2,3,4,5-tetramethoxybenzene, b-phellandrene, 1,3,8-p-menthatriene, b-pinene, terpinolene, apiin, oxypeucedanin and falcarinol. Parsley has a long tradition of use in the treatment of urinary tract disorders, and modern in vitro and in vivo studies reveal numerous effects of various parsley preparations such as diuretic, antiurolithiasis, hypouricemic, hypolipidemic, hypoglycemic, hypotensive, antioxidant, anti-inflammatory and antiplatelet effect. Today, apart from its medical application, parsley is one of the most commonly used culinary herbs.