Meloxicam emulgels for topical management of rheumatism: Formulation development, in vitro and in vivo characterization.

PURPOSE: The study designed, formulated and evaluated meloxicam emulgels as a potential alternative topical treatment option for rheumatism. METHODS: A 32 factorial design was employed to formulate nine preliminary meloxicam emulgels (Formulations F1 - F9). The influences of carbopol-934 and menthol as gelling agent and drug release enhancer, respectively, were correlated with four pharmaceutical properties of the formulated emulgels namely viscosity, spreadability, and cumulative drug release at one hour and at eight hours. Using the generated data and applying the Design Expert® modelling software, two optimized meloxicam emulgels (Formulations F10 and F11) were designed, formulated and evaluated. In vivo anti-inflammatory efficacy was conducted using carrageenan-induced rat paw oedema method. Drug release kinetics was modelled using DDSolver® dissolution software. RESULTS: All formulations were homogenous with no observable grittiness or phase separation. The optimized Formulations F10 and F11 had pH 6.5 and 6.4, viscosity of 23656 and 24524 mPa.s, spreadability of 9.9 and 9.5 cm, and drug content of 90.4% and 92.9%, respectively, all within optimal values. The cumulative percentage of drug released was 21.0% and 22.9% after one hour and 50.1% and 55.8% after eight hours for Formulations F10 and F11, respectively. Drug release kinetics exhibited Fickian diffusion best described by Korsmeyer-Peppas model. Paw volume inhibition by Formulation F11 at two and three hours after carrageenan injection was statistically significant (p < 0.05). CONCLUSION: The optimized meloxicam emulgels had high pharmaceutical quality and were pharmacologically active. Further optimization could potentially provide a safe and efficacious alternative treatment option for rheumatism.

Improvement of the chemical inhibition phenotyping assay by cross-reactivity correction.

BACKGROUND: The fraction of an absorbed drug metabolized by the different hepatic cytochrome P450 (CYP) enzymes, relative to total hepatic CYP metabolism (fmCYP), can be estimated by measuring the inhibitory effects of presumably selective CYP inhibitors on the intrinsic metabolic clearance of a drug using human liver microsomes. However, the chemical inhibition data are often affected by cross-reactivities of the chemical inhibitors used in this assay. METHODS: To overcome this drawback, the cross-reactivities exhibited by six chemical inhibitors (furafylline, montelukast, sulfaphenazole, ticlopidine, quinidine and ketoconazole) were quantified using specific CYP enzyme marker reactions. The determined cross-reactivities were used to correct the in vitro fmCYPs of nine marketed drugs. The corrected values were compared with reference data obtained by physiologically based pharmacokinetics simulation using the software SimCYP. RESULTS: Uncorrected in vitro fmCYPs of the nine drugs showed poor linear correlation with their reference data (R2=0.443). Correction by factoring in inhibitor cross-reactivities significantly improved the correlation (R2=0.736). CONCLUSIONS: Correcting in vitro chemical inhibition results for cross-reactivities appear to offer a straightforward and easily adoptable approach to provide improved fmCYP data for a drug.

Chloroquine-containing compounds: a patent review (2010 - 2014).

INTRODUCTION: Chloroquine (CQ) has been well known for its antimalarial effects since World War II. However, it is gradually being phased out from clinical use against malaria due to emergence of CQ-resistant Plasmodium falciparum strains. Besides low cost and tolerability, ongoing research has revealed interesting biochemical properties of CQ that have inspired its repurposing/repositioning in the management of various infectious/noninfectious diseases. Consequently, several novel compounds and compositions based on its scaffold have been studied and patented. AREAS COVERED: In this review, patents describing CQ and its derivatives/compositions over the last 5 years are analyzed. The review highlights the rationale, chemical structures, biological evaluation and potential therapeutic application of CQ, its derivatives and compositions. EXPERT OPINION: Repurposing efforts have dominantly focused on racemic CQ with no studies exploring the effect of the (R) and (S) enantiomers, which might potentially have additional benefits in other diseases. Additionally, evaluating other similarly acting antimalarials in clinical use and structural analogs could help maximize the intrinsic value of the 4-aminoquinolines. With regard to cancer therapy, successful repurposing of CQ-containing compounds will require linking the mode of action of these antimalarials with the signaling pathways that drive cancer cell proliferation to facilitate the development of a 4-amino-7-chloroquinoline that can be used as a synergistic partner in anticancer combination chemotherapy.

In silico comparison of antimycobacterial natural products with known antituberculosis drugs.

The chemical space based on physicochemical properties and structural features of a diverse group of natural products with reported in vitro activity against different Mycobacterium tuberculosis strains is investigated using in silico tools. This is compared to the chemical space occupied by drugs currently recommended for the treatment of various forms of tuberculosis as well as compounds in preclinical and clinical development. Docking studies exploring possible binding affinities and modes of two main clusters of natural products on two different mycobacterial targets are also reported. Our docking results suggest that scytoscalarol, an antibacterial and antifungal guanidine-bearing sesterterpene, can inhibit arabinosyltransferase Mtb EmbC, and the ß-carboline alkaloids 8-hydroxymanzamine A and manzamine A can bind to the oxidoreductase of Mtb INHA. On this basis, these products showing high binding affinities to the two targets in silico could be rationally selected for in vitro testing against these targets and/or semisynthetic modification.

Artemisinin derivatives: a patent review (2006 - present).

INTRODUCTION: The isolation of artemisinin from an ancient Chinese remedy in the early 1970s heralded the beginning of a new era in antimalarial drug therapy culminating in artemisinin-based combination therapies currently being the mainstay of malaria treatment worldwide. Ongoing research on this compound and its derivatives has revealed its potential use in treating other infectious and noninfectious diseases. AREAS COVERED: This review provides a summary of patents published globally from January 2006 to June 2012 covering promising artemisinin derivatives and artemisinin-based drug combinations developed for use in various therapeutic areas. EXPERT OPINION: The diversity of semi-synthetic artemisinin derivatives has been limited to the same design strategy of modifying the artemisinin molecule at the same positions due to inherent synthetic challenges. To address this, future endeavors should include: the use of biotransformation strategies to modify other positions in the sesquiterpene ring while retaining the endoperoxide bridge; the design and synthesis of synthetic ozonides based on the pharmacophoric endoperoxide motif and drug repositioning approaches to artemisinin-based combination therapy. A better understanding of the mechanism of action of artemisinin derivatives and their biomolecular targets may provide an invaluable tool for the development of derivatives with a wider array of activity and greater clinical utility than currently appreciated.

Identification and characterization of reactive metabolites in natural products-driven drug discovery.

Toxicity of natural products arising from their metabolic biotransformation into reactive chemical intermediates is an important reason for high attrition rates in early drug discovery efforts. Screening promising natural products for their likelihood to form such metabolites is therefore an important step in identifying potential liabilities in the drug development process. However, such screening is complicated by the need to have test methods that are sensitive, reliable, accurate, efficient, and cost-effective enough to allow for routine identification and characterization of the reactive metabolites. These metabolites are typically formed in minute quantities, usually through minor metabolic pathways, and, due to their highly reactive and therefore transient chemical nature, pose considerable analytical challenges in attempts to determine their properties. Understanding the formation of reactive metabolites may be used as the basis for synthetic chemical modification of parent natural products aimed at bypassing such harmful bioactivation. This paper highlights the general principles and protocols commonly used to predict and study the formation of reactive metabolites in vitro and how the data obtained from such studies can be used in the development of safer drugs from natural products.