Current Drug Therapy (v.11, #1)

Meet Our Editorial Board Member by Eduard Vieta (1-1).

Warfarin was the only oral anticoagulant available for the treatment of venous thromboembolism for about half a century until the recent approval of novel oral agents dabigatran, rivoraxaban and apixaban. This presents new classes of medications less cumbersome to use. They do not require frequent laboratory monitoring or have nurmerous drug interactions. On the other hand it also poses a challenge to the physicians deciding which agent to use in specific patient populations, how to predict the bleeding risk compared to warfarin and between the different novel agents and how to manage bleeding with relatively recent discovery of few potential antidotes. This review summarizes the major trials that led to the approval of these agents and their exclusion criteria helping physicians understand which patient types might not benefit from these agents. It provides clinical pearls invaluable in everyday practice such as transitioning between traditional and novel anticoagulants, dose adjustments for high risk populations, drug interactions and cost analysis. Futhermore, the review provides direct comparisons with warfarin and indirect comparisons among the novel agents in terms of efficacy and bleeding risk narrating the numbers of patients with intracranial, gastrointestinal and fatal hemorrhages in each of the major trials. We hope that this review will help the physicians inform their patients about the benefits and risks of these agents and enable them to make an informed selection of the most appropriate anticoagulant.

Phosphodiesterase 4 (PDE4) inhibitors can be effective drugs for treating inflammation in different tissues/organs caused by conditions such as asthma, chronic obstructive pulmonary disease (COPD), psoriasis, and Alzheimer's disease. It has been demonstrated that PDE4 inhibitors used for drug therapy provide some advantages over conventional formulations, including sensitivity to selective inhibitors, unique tissue distribution, and ease of oral administration. To date, the U.S. Food and Drug Administration (USFDA) had approved two PDE4 inhibitors, roflumilast (Daxas®, Daliresp®) and apremilast (Otezla®), for treating respective COPD and plaque psoriasis. Several pharmaceutical companies and academic laboratories continuously develop novel PDE4 inhibitors for clinical application. A concern pertaining to the development of PDE4 inhibitors is the high occurrence rate of side effects such as emesis, nausea, and headache. This review describes recent developments using PDE4 inhibitors for inflammation management. Special attention is paid to the use of PDE4 inhibitors in treating pulmonary and cutaneous inflammation. This review article focuses on issues related to animal and human studies. The action mode of the inhibitors is also addressed.

Probiotics and Different Efficacy, How it can be Managed? by Behzad Badakhsh, Nourkhoda Sadeghifard, Morovat Taherikalani, Firoozeh Valian, Arman Rostamzad, Sobhan Ghafourian (41-46).
The use of probiotics and obtained results from some studies and meta-analysis made it essential to search for the literature about probiotics. For this reason, the current review triesto explain and focus on gastrointestinal tract. On the other hand, reliable designing of probiotics takes into consideration the type of strain and diseases, which are discussed, in the current review.

Development and Evaluation of Novel Tabletted Microspheres for Controlled Release of Glimepiride by Manisha S. Karpe, Dhanashree H. Surve, Kisan R. Jadhav, Vilasrao J. Kadam (47-57).
Purpose: To design and evaluate sustained release microspheres incorporated in orally disintegrating tablet for anti-diabetic drug Glimepiride and compare it with conventional tablet.
Method: Glimepiride was encapsulated with different amount of ethyl cellulose polymer by an emulsion solvent evaporation technique and the physicochemical properties of the formulation were characterized. Spherical microspheres with particle size 125 - 250 ?m were prepared. Optimization was done using 32 randomized full factorial design (Software used: Statease Design-Expert). Microspheres were characterized by Scanning electron microscopy, differential scanning calorimetry, and X-ray diffraction. A single dose randomized study was conducted on male wistar rats for bioequivalance testing. A single blind study was conducted for taste masking test and disintegration time in human volunteers.
Results: The formulations were evaluated for pharmacokinetic parameters. The optimized formulation gave Cmax value more than conventional tablet. The controlled release of drug also provides for higher plasma drug content and improved bioavailability. Particle size was dependent on stirring speed and drug release was dependent on polymer concentration. The in vitro drug release was studied in two different pH media (pH 1.2 for 2 hours, pH 6.8 up to 12 hours). The drug release mechanism of optimized formulation can be explained with first order model which describes the concentration dependent drug release. The entrapment efficiency of these formulations was 80 - 100 %. Microspheres obtained showed good flow properties. The major factors influencing % entrapment efficiency and % drug release were found to be polymer concentration and stirring speed, respectively.

Zolmitriptan is the drug of choice for the treatment of migraine with or without aura. Oral bioavailability of drug is 40% due to high first pass metabolism. Elimination half life is 3 hrs and drug degradation occurs in acidic environment of GIT. To overcome these problems present research was aimed to prepare intestinal targeted delivery. This was prepared by compression coating technique as maximum absorption of drug occurs in small intestine. 32 factorial design was applied with independent variables polyox N12K and methacrylic acid. Core tablet consists of croscarmellose sodium as superdisintegrant, avicel as binder, dicalcium phosphate as diluent and zolmitriptan as drug. Outer coating of polyox N12K and methacrylic acid was applied in compression coating. Optimized batch F8 consist of polyox N12K (60%) & methacrylic acid (3%). In-vitro release study in simulated media indicated presence of the tablet in small intestine giving burst release. In-vivo placebo X- ray radiographic technique for F8 showed that tablet was not adhered throughout GIT and bypass stomach. This indicated F8 can be a potential to achieve the targeted site delivery.

Prochlorperazine maleate, a well known antiemetic is used in the treatment and prevention of nausea and vomiting. The dosage of the drug is usually 5 or 10 mg thrice or four times a day, because of its short biological half life (6-8 hours). The bioavailability of drug is 12.5%. Due to the solubility of drug in acidic pH, the drug is absorbed rapidly from stomach. Present study was aimed to formulate and evaluate effervescent floating matrix tablets of Prochlorperazine maleate. Hydroxyethyl cellulose HHX (Natrosol HHX) and hydroxypropyl cellulose (HPC-H) were used as release retarding agents. Sodium bicarbonate and citric acid were used as gas forming agents. Floating tablet of prochlorperazine maleate was prepared to enhance the bioavailability of drug, to prolong the gastric retention time (GRT) and to reduce the frequency of administration. The formulations were prepared by direct compression method. The tablets were evaluated for pre-compression and post-compression parameters. 32 full factorial designs were used to optimize the concentration of release retarding agents. From the factorial batches, formulation H7 containing 70% of hydroxyethyl cellulose HHX and 12% hydroxypropyl cellulose - H was found to be the optimized batch. Formulation H7 followed Korsmeyer Peppas release kinetics, with sustained drug release of 93.64±6.4 % and floating for 10 hours. In-vivo X-ray placebo study of optimized batch (H7) showed retention of tablet in stomach for 6±0.5 hours. Thus, the study proved the successful floating delivery of drug in stomach.