Current Drug Therapy (v.8, #3)

Benzimidazole Derivatives as Centerally Acting Agents by Hassan Y. Aboul-Enein, Ahmed A. El Rashedy (145-154).
Benzimidazole derivatives play an important role in medical field with so many Pharmacological activities,such as selective neuropeptides YY1 receptor antagonists, gamma-amino butyric acid (GABA) agonists, and 5-HT3antagonists, anticonvulsant and other activities encouraged the development of some more potent and significantcompounds. This review presents different substituted benzimidazole derivatives which possess potential along centralacting activity.

Aim: The objective was to assess the effect of inhaled doses of GW870086, a novel selective corticosteroid, onallergen-induced early and late asthmatic responses (EAR/LAR).;Methods: Twenty-four males with mild asthma were randomised in a double-blind, three-way crossover study to receiveGW870086 0.25 mg, 1 mg and 3 mg once-daily, fluticasone propionate (FP) 0.25 mg twice-daily or placebo for 13 days.;Results: Change from baseline in weighted mean LAR (95% CI) were -0.340 L (-0.567, -0.113), -0.396 L (-0.626, -0.167)and -0.248 L (-0.471,-0.024) for GW870086 0.25 mg, 1 mg and 3 mg, respectively, -0.146 L (-0.371, 0.078) for FP0.25 mg and -0.550 L (-0.744, -0.356) for placebo. Reductions (vs. placebo) for GW870086 0.25 mg and 3 mg, and FP0.25 mg achieved statistical significance. GW870086 3 mg demonstrated attenuation of the weighted mean EAR (-0.634 L [-0.885; -0.383]); however, compared with placebo this was not significant. Methacholine PC20 was significantlyincreased (vs. placebo) after GW870086 3 mg and FP 0.25 mg. Exhaled NO was reduced (vs. placebo), achievingstatistical significance after all treatments.;Conclusion: GW870086 3 mg demonstrated anti-inflammatory activity and offered protection from airway hyperresponsiveness.

The Potential Effect of Carvedilol Against Osteoporosis in Ovariectomized Rats by Vivian Boshra, Gehan Abdel Hamid El Wakeel (164-170).
Both osteoporosis and hypertension are major diseases in aging populations. This work was provided toinvestigate the possible effect of the nonselective beta adrenoceptor antagonist; carvedilol against postmenopausalosteoporosis in adult rats. Ovariectomized rats were gavaged with carvedilol (10 mg/kg) daily for 60 days. Serum levelsof estradiol, calcium and osteoblastic markers (alkaline phosphatase and osteocalcin) were measured. The bone resorbingcytokines (TNF- α and IL-6) were also evaluated. The oxidative stress markers were determined via measuring the lipidperoxidation product and the anti-oxidant markers in the serum. The bones were prepared for histomorphometric study. Incomparison to the ovariectomized rats, carvedilol caused significant attenuation of the bone loss, biomechanical fragility,bone resorbing cytokines and oxidative stress. Current evidence suggests that administration of carvedilol has a beneficialeffect on the bone quality in OVX rats via its antioxidant effect and attenuation of the bone resorbing cytokines.

Since 1972, I have been treating children with amphetamines and somewhat later with methylphenidate(Ritalin) for Minimal Brain Damage, a diagnostic term used in those early years for children with Attention DeficitHyperactivity Disorder (ADHD). Similar to other colleagues, I have also noted a continuous rise in the interest,understanding, and rate of diagnosis and drug treatment given to children, adolescents and adults of all ages with ADHD.In the "Time magazine", health & family section of September 22, 2010 the title, "ADHD: A Global Epidemic or Just aBunch of Fidgety Kids?" is not just a reminder by the journalist John Cloud of the new worldwide epidemic of ADHD. Heas many professionals in the field of ADHD, "raises a brow" considering the accuracy of the diagnosis when faced withthe fact that an increase of 53% in treated boys and 69% in treated girls for ADHD with psycho-stimulants of whichMethylphenidate (Ritalin) was the most widely used was observed in Germany during the period of 2000-2007.Moreover, the number of treated youngsters 15-18 years of age has doubled. Most recently it was reported that an increaseof about 24% in the rate of diagnosis of ADHD from 2001-2010 was observed in the USA. Unfortunately, there is also acontinuous increase in the number of individuals without ADHD who are given (or are taking) Ritalin for cognitiveenhancement. Most recently some authorities recommend starting treatment even in children as young as 3.5 years.Ritalin, a psychotrophic stimulant may be used by children for many years following sometimes a short diagnostic clinicvisit, and rarely without such a procedure. Considering the above, the present paper will review past and recent knowledgeon methylphenidate, its chemistry, pharmacology, mechanism and site of action, efficacy, side effects and use forconditions other than ADHD. Several dilemmas related to possible causes of the "Ritalin epidemic" will be criticallydiscussed.

Recent Advances in Permeation Enhancement Techniques for Transdermal Drug Delivery Systems: A Review by Sunil Kamboj, Vikas Jhawat, Vipin Saini, Suman Bala (181-188).
Transdermal route is preferred due to its numerous advantages over other routes. Stratum corneum and otherskin layers are the foremost obstacles in employing skin as a drug delivery route. So various penetration enhancementtechniques are utilized which cause the delivery of drug through the skin in proper amounts and at a predetermined rate.Permeation enhancers are the agents which do not have any therapeutic activity themselves but these increase thepermeability of drug through the skin. Numerous chemical agents from natural and synthetic origins are evaluated fortheir penetration enhancement ability. Other than chemical agents, various novel drug delivery systems such as nanoparticles,liposomes, niosomes, transferosomes and ethosomes etc; and various physical means of skin ablaze are also useful fordrug penetration through skin. The focus of this review is to discuss various permeation enhancement techniques foreffective delivery of drugs through skin.

Microtubule Targeting Agents: A Benchmark in Cancer Therapy by Verma Nitika, Khatri Kapil (189-196).
The treatment of many diseases owes much to the important medicines that have been derived from plants,cancer is no exception. Cancer is a class of diseases characterized by out-of-control cell growth. Researchers havedeveloped many agents which have shown brilliant therapeutic results against cancerous cells out of which themicrotubule-targeting agents (MTAs) have made significant contributions to cancer therapy over the past 50 years. Thesedynamic tubulin structures can be targeted for the treatment of cancer due to their critical role in mitosis and other cellularprocesses. MTAs cause stabilisation (MSAs) or depolymerisation (MDAs) of the microtubules and hence result inapoptosis. This therapy has been frequently used in the treatment of advanced ovarian, breast, lung, head and neck, andprostate cancer, and is increasingly being used in early stage disease. Taxanes (e.g. paclitaxel, docetaxel) and epothilones(e.g. ixabepilone) are microtubule-targeting agents, which disrupt cellular processes and induce apoptosis. Nocodazole,Chamaecypanone C, Discodermolide, Noscapine, Laulimalide, and Eribulin are similar natural agents with convincingtherapeutic efficacy in this field. Collectively these findings suggest mechanisms and therapies by which growthconditions may contribute to resistance to rapid killing by microtubule-disrupting drugs.

Hydatid Disease: Current Status of Chemotherapy and Drug Delivery Systems by Maria C. Elissondo, Jose M. Bermudez, Gabriela V. Ullio Gamboa, Patricia E. Pensel, Alicia G. Cid, Maria M. Juarez, Daniel A. Allemandi, Santiago D. Palma (197-205).
Human echinococcosis or hydatid disease still causes serious health problems with a worldwide geographicaldistribution. This parasitic infection is a chronic, complex, and still neglected disease. Currently four treatment modalitiesare in use: surgery, PAIR (puncture, aspiration, injection of protoscolicidal agent, reaspiration), chemotherapy and a“watch and wait” approach for inactive, clinically silent cysts. Over the past 30 years, chemotherapy with benzimidazoles(BZ), like albendazole and mebendazole, has been used increasingly to treat this pathology. Unfortunately, 20%-40% ofthe cases do not respond favorably to such chemotherapy and these drugs produce stabilization, rather than cure in themajority of patients. However, the overall efficacy of BZ has been overstated in the past. With regard to these difficulties,novel therapeutical tools are needed to optimize treatment of human echinococcosis.;On the one hand, a number of compounds have been investigated, either using in vitro cultured parasites and/or applyingto in vivo rodent models. Tested compounds include BZ derivatives such as flubendazole, and oxfendazole, as well asother anti-infective agents like ivermectin, nitazoxanide, genistein, artemisinin, timol, rapamycin, and anti-cancer agentssuch as 2-methoxyestradiol and cyclosporine A. Although some of these compounds showed promising activities in vitro,and also in the rodent models, they have not been yet translated to clinical applications.;On the other hand, different drug delivery systems have been developed in order to improve the efficacy of several activepharmaceutical ingredients (APIs) such as oil in water emulsion, liposomes and nanoparticles among others.;The present review article summarizes the chemotherapeutic state-of-the-art and the research done in the field of drugdelivery systems regarded human echinococcosis.

Preparation and Evaluation of Novel Expandable Drug Delivery System with Captopril by Dharani Sathish, Subedari Himabindu, Panakanti Pavan Kumar, Yamsani M. Rao (206-214).
Aims: The purpose of this research is to develop a novel expandable gastroretentive dosage form (GRDF),based on an unfolding mechanism. It consists of a drug loaded bilayer polymeric film, folded into a hard gelatin capsule.Gastric retention is achieved due to unfolding of the dosage form within 15-20 min. Captopril is selected as the drugcandidate for this work. Due to its narrow absorption window, Captopril has to be administered to the upper parts of theintestine in order to maintain sustained therapeutic levels. This may be achieved by a GRDF.;Methodolgy: Films were prepared by solvent-casting technique using Ethyl cellulose, HPMC E15 and Eudragit RLPO aspolymers and dibutyl-phthalate as the plasticizer in both layers. The film with zigzag folding in the capsule was shown tounfold in the gastric juice and provide drug release up to 12 h in the acidic medium. The films were evaluated for weight& thickness variation, mechanical properties, in vitro drug release and unfolding behaviour based on the mechanical shapememory of polymers. Absence of drug polymer interaction and uniform drug dispersion in the polymeric layers wasrevealed by DSC, XRD and SEM studies. The GRDF location in the gastrointestinal tract was determined by X-raystudies.;Results: X-ray studies revealed that the GRDF is retained in the stomach up to 6± 0.5 h in fasting condition and 8 h in fedstate.;Conclusion: The polymers used in the development of GRDFs were safe and proper combination of these polymers willyield a novel expandable GRDF with good in vitro drug release in acidic media, mechanical properties, unfoldingbehaviour. These outcomes demonstrate that the GRDF may be used to improve Captopril therapy and can be applied toextend the absorption of other narrow absorption window drugs that require continuous input.