Recent Patents on Anti-Infective Drug Discovery (v.11, #1)

Meet Our Editorial Board Member by José A.G. Agúndez (1-1).

Preface by Dieter Kabelitz (2-2).

Lipid-based Vesicular Nanocargoes as Nanotherapeutic Targets for the Effective Management of Rheumatoid Arthritis by Mahfoozur Rahman, Sarwar Beg, Gajanand Sharma, Sumant Saini, Rehan A. Rub, Preeti Aneja, Firoz Anwar, Mohammad A. Alam, Vikas Kumar (3-15).
Background: Rheumatoid arthritis (RA) is an immune mediated joint-based chronic inflammatory disorder recognized by joint inflammation, destruction, pain and remission. Currently, numerous pharmacotherapeutic strategies have gained immense popularity in RA therapy and improving the patient life.
Methods: Besides, it exhibits numerous drawbacks such as requirement of high dose of drugs, unavoidable adverse effects and diseases remission. Thus, use of currently available pharmacotherapeutics employing conventional formulations can only provide therapeutic effects to a certain extent.
Results: Recent advancements in nanotechnology-based lipidic vesicular nanocarriers have led provided improved efficacy and safety for the anti-rheumatic drugs. These include liposomes, stealth liposomes, ethosomes, transfersomes, etc., which have shown their potential to improve the therapeutic efficacy of antirheumatic drugs with lesser toxicity. Although the results of animal models for use of lipid vesicular nanocarriers for drug targeting in RA have been found to be highly promising, but lack of sufficient data in a clinical setup are still evident to demonstrate their practical utility in patient populations. In this regard, considerable research studies are required for evaluating the efficacy and safety of the aforementioned nanocarriers in RA through clinical studies.
Conclusion: The present review, therefore, covers the brief pathophysiology of RA, current medication and their challenges in RA therapy. Besides, an extensive account on recent advancements in novel lipid vesicular nanocarriers in RA therapy has also been addressed with special emphasis on the patent literature too.

Hybolites Revisited by Victor Norris, Cecile Verrier, Marc Feuilloley (16-31).
Background: Hyperstructures are large assemblies of molecules and macromolecules that perform functions such as metabolism (including RNA and protein synthesis and degradation), transport, DNA replication, cell division, signalling and chemotaxis.
Methods: Such hyperstructures might be manipulated by hybrid metabolites or hybolites made by a pairwise, covalently linked combination of the thousands of small molecules involved in metabolism and signalling.
Results: Here, we review recent evidence for hyperstructures in prokaryotes and for interactions between hyperstructures as a determinant of the phenotype.
We also mention extending hybolite therapy to eukaryotes, consider new designs for hybolites, and discuss relevant patents.

Background: Inflammatory bowel disease (IBD) is one of the five most prevalent gastrointestinal disease burdens which commonly require lifetime care. Worldwide incidence rate of ulcerative colitis and Crohn's disease is about 16.8% and 13.4% respectively. Colitis is an inflammation of the colon. Colon targeted drug delivery will direct the drug to the colon. The drug will reach at the site of action and hence its side effects as well as dose can be reduced. Recent patent describes treatment of ulcerative colitis using anti CD3 antibodies, with nicotine and anti-depressant drugs, budesonide foam etc.
Objective: Present study deals with optimization of site targeted methylprednisolone delivery for treatment of colitis.
Method: Chitosan and Eudragit RS 100 were used as coating polymers. Tablets were prepared by press coated technology. The core tablets contain drug, avicel as binder, croscarmellose sodium as super disintegrant and dicalcium phosphate as diluent. Drug excipient compatibility was carried out using FTIR, UV and DSC. Design of experiment was used to optimize the formulation. Tablets were evaluated for thickness, weight variation, hardness, swelling index, in-vitro drug release and release of drug in simulated media.
Results: Optimized batch (B2) contained chitosan 40% and eudragit RS 100 17.5%. B2 showed in-vitro drug release 85.65 ± 7.6% in 6.8 pH phosphate buffer and 96.7 ±9.1% in simulated media after 7.5 hours.
Conclusion: In-vivo x-ray placebo study for formulation B2 had shown that the tablet reached to the ascending colon after 5 hours. This indicated a potential site targeted delivery of optimized batch B2.

Background: Allium cepa has been in use in traditional medicine in the treatment of diabetes mellitus. The aqueous and ethanolic extracts have been found effective in lowering blood glucose levels in experimental diabetic rats and guinea pigs.
Methods: The study was carried out to isolate the active principle responsible for the observed hypoglycaemic effect in experimental animals. Freeze-dried aqueous extract of Allium cepa was separated into various fractions using column chromatography with silica gel as a stationary phase. The column was eluted with various ratios of mixtures of hexane, chloroform, ethyl acetate and methanol. These column fractions obtained were tested for hypoglycaemic effects in alloxan-induced diabetic male rats. The identified active fraction was further separated by means of preparative thin layer chromatography (P-TLC) using silica gel as stationary phase and mixture of solvents chloroform, ethyl acetate, and methanol in the ratio of 10: 4: 1 respectively as the mobile phase. Pre-coated P-TLC plates were used and the fraction bands were identified under u.v. lamp and by spraying with concentrated sulphuric acidvanillin reagent. The isolated bands (Rf 0.438) were scrapped off from the P-TLC plates, redissolved in absolute methanol, filtered and concentrated to dryness.
Results: The isolated compound's structure was determined be means of one and two dimensional nuclear magnetic resonance spectroscopy as well as comparison with literature data. The isolated compound given at 25 mg/kg dose reduced blood glucose in diabetic rats in manner which was comparable to the effect obtained with 2 mg/kg of glibenclamide (p < 0.05). The structure of the compound was found to be that of kaempferol- 3-O- - D 6{P-coumaroyl} glucopyranoside.
Conclusion: The research findings have supported the claims that extracts of Allium cepa possess glucose lowering properties in experimental diabetic animals.

Effect of Pistacia atlantica Fruit and Leaf Extracts on Hydatid Cyst Protoscolices by Mohammad Zibaei, Reza Rostamipour, Hassan Nayebzadeh (53-58).
Background: Treatment of human hydatidosis is mainly surgical, with chemical treatment being reserved as a coadjuvant treatment. Use of effective protoscolicidal agents during surgery of hydatid disease is essential to reduce the recurrence rate.
Objective: The aim of this study was to investigate the scolicidal effects of Pistacia atlantica leaf and fruit hydroalcoholic extracts on protoscolices of hydatid cyst.
Method: Echinococcus granulosus protoscolices were obtained from 50 sheep infected with hydatid cysts. Various concentrations of plant hydroalcoholic extracts were used in different exposure times for viability assay of protoscolices.
Results: The scolicidal effects of the hydroalcoholic extracts of the leaf, fresh and dried fruits were significant compared to the control groups (P < 0.05). Among the Pistacia atlantica extracts tested, 0.1% (mg/ml) concentrations of fresh fruit extract (99.09 ± 1.27) and leaf extract (89.25 ± 18.42) had strong scolicidal effects in 360 min, of exposure times and the mortality rate decreased with the lower concentration.
Conclusion: Information from the current study has the strong scolicidal effect of fresh fruit hydroalcoholic extract of Pistacia atlantica on protoscoleces, which may be used as a scolicidal agent during the surgery techniques.

Effect of Low Dose Oral Vitamin-D and Calcium Replacement in HIV Patients by Satyajit Das, Shyamalie Bopitya, Ananya R. Chowdhury, Archik Das, Huda Taha (59-67).
Background: There is high prevalence of vitamin-D deficiency and abnormal bone mineral density (BMD) in HIV patients. Our aim is to find out the effect of replacement of low dose oral vitamin-D (800 International unit) with calcium (500mg) as a once daily regimen along with antiretroviral (ARV) on serum vitamin-D and parathyroid hormone (PTH) level and bone mineral density (BMD) changes on patients with HIV infection who have vitamin- D deficiency.
Methods: This is a non-randomised, open label study. We collected information about demography, viral load, CD-4 count, fracture risk factors. We measured serum 25(OH)D, parathyroid hormone (intact PTH), inorganic phosphate, corrected calcium, alkaline phosphatase (ALP) and BMD of hip and spine at baseline and after 12 months of routine follow up. Patients were treatment experienced and were divided into tenofovir containing, efavirenz containing, and protease Inhibitor (PI) containing regimens.
Results: The study included 87 treatment experienced HIV patients with mean age 42.8 (+/-7.8) years, 55 (63%) females, 73 (84%) black African ethnicity, CD4 count 451.7 (+/-184.6) cells/dL, plasma VL 1.6 log (+/-0.03) copies/mL, exposure to antiretroviral therapy 43.2 (+/-30.2) months and duration of illness 58.4 (+/- 24.1) months. Forty four patients agreed to take vitamin-D with calcium replacement and 43 patients did not agree to take the replacement.
After 12 months of follow up patients on vitamin D and calcium replacement (n=44) had significant increase in vitamin-D level (15.4+/-6.2 vs. 55.9+/-22.6, p=0.0001), reduction in PTH (8.04 +/-7.5, vs. 4.7 +/-1.8, p=0.005), alkaline phosphatase (111.1 +/-79.1 vs. 90.2+/-42.2, p=0.038) and increase in corrected calcium (2.18 +/-0.09 vs. 2.19 +/-0.09 p=0.001). In patients not on vitamin-D replacement (n=43), there was increase in vitamin-D (16.9 +/-12.1 vs. 49.4 +/-29.2, p=0.001) and corrected calcium (2.12 +/-0.09 vs. 2.16 +/-0.08 p=0.0001) level, but PTH and ALP did not change. BMD of hip and spine did not show any significant change in either of the two groups. In multivariate analysis that included all significant variables, vitamin-D and calcium replacement independently was associated with increase in vitamin-D level (OR 1.07, CI 1.02, 1.12, p=0.005), decrease in PTH level (OR 0.53, CI 0.35, 0.82, p=0.004), but not with change in corrected calcium, alkaline phosphatase, BMD of hip or spine.
Conclusion: After 12 months of follow up, replacement of low dose once daily oral vitamin-D with calcium in treatment experienced HIV patients with vitamin-D deficiency can increase vitamin-D level, reduce PTH level without any change in BMD of hip and spine.