As per the United States Food and Drug Administration, orphan drugs are defined as drugs used in diseases or circumstances which occur so infrequently in USA, that there is no reasonable expectation that the cost of developing and making available, a drug for such disease or condition will be recovered from its sales in USA. In this article, the current state of orphan drugs in different countries and the benefits provided by the drug authorities/government of the country for the development of drugs for rare disease is discussed.

Indians are more prone to premature coronary artery disease. High serum homocysteine levels have been recognized as one of the novel risk factors of coronary artery disease. Hyperhomocystinemia has been associated with increased risk of atherosclerosis and myocardial infarction by a number of prospective case-control studies. A variety of genetic mutations, nutritional deficiencies including low intakes of folate, vitamin B12 and B6, disease states, and drugs can elevate homocysteine concentrations. It has been suggested that taking combination of vitamin B6, vitamin B12, folic acid, trimethyl glycine or simply folate may be used to bring down homocysteine levels. This article reviews the biochemistry, homocysteine metabolism, pathogenesis,and etiology of hyperhomocysteinemia, along with its association with coronary artery disease.

The significance of the use of grapefruit juice as i t relates to drug-drug interaction potential, via cytochrome P450 (CYP) 3A4 isozyme, has been a topic of considerable interest for over a decade now. Drugs belonging to diversified chemical classes have exhibited a significant pharmacokinetic and/or pharmacodynamic interaction when concomitantly administered with grapefruit juice. Owing to the inhibition of the intestinal CYP 3A4 enzyme, the exposure levels of the ingested drug substrate have been increased by several folds following a single intake of grapefruit juice. While many investigations have been performed to identify active ingredient(s) in grapefruit juice responsible for this profound interaction resulting in an increased bioavailability, some recent reports suggest that grapefruit juice may impede the bioavailability of a very few drugs due to alteration of the micro-environment of absorption. Therefore, from a clinical viewpoint, caution needs to be exercised when co-administering CYP 3A4 substrates with grapefruit juice. Additionally, molecules that are substrates to P-glycoprotein efflux transporter pumps may also get affected by the inhibitory interaction of grapefruit juice. In some situations, the inhibitory interaction exerted by grapefruit juice may be capitalized to allow dose reduction of CYP3A4 substrate(s). This review covers many aspects of drug-drug interaction potential upon the ingestion of grapefruit juice.

Semi synthetic phospholipid, dipalmitoylphosphatidylcholine, with or without cholesterol was used to study the encapsulation efficiency of diclofenac sodium into liposomes as well as to investigate its retention into liposomes. To improve encapsulation efficiency of diclofenac sodium into liposomes, natural phospholipids from Triticum sp. (wheat germ) and chitosan for coated liposomes were used. Diclofenac sodium was encapsulated into uncoated and coated liposomes using the thin film hydration method, with an efficiency of more than 90 %. Improvement in the encapsulation efficiency of diclofenac sodium into liposomes, was achieved by employing phosphatidylethanolamine, dicetyl phosphate and chitosan. The encapsulation efficiency reached a maximum when liposomes were prepared from Triticum sp. lipids and was 99 % compared to 59 % when dipalmitoylphosphatidylcholine was used. Results showed that the presence of cholesterol in the dipalmitoylphosphatidylcholine liposome bilayers produced a significant decrease in the encapsulation efficiency of diclofenac sodium. Chitosan-coated liposomes (dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylcholinelcholesterol and Triticum sp. lipids) were prepared, and their encapsulation efficiency was studied. Encapsulation efficiency was affected by chitosan-coating, due to the presence of dicetyl phosphate rather than the presence of chitosan. The release of encapsulated diclofenac sodium from uncoated and coated liposomes in pH 7.4 normal saline at 37° was studied and DSC technique was employed to explain the results from drug release and the influence of cholesterol into uncoated liposome bilayers.

A set of sixty-four compounds of indomethacin derivatives was subjected to three-dimensional quantitative structure activity relationship analysis using comparative molecular field analysis and comparative molecular similarity indices methods. The comparative molecular field analysis model gave cross-validated and conventional r2 values of 0.742 and 0.992, respectively, for the forty-five compounds of training set with optimum number of components as 6.The comparative molecular similarity indices model has cross-validated and conventional r2 values of 0. 594 and 0.935, respectively, for the forty-five compounds of training set with optimum number of components as 4. Nineteen compounds were used to validate the comparative molecular field analysis and comparative molecular similarity indices models, which were not included in the model generation. The comparative molecular field analysis and the comparative molecular similarity indices results have been compared. The comparative molecular field analysis model was found to be highly predictive and it can be used to design potent cyclooxygenase-2 inhibitors prior to their synthesis.

Orodispersible tablets are better choice for the pediatric and geriatric patients. Present study demonstrates the use of factorial design in the formulation of orodispersible tablets of rofecoxib. Preliminary screening of three superdisintegrants namely sodium starch glycolate, crospovidone and croscarmellose sodium was carried out (batches AA1 to AA9) and crospovidone was found most effective giving lowest disintegration time and wetting time. Batches AA10 to AA12 were prepared to optimize the amount of crospovidone and the optimum concentration of crospovidone was found to be around 10%. Mannitol was incorporated as a diluent to improve palatability and to impart sweet taste as well as to keep the tablet weight (100 mg) constant in all the batches. From the preliminary results, a 32full factorial design was employed for preparation of tablets possessing optimized characteristics (batches AA13 to AA21). The percentage of crospovidone (X1) and mannitol (X2) were selected as independent variables. Wetting time and disintegration time were selected as dependent variables (response; Y). Full and refined models were derived for the prediction of the response variabley. Based on the results of multiple linear regression analysis, it was concluded that lower disintegration time and wetting time could be obtained when X1 is kept at high level and X2 is kept at low level. Promising batch (batch AA18) was compared with two marketed samples (brand A and B) of rofecoxib tablets for in vitro drug release after 30 min in three dissolution media. Tablets of batch AA18 exhibited better drug dissolution after 30 min than, the tablets of brand A and B in all the dissolution media.

The hydrolysis kinetics of mutual prodrugs of ibuprofen was investigated using high performance liquid chromatographic method. The hydrolysis kinetics of prodrugs was studied to access their utility as a prodrug. These kinetic studies were performed in 0.1N hydrochloric acid (pH 1.2), 10% rat gastric mucosal homogenate, phosphate buffer (pH 7.4), 10% rat intestinal homogenate, 80% human plasma (pH 7.4) and 10% rat liver homogenate at 37°. The influence of pH on the chemical stability of prodrugs was also studied in phosphate buffer (pH 3.6 to 7.2). The results indicate that these derivatives have undergone pH-dependent hydrolysis and rate of hydrolysis of the prodrugs has been increased in phosphate buffer (pH 7.4) as against 0.1N hydrochloric acid (pH 1.2). The rate of hydrolysis of prodrugs showed an increase in 10% rat gastric mucosal and 10% rat intestinal homogenate. But the kinetic studies performed in 80% human plasma and 10% rat liver homogenate showed about five to six fold increase in hydrolysis as compared to other fluid models.

Micropellets of verapamil hydrochloride were formulated by ionotropic gelation technique using sodium alginate, hydroxypropylmethylcellulose and hydroxypropylcellulose. Prepared micropellets were evaluated for flow behavior, drug entrapment efficiency, in vitro dissolution and stability ' studies, including scanning electron microscopy and optical microscopy. Of the nine formulations prepared and evaluated formulations F3, F6 and F9 were found to show satisfactory results. The release of the drug from the micropellets was found to be following non-Fickian diffusion; Drug diffusion coefficient and correlation coefficient were also assessed using various mathematical models. From the study it was concluded that, prolonged release verapamil hydrochloride micropellets could be achieved with success using ionotropic gelation technique.

In the present research, an attempt has been made to develop controlled-release formulations of propranolol hydrochloride using guar gum as a carrier and also to study the influence of some cellulose ethers like sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose and ethylcellulose on the in vitro release of propranolol hydrochloride from guar gum matrix tablets. In vitro release studies indicated that 30 % of guar gum was the minimum concentration of guar gum that can be used to sustain the release for 12 h. Combination of guar gum and cellulose ethers were found to be effective in retarding the release of propranolol hydrochloride, The ratios of guar gum:cellulose ethers which showed better retarding of drug release were, 1:1 2:1, 2:1 and 5:1 for guar gum:sodium carboxymethylcellulose, guar gum:hydroxypropylmethylcellulose, guar gum:hydroxypropylcellulose and guar gum:ethylcellulose, respectively. In vitro dissolution kinetics followed a first order release via Fickian diffusion controlled mechanism. IR spectroscopy revealed that there was no interaction between the drug and the polymers used in the investigation.

In the present study, malnutrition was induced in adult rats by feeding a protein deficient (7% protein) diet for 36 d in order to study its effect on morphine analgesia and on brain serotonergic activity. In the early phase of malnutrition, both, morphine analgesia and serotonergic neuronal activity were increased concomitantly when compared to that of their respective control values from nourished adult rats. On the contrary, both morphine analgesia and serotonergic neuronal activity in brain were decreased in the late phase of protein deprivation. These results indicate that morphine analgesia in malnourished adult rats is primarily governed by serotonergic neuronal activity of the brain. In contrast to above, malnourished adult rats also showed an exposure dependent progressive decrease in the analgesic effect of morphine while malnourished rats rehabilitated on protein-rich diet for a period of two weeks did not show such anomaly. The decrease in morphine analgesia on its repeated exposure in malnourished adult rats may be related to the decrease in formation of N-normorphine, an active metabolite of morphine responsible for its analgesic effect, due to decrease in microsomal mixed function oxidase activity in the brain and liver.

Benzofuran chalcones (2a-i) were prepared by the reaction of 2-acetylbenzofuran (1) with different aromatic aldehydes in the presence of a strong base. Cyclocondensation of benzofuran chalcones with guanidine hydrochloride, thiourea and urea resulted in the formation of various aminopyrimidines (3a-i), thiopyrimidines (4a-i) and hydroxy pyrimidines (5a-i), respectively. The structures of all the compounds (2,3,4,5 a-i) have been established on the basis of analytical and spectral data. All the compounds have been screened for antitumour and antimicrobial activities. Compounds 3b and 3d showed significant antitumour activity. While compounds 4d and 4h showed only moderate activity against Staphylococcus aureus at 500 μg/ml, compounds 4h, 4i, 5a, 5b, 5h and 5i showed promising activity against Candida albicans at 500 μg/ml concentrations.

The present research was designed to synthesize some 2-naphthyloxy derivatives of N,N-substituted acetamides employing the secondary amino moiety and insertion of-OCH2-group between the aromatic ring and the side chain.2-Naphthol was condensed with methylchloroacetate followed by fusion with different amines to give target compounds 3a-3f. The compounds synthesized after pharmacological investigations have been found to possess significant antiamnesic activity when compared with piracetam. Compounds 3b, 3d, 3f showed dose dependent antiamnesic effect with 3b being most potent. Further, neuropsychopharmacological studies (hypnotic, anticonvulsant, antianxiety, locomotor, muscle relaxant, antidepressant and antiamnesic activities) on 3b confirmed its memory enhancing potential which was comparable to piracetam, a known nootropic agent.

The combined antibacterial effect of the leaf extracts of Dissotis theifolia with some disc antibiotics was investigated. Extraction of the dried pulverized leaves of the plant was carried out using maceration method and some portion of the extract further fractionated in a chromatographic column. The antibiogram of the test microorganisms was determined using the agar-diffusion method while the in vitro activity of the combination of sub-bacteriostatic concentrations of the extract and column fraction F2 with some disc antibiotics was evaluated using the overlay inoculum susceptibility disc method. Fractionation of the extract yielded three column fractions (F1-F3) with only F2 showing remarkable antibacterial activity. Results of the antibiograms clearly demonstrated the resistance and susceptibility pattern of the test isolates against the disc antibiotics. Combinations of most of the disc antibiotics with the extract and column fraction F2 of D. theifolia produced antagonistic (P≤0.05) and indifferent effects (P≤0.05), respectively.

Two simple and sensitive spectroscopic methods in ultraviolet and visible region were developed for the estimation of cefdinir in pharmaceutical dosage forms. In method A cefdinir showed absorption maximum at 287 nm in 0.1 M phosphate buffer (pH 7.0), whereas in method B, it reacted with Folin-Ciocalteu reagent under alkaline conditions forming a blue coloured chromogen having absorption maximum at 720 nm. These methods obey Beer's law in the concentration range of 3 to 17 μg/ml and 4 to 20 μg/ml, respectively. The methods are statistically evaluated for accuracy and precision.

Administration of alcoholic extracts of roots of Boerhaavia erecta L. and B. rependa L protect the liver from the toxic effect of CCI4 by restoring the levels of serum bilirubin, serum total protein, albumin and subsequent decrease in the levels of serum globulin in experimental rats. The serum alanine transaminase, aspartate transaminase and alkaline phosphatase activities were also restored as compared to the normal rats. The hepatoprotective activity was evaluated to be more in B. erecta root extract treated groups.

Roxithromycin, a macrolide antibiotic, is extremely bitter in taste. The present study deals with various techniques utilized for taste masking of roxithromycin viz granulation with Eudragit E 100 and complexation with ion exchange resins. Of these, complexation with ion exchange resins yielded complete taste masking. The drug resin complexation procedure was optimized with respect to parameters like taste of the resinate, drug to resin ratio and volume of medium. The complexation between roxithromycin and ion exchange resin was confirmed by differential scanning calorimetry. The taste-masked complex was then formulated into palatable mouth-dissolve tablets. The tablets were evaluated for various quality control parameters. Taste evaluation of the tablets showed complete masking of the bitterness of the drug. In vitro release studies revealed complete drug elution from the complex after a period of 30 min in pH 1.2 buffer.

Hypocotyl cultures were developed from explants obtained from in vitro germinated seedlings of Solanum platanifolium Sims (Family-Solanaceae) on modified Murashige and Skoog's agar-solidified medium supplemented with 6-benzylaminopurine (2 ppm) and α-napthaleneacetic acid (1 ppm). Shoots originated from callus were transferred to modified Murashige and Skoog's medium and modified White's medium supplemented with different growth adjuvants. 6-benzylaminopurine (4 ppm) produced optimum growth of somatic shoots on MS medium. Chemical analysis of different tissues grown showed that organogenesis enhanced solasodine production.

Petroleum ether extract of Caesalpinia pulcherrima was examined in HCl/ethanol and aspirin and pylorus ligation models in the rat. Pretreatment of the extract prevented the formation of gastric lesions in HCl/ethanol model. In aspirin and pylorus ligation model, the extract was able to significantly reduce the ulcer score and increase in mucus content, but had no effect on gastric juice volume or acid content. Thus the results indicate that the extracts' antiulcerogenic effect is attributable to augmentation of gastric defense mechanisms.

Novel structural feature containing 4-[1-oxo-(substituted aryl)-2-propenyl]-3-phenylsydnones were synthesized and screened for anticancer activity. These compounds contain two pharmacophores,a,b unsaturated ketone moiety and sydnone nucleus. Three compounds were synthesized, and all of the three exhibited promising in vitro cytotoxicity In 56 cell lines representing cancers of non-small cell lung, colon, CNS, melanoma, ovarian, prostrate, breast and leukemia. Average growth inhibition of 50% was in the range of 1.7-3.5 μM. Methyl derivative was highly selective against SNB-75 tumor cell line of CNS. It was active at less than one nano mole. However, in vivo the activity was moderate by hollow fiber assay model.

Some novel organometallic compounds were prepared by complexing the antibiotics, tetracycline, azithromycin, cefotaxime, cephalexine, and antibacterials, ofloxacin, norfloxacin and gatifloxacin with bismuth citrate. They were characterized by UV, IR, NMR and elemental analysis-Their antibacterial activity against Helicobacter pylori and other microorganisms was investigated. Tetracycline- bismuth citrate was found to possess strong activity against H. pylori with a lowest inhibitory concentration of 125 mg/l. These complexes exhibited moderate activity against Escherichia coli, Klebsiella pneumoniae, Bacillus pumilis, Staphylococcus aureus and Candida albicans. The findings suggest that the activity of these organometallic compounds might be specifically directed agafhst H. pylori.

A simple, accurate and sensitive spectrofluorimetric procedure was developed for the estimation of cefdinir containing heterocyclic fused ring structure, in 1 M sodium hydroxide at 95° for 1 h, which shows strong fluorescence having excitation and emission wavelength 262 and 530 nm, respectively. Linear relationship for the fluorescence intensity was obtained in the range of 0.2-1 μg/ml. The method was statistically validated and was applied successfully to determine the cefdinir in pharmaceutical dosage form.

The present investigation was taken up to study the effect of long term treatment (30 days) of various potassium channel openers and blockers on serum insulin, glucose, T3, TSH and plasma cortisol in rats. Treatment with cromakalim for 30 days produced a significant decrease in serum insulin levels in rats. However, treatment with pinacidil and glibenclamide produced a significant increase in serum insulin levels. KRN 2391 did not produce any effect on serum insulin levels. Glucose levels were decreased significantly only with glibenclamide and no significant alteration in serum glucose levels was observed with any of the potassium channel openers. Serum T3 levels were significantly increased with cromakalim and glibenclamide. However no significant alteration in serum T3 levels was observed with pinacidil and KRN 2391. Serum TSH levels were significantly decreased with pinacidil. No significant alteration was observed in serum TSH levels by other potassium channel modulators. Serum cortisol levels were significantly decreased with all the three potassium channel openers while glibenclamide did not produce any significant change in serum cortisol levels. Our data suggest that potassium channels may be involved in the release of hormones other than insulin. It also indicates that there is involvement of different types of potassium channels in the action of different potassium channel modulators.

A simple, fast, precise and accurate liquid chromatographic method was developed for the simultaneous estimation of tizanidine, diclofenac potassium and paracetamol in tablets. This combination is used for spasm and pain associated with musculoskeletal disorders. Drugs are chromatographed on a reverse phase Luna C18 column using a mobile phase, 25 mM phosphate buffer (pH 7.0) and acetonitrile in the ratio of 40:60 v/v. Carbamazepine was used as an internal standard. The retention time of Tizanidine, Diclofenac potassium, Paracetamol and carbamazepine was 5.00, 8.61, 3.43 and 11.68 min respectively. The validation of the proposed method was also carried out. The method was found to be linear (correlation co-efficient r>0.999), precise (residual standard deviation: 0.51% for paracetamol, 0.42% for diclofenac potassium and 0.81% for tizanidine), accurate (overall average recovery yields: 99.0% for tizanidine, 99.3% for diclofenac potassium and 98.6% for paracetamol) and selective. Due to its simplicity and accuracy the proposed method can be used for routine quality control analysis of these drugs in combination tablets.

A red pigment was obtained from dried juice of Beta vulgaris Linn, which exhibited a λmax of 533 nm and 484 nm indicative of the presence of betacyanins (red) and betaxanthins (yellow), respectively. The influence of temperature and pH on the stability of the red pigment in pharmaceutical liquid oral bases was investigated. The colour was also evaluated for its stability in its adsorbed form on microcrystalline cellulose, lactose and dextrose. The colour was found to exhibit highest stability in adsorbed form with microcrystalline cellulose.

A reverse phase high performance liquid chromatography method was developed for the simultaneous estimation of rofecoxib and tizanidine in tablet formulations. The separation was achieved by Luna C18 column and methanol : phosphate buffer pH 3.5 (55:45 v/v) as eluent, at a flow rate of 1 ml/min. Detection was carried out at 240 nm. Valdecoxib was used as an internal standard. The retention time of rofecoxib and tizanidine was found to be 4.53 and 5.92 min, respectively. The method has been validated for linearity accuracy and precision. Linearity for tizanidine and rofecoxib were in the range of 0.6-1.4 μg/ml and 7.5-17.5 μg/ml, respectively. The mean recoveries obtained for tizanidine and rofecoxib were 98.73% and 99.70%, respectively. The developed method was found to be accurate, precise, selective and rapid for simultaneous estimation of rofecoxib and tizanidine in tablets.

Antioxidant activities of some antitubercular drugs were evaluated by using a simple, accurate and reproducible method. Ascorbic acid was used as a control In the study. The antioxidant activities of antitubercular drugs were less as compared to ascorbic acid.

Delayed release doxycycline hyclate capsules were prepared with suitable blend of doxycycline hyclate-coated nonpareil seed pellets and doxycycline hyclate delayed release pellets. The delayed release pellets were prepared by coating the doxycycline hyclate-coated pellets with hydroxypropylmethylcellulose phthalate-55 polymer solution. A concentration of polymer in the range of 15 to 20% was found to comply with drug release test as specified in the USP in acid medium but failed to meet the requirements in buffer medium (pH 5.5). The inclusion of sodium starch glycolate (1-3%) in both doxycycline-coated and delayed release pellets preparation stages was found to enhance the release of the drug in the buffer medium without altering its release in acid medium. The blend of delayed release pellets (75%) and drug-coated pellets (25%) in delayed release doxycycline hyclate capsules produced an optimum in vitro drug release in both the media.

Phytochemical investigations of the whole plant Swertia nervosa yielded three tetraoxygenated xanthones namely 1,8-dihydroxy-3, 7-dimethoxyxanthone, swertiaperennine (1), 1-hydroxy-3, 7, 8-trimethoxyxanthone, decussatin (2) and 1,7-dihydroxy-3,8-dimethoxy-xanthone gentiacaulein (3). The spectral details of these compounds have been presented.