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Journal of Pharmaceutical Negative Results
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   Table of Contents - Current issue
January-December 2016
Volume 7 | Issue 1
Page Nos. 1-53

Online since Friday, February 19, 2016

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Propylthiouracil in treating psoriasis, a promise that failed: A hospital-based prospective study of propylthiouracil in the treatment of psoriasis p. 1
Murugaiyan Rangaraj, Kaliaperumal Karthikeyan
Introduction: Psoriasis is a common skin disorder with no cure and definite treatment options. Propylthiouracil (PTU), an antithyroid drug, has been found to be effective in treating psoriasis in certain studies. This prompted us to conduct a study to assess the effectiveness of PTU in treating patients with psoriasis. Aims: The primary objective of our study was to assess the efficacy of PTU as a safe and effective agent in the management of psoriasis. Settings and Design: This study was a clinical prospective study conducted over a period of 3 months. Materials and Methods: Thirty one patients with psoriasis and those fulfilling the inclusion criteria were treated with PTU (100 mg thrice a day) and topical emollient, and were followed up for 12 weeks. Psoriasis Area Severity Index (PASI) at the baseline and at the end of the study were compared. Patients who attained PASI score 50 were considered to respond to the treatment. Statistical Analysis Used: Mean values of variables. Results: The mean PASI score at the beginning of the treatment with PTU was 17.6. The mean PASI score at the end of the study was 16.06. Conclusions: We found PTU to be ineffective in reducing both the symptoms and severity of psoriasis. It is also intriguing to note that PTU, which was found to be effective in treating psoriasis almost two decades ago, has never been used widely in practice. Probably, this bears testimony to the fact that PTU is not as effective as it was promised to be.
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Rofecoxib-induced deleterious effects escape detection by organismal performance assays p. 4
Shannon M Gaukler, James S Ruff, Linda C Morrison, Wayne K Potts
Background: Organismal performance assays (OPAs) are a unique method of toxicity quantification used to assess the safety of potentially toxic compounds such as pharmaceuticals. OPAs utilize genetically diverse wild mice (Mus musculus) housed in large seminatural enclosures wherein exposed individuals compete directly with controls for resources. Previously, OPAs have been successful in detecting adverse effects in mice that were exposed to paroxetine. Here, we further test OPAs' utility in pharmaceutical safety assessment by testing OPAs with rofecoxib, a drug with known adverse effects on humans. Materials and Methods: We exposed mice to rofecoxib (~37.5 mg/kg/day) during gestation and into early adulthood. Exposure ceased when individuals were released into enclosures. Five independent populations were established and rofecoxib-exposed individuals (n = 58) competed directly with control individuals (n = 58) over 28 weeks. Organismal performance was determined by quantifying reproduction, survival, and male competitive ability. Results: In enclosures, rofecoxib-exposed males had equal reproduction, survival, and competitive ability. Rofecoxib-exposed females had equal survival compared to controls but experienced 40% higher reproductive output. Conclusions: The adverse health effects of rofecoxib seen in humans escaped detection by OPAs, just as they had during traditional preclinical assays. These results may be explained by the exposure design (in the enclosures, all animals were on the control diet), the relatively short duration of exposure, species differences, or because the health benefits of the drug negated the side effects. Similar to numerous assays used in preclinical trials, OPAs cannot reveal all maladies, despite their demonstrated sensitivity in detecting cryptic toxicity from numerous exposures.
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Effect of topical gel prepared with hydroalcoholic extract of Echinacea purpurea on treatment of Leishmania major-induced cutaneous leishmaniasis in BALB/C mice p. 12
Bahador Sarkari, Hossein Sattari, Mahmoud Reza Moein, Ali Mohammad Tamadon, Reza Shahriari Rad, Qasem Asgari
Aim: This study aimed to investigate the effect of alcoholic extract of Echinacea purpurea as a topical gel for the treatment of Leishmania major-induced cutaneous leishmaniasis (CL) in BALB/c mice. Materials and Methods: Leishmania major was inoculated into the tail base of 28 BALB/c mice and the mice were then assigned into four groups, with seven mice in each group. Hydroalcoholic extract of Echinacea purpurea was prepared and 3% carboxymethylcellulose was used for the topical gels. After the development of skin lesions, the gel base without drug and 10% and 20% Echinacea gel, respectively, were applied for the treatment of skin lesions in three groups of mice for 20 days, two times per day. The forth group remained as the control without receiving any treatment. Sizes of the lesions were frequently measured and recorded. The collected data were analyzed by SPSS using the Kruskal-Wallis one-way analysis of variance test. Results: The sizes of the lesions at the tail base of BALB/c mice were found to be increasing in both the treated and untreated mice. Although there were differences in the mean size of the lesions between the control group and those that received various concentration of Echinacea gel, (10% or 20%) the differences were not statistically significant (P > 0.05). Conclusion: The results showed that topical 10% and 20% gel of Echinacea purpurea extract is not considerably effective in the treatment or control of CL.
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Insignificant antifungal activity of plant extracts on Malassezia furfur p. 16
Sreelatha Gopalakrishnan Lalitha, Lakshmeesha Thimappa Ramachandrappa, Soumya Krishnamurthy, Jayashree Basavaraju, Sharmila Thirumale
Objective: The aim of present study was to investigate the antimalassezial potential of the selected plant extracts known to possess medicinal values. Materials and Methods: The crude extracts of five botanicals were evaluated against Malassezia furfur. The dried and pulverized plant material was extracted with water and also successively extracted with hexane, chloroform, and methanol, using the Soxhlet apparatus. The antimicrobial activity assay was done by disk diffusion and 96-well plate microdilution method. Results: The results point toward the fact that all the tested extracts extracted in solvents of different polarities exhibited no antifungal activity. Conclusion: The tested extracts did not have, or had too little, antifungal activity to be used as a promising source of novel antimicrobial substances against M. furfur.
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Lack of anthelmintic activity of Kalanchoe pinnata fresh leaves p. 21
Rohan Sharadanand Phatak
Objective: The main objective was to explore the anthelmintic capacity of Kalanchoe pinnata (K. pinnata). Materials and Methods: Petroleum ether and methanolic extracts of K. pinnata were extracted by maceration methods. Both the extracts were investigated for their anthelmintic activity against Pheretima posthuma. Different concentrations of 25 mg/mL, 50 mg/mL, 100 mg/mL, and 200 mg/mL of both extracts were studied by determining time of paralysis (PT) and time of death (DT) of the earthworms. Results: Both the extracts have exhibited no anthelmintic activity even at the highest concentration of 200 mg/mL. A concentration of 15 mg/mL of albendazole was used as standard reference or positive control while normal saline was used as negative control. Conclusion: This study has revealed that in vitro anthelmintic activity of K. pinnata leaves lacks anthelmintic property. Both the extracts of this plant have displayed no vermicide activity against the earthworms used in the study.
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Absence of anticonvulsant activity in Asparagus adscendens Roxb. hydroethanolic root extract against acute pentylenetetrazol and maximal electroshock-induced convulsion mice models p. 25
Priyanka Pahwa, Rajesh Kumar Goel
Introduction: The use of Asparagus adscendens (family:Liliaceae) root powder has been reported traditionally for the treatment of epilepsy. But, it is yet to be validated pharmacologically. Therefore, the present study was undertaken to explore the anticonvulsant effect of the roots in the experimental animal models of convulsions. Materials and Methods: The anticonvulsant effect of hydroethanolic root extract of A. adscendens (AAE) was studied at 25, 50, and 100 mg/kg; intraperitoneally (i.p.) in maximal electroshock (MES), and at 25, 50, 100, and 200 mg/kg; i.p. doses in pentylenetetrazol (PTZ) test in mice. The duration of tonic hind limb extension (s) and latency to tonic-clonic convulsions (min) was noted in MES and PTZ tests, respectively. Phenytoin (25 mg/kg; i.p.) and diazepam (5 mg/kg; i.p.) served as reference standards in MES and PTZ tests, respectively. Percentage mortality was also noted. Results: The AAE treatment did not show any protective effect with regard to induction and duration of tonic hind limb extensor in MES test and latency to tonic-clonic convulsions in PTZ test, as compared to their respective controls. Conclusions: The results obtained from the experiments indicate that the AAE lacks anticonvulsant activity in MES- and PTZ-induced convulsion tests.
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Insignificant effect of ethanol extract of Dipterocarpus turbinatus (Dipterocarpaceae) bark on selected parameter in alloxan-induced diabetic rats p. 29
Diptanu Biswas, Shivraj T Gouda, Narayanaswamy Lachmanan Gowrishankar
Objective: The present investigation was designed to find out the antidiabetic potency of ethanol extract of the bark of Dipterocarpus turbinatus by alloxan monohydrate-induced diabetic rats. Materials and Methods: The bark powder of D. turbinatus was extracted with different solvents (according to the polarity of the solvent). Preliminary phytochemical evaluation of the plants showed different chemical entities including alkaloids, steroids, flavonoids, terpenoids, and tannins. Ethanol extracts (200 mg/kg and 400 mg/kg body weight) were used for antidiabetic study. Oral administration of ethanol extract of the stem bark of D. turbinatus in alloxan monohydrate (150 mg/kg) induces diabetic rats for 14 days. Results and Discussion: Various parameters such as blood glucose level, body weight, and various biochemical parameters (plasma cholesterol, serum creatinine, and urea) were measured by the spectrophotometric method. There was no significant reduction seen in the blood glucose as compared with the diabetic control from the 200 mg/kg dose (P < 0005), and no positive effect could be shown on biochemical parameters as compared with the diabetic control group in both concentrations (200 mg/kg and 400 mg/kg). Conclusion: On the basis of this investigation, we may partially conclude that D. turbinatus is not a potent antidiabetic agent.
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Insignificant anticonvulsant activity of Padina tetrastromatica (Brown macroalgae) in mice p. 33
Subhash R Yende, Uday N Harle, Abhay M Ittadwar
Introduction: Marine macroalgae or seaweeds are found in the coastal region have created a promising significance in the biomedical area, mainly because of their contents of bioactive substances. The objective of the present study was to investigate the anticonvulsant activity of chloroform and ethanol extracts of Padina tetrastromatica (PT), a marine macroalgae (brown algae) in mice. Materials and Methods: The anticonvulsant activity of chloroform and ethanol extracts of PT was studied at 400 and 600 mg/kg, against maximal electroshock (MES) and pentylenetetrazole (PTZ) induced convulsion in mice. The duration of tonic hind limb extension (THLE), latency to onset of clonic convulsions and percent protection was noted in MES and PTZ tests, respectively. Phenytoin (25 mg/kg) and phenobarbitone (20 mg/kg) served as reference standards. Results: The chloroform extract of PT at 600 mg/kg significantly decreased the duration of THLE, while ethanol extract did not alter the duration of THLE in MES model. Further, chloroform and ethanol extracts of PT was found to be ineffective as an anticonvulsant when assessed by PTZ-induced convulsive model, as compared to their respective vehicle-treated groups. Conclusion: From the results of the present study it can be concluded that the chloroform extract of PT at 600 mg/kg showed significant anticonvulsant activity, while other extracts lack anticonvulsant activity in MES and PTZ model. However, further studies are required using different animal models to support these findings.
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A study of adherence of drug promotional literatures from various clinical specialties to the World Health Organization ethical criteria for drug promotion p. 37
Siri Hoovinahole, Ashwin Kamath
Introduction: Doctors-prescribing practices are influenced by drug promotional activities. Studies have shown that drug promotional literatures (DPLs) do not conform to the established regulations in many countries. However, whether the non-conformance is more likely in a particular clinical specialty needs to be determined. The objective of our study was to assess the adherence of DPLs sampled from various clinical specialties to the World Health Organization (WHO) criteria for ethical drug promotion and determine the presence of any difference. Methodology: Thirty DPLs were collected from each of the five clinical specialty clinics (General Medicine, Surgery, Obstetrics and Gynecology, Pediatrics and Psychiatry) of a University Teaching Hospital. Each promotional literature was evaluated for adherence to the individual WHO ethical criteria's for drug promotion. Results: More than 80% of the promotional literatures from all the clinical specialties did not contain information on dosage modification, contraindications, precautions, adverse effects, drug interactions, drug over dosage, excipients, storage and shelf-life, and legal category of the drugs. Nearly 19.33% of the DPL were for vitamins, minerals, and nutritional supplements; 13.33% for antimicrobials and 10% for anti-anxiety medications. Conclusions: Our study shows that most of the DPLs across clinical specialties failed to adhere to many of the WHO criteria of ethical drug promotion. The information lacking in the DPLs is critical for rational decision making. Considering that these irregularities are present across clinical specialties, it is important to strengthen the regulations governing drug promotion.
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2,2,4-Triamino-5(2H)-oxazolone is a weak substrate for nucleotide excision repair p. 42
Katsuhito Kino, Kaoru Sugasawa, Hiroshi Miyazawa, Fumio Hanaoka
Objective: 2,2,4-Triamino-5(2H)-oxazolone (Oz) is a guanine lesion produced by reactive oxygen radicals and photosensitized oxidation. This nucleobase is a potentially mutagenic lesion, and is removed by several base excision repair enzymes. Our purpose is to analyze whether Oz is the substrate of nucleotide excision repair (NER). Materials and Methods: A lymphoblastoid cell line from the patient with xeroderma pigmentosum (XP) complementation group C (XP3BE) was used. Cell-free NER reactions with covalently closed circular DNAs containing the Oz lesion were performed using the XP3BE whole cell extracts with or without the XPC-RAD23B complex. In addition, DNA fragments (180 bp in length) containing the Oz lesion were used for binding reactions with the XPC-RAD23B complex. Results: We analyzed the cell-free NER activity on Oz and the binding affinity of XPC-RAD23B, which initiates NER. Human cell-free NER activity on Oz was detected, though the reactivity to Oz was lower than that on ultra violet (UV)-induced pyrimidine (6-4) pyrimidone photoproduct (6-4PP). Also, binding of XPC-RAD23B with Oz was lower than that with 6-4PP. Conclusion: Because of the low binding affinity of Oz for XPC-RAD23B, NER efficiency on Oz is very low. Therefore, general NER is not the appropriate repair system for Oz.
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Dipyridamole in heart failure due to dilated cardiomyopathy: A pilot study p. 46
Francesco Stea, Kálmán Havasi, Rosa Sicari, Zoltán Rózsavölgyi, Maria Aurora Morales, Attila Somfay, Eugenio Picano, Albert Varga
Introduction: Dipyridamole (DIP) might be beneficial in heart failure (HF). It has been reported to improve symptoms in observational, small-scale studies. The PRoFESS study for secondary prevention of stroke observed a reduction in the risk of HF with acetylsalicylic acid (ASA) plus DIP in comparison with clopidogrel. The present pilot study was aimed at assessing the clinical effects of DIP and ASA in dilated cardiomyopathy. Materials and Methods: Nineteen outpatients with nonischemic HF, New York Heart Association (NYHA) Class II, ejection fraction (EF) <40%, were randomized to ASA 25 mg, or ASA 25 mg plus DIP 200 mg (ASA + DIP), twice daily. They were evaluated at baseline and after 6 months for symptoms, EF, and exercise capacity through 6-min walk test. Results: Eleven subjects were in the ASA group and 8 in the ASA + DIP. Dyspnea improved, without differences between the two arms: n = 6/5/0/0 for NYHA I/II/III/IV in ASA, n = 4/3/1/0 in ASA + DIP. EF increased in both groups (ASA: from 34 [28-35%] to 40 [32-46%]; ASA + DIP from 32.5 [25.75-34%] to 36 [31.5-46%]). No change in meters walked or points in the Borg scale was observed. In a similar population, an adequately powered study would need to recruit 38 subjects. Conclusion: The study, although underpowered, did not show any difference between the two treatment strategies. While this appears in contrast with previous studies, the strict inclusion criteria, the randomized, double-blind design, and the clinical end-points give strength to our findings. A properly sized trial would be within the capabilities of a single center.
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Sibutramine: A banned innocent antiobesity drug p. 53
Majid Malaki
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