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Journal of Pharmaceutical Negative Results
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   2015| January-December  | Volume 6 | Issue 1  
    Online since May 20, 2015

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Nonprotective role of losartan in cisplatin-induced nephrotoxicity in ovariectomized rat model treated with estradiol
Fereshteh Ghadirian, Mehdi Nematbakhsh, Shahla Roozbehani, Safoora Mazaheri, Ardeshir Talebi, Zahra Pezeshki, Farzaneh Ashrafi
January-December 2015, 6(1):2-6
Objective: The aim was to study the role of losartan on cisplatin (CP)-induced nephrotoxicity in an estradiol replacement rat model. Materials and Methods: Forty-seven female Wistar rats were ovariectomized and divided into seven groups. Groups 1 and 2 were treated with placebo (sesame oil) on a weekly basis for 4 weeks, and then they received saline or CP (2.5 mg/kg/day) for the next 7 days, respectively. Group 3 received estradiol (250 μg/kg/week) for 4 weeks, and then treated with losartan (10 mg/kg/day) for the next 10 days while from day 3; they also received CP for 7 days. Group 4 had treatment regimen the same as Group 3, except saline instead of losartan. Groups 5 and 6 were treated similar to Groups 3 and 4, respectively, but the dose of estradiol was doubled. Finally, Group 7 was treated as Group 3 except vehicle instead of estradiol. At the end of the experiment, blood samples were obtained to measure blood urea nitrogen (BUN), creatinine (Cr), nitric oxide metabolite (nitrite) and malondialdehyde (MDA). The kidney tissues were also subjected to pathology investigations. Results: Cisplatin significantly increased the serum level of BUN, Cr, and MDA (P < 0.05). CP also increased kidney weight (KW) and kidney tissue damage score (KTDS), and decreased bodyweight significantly (P < 0.05). There is a significant difference in KTDS, weight changes and serum level of MDA between positive control groups compared with the groups received combination of losartan and CP (P < 0.05). Conclusions: It seems that the estrogen could promote CP-induced nephrotoxicity. Losartan also did not intensify CP-induced nephrotoxicity. Accordingly, supplementation of losartan to attenuate CP-induced nephrotoxicity in ovariectomized model treated with estradiol is not suggested.
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Assessment of aqueous extract of Lemon verbena on anxiety-like behavior in rats
Mojgan Veisi, Siamak Shahidi, Alireza Komaki, Abdolrahman Sarihi
January-December 2015, 6(1):37-39
Aim: The purpose of the present study was to evaluate the anxiolytic effects of the aqueous extract of Lemon verbena on rats. Materials and Methods: In this study, aqueous extract of Lemon verbena leaves was prepared, and then male Wistar rats (200-230 g) were divided randomly into six experimental groups. Each group received a single intraperitoneal (IP) injection of saline, aqueous extract of Lemon verbena (10 mg/kg, 100 mg/kg, 500 mg/kg, 1,000 mg/kg)or diazepam, respectively. The level of anxiety was asserted by an elevated plus maze (EPM) 20 min after treatment. Statistical Analysis Used: Results were analyzed by one-way analysis of variance (ANOVA) and Tukey's post-hoc test. The results were expressed as mean ± standard error of mean (SEM). The differences were considered significant at P < 0.05. Results: The results of this study showed that there was a significant difference in the number of entrances into the open arms, spent time in the open arms and number of total entrances into the open and closed arms of the EPM between control, diazepam and extract-receiving groups (10 mg/kg, 100 mg/kg, 500 mg/kg, 1,000 mg/kg) and control. The numbers of entrances into the open arms, spent time in the open arms in extract receiving groups were significantly less than control group. Conclusion: These results indicated that acute administration of aqueous extract of Lemon verbena (≥10 mg/kg) increased anxiety-like behavior in rats in the EPM.
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Prospective on publishing negative results
Subramani Parasuraman
January-December 2015, 6(1):1-1
  - 3,634 8,402
Insignificant antitubercular activity of pyrazoline, phenyl pyrazoline and isoxazoline moiety in lupeol
Vandana Khattar, Ankita Wal, AK Rai
January-December 2015, 6(1):11-19
Aim: The Present study is to investigate the antimycobacterial activity of pyrazoline, phenyl pyrazoline and isooxazoline moiety containing lupeol. The main purpose to show insignificant antimicrobial activity of these lupeol derivatives and hence that further researchers do not waste time to investigate antitubercular activity of these group containing lupeol derivatives. Materials and Methods: Lupeol has been isolated from Crataeva nurvala and its reported antitubercular activity prompted to prepare semisynthetic derivatives to know how much they show antitubercular activity. Newer substituted derivatives of lupeol were synthesized by firstly oxidation of lupeol to lupeol aldehyde followed by replacement of aldehydic group by various groups as pyrazoline, phenyl pyrazoline and Isooxazoline. These Pyrozoline, Phenyl pyrazoline and Isooxazoline derivatives are synthetic analogues of the naturally occurring triterpenoid lupeol from the plant crataeva nurvala, were tested for their spectral data and conformation of the groups, then tested these derivatives of lupeol for antitubercular activity against Mycobacterium tuberculosis (MTB) strain H37Rv using the Microplate Alamar Blue Assay. Result: The result indicate that pyrazoline, Phenyl pyrazoline and Isooxazoline moiety containing lupeol derivatives did not show antimycobacterial activity against MTB at 50 μgm/ml. Conclusion: Pyrazoline, Phenyl pyrazoline and Isooxazoline derivative of lupeol did not have significant antimycobacterial activity. Thus, further optimization of it is needed.
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Lack of in vitro antihyaluronidase activity of methanolic leaf extract of Indigofera tinctoria L and methanolic stem bark extract of Stereospermum suaveolens DC
Chathuranga Bharathee Ranaweera, Walimuni Prabhashini Abeysekara, Ranjith Pathirana, Wanigasekara Daya Ratnasooriya
January-December 2015, 6(1):40-43
Objective: To assess the antihyaluronidase activity of methanolic leaf extract of Indigofera tinctoria L (I. tinctoria) (family: Fabaceae/Leguminosae) and stem bark extract of Stereospermum suaveolens DC (S. suaveolens) (family: Bignoniaceae) in vitro with a view to develop an antiaging skin formulation. Materials and Methods: The antihyaluronidase activity of different concentrations (0.19 mg/mL, 0.38 mg/mL, 0.75 mg/mL, 1.5 mg/mL, and 3.0 mg/mL) of methanolic leaf extract of I. tinctoria, methanolic stem bark extract of S. suaveolens, and reference drug epigallocatechin gallate (EGCG) of different concentrations (12.5 μg/mL, 25 μg/mL, 50 μg/mL, 100 μg/mL, and 200 μg/mL) were determined spectrophotometrically using hyaluronic acid (from rooster combs) and bovine testicular hyaluronidase. Results: There is no in vitro antihyaluronidase activity in the methanolic extracts of I. tinctoria leaves and S. suaveolens stem bark even at high concentrations. On the contrary, EGCG, the reference agent, showed marked concentration-dependent (r2 = 0.92) antihyluronidase activity [in terms of percentage inhibition: half maximal inhibitory concentration (IC 50 ) 92.64 ± 0.64 μg/mL]. Conclusion: It is unlikely that skin antiaging effects of I. tinctoria leaves and S. suaveolens stem bark, as claimed in traditional and folk medicines in Sri Lanka, are mediated via antihyaluronidase activity.
  - 3,359 334
The prolyl oligopeptidase inhibitor KYP-2047 is not readily bioavailable to bloodstream form trypanosomes and human myelocytic leukemia cells
Chinenye Ajoko, Dietmar Steverding
January-December 2015, 6(1):7-10
Introduction: Only three drugs are currently available for treatment of the neurological stage of human African sleeping sickness caused by the protozoan parasite Trypanosoma brucei. As these drugs have serious side effects and are difficult to administer, new and safe antitrypanosomal medications are urgently required. Research in recent years has shown that prolyl oligopeptidase (POP) inhibitors are promising trypanocidal agents. As the novel POP inhibitor KYP-2047 can cross the blood-brain barrier, we aimed to test whether this compound would prove to be a promising anti-trypanosomal drug candidate. Materials and Methods: The efficacy of KYP-2047 to inhibit trypanosome and human POP was evaluated with cell lysates using the fluorogenic peptide substrate Suc-Gly-Pro-Leu-Gly-Pro-AMC. The trypanocidal and cytotoxic activity of KYP-2047 was studied in vitro using bloodstream forms of T. brucei and human myelocytic leukemia HL-60 cells. The bioavailability of KYP-2047 to T. brucei and HL-60 cells was determined by incubation of cells with the inhibitor for 24 h, followed by measuring the residual POP activity. Results: KYP-2047 inactivated POP in cell lysates of T. brucei and HL-60 cells with IC 50 values in the mid nanomolar range indicating that the compound is a very potent inhibitor of the trypanosome and human enzyme. However, KYP-2047 did not affect the growth of T. brucei and HL-60 cells. Upon incubation of the cells with 100 μM KYP-2047, POP activity was inhibited between 20% and 80% which is too low to have any effect on cell growth. Conclusion: The absence of trypanocidal and cytotoxic activity of KYP-2047 is due to low bioavailability of the inhibitor to bloodstream forms of T. brucei and human HL-60 cells.
  - 4,129 1,170
Insignificant in vitro falcipain-2 inhibitory activity of novel 2-(4-(substituted benzoyl) piperazine-1-yl)-N-phenylacetamide derivatives
Sourabh Mundra, Mahesh Radhakrishnan
January-December 2015, 6(1):20-26
Background: The cysteine protease, falcipain-2 (FP-2) is an important drug target for the management of infection by the human malaria parasite Plasmodium falciparum. The rapid emergence of resistance is the main problem with all antimalarial agents. Hence, the discovery of novel, effective drugs to counter the spread of malaria parasites that are resistant toward existing agents, especially drugs that can act on new targets, is urgently necessary. Materials and Methods: A novel series of 2-(4-(substituted benzoyl) piperazine-1-yl)-N-phenylacetamide derivatives was designed using the ligand-based approach, employing a three-point pharmacophore model. It consists of an aromatic group (monocyclic/bicyclic), which is attached to the hydrophobic moiety; commonly an aromatic residue through hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) atom(s) acting as the linker. The new chemical entities were synthesized from the key intermediate N-phenyl-2-(piperazine-1-yl) acetamide, by coupling it with various substituted acids in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) and 1 hydroxybenzotriazole (HOBt). The obtained compounds' structures were confirmed by 1 H NMR and by mass spectral data. Results: All the synthesized compounds were evaluated for their in vitro FP-2 inhibitory activity. Two compounds 5l and 5q showed very weak enzyme inhibition activities (3-5%) and the remaining 15 compounds showed no inhibition at 10 μm concentrations. However, unlike other reported FP-2 inhibitors, none of these molecules showed potent activity. Conclusion: This series of compounds did not have or had very less antimalarial activity.
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Insignificant activity of extracts of Gmelina asiatica and Ipomoea digitata against skin pathogens
Chandrika Mahendra, D Vishakante Gowda, U Venkata Babu
January-December 2015, 6(1):27-32
Objective: To study the antimicrobial activity of Gmelina asiatica aerial parts and Ipomoea digitata tubers against organisms causing acne, dandruff, and body malodor. Materials and Methods: The plant materials were extracted with petroleum ether, chloroform, ethyl acetate, and methanol using Soxhlet extraction unit. The extracts were tested for antimicrobial activity against Malassezia furfur, Propionibacterium acnes, and Corynebacterium diphtheriae at 1 mg/mL, 20 mg/mL, and 50 mg/mL concentrations, respectively. Results: The chloroform and ethyl acetate extracts of I. digitata showed mild antibacterial activity against C. diphtheriae at 20 mg/mL and 50 mg/mL concentration levels (13-14 mm), respectively and did not show any activity against P. acnes. The petroleum ether extract exhibited a zone of inhibition against C. diphtheriae at 50 mg/mL. The petroleum ether, chloroform, and ethyl acetate extracts of G. asiatica showed zones of inhibition in the range 12-13 mm, and of P. acnes and C. diphtheria, at 50 mg/mL. None of the extracts showed activity against M. furfur. The methanol extracts of both the plants failed to show any activity against all the selected organisms. Conclusion: The study showed that the plant extracts exhibit weak antimicrobial activity at the levels tested. Therefore, the extracts evaluated in this study cannot be used as alternatives to existing antimicrobial agents for acne, dandruff, and body malodor.
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Absence of anti-Staphylococcus aureus (MRSA) activity of secondary metabolite actinomycetes associated sponges from Pulau Panjang, Indonesia
Yatnita Parama Cita, Farid Kamal Muzaki, Nurlita Abdulgani, Syamsudin Abdillah
January-December 2015, 6(1):33-36
Objective: To study the anti-Staphylococcus aureus MRSA of the secondary metabolite actinomycetes associated sponges from Pulau Panjang, Central Java, Indonesia. Materials and Methods: The sponge samples were taken by scuba diving in Pulau Panjang, and the sponge was identified using external morphology as well as identification of spicules from the fresh preparation. Isolation of actinomycetes associated with sponge was conducted by means of direct plating. The symbion bacteria were planted (scratched in a circular way) on agar medium Zobell 2216E, medium actinomycetes using the existing method, namely, S.aureus MRSA and E. coli MRSA. Results: The results of identification from 6 sponges were Phakettia euctimenna, Gelliodes fibolatus, Lamellodysidea herbacea, Clathria reindwardtii and Callyspongia sp, while antibacterial assay for the secondary metabolite actinomycetes associated sponges showed negative results. Conclusion: Secondary metabolite actinomycetes associated sponges from Pulau Panjang were not found to have antibacterial activity against S. aureus MRSA.
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