Unsuccessful story of ABT-639 in neuropathic pain in different phases of clinical trials Jasmine Sharma, Nirmal Singh, Amteshwar Singh Jaggi Journal of Pharmaceutical Negative Results 2019 10(1):1-5 Neuropathic pain is a chronic pain state caused by injury of the nervous system, and there are various conditions associated with it such as diabetic neuropathy, postherpetic neuralgia, cancer pain, trigeminal neuralgia, cervical radiculopathy, and anticancer and anti-HIV-induced neuropathic pain. The pathophysiological role of voltage-gated T-type calcium channels in neuropathic pain has been well documented. ABT-639 is a peripherally acting, selective T-type calcium channel blocker, and it is shown to efficiently reduce nociceptive and neuropathic pain in rats in multiple models. However, three clinical studies exploring the role of single dose or multiple doses of ABT-639 (100 mg) in diabetic neuropathy have not found significant pain-attenuating actions. The present review discusses the unsuccessful clinical trials of peripherally acting ABT-639 in patients with diabetic neuropathy.

Oxidative stress biomarkers in bipolar disorder with suicidal behavior: A systematic review Nurul Ain Mohamad Kamal, Jiann Lin Loo, Jo Aan Goon, Hanafi Ahmad Damanhuri, Shalisah Sharip, Suriati Mohamed Saini, Jemaima Che Hamzah, Lai Fong Chan Journal of Pharmaceutical Negative Results 2019 10(1):6-15 Oxidative stress has been implicated in suicidal behavior and bipolar disorder (BD), respectively. However, the role of oxidative stress as a biomarker of suicidal behavior in BD remains inconclusive. This systematic review aims to determine the association between oxidative stress biomarkers and suicidal behavior among BD patients. All human studies from Scopus and Ovid Medline up until August 2017 on suicidal behavior, BD, and oxidative stress biomarkers were included according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of five studies met the eligibility criteria, of which 4 were case–control studies. Three studies identified at least one biomarker with significant association between suicidal acts and oxidative stress biomarkers (i.e., increased lipid peroxidation and NOS3 rs 1799983 TT genotype) in previous suicide attempt and increased deoxyribonucleic acid damage in suicide among sample populations with BD patients. No study reported conclusive associations between Ala-9 Val manganese superoxide dismutase or Pro 197 Leu glutathione peroxidase gene polymorphisms; or levels of nitric oxide metabolites, plasma total antioxidant potential, and malondialdehyde with suicidal acts among BD patients. Based on this systematic review, there is limited evidence of any association of the association between oxidative stress biomarkers and suicidal acts in BD patients. Definitive conclusions could not be ascertained due to lack of homogenous properly controlled and adequately powered studies. Future systematically well-designed and larger, prospective studies are warranted to clarify the role of oxidative stress pathways in the pathophysiology of suicidal behavior in BD.

Synthesis and evaluation of the antibacterial effect of titanium dioxide nanoparticles in comparison with ampicillin, colistin, and ertapenem on Staphylococcus aureus Mahmoud Bahmani, Morovat Taherikalani, Mojtaba Khaksarian, Mahmoud Rafieian-Kopaei, Behnam Ashrafi, Mohammadreza Nazer, Setareh Soroush, Naser Abbasi, Rouhollah Heydari, Leila Zarei, Mohsen Alizadeh Journal of Pharmaceutical Negative Results 2019 10(1):16-20 Objectives: Today, the emergence of antibiotic-resistant strains and the acquisition of antibiotic resistance have caused many problems in the treatment of Staphylococcus aureus infection and is one of the most important health issues. At present, nanotechnology has a significant impact on the various fields including pharmacology, health, medicine, and food. This study aimed to synthesize the titanium dioxide nanoparticles (Tio2NPs) and its antibacterial effect on S. aureus compared with conventional antibiotics. Materials and Methods: In this study, Tio2NPs were tested on S. aureus compared with a number of antibiotics. First, Tio2NPs were synthesized. The shape and size of the particles as well as the synthesis quality were investigated using scanning electron microscopy (SEM), atomic force microscopy (AFM), dynamic light scattering, zeta potential and X-ray diffraction, and Fourier-transform infrared spectroscopy. The antimicrobial effect of Tio2NPs on S. aureus strain (ATCC 12600) was then studied by disc diffusion method. Antibiotics of ampicillin, colistin, and ertapenem were used as control group. Results: Based on the results and given that the polydispersity index of the samples was below 0.5 (0.466), the other sample was estimated at 347.9 nm. The zeta potential of Tio2 sample was estimated at −9.48 indicating the stability of the nanoparticle and its suspension in a suitable amount per unit of time in the solution. The results of the AFM showed that the lower mean value obtained for the Tio2NPs was 0.5 nm, and the growth of the nanoparticles was noticeable in some regions and uniform and low in some others. The result of SEM showed that the size of the nanoparticle was 28.45–34.14 nm. The best inhibition zone diameter was obtained for ampicillin (30.66 mm), followed by ertapenem (15 mm) and Tio2(10 mm). Colistin without inhibition zone was identified as ineffective group. Conclusion: Due to the development of drug resistance to antibiotics, the production and synthesis of antimicrobial agents is one of the requirements of the current time. Due to the excellent synthesis of Tio2 and the presence of very fine nanoparticles, it can be used as a strong antimicrobial compound, especially on S. aureus infection.

Optimization of scaffolds for localized drug delivery: An In vitro study Archana A Gupta, Supriya Kheur, Ravindra V Badhe, Anagha Godse, Ankita Shinkar, A Thirumal Raj Journal of Pharmaceutical Negative Results 2019 10(1):21-24 Background: In oncology, major surgical interventions are often followed by an interim period of 3–6 months allowing the patient to recover, following which conventional radiotherapy and chemotherapy are initiated. Lack of therapeutic interventions in the interim period allows proliferation of the residual tumor cells. Thus, introducing a treatment modality in the interim period which inhibits tumor cells without exuberating the postsurgical morbidity is the need of the hour. The objective of the study is to fabricate biodegradable cross-linked scaffolds incorporated with an anticancer drug and optimization of scaffolds for drug release. Materials and Methods: Qualitative and quantitative characterization of the drug was done with the help of high-performance liquid chromatography (HPLC) and ultraviolet (UV) analysis. Three-dimensional (3D) discs of biodegradable scaffolds were prepared with anticancer drugs in aqueous solution in different concentrations along with crosslinkers. Discs were studied for their release kinetics with the help of HPLC. Results: HPLC analysis of the 3D-discs revealed negative results. There was no sign of cisplatin absorbance after the scaffold immersion in the solution. The results were attributed to the rapid degradation of the drug. Conclusions: Although scaffold-mediated local chemotherapy holds a great potential to replace conventional chemotherapy as a postsurgical treatment modality, several practical limitations need to be addressed. Modification in the research methodology including a shorter time for preparing the scaffold and freeze-drying the scaffold material using lyophilization instead of normal drying could prevent degradation of the drug.

Hibiscus sabdariffa linn fruits methanolic extract and fractions mediated glucose uptake stimulation and glucose transporter 4 regulation Raheem Mohssin Shadhan, Siti Pauliena Mohd Bohari, Zainah Adam, Haryati Jamaluddin Journal of Pharmaceutical Negative Results 2019 10(1):25-31 Objective: As such, this study reports the effects of Hibiscus sabdariffa Linn fruit methanolic extract and fractions (ethyl acetate, n-hexane, and butanol) on glucose uptake stimulation, as well as regulation of glucose transporter-4 (GLUT4) in L6 myotubes and 3T3F442A adipocytes cells. Materials and Methods: The stimulating effects of methanolic extract and fractions of H. sabdariffa Linn fruit on glucose uptake in 3T3F442A adipocytes through in vitro assay assessment are reported. The GLUT4 translocation of L6 myotubes membrane was also investigated. Results: The outcomes of this study revealed that methanolic extract and fractions were unable to induce glucose uptake in 3T3F442A adipocytes. In addition, the methanolic extract and fractions were incapable of enhancing both the distribution and the regulation of GLUT4 in L6 myotubes, in relation to the control. Conclusion: The systematic empirical works performed in this study conclude that the H. sabdariffa Linn derivatives are unsuitable potentials for the progression of new anti-diabetic drugs.

Biological evaluation of certain plants of family salicaceae and arecaceae Naglaa Ismail Afifi, Abeer Sayed Moawad, Mohamed Ahmed Zaki, Mona Hafez Hetta, Rabab Mohammed Mohammed Journal of Pharmaceutical Negative Results 2019 10(1):32-35 Objective: There is an increasing interest in the use of natural products to oppose human diseases. The leaves of Flacourtia rukam Zoll and A. Mortizi, Archontophoenix alexandrae (Wendl. and Drude), and Dictyosperma album (Bory) H. Wendl. and Drude ex. Scheff were selected for phytochemical and biological screening to search for new natural drugs. Total ethanolic extracts of the mentioned plants were subjected to preliminary phytochemical screening followed by screening their cytotoxic, antimalarial, antimicrobial, and anti-inflammatory activities. Materials and Methods: The extracts were tested for the presence of various phytochemicals. The cytotoxic activity was determined against five human cancer cell lines: melanoma, breast, oral, ovarian, and cervical cancers and two noncancerous cell lines. The antimalarial activity was determined against chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum depending on the plasmodial lactate dehydrogenase activity. Antimicrobial screening was continued using the modified version of the CLSI method whereas anti-inflammatory activity was determined by measuring the activity of inducible nitric oxide synthase (iNOS). Results: Preliminary phytochemical screening indicated the absence of alkaloids, anthraquinones, and saponins in all the extracts. The latter showed no toxicity against the tested cancer cell lines and no activity against the tested microbes. The extract of D. album lacks the activity against D6 and showed a moderate activity against W2 P. falciparum (IC50= 41.7 μ/mL). D. album extract showed no inhibition for iNOS as contrary to F. rukam and A. alexandrae extracts which showed a good inhibition (IC50= 20 and 100 μ/mL, respectively). Conclusion: All tested extracts lack cytotoxic and antimicrobial activities.

Neurobehavioral activity study of methanolic whole plants extract of Cyperus rotundus Linn. Imonul Kabir, Subir Biswas, Md Asaduzzaman, Md Islam Molla, Md Rajdoula Rafe Journal of Pharmaceutical Negative Results 2019 10(1):36-40 Background: Cyperus rotundus commonly known as “nutgrass” is extensively used in traditional Chinese and Indian Ayurvedic medicine. It is traditionally used to treat fevers, digestive disorders, wound, and bruises. Materials and Methods: This study evaluated the sedative-hypnotic and antidepressant effect of the methanolic extract of C. rotundus (MECR). To perform this study, the whole plants of C. rotundus were taken for extraction with methanol following soaking process and tested for acute toxicity on mice first. The sedative and hypnotic activity were then studied performing hole board and open field tests in albino mice model at the doses of 100 and 200 mg/kg body weight of MECR. Diazepam at the dose of 1 mg/kg was utilized as a standard drug in both experiments. Similarly, antidepressant activity test was also performed using forced swimming test and tail suspension test. Nortriptyline was used as a standard to assess antidepressant activity. Results: We found that MECR produced an insignificant dose-dependent effects against locomotors activity of mice both in hole cross and open field tests. Besides, it was also noticed after analyzing forced swimming and tail suspension test that it has no significant antidepressant activity. Conclusion: Taken together, our study suggests that MECR do not possess notable sedative-hypnotic and antidepressant or neurobehavioral properties.

Effect of ethanolic extract of leaves of Solanum trilobatum on scopolamine-induced memory impairment in Sprague Dawley rats Subramani Parasuraman, Siaw Sze Hoong, Parayil Varghese Christapher, Lim Nian Zou, David Lim De Wei, Sunderesan Loshini, Teoh Huey Ching, Chong Hao Leong Journal of Pharmaceutical Negative Results 2019 10(1):41-46 Objective: The objective of the study is to determine the effect of ethanolic extract of leaves of Solanum trilobatum (EEST) on scopolamine-induced memory impairment in Sprague Dawley (SD) rats. Materials and Methods: The leaves of S. trilobatum were extracted with ethanol and used for the study. The SD rats were divided into six groups each consist of six animals, namely normal control; scopolamine control; donepezil treated 3 mg/kg; and EEST treated 100, 200, and 400 mg/kg, respectively. Except normal control, all other animals were administered with intraperitoneal injection of scopolamine (1 mg/kg body weight) for 21 days to induce memory impairment. Donepezil and EEST were administered once daily through oral gavage for 21 consecutive days. On prestudy, 7th, 14th, and 21st days of the experiment, the animals' locomotor activity, muscle grip strength and escape latency time (ELT) were measured. At the end of the study, blood samples were collected from all the animals and they were sacrificed; the organs such as brain, liver, lung, heart, kidney, and stomach were harvested, and absolute organ weight was measured. Blood samples were used for the biochemical analysis. Results: The rats treated with EEST 100, 200, and 400 mg/kg did not show any change in locomotor activity and grip strength and significantly reduced motor resistance. The animals treated with donepezil showed a significant reduction in ELT. The animals treated with EEST 100 and 200 mg/kg showed significant increases in ELT, whereas animals treated with EEST 400 mg/kg did not show significant changes in ELT compared with that of prestudy. At the end of the study, EEST-treated animals did not show significant changes in biochemical parameters, whereas donepezil-treated animals showed a significant increase in cholesterol level compared with control animals. Furthermore, EEST did not affect regular body weight gain, absolute and relative organ weight. Conclusion: EEST did not show neuroprotective effect at lower doses in rats, but the high dose (400 mg/kg) prevented scopolamine-induced memory impairment, and this effect is not significant when compared with standard donepezil.

Effects of Vitamin D3 supplementation on the hematological indices in women presented with iron deficiency anemia: An open-labeled clinical trial Marwan S. M Al-Nimer, Raz M HamaSalih Journal of Pharmaceutical Negative Results 2019 10(1):47-51 Objectives: Vitamin D inhibits erythropoiesis in healthy, young individuals, despite its positive effect on the absorption of iron. This study aimed to investigate the effects of Vitamin D supplements as add-on therapy on the hematological indices of adults presented with iron deficiency anemia (IDA). Materials and Methods: Eighty-two women aged 20–45 years with IDA were recruited from Shar Teaching Hospital and the Center of Blood Diseases in Sulaimani city, North Iraq. The patients were grouped into Group I (n = 35) treated with elemental iron and Group II (n = 47) treated with elemental iron plus Vitamin D3 supplements (oral dose of 300,000 IU every 2 weeks), for 8 weeks. Hematological indices and the serum ferritin were determined before the treatment and after 8 weeks of treatment. Results: Vitamin D3 supplements significantly elevate the total white cell count and decreased platelet indices values. It decreased the platelet-to-lymphocyte ratio significantly from 123.24 ± 32.00 to 107.68 ± 30.06, P < 0.001. The serum ferritin level did not normalize after 8 weeks of treatment with elemental iron and Vitamin D3 supplements. Conclusions: Vitamin D3 supplement as the add-on therapy is less effective in IDA, and it impacts negatively against the blood platelet indices.

Effect of Otostegia persica extract on blood glucose in patients with type II diabetes Ghazal Ataabadi, Najmeh Shahinfar, Gashtasb Mardani, Mostafa Gholami Journal of Pharmaceutical Negative Results 2019 10(1):52-56 Introduction: Type 2 diabetes mellitus is an important metabolic disease that causes disability and involves small and large vessels. Many herbal drugs have been used for the treatment of high blood sugar (BS) with promising results. One of these medicinal drugs used conventionally in medicine by the people and active physicians is Otostegia persica. The aim of this study was to investigate the effect of O. persica extract on blood glucose in diabetic patients with insulin therapy. Materials and Methods: A total of 56 patients with type 2 diabetes were included in the study and were divided into two groups of 28 each. The intervention and nonintervention groups included 22 (78.6%) and 6 (21.4%) female patients as well as 19 (67.9%) and 9 (32.1%) male patients, respectively. Results: Due to homogenization resulting from random selection among aspartate transaminase, alanine transaminase, creatinine, insulin, blood urea nitrogen, Antibiotics (Antib), An mdaB mutant strain in a quinone reductase (MdaB) variables, significant differences were not observed between the two groups of participants before the study. Furthermore, there was no significant difference among the variables of H1c, BS5, HD1, fasting BS (FBS), low-density lipoprotein (LDL), and triglycerides in two groups before the study. However, there were differences among variables H1c, BS5, FBS, high-density lipoprotein (HDL), LDL, and HDL between the two groups of participants after the study, but they were not statistically significant (P > 0.05). Conclusions: The results of the test did not show statistically significant differences among these variables during 3 months. Therefore, in order to conclude more comprehensive and safer application for diabetes treatment, it is suggested to examine the effects of these drugs in a more extensive area using oral and injection doses as well as investigate pure effects of active materials.