Test Drug Research Articles

A Scoping Review of Australian Literature on People Who Use MDMA and Their Harm Reduction Practices

Background: Discourses around MDMA are often predominantly concerned with identifying risk and characterizing harm. Reluctance from Australian governments to reform drug policy and implement harm reduction services has created a policy and service gap, and it is therefore pertinent to consider how people who use MDMA mediate potential harms, and how this knowledge can inform approaches to drug use and policy reform. This community-led scoping review aimed to identify Australian literature on the practices of harm reduction strategies by people who use MDMA. Methods: Seven topic-specific and multidisciplinary databases were searched in February 2023 in line with conventional scoping review methodology. Eligible articles were published from 2002 onwards, reported on the voices of people who use MDMA as primary evidence within the context of Australia, and included at least one strategy to reduce harm. Data were analyzed by drawing on conventional content analysis and thematic analysis frameworks. Results: Twenty-three peer-reviewed and gray literature sources were included. Five key themes were identified on how people mediate harms and enhance the pleasurable aspects of MDMA use: drug consumption practices, planning and preparation, testing drugs, accessing health services, and community care practices. Conclusion: The results suggest that people who use MDMA take care to identify and reduce unwanted harms. The way people who use MDMA make decisions around drugs is mediated by peer groups and online technologies, as well as broader social and cultural contexts of drug use and drug prohibition. More qualitative, participatory, and action research projects are recommended to accurately reflect the views and needs of people who use MDMA and meaningfully shape service reform.

DDDR-29. TARGETING FGFR FUSIONS: A CASE OF CATEQUENTINIB (AL3818) AND TEMOZOLOMIDE COMBINATION THERAPY FOR RECURRENT MGMT METHYLATED TACC-FGFR FUSION POSITIVE GLIOBLASTOMA

Abstract BACKGROUND There is no gold-standard for the management of recurrent glioblastoma (GBM). However, advances at the interface of molecular testing and rational drug design have opened avenues for personalized medicine. Here we describe the case of a 52-year-old patient with recurrent GBM (WHO grade 4) with known FGFR3-TACC3 fusion and MGMT promoter methylation by Caris molecular profiling. Initial treatment included radiotherapy with concomitant and adjuvant temozolomide. However, after 18 months off therapy, the patient became clinically and radiographically progressive with multifocal disease. Herein, we describe our experience with temozolomide and catequentinib (AL3818) in a single patient. METHODS We reviewed the available literature on targeting FGFR3-TACC3 fusion positive glioblastoma with catequentinib (1-[[[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-Yl] oxy] methyl] cyclopropanamine dihydrochloride). Catequentinib is an oral small-molecule pan-kinase inhibitor with selective VEGFR2 inhibition, it is under investigation in multiple phase 2 and 3 clinical trials and can safely be administered concomitantly with temozolomide. We obtained single-patient Investigational New Drug (IND) approval and free drug was shipped directly from the manufacturer (Advenchen Laboratories; Jiangsu Chia-Tai Tianqing Pharmaceutical) to our institution’s investigational chemotherapy pharmacy. We administered catequentinib 12 mg by mouth for 14 days on and 7 days off of a 21-day cycle along with temozolomide 50mg/m2/day of a 28-day cycle with routine monitoring of laboratory parameters. RESULTS The combination of temozolomide and catequentinib was well-tolerated, resulted in clinical stability, and partial radiographic response at 3-month follow-up. CONCLUSION Catequentinib in combination with metronomic temozolomide was well tolerated in this single patient. This patient’s response shows the promise of intentional, patient-specific care at the intersection of molecular testing and rational drug design. The patient will continue therapy and updated clinical and radiographic outcomes will be presented.

Safety Assessment of AYUSH SC-3 through Acute and 90 Days Repeated Dose Oral Toxicity Study

The present study is focused on establishing the safety of the formulation through acute and 90 days of repeated oral dose toxicity as per the Organization for Economic Cooperation and Development (OECD) guidelines. During the acute toxicity test, the drug was orally administered at a limited test dose of 2000 mg/kg. Clinical signs, feed and body weight were recorded. At the end of 14 days, the animals were euthanized and subjected to a detailed post-mortem examination (necropsy). As per OECD, 408 the 90 days repeated dose oral toxicity study was carried out with three different doses of test drug i.e., 1500, 1000 and 500 mg/kg. Cage side observations, body weight and feed intake were recorded. Upon termination of the study, urine analysis, haematology and clinical biochemical examinations were performed. Finally, the rats were subjected to euthanasia, a gross necropsy was conducted and vital organs were weighed and made prone for histopathological evaluation. Cage-side observation of AYUSH-SC-3 treated animals showed no signs of toxicity, and the mortality or moribund state was observed in both of the studies. No significant change in body weight and feed intake was seen in AYUSH-SC-3 treated animals. Gross morphology and necropsy findings of the animals revealed no treatment-related. Haematological and biochemical parameters of rats treated with AYUSH-SC-3 were found to be non-significant when compared to the control group. Necropsy findings and relative organ weights did not change significantly. Further, the histopathological analysis of major organs showed no major lesions and treatment-related changes. The LD50 of AYUSH SC-3 is greater than 2000 mg/kg and NOAEL is up to 1500 mg/kg.

Characterization of anti-drug antibody dynamics using a bivariate mixed hidden-markov model by nonlinear-mixed effects approach

Biological therapies may act as immunogenic triggers leading to the formation of anti-drug antibodies (ADAs). Population pharmacokinetic (PK) models can be used to characterize the relationship between ADA and drug disposition but often rely on the ADA bioassay results, which may not be sufficiently sensitive to inform on this characterization.In this work, a methodology that could help to further elucidate the underlying ADA production and impact on the drug disposition was explored. A mixed hidden-Markov model (MHMM) was developed to characterize the underlying (hidden) formation of ADA against the biologic, using certolizumab pegol (CZP), as a test drug. CZP is a PEGylated Fc free TNF-inhibitor used in the treatment of rheumatoid arthritis and other chronic inflammatory diseases.The bivariate MHMM used information from plasma drug concentrations and ADA measurements, from six clinical studies (n = 845), that were correlated through a bivariate Gaussian function to infer about two hidden states; production and no-production of ADA influencing PK. Estimation of inter-individual variability was not supported in this case. Parameters associated with the observed part of the model were reasonably well estimated while parameters associated with the hidden part were less precise. Individual state sequences obtained using a Viterbi algorithm suggested that the model was able to determine the start of ADA production for each individual, being a more assay-independent methodology than traditional population PK. The model serves as a basis for identification of covariates influencing the ADA formation, and thus has the potential to identify aspects that minimize its impact on PK and/or efficacy.

Exploring the benefits of in-diet versus repeated oral dosing of saracatinib (AZD0530) in chronic studies: insights into pharmacokinetics and animal welfare.

Saracatinib/AZD0530 (SAR), a Src tyrosine kinase inhibitor, mitigates seizure-induced brain pathology in epilepsy models upon repeated oral dosing. However, repeated dosing is stressful and can be challenging in some seizing animals. To overcome this issue, we have incorporated SAR-in-Diet and compared serum pharmacokinetics (PK) and brain concentrations with conventional repeated oral dosing. Saracatinib in solution or in-diet was stable at room temperature for >4 weeks (97 ± 1.56%). Adult Sprague Dawley rats on SAR-in-Diet consumed ~1.7 g/day less compared to regular diet (16.82 ± 0.6 vs. 18.50 ± 0.5 g/day), but the weight gain/day was unaffected (2.63 ± 0.5 g/day vs. 2.83 ± 0.2 g/day). Importantly, we achieved the anticipated SAR dose range from 2.5-18.7 mg/kg of rat in response to varying concentrations of SAR-in-Diet from 54 to 260 ppm of feed, respectively. There was a strong and significant correlation between SAR-in-Diet dose (mg/kg) and serum saracatinib concentrations (ng/ml). Serum concentrations also did not vary significantly between SAR-in-Diet and repeated oral dosing. The hippocampal saracatinib concentrations derived from SAR-in-Diet treatment were higher than those derived after repeated oral dosing (day 3, 546.8 ± 219.7 ng/g vs. 238.6 ± 143 ng/g; day 7, 300.7 ± 43.4 ng/g vs. 271.1 ± 62.33 ng/g). Saracatinib stability at room temperature and high serum and hippocampal concentrations in animals fed on SAR-in-Diet are useful to titer the saracatinib dose for future animal disease models. Overall, test drugs in the diet is an experimental approach that addresses issues related to handling stress-induced variables in animal experiments.

Evaluation of Diuretic Activity of Siddha Poly Herbal Formulation <i>Vithu Vagai Chooranam</i> in Rodents

The current pharmacological investigation was performed to study the diuretic activity of Siddha polyherbal formulation Vithu Vagai Chooranam (VVC) in Wistar albino rats using the Lipschitz method. The animals were divided into four Groups (I, II, III, and IV) of six rats (n = 6) each. Group I served as control treated with milk (1ml/kg p.o), and Group II received Standard furosemide (10 mg/kg, p.o). Groups III and Group IV were treated with test drug at a dose of 70mg/kg and 90mg/kg, p.o, respectively. The urine volume, pH, and electrolyte concentration (Na+, K+ and Cl-) were estimated at the end of 24 hours. Diuretic index, Lipschitz values, and natriuretic index were also calculated from the results to make a comparison with control and furosemide-treated groups. Statistical analysis was carried out using a one-way analysis of variance, followed by Dunnett’s ‘t’ test. Oral administration of VVC at both doses significantly increased the urine output and concentration of urinary electrolytes (p < 0.01). The VVC-induced diuresis pattern was almost like that of frusemide. The findings revealed that the Vithu vagai chooranam possessed significant diuretic activity in experimental rats.

Pharmacological activity of calcium lactate on a model of dysbiosis in rats

Relevance. Under the influence of endogenous and /or exogenous factors, the intestinal microflora inhabiting all parts of the gastrointestinal tract may change, which disrupts the normal course of physiological processes, and in some cases leads to severe pathological conditions. One of the reasons for the development of intestinal dysbiosis is the use of antibacterial drugs. Thus, the search and development of means for the prevention and treatment of dysbiosis is an urgent task.Goal. The aim of the study was to evaluate the effectiveness of a candidate for a calcium lactate-based drug with repeated intragastric administration on a model of antibiotic-induced dysbiosis in rats.Methods. The study used 40 male Wistar rats (four groups of 10 animals each). A model of antibiotic-induced intestinal dysbiosis was tested in rats by a course of intragastric administration of a combination of amoxicillin and clavulanic acid for 7 days at a dose of 75 mg/kg. The development of dysbiosis was confirmed by a change in the quantitative composition of representatives of the intestinal microbiota. Similarly, for 7 days, the test drug was administered in doses of 5 mg/kg, 25 mg/kg, 125 mg /kg daily 2 hours after the introduction of the pathology inducer. The control group received a 1 % starch solution.Results. The peak of dysbiosis development was recorded on the 4th day of pathology induction. The use of calcium lactate at a dose of 5 mg/kg did not have a significant effect, while in the groups receiving calcium lactate at doses of 25 mg/kg and 125 mg/kg, there was a statistically significant (Mann-Whitney criterion, p < 0.05) decrease in the severity of the pathological process compared with the negative control group.Conclusion. According to the results of this study, it was found that the use of calcium lactate in doses of 25 mg/kg and 125 mg/kg contributed to a faster disappearance of symptoms of dysbiosis and normalization of the intestinal microbiota in comparison with animals that did not receive treatment.

Pharmacological investigation of vitamin E with combined oral contraceptives on INHBA gene against PCOS that intricate through melatonin PKC pathway

The most prevalent endocrine and metabolic condition in women of reproductive age are polycystic ovary syndrome (PCOS) with significant risk factors such as circadian rhythm and melatonin disruption. The aim of this study is to assess the effect of vitamin E in combination with a combined oral contraceptive (COC) on continuous light-induced PCOS using hormonal measures, oxidative stress (OS) indicators, and the inhibin beta-A (INHBA) gene, which targets the melatonin protein kinase C (PKC) pathway. An in silico technique anticipated INHBA's binding affinity for vitamin E and COC. For the in vivo investigation (IAEC/240/2021), female SD rats were divided into six groups and subjected to a 16-week induction period, followed by a 2-month test drug treatment with drospirenone (DRSP) as a standard. Serum testosterone, FSH, melatonin, and OS were calculated as hormonal markers. The expression of the INHBA gene was studied to see if it could be linked to the circadian rhythm and OS via the melatonin PKC pathway. According to the in silico study, vitamin E and DRSP had higher binding energy for the INHBA (–8.6 kcal/mol and –8.4 kcal/mol, respectively). When compared to the control group, in vivo results showed a substantial decrease in testosterone levels (p = .05), as well as changes in FSH (p = .78) and melatonin (p = .13). IHNBA gene expression has also dramatically increased, stimulating FSH production in the pituitary gland. Vitamin E and COC concomitantly are beneficial against PCOS because it modulates OS, which in turn influences circadian rhythm and the melatonin PKC pathway.

Abstract 23 — Ameliorative Effect of Biogenic Silver Nanoparticles Mediated with Naringin Against Collagen Induced Rheumatoid Arthritis in Rodents by Acting on Inflammation and Gut Microbiota

Background Rheumatoid arthritis (RA) hallmarked by functional impairment in joints due to inflammation, destruction and erosion of cartilages and bones. RA accounts as a major healthcare burden globally, hence there is a requirement of a novel therapeutic approach. Naringin is a flavanone glycoside possessing a variety of pharmacological activities in addition to anti-inflammatory and antioxidant properties. Among various metal oxide nanoparticles, silver nanoparticle drawing the attention of researchers as it possesses anti-inflammatory activity and utilized widely as a delivery vehicle for various natural anti-inflammatory drugs against RA. The study was designed to explore the effect of biogenic silver nanoparticles mediated with naringin (NAgNP) against RA induced by type II collagen, inflammation and gut microbiota in wistar rats. Methods NAgNPs were synthesized by co-precipitation method and characterized by various characterization techniques. Rats were employed for the study and randomized into five groups. Except control group, each group was treated with bovine type-II collagen (intradermal injection, 100 [Formula: see text] g) suspended in Freund’s complete adjuvant. On day 21 of the study, bovine type-II collagen and booster incomplete Freund’s adjuvant were again provided. Vehicle (Con), Methotrexate (Std, 3 mg/kg) and Test drugs, i.e., NAgNP, at three different dose levels (2, 4 and 8 mg/kg) were given in respective groups for consecutive 21 days. On the last day of study, various biochemical parameters including pro-inflammatory cytokine level in serum and the status of gut microbiome population were assessed with Illumina HiSeq. Results Characterization techniques confirmed the formation of spherical NAgNP with a size range of 80-100 nm. Data revealed that the groups administered with NAgNP exhibited a statistically significant decrease in (p < 0.01) rat paw swelling as well as arthritis scores than the control group. Different inflammatory markers such as IL-1[Formula: see text], IL-6, IL-7 and TNF-[Formula: see text] were found to be significantly reduced as compared to the control group. Significant improvement in the gut microbial population by alleviating the relative level of various microbes associated with inflammation was also observed. Conclusion NAgNP can be utilized as a beneficial candidate in the management of RA by the mechanism of amelioration of inflammation and gut microbiota.

ANTI-INFLAMMATORY ACTIVITY OF SIDDHA POLYHERBAL FORMULATION SEVVIYADHI CHOORANAM ON CARRAGEENAN INDUCED PAW EDEMA IN WISTAR ALBINO RATS

Objective: The aim of the study was to explore the anti-inflammatory activity of Siddha polyherbal formulation Sevviyadhi chooranam in Carrageenan induced paw edema in wistar albino rats, and compared with the standard drug Indomethacin. Methods: The Siddha polyherbal formulation Sevviyadhi chooranam indicated for sinusitis was prepared based on GMP (Good Clinical Practice) guidelines. Study procedure was approved by Institutional Animal Ethics Committee (IAEC). The experimental animals were measured for paw edema volume at 1, 2, 3, 4, 5 h using Plethysmometer (Model 7150 UGO Basile, Italy). Edema was expressed as mean increase in paw volume relative to control animals. And then, findings were compared with Indomethacin (Standard drug). Results: The findings revealed that test drug Sevviyadhi chooranam at higher dosage 200 mg/kg (Group V) had equal effect on anti-inflammatory activity with percentage protection of 93.2% when compared with the standard drug Indomethacin at about 40 mg/kg (Group III) with percentage protection 93.2%. However, the test drug Sevviyadhi chooranam at a higher dosage 200 mg/kg (Group V) with a percentage protection 93.2% was highly effective when compared with lower dosage about 100 mg/kg (Group IV) with a percentage protection 27.12%. Hence, the study resulted that the Siddha polyherbal formulation Sevviyadhi chooranam has an optimistic anti-inflammatory activity with more therapeutic value. Conclusion: The study concluded that the Siddha polyherbal formulation Sevviyadhi chooranam has a promising anti-inflammatory activity, probably due to the presence of biologically active phytocompounds. However, it is important to admit that there are some scientific evidences of the potential actions of these phytocompounds in anti-inflammatory activity.

Physicochemical, Heavy Metal Analysis, HPTLC, Gas Chromatography-Mass Spectrometry, Antibacterial, and Antioxidant Activity of an Ethanol Extract of Viola pilosa Blume Whole Plant

IntroductionQuality control of herbal products remains a big challenge. There needs to be more than the physicochemical parameters to authenticate and differentiate adulterants in medicinal plants. Viola pilosa is one of the herbs used to treat various bodily ailments. This study aims to evaluate the quality control, HPTLC, and gas chromatography-mass spectrometry (GC-MS) fingerprint profiles of the whole plant of V pilosa. The in-vitro antimicrobial and antioxidant activities of the ethanolic extract of V pilosa were also studied. MethodsThe physicochemical standardisation and the heavy metal analysis of the whole plant of V pilosa coarse powder were carried out using standard methods. High-performance Thin layer chromatography and Gas chromatography - Mass spectroscopy (HPTLC and GC-MS) analyses of the ethanol extract of V pilosa were performed using standard methods. The in-vitro antioxidant properties of the ethanolic extract on DPPH and its antimicrobial effects against different microbes were also investigated. ResultsThe physicochemical properties of V pilosa have shown that all the parameters were within the permissible limits. The HPTLC fingerprint profile of the ethanolic extract exhibited 14 peaks under UV 254 nm and seven peaks under UV 366 nm. The GC-MS analysis illustrated the presence of 10 bioactive compounds in the test sample. The ethanolic extract showed significant antimicrobial activity against certain organisms and promising antioxidant activity. ConclusionsThe quality control findings revealed that the test drug was free from adulterations. The physicochemical constants, HPTLC, and GC-MS profiles of V pilosa can be essential data in the future. This herb's ethanolic extract may treat infectious and inflammatory diseases.

Comparative Physicochemical Evaluation and Acute Toxicity Study of Crude and Processed (Detoxified) Samples of <i>Saqmunia</i> (<i>Convolvulus scammonia</i> L.) in Albino Wistar Rats

Background and Objectives: Tadbīr va Islāh-i-Adwiya (detoxification/rectification of drugs) is a distinctive concept of Unani medicine in which drugs that are toxic by nature are detoxified before being administered to the human body. In Unani medicine, the resin called Saqmunia which is a derivative of the rhizome of Convolvulus scammonia, is used for therapeutic purposes. So far, limited research studies have been carried out to appraise the age-old concept of detoxification of Unani drugs. Therefore, the present study was designed to explore the physicochemical characteristics and acute toxicity of crude and detoxified samples of Saqmunia in albino Wistar rats. Methods: Saqmunia was detoxified through the tashwiya (roasting) method using apple and cow dung cakes. The physicochemical standardization includes moisture content, different ash values, extractive values; pH, fluorescence analysis, and TLC were performed. The acute toxicity study of both samples of Saqmunia was carried out at 300 and 2000 mg/kg dose levels in female albino Wistar rats. The data were analyzed using Oneway ANOVA followed by Dunnett’s comparison test. Results: The findings of the physicochemical standardization of crude and detoxified Saqmunia were found to be within an accepted range. The acute toxicity study has shown that the non-detoxified form of the test drug produced maximum toxicities, even causing death in rats. The LD50 of crude and detoxified Saqmunia was found to be 1000 mg and > 2000 mg/kg, respectively, in rats. Conclusions: The present study has suggested that Saqmunia used in this study was of good quality, and the physicochemical constants found in this study may be taken as a reference for future studies. Moreover, the acute toxicity study validates the Unani concept of detoxification of drugs, as is evident from the minimal toxic effects found in the detoxified sample of Saqmunia as compared to the crude sample in rats.

Amaranthus viridis improves relative anxiety behaviour and cognitive deficit in rotenone induced Parkinsonism in albino rats

Background: Parkinson’s disease (PD) is typically characterised by motor shortfalls. However, non-motor symptoms like mood disorders (anxiety, depression) and impaired cognition are also associated features. Previous studies have demonstrated a neuroprotective effect a plant against a disease. Consequently, this current study was focused on assessing its efficacy in extenuating non-motor shortfalls such as anxiety-like behaviour and impaired cognition induced by rotenone. Methods: PD was induced in rats by administering rotenone (10 mg/kg BW orally) for 28 days. The vehicle and the test drug were given orally daily for one hour prior to rotenone administration. The protective effect of methanol extract of A. viridis (500 mg/kg BW) was assessed through an array of tests; elevated plus maze test, Morris water maze test, and novel object recognition test. The rats were sacrificed on day 28th and neurobiochemical analyses of the hippocampus were performed using HPLC. Results: The findings of this study showed that co-administration of A. viridis reversed the rotenone-induced anxiety-like behaviour and cognitive shortfalls to a significant extent (p<0.001). It also restored the hippocampal neurotransmitters [(5-hydroxytryptamine (5-HT), 5-hydroxy indole acetic acid (5-HIAA), and dopamine (Da)] significantly (p<0.001). Conclusions: Amaranthus viridis offered neuroprotective effects that ameliorate non-motor symptoms in PD. This could be a novel insight into the therapy of PD. This study provides scientific evidence that A. viridis attenuates non-motor symptoms like anxiety-like behaviour and cognitive deficits in Parkinsonism. This extract can be a potential candidate in herbal formulations as a neuroprotectant against PD.

Y-site injection physical compatibility of remdesivir with select intravenous drugs used in palliative care and for treating coronavirus disease 2019.

No compatibility tests are available for remdesivir other than 0.9% sodium chloride. In this study, we aimed to evaluate the physical compatibility of remdesivir with drugs used in palliative care and COVID-19 treatment. Remdesivir was tested for compatibility with 10 different drugs (fentanyl, morphine, hydromorphone, oxycodone, heparin, furosemide, octreotide, acetated Ringer's injection, 2-in-1 peripheral parenteral nutrition, and 2-in-1 total parenteral nutrition). Remdesivir was formulated to a final concentration of 1 mg/mL, and the other drugs were prepared at clinical concentrations. Three test solutions were used for compatibility testing, with remdesivir and the target drugs compounded in a 1:1 ratio. Appearance measurements, including Tyndall effect, turbidity, and pH, were performed immediately after mixing and at 1 h and 4 h after mixing. Changes in appearance, including the Tyndall effect, turbidity (turbidity change of ≥ 0.5 nephelometric turbidity unit [NTU] based on control solution for each test drug), and pH (a change of ≥ 10% based on the pH immediately after mixing) were used to determine physical compatibility. All the drugs tested were compatible with remdesivir. The combination of remdesivir and furosemide produced the highest turbidity (0.23 ± 0.03 NTU) 1 h after mixing. The lowest and highest pH values were observed at 4 h after mixing for the combinations of remdesivir and morphine (3.23 ± 0.02) and remdesivir and furosemide (8.81 ± 0.06). The drugs tested in this study show Y-site physical compatibility with remdesivir.

Comprehensive Evaluation of the Clinical Efficacy of an Anti-Diabetic Polyherbal Formulation

Background: There are several clinical studies examining the health advantages of several single medicinal herbs utilized in traditional blood glucose-lowering treatments. But very few or no studies on herbal formulations were made as Polyherbal for the same goal. As a result, it is now necessary to confirm that patients with hyperglycemia can benefit from such Polyherbal medicines as Dolabi. Methods: This prospective open-label, herbal coded test drug-controlled, randomized trial was conducted at the Munshiganj and Dhaka area in Bangladesh. We enrolled 108 male and 104 female patients of 30-70 years with primary and moderate hyperglycemia. They were recruited from the OPD of an Unani & Ayurvedic hospital in Munshiganj and different Unani clinics in Dhaka, Bangladesh after fulfilling the inclusion criteria. Patients were randomly assigned to receive metformin hydrochloride 500 mg two times daily and 2 tablets of Dolabi two times daily by using a random numbers table with the help of an assistant. Blood samples, height, weight, blood pressure, and personal data were recorded—laboratory results were obtained at the study baseline, after 1.5 months and after 3 months of intervention. Results: In the case of the test drug, results showed a significant decrease in blood glucose level between the baseline and after 3 months, in males, it was from 9.83±1.17 to 7.72±1.06 mg/dL for fasting glucose, from 16.60±2.35 to 8.23±1.17 mg/dL for 2 hours PP glucose, from 9.33±1.17 to 7.45±2.03 percent for HbA1c and for Insulin it reduces from 183.10±27.59 to 168.10±29.59 pmol/ L. The control drug metformin hydrochloride also showed a significant decrease in blood glucose level between baseline and after 3 months, in the case of males it was from 9.99±2.52 to 6.97±1.76 mg/dL for fasting glucose, from 17.43±5.05 to 7.89±2.42 mg/dL for 2 hours PP glucose, from 10.43±2.36 to 6.87±1.18 percent for HbA1c and for Insulin it reduces from 198.75±30.61 to 183.75±30.61p mol/L. In the case of females the test drug showed a significant reduction in fasting glucose, 2 hours PP glucose, HbA1c and Insulin between the baseline and after 3 months, it was from 10.02±1.11 to 7.78±0.93 mg/dL, from 16.88±2.21 to 8.16±1.11 mg/dL, from 9.84±1.04 to 7.45±1.03 percent and from 199.47±30.90 to 173.47±30.90 mg/dL respectively. In the case of females, the control drug showed a significant reduction in fasting glucose, 2 hours PP glucose, HbA1c and Insulin between baseline and after 3 months, it was from 10.18±1.92 to 6.71±1.59 mg/dL, from 18.70±3.88 to 7.60±3.74 mg/dL, from 10.58±1.08 to 6.98±1.08 percent and from 200.00±31.83 to 188.00±31.83 mg/dL respectively. Conclusions: We can infer the following from the present study’s findings: The polyherbal formulation Dolabi is able to reduce the blood glucose level. It can be an effective drug for primary hyperglycemic patients.

Sclareol exerts synergistic antidepressant effects with quercetin and caffeine, possibly suppressing GABAergic transmission in chicks

This study evaluated the effects of sclareol (SCL) with or without caffeine (CAF) and quercetin (QUR) using in-vivo and in-silico studies. For this, 5-day-old chicks weighing between 45 and 48 g were randomly divided into five groups and treated accordingly. The chicks were monitored to compare the occurrence, latency, and duration of sleep as well as the loss and gain of righting reflex in response to SCL-10 mg/kg, CAF-10 mg/kg, and QUR-50 mg/kg using a thiopental sodium (TS)-induced sleeping model. Data were analyzed by one-way ANOVA followed by t-Student–Newman-Keuls' as a posthoc test at 95% confidence intervals with multiple comparisons. An in-silico study was also performed to investigate the possible antidepressant mechanisms of the test and/or standard drugs with different subunits of GABAA receptors. In comparison to the SCL, CAF, and QUR individual groups, SCL+CAF+QUR significantly increased the latency while decreasing the length of sleep. The incidence of loss and gain of the righting reflex was also modulated in the combination group. SCL showed better interaction with GABAA (α2 and α5) subunits than QUR with α2, α3, and α5. All these compounds showed stronger interactions with the GABAA receptor subunits than the standard CAF. Taken together, SCL, CAF, and QUR reduced the TS-induced righting reflex and sleeping time in the combination group more than in the individual treatments. SCL may show its antidepressant effects, possibly through interactions with GABAA receptor subunits.

Efficacy of methenamine with methylthioninium in the treatment of dysuria: a randomized clinical study

Introduction and hypothesisDysuria is a common symptom present in several urological and gynecological conditions. Management relies on the underlying disease but may require additional symptomatic treatment. This study evaluated the combination of methenamine 250 mg and methylthioninium chloride 20 mg in the treatment of dysuria versus phenazopyridine.MethodsThis was a multicenter, single-blind, randomized, superiority clinical trial, including individuals over 18 with dysuria and a score ≥ 5 points on the pre-treatment categorical scale for pain. The primary outcome was the proportion of participants presenting excellent clinical response within 24 h after treatment. Improvement up to 72 h, time to reach improvement, sustained healing, investigators’ opinion, and safety were also evaluated.ResultsThree hundred and fifteen participants were evaluated. Demographic characteristics and symptoms of dysuria were comparable between groups at baseline. The difference in the excellent response rate between treatments within 24 h was 12.7% (95% CI 6.16, 19.21) for pain, 9.4% (95% CI 3.32, 15.39) for burning, and 12.7% (95% CI 6.37, 18.99) for burning on urination, all in favor of the test drug, which was also superior from 36 to 48 h. Treatments were similar concerning time to reach the absence of symptoms and in the percentage of participants with sustained healing after 72 h.ConclusionsThe association of methenamine with methylthioninium is superior to phenazopyridine in the treatment of dysuria.

Drug repurposing for the identification of new Bcl-2 inhibitors: In vitro, STD-NMR, molecular docking, and dynamic simulation studies

BackgroundThe anti-apoptotic protein B-Cell Lymphoma 2 (Bcl-2) is a key target for the development of anti-cancer agents, as its overexpression can render cancer cells resistant to chemotherapeutic treatments. Aims and objectivesThe current study has systematically evaluated a library of FDA-approved drugs for Bcl-2 inhibition using a drug repurposing strategy via in vitro, biophysical, and in-silico techniques. Materials and methodsIn vitro anticancer activity was performed, followed by apoptosis assay. The selected compounds were subjected to Saturation Transfer Difference Nuclear Magnetic Resonance (STD-NMR) spectroscopy, molecular docking, and molecular dynamic simulation for ligand-protein interactions. Key findingsIn the initial screening, seventy-five (75) drugs were evaluated against the HL-60 (human blood promyelocytic leukemia) cancer cell line. Among them, paroxetine HCl, carvedilol, clomipramine HCl, and clomifene citrate showed significant anti-proliferative activity (IC50 = 9.733 ± 0.524, 11.940 ± 0.079, 12.376 ± 1.242, and 6.155 ± 0.363 μM, respectively), in comparison to the reference drug venetoclax (IC50 = 7.086 ± 0.041 μM). This indicated that the test drugs have comparable IC50 values to the standard drug. Furthermore, the drugs were able to induce apoptosis in HL-60 cells. These drugs showed interactions with Bcl-2 protein in STD-NMR analysis. Docking and MD simulation studies further supported the interaction of these drugs with Bcl-2 protein, mainly via hydrophobic contacts leading to stable drug-Bcl-2 complexes. SignificanceThis study, identifies paroxetine HCl, carvedilol, clomipramine HCl, and clomifene citrate as significant Bcl-2 inhibitors and needs further pre-clinical and clinical studies for potential anti-cancer agents' evaluation.

Standardisation of different extracts of detoxified Nux-vomica seeds with its comparative study by TLC and HPTLC

IntroductionDetoxified Nux-vomica (detoxified Strychnos nux-vomica Linn.) is a very popular crude herb used in Unani and Ayurvedic pathy after detoxification for many years. The first person to identify Nux-vomica with the Indian drug kuchla was Haji Zainuddin. Detoxified Nux-vomica has significant effects on various disorders like rheumatic arthritis, inflammation, and gout (Anonyms, 2007; Bentley and Trimen, 1983). It has proved the best remedy for paralysis, nervous disorders, nervous debility, tremor, diarrhoea, and mental emotions (Nadkarni, 2000). The present study is designed to develop the qualitative as well as quantitative parameters of crudely detoxified Nux-vomica seeds and their comparative study by Thin layer chromatography (TLC) and High-performance thin layer chromatography (HPTLC). MethodsOrganoleptic characters, ash values, extractive values, phytochemical analysis, fluorescence analysis, TLC and HPTLC profiles, etc. were the parameters used for the standardisation of the test drug. ResultsTotal ash values, water, alcohol, ether-soluble extractive values, and volatile oil percentages were found to be 1.925%, 6.54%, 3.25%, 3.20%, and 2.00%, respectively. The TLC profile of Detoxified Nux-vomica shows three spots for aqueous extract and five spots for hydroalcoholic extract in Toluene: Ethyl Acetate: Triethylamine (7:2:1) and four spots in Methanol: Ethyl Acetate: Triethylamine (0.5:8.5:1) with exposure in Dragendorff’s Reagent. The percentage yield of strychnine in the hydro-alcoholic and aqueous extracts of Detoxified Nux-vomica is 7.48 and 2.10, while it is 6.17 and 1.85 for brucine, respectively. ConclusionThe present study used secondary data for the identification and quantification of active constituents in detoxified Nux vomica seeds.

Experimental evaluation of analgesic activity of Naga Parpam: An Siddha formulation

Background : Prolonged usage of NSAIDs and corticosteroids was associated with serious side effects. Siddha is an ancient system of medicine, promotes the utilization of herbal anad elemental formulations. Interestingly, certain elements considered toxic in modern medicine, such as Arsenic (As), Cadmium (Cd), Mercury (Hg), Iron (Fe), Silver (Ag), Gold (Au), etc., have been employed in Siddha herbo mineral formulation for the treatment of illness, a practice that dates back to ancient times. Introduction Pain is a widely recognized indicator of poor health, the analgesic medications are employed to alleviate it. In Siddha classics, pain is considered a separate disease called Soolai. Naga Parpam is one of the herbo metal preparations with analgesic potential but no scientific evaluation there. Aim: To evaluate the analgesic activity of Naga parpam in experimental rats using Tail immersion method. Materials and methods : After obtaining permission from the IAEC, the animals were separated into 5 groups of 6 animals Each Group 1 (control) received ghee orally, and Group 2 (standard) received Pentazocine in dose 10 mg/kg intraperitoneally. The test drug Naga parpam was mixed with the adjuvant Ghee and administrated per oral route to three groups (Group 3,4,5), Group 3 (test) received Naga Parpam in low dose 6 mg/kg, Group 4 (test) received mid dose 12 mg/kg, Group 5 (test) received high dose – 24 mg/kg ). Statistical analysis : One-way ANOVA followed by the Dunnett test P < 0.05 was considered to be significant. Results : The test drug Naga parpam has significant analgesic activity in the tail flick method (P <0.01) by increasing the reaction time of the rats. Conclusion : The present study indicates that the test drug Naga parpam possesses significant central analgesic activity in the tail flick method.