3', 4'-dihydroxyflavone ameliorates paclitaxel model of peripheral neuropathy in mice by modulating KATP channel, adenosine (A3) and GABAA (α2 subunit) receptors.

Paclitaxel is a widely used cancer chemotherapeutic agent for many solid tumors; but peripheral neuropathy is a major limitation for its clinical use. Studies have demonstrated the usefulness of flavone derivatives in chemotherapy induced peripheral neuropathy. The present study evaluates the anti-neuropathic effect of 3', 4'-dihydroxyflavone on paclitaxel-induced peripheral neuropathy and the underlying mechanisms. Paclitaxel was administered to mice in a single dose of 10 mg/kg, i.p.The neuropathic behavioural parameters such as mechanical allodynia, cold allodynia and thermal hyperalgesia were assessed 24 h later. The test compound 3', 4'-dihydroxyflavone (50,100 or 200 mg/kg,s.c) was administered 30 min prior to the assessment of behavioral parameters. The possible mechanisms involving KATP channels, adenosine and GABAA receptors were explored by employing suitable interacting drugs. Molecular docking studies to predict the binding interactions of 3', 4'-dihydroxyflavone at the above targets were also carried out. The test compound 3', 4'-dihydroxyflavoneexhibited a significant reduction in paw withdrawal response score in both mechanical and cold allodynia and also increased the tail flick response time in thermal hyperalgesia due to paclitaxel-induced neuropathy. The anti-neuropathic effect of 3', 4'-dihydroxyflavonewas significantly reversed by pre-treatment with glibenclamide, caffeine or bicuculline revealing the involvement of KATP channels, adenosine and GABAA receptors respectively. Furthermore, the molecular docking studies indicated a favourable binding affinity and good H-bond interaction of 3', 4'-dihydroxyflavone at these targets. The findings of the present study suggests that, 3', 4'-dihydroxyflavone has anti-neuropathic effect against paclitaxel-induced peripheral neuropathy through mechanisms that involve KATP channels, adenosine (A3) and GABAA (α2 subunit) receptors.

Molecular biomarkers NOTCH1, CD44, BMI1, and TP53 in oral squamous cell carcinoma.

It is of interest to evaluate NOTCH1, CD44, BMI1, and TP53 genes in the epiglottis, tongue, and hard palate of oral malignancies (OM) with healthy controls. This was a prospective and cross-sectional study of 60 individuals with oral malignancies (OM) (20 each of tongue, epiglottis, and hard palate) studied at Malla Reddy Medical College and tertiary care hospitals in Hyderabad. Adults aged ≥ 18 years and diagnosed with oral cancer were included in the study. Those who had cancer in more than one area were excluded from the study. Blood samples of individuals with tongue or epiglottis or hard palate were taken for testing the expression of NOTCH1, CD44, TP53, and BMI1 genes. They were analysed by the genomic sequencing method. One-way ANOVA with Bonferroni's t-test was used for statistical analysis. Expression of NOTCH1, CD44, BMI1, and TP53 genes were significantly higher in epiglottis, tongue, and hard palate compared to healthy control samples (p < 0.001). All four genes were expressed in all three areas of OM. However, they were not significant between them. Further analysis revealed that NOTCH1, CD44, TP53, and BMI1 genes did not show any difference in HPV-positive and HPV-negative samples. Comparing the T stages of cancer Notch1, gene expression was significantly higher in stages 1 and 2 compared to 3 and 4. The CD44, TP53, and BMI1 did not show any differences in the T stage. However, the difference in HPV in all T stages was very minimal. Data showed that irrespective of the areas of cancer (epiglottis, tongue, and hard palate) NOTCH1, CD44, TP53, and BMI1 genes were expressed equally. The expression was not very much dependent on HPV positive (+ve) or negative (-ve). However the T-stage was showing higher expression compared to control group. Since the expression of these genes was very high in all the three malignancies, they may be used as early biomarkers to detect cancer of epiglottis, tongue, and hard palate.

Modulation of PPAR-γ, SREBP-1c and inflammatory mediators by luteolin ameliorates ß-cell dysfunction and renal damage in a rat model of type-2 diabetes mellitus.

BACKGROUND: Natural products have been recommended as a complementary therapy for type 2 diabetes mellitus (T2DM) due to constraints of safety and tolerability of existing anti-diabetic agents. Luteolin exhibits anti-diabetic and anti-inflammatory effects. Hence, the impact of luteolin on glucose homoeostasis and organ damage was investigated in high-fat diet (HFD) and streptozotocin (STZ) induced T2DM in rats. METHODS AND RESULTS: Male Wistar rats were maintained on HFD (provided 55% energy as fat) for 10 days. Subsequently, a single dose of 40 mg/kg STZ was injected intraperitoneally on the 11th day. Seventy-two hours after STZ administration, diabetic rats with established hyperglycemia (fasting serum glucose > 200 mg/dL) were randomized into different groups having six rats each and orally administered either 0.5% hydroxy propyl cellulose or pioglitazone (10 mg/kg) or luteolin (50 mg/kg or 100 mg/kg) once daily for 28 days, while continuing HFD for respective groups. Luteolin significantly reduced hyperglycaemia, homoeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) levels, and improved hypoinsulinemia and HOMA of b-cell function (HOMA-B) in a dose-dependent manner. Increased TNF-α, IL-6 and NFκB levels in diabetic rats were significantly regulated. Additionally, luteolin significantly augmented PPAR-γ expression while attenuating sterol regulatory element binding protein-1c (SREBP-1c) expression. Histopathological scrutiny validated that luteolin effectively attenuated HFD-STZ-induced injury in pancreatic ß-cells and kidneys to near normalcy. CONCLUSION: Our study showed that luteolin ameliorated hyperglycemia and improved hypoinsulinemia, ß-cell dysfunction, and renal impairment in HFD-STZ-induced diabetic rats by attenuating inflammation and dysregulated cytokine secretion through modulation of PPAR-γ, TNF-α, IL-6 and NF-kB expression and down-regulation of SREBP-1c.

A Comparative Study to Assess the Accommodation and Vergence Relationship of Myopia in Indian Adolescent.

Background: Accommodation and Vergence disorder are diverse visual anomalies which can interfere with a child's school performance and impair one's ability to function efficiently. Its association with refractive error and its intervention were studied less in Indian myopia children; hence, there is a need for research in such setting. Method: One hundred and fifty Indian adolescents aged 10 to 17 years were divided into three refractive error groups (high, moderate, and low myopia). Baseline vision examination and a comprehensive binocular vision assessment were performed on all eligible adolescents. Vision therapy was provided to participants whose parents gave consent on behalf of the children. Chi-square analysis was utilized to look at the association between the groups of refractive errors. To compare the mean constants of the experimental and control groups, a two-way RM ANOVA was performed. Results: The most common dysfunction found in low myopia (75.3%), and moderate myopia (54%) was convergence insufficiency. High myopes (62.8%) were found to have combined convergence and accommodative insufficiency followed by accommodative dysfunction (14%) and basic exophoria (6%). In moderate myopia, a significant relationship was found between this dysfunction and refractive error. The experimental group in the overall sample showed statistically significant improvement after vision therapy (P<0.001), in comparison to the control group. Conclusion: Refractive error is linked to accommodative and convergence insufficiency. Thus, vergence and accommodative impairment must be tested for all myopic children, and vision therapy should be advised along with spectacle prescription for efficient binocular vision.

A randomized controlled trial to evaluate the efficacy of electrical vestibular nerve stimulation (VeNS), compared to a sham control for the management of sleep in young adults.

OBJECTIVES: Preliminary research suggests that electrical vestibular nerve stimulation (VeNS) may improve sleep outcomes by influencing the hypothalamus and brainstem nuclei involved in regulating the circadian rhythm and wakefulness. This randomised, sham-controlled trial aimed to assess the effectiveness of VeNS on insomnia in young adults. METHODS: Eighty adults aged 18-24 years were randomly allocated to the intervention (n=40) and control groups (n=40). The intervention group was provided with 30 min per day of VeNS with five sessions weekly for four weeks, while the control group received sham stimulation for the same period. Baseline Insomnia Sleep Index (ISI) scores were recorded weekly. At baseline and at day 28, questionnaires to evaluate emotional states of depression, anxiety and stress, and quality of life (QoL) were completed. The primary outcome was change in ISI with comparison between baseline and day 28. RESULTS: The VeNS group significantly reduced their mean ISI score after 7 days usage (p<0.001). At day 28 it was found that mean ISI scores had reduced from 19 to 11 in the VeNS group, and from 19 to 18 in the sham group, and the difference between the groups was significant (p<0.001). Moreover, application of VeNS appeared to significantly improve emotional state and QoL outcomes. CONCLUSIONS: This trial demonstrates that regular VeNS usage over four weeks leads to a clinically meaningful decrease in ISI scores in young adults with insomnia. VeNS may have potential as a drug-free and non-invasive therapy to improve sleep outcomes by positively influencing the hypothalamic and brainstem nuclei.

Luteolin Mitigates Diabetic Dyslipidemia in Rats by Modulating ACAT-2, PPARα, SREBP-2 Proteins, and Oxidative Stress.

Diabetic dyslipidemia is a crucial link between type-2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular diseases (ASCVD). Natural biologically active substances have been advocated as complementary remedies for ASCVD and T2DM. Luteolin, a flavonoid, exhibits antioxidant, hypolipidemic, and antiatherogenic effects. Hence, we aimed to determine influence of luteolin on lipid homeostasis and hepatic damage in rats with T2DM induced by high-fat-diet (HFD) and streptozotocin (STZ). After being fed HFD for 10 days, male Wistar rats received 40 mg/kg STZ intraperitoneal injection on 11th day. Seventy-two hours later, hyperglycemic rats (fasting glucose > 200 mg/dL) were randomized into groups, and oral hydroxy-propyl-cellulose, atorvastatin (5 mg/kg), or luteolin (50 mg/kg or 100 mg/kg) administered daily, while continuing HFD for 28 days. Luteolin significantly ameliorated dyslipidemia levels and concomitantly improved atherogenic index of plasma in a dose-dependent manner. Increased levels of malondialdehyde and diminished levels of superoxide dismutase, catalase, and glutathione in HFD-STZ-diabetic rats were significantly regulated by luteolin. Luteolin significantly intensified PPARα expression while decreasing expression of acyl-coenzyme A:cholesterol acyltransferase-2 (ACAT-2) and sterol regulatory element binding protein-2 (SREBP-2) proteins. Moreover, luteolin effectively alleviated hepatic impairment in HFD-STZ-diabetic rats to near-normal control levels. The findings of the present study expound mechanisms by which luteolin mitigated diabetic dyslipidemia and alleviated hepatic impairment in HFD-STZ-diabetic rats by amelioration of oxidative stress, modulation of PPARα expression, and downregulation of ACAT-2 and SREBP-2. In conclusion, our results imply that luteolin may be efficacious in management of dyslipidemia in T2DM, and future research may be essential to substantiate our findings.

Rhizophora mucronata Lam. (Mangrove) Bark Extract Reduces Ethanol-Induced Liver Cell Death and Oxidative Stress in Swiss Albino Mice: In Vivo and In Silico Studies.

The bark extract of Rhizophora mucronata (BERM) was recently reported for its prominent in vitro protective effects against liver cell line toxicity caused by various toxicants, including ethanol. Here, we aimed to verify the in vivo hepatoprotective effects of BERM against ethanol intoxication with the prediction of potential targets employing in silico studies. An oral administration of different concentrations (100, 200 and 400 mg/kg body weight) of BERM before high-dose ethanol via intraperitoneal injection was performed in mice. On day 7, liver sections were dissected for histopathological examination. The ethanol intoxication caused liver injury and large areas of necrosis. The pre-BERM administration decreased the ethanol-induced liver damage marker tumor necrosis factor-alpha (TNF-α) expression, reduced hepatotoxicity revealed by nuclear deoxyribonucleic acid (DNA) fragmentation and decreased oxidative stress indicated by malondialdehyde and glutathione contents. Our in silico studies have identified BERM-derived metabolites exhibiting the highest predicted antioxidant and free radical scavenger activities. Molecular docking studies showed that most of the metabolites were predicted to be enzyme inhibitors such as carbonic anhydrase inhibitors, which were reported to stimulate the antioxidant defense system. The metabolites predominantly presented acceptable pharmacokinetics and safety profiles, suggesting them as promising new antioxidant agents. Altogether, the BERM extract exerts antioxidative activities and shows promising hepatoprotective effects against ethanol intoxication. Identification of related bioactive compounds will be of interest for future use at physiological concentrations in ethanol-intoxicated individuals.

Embelin and levodopa combination therapy for improved Parkinson's disease treatment.

Parkinson's disease (PD), a progressive neurodegenerative disorder, affects dopaminergic neurons. Oxidative stress and gut damage play critical roles in PD pathogenesis. Inhibition of oxidative stress and gut damage can prevent neuronal death and delay PD progression. The objective of this study was to evaluate the therapeutic effect of embelin or the combination with levodopa (LD) in a rotenone-induced PD mouse model. At the end of experimentation, the mice were sacrificed and the midbrain was used to evaluate various biochemical parameters, such as nitric oxide, peroxynitrite, urea, and lipid peroxidation. In the substantia nigra (midbrain), tyrosine hydroxylase (TH) expression was examined by immunohistochemistry, and Nurr1 expression was evaluated by western blotting. Gut histopathology was evaluated on tissue sections stained with hematoxylin and eosin. In silico molecular docking studies of embelin and α-synuclein (α-syn) fibrils were also performed. Embelin alone or in combination with LD ameliorated oxidative stress and gut damage. TH and Nurr1 protein levels were also significantly restored. Docking studies confirmed the affinity of embelin toward α-syn. Taken together, embelin could be a promising drug for the treatment of PD, especially when combined with LD.

Safety evaluation of antibacterial and analgesic autoinjector devices for rapid administration during emergency situations: a crossover study in rabbits.

Objective: The objective of the present study was to evaluate the safety and tolerability of autoinjector devices (AIDs) in rabbits by intramuscular (i.m.) administration, using haematological and biochemical markers. Introduction: Emergency and mass casualty situations require immediate drug delivery for which AIDs are preferred. The tolerability of amikacin as antibacterial and buprenorphine as analgesic AID has been studied in rats by intraperitoneal administration. In the present study, it was evaluated in rabbits by i.m. administration. Methods: Water-filled glass cartridges (2.3-2.4 mL) were converted to amikacin (106 mg/mL) and buprenorphine (0.128 mg/mL) cartridges. Dual dose AID was used for i.m. administration (1.2 mL). The study was done as a crossover design on 12 rabbits. Initially, three rabbits each were given manually or AID, 57 mg/kg amikacin, and three rabbits each by manual or by AID, 0.07 mg/kg buprenorphine for 7 days. After 1 month, the injections were changed in the rabbits. In the place of manual injection, AID and in the place of amikacin, buprenorphine injection was given. This ensured that all rabbits received 14 injections, 7 manual and 7 AID consisting of 7 amikacin and 7 buprenorphine. 24 h before and 24 h after last drug administrations, blood was withdrawn from ear vein for haematological and biochemical estimations. Results: The rabbits were healthy, active and no sign of any injection-related changes were observed after administration of amikacin and buprenorphine by manually or by AID. The haematological and biochemical parameters showed similar changes in manual and AID administration of amikacin and buprenorphine. Conclusion: The present study of amikacin and buprenorphine by AID shows the safety of the device and is recommended for further experimentation. These AIDs are intended for self-administration during emergency and mass causality situation and are suitable for adults and children, as well as farm and pet animals.

Anti-neuropathic effect of 7,3'-dihydroxyflavone in paclitaxel induced peripheral neuropathy in mice involving GABAA, KATP channel and adenosine receptors.

Peripheral neuropathy induced by chemotherapeutic agents is the most common dose-limiting adverse effect observed in patients during and after treatment of malignancies. Many flavones have been reported to ameliorate neuropathy of different origin in experimental animals and their possible mode of action explored. The present study aims to investigate 7,3'-dihydroxyflavone for its anti-neuropathic effect against paclitaxel induced peripheral neuropathy in mice by employing behavioural tests such as mechanical allodynia, cold allodynia and thermal hyperalgesia. The possible involvement of GABAA, KATP channels and adenosine receptors in the anti-neuropathic effect of 7,3'-dihydroxyflavone was also studied by employing suitable interacting drugs. Treatment with 7,3'-dihydroxyflavone (50, 100 or 200 mg/kg, s.c) significantly and dose-dependently reduced the paw withdrawal response score in both mechanical and cold allodynia and also increased the tail flick response time in thermal hyperalgesia due to paclitaxel-induced neuropathy. Pre-treatment with glibenclamide (10 mg/kg, i.p), caffeine (50 mg/kg, i.p) or bicuculline (2 mg/kg, i.p) significantly reversed the anti-neuropathic effect of 7,3'-dihydroxyflavone in behavioral tests. In conclusion, the present investigation identified 7,3'-dihydroxyflavone as a potential candidate with anti-neuropathic effect against paclitaxel induced peripheral neuropathy involving KATP channels, adenosine and GABAA receptors.

Efficacy of different intensity of aquatic exercise in enhancing remyelination and neuronal plasticity using cuprizone model in male Wistar rats.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS). Most exercise studies concentrate on the impact of exercise on cardiovascular system; this study aims to present the effects of exercise of varying intensity on the nervous system. Most recently in MS, positive outcomes were obtained with resistance and high-intensity exercises. This study also analyzes the effects of a prior conditioning program before the induction of demyelination and subsequent neuroprotective effects of such program. OBJECTIVES: To study and determine the neuroprotective and remyelinating effects of different intensity of aquatic exercise and a preconditioning exercise program on demyelination induced by oral administration of cuprizone (Cup). MATERIAL AND METHODS: Six groups of animals, each containing 6 rats, were used in the study. The groups were as follows: group I - control group; group II - Cup group; group III - treated with methylprednisolone (MP); group IV - treated with low-intensity exercise (LIE), free swimming for 40 min and high-intensity exercise (HIE); group V - treated with a resistance of 9% body weight and free swimming for 40 min; group VI - treated with preconditioning exercise (free swimming for 40 min for 3 weeks) before Cup administration followed by the same exercise protocol as for group V. All data were analyzed using one-way analysis of variance (ANOVA) with Tukey's test, by means of SigmaPlot v. 14.5 software. RESULTS: Similarly to the MP group, group VI showed a positive outcome. A value of p < 0.001 was considered statistically significant. Also, group VI showed improved areas of remyelination in histopathology, an increased expression of myelin basic protein (MBP), reduced expression of glial fibrillary acidic protein (GFAP) in corpus callosum, and improved gene expression of brain-derived neurotrophic factor (BDNF) in the hippocampus region. CONCLUSIONS: General fitness achieved through a preconditioning program combined with HIE showed neuroprotective effects, as evidenced by increased areas of remyelination and improved neuronal plasticity, observed mostly in group VI (conditioning+HIE).

Molecular Studies on the Nephroprotective Potential of Celastrus paniculatus against Lead-Acetate-Induced Nephrotoxicity in Experimental Rats: Role of the PI3K/AKT Signaling Pathway.

Chemicals can induce nephrotoxicity, with damage to different segments of the nephron and deterioration of renal function. Nephrotoxicity due to exposure to a toxin such as carbon tetrachloride, sodium oxalate, or heavy metals is the most common cause of kidney injury. The current study aimed to evaluate the protective effects of Celastrus paniculatus seed extract against lead-acetate-induced nephrotoxicity by evaluating the histopathology, immunohistochemistry, ultrastructure, and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Twenty-four rats were divided into four groups (n = 6 per group): group 1 contained normal animals and served as the control; group 2 received lead acetate (30 mg/kg body weight (b.w.)/day, oral); group 3 received lead acetate and the standard drug N-acetylcysteine (NAC, 200 mg/kg b.w./day, oral); and group 4 received lead acetate and the ethanolic extract of C. paniculatus seed (EECP; 800 mg/kg b.w./day, oral). Treatment was given for 28 consecutive days. The data were analyzed using one-way analysis of variance with SIGMA PLOT 13 using SYSTAT software followed by Newman-Keul's test for comparison between the groups. EECP ameliorated the adverse changes caused by lead acetate. PI3K and AKT messenger RNA (mRNA) levels were diminished in lead-acetate-treated rats. Treatment with EECP inhibited the occurrence of shrunken cells, the atrophy of glomeruli, and degenerative changes in renal tubules caused by lead acetate. Interestingly, the PI3K and AKT mRNA levels were significantly increased in EECP-treated animals. Our results clearly evidence for the first time that C. paniculatus seed extract inhibits lead-acetate-induced detrimental changes in kidneys by regulating PI3K/AKT signaling pathways.

Autoinjector - A smart device for emergency cum personal therapy.

Autoinjectors are self-injectable devices; they are important class of medical devices which can deliver drugs through subcutaneous or intramuscular route. They enclose prefilled syringes or cartridges which are driven by a spring system. The major benefits of this device are easy self-administration, improved patient compliance, reduced anxiety, and dosage accuracy. Immediate treatment during emergency conditions such as anaphylaxis, migraine, and status epilepticus or for chronic conditions like psoriasis, diabetes, multiple sclerosis, and rheumatoid arthritis, Reformulation of first-generation biologics, technical advancements, innovative designs, patient compliance, overwhelming interest for self-administration all these made entry of more and more autoinjectors into use. In this review, intensive efforts have been made for exploring the different types of currently available autoinjectors for the management of emergency and chronic diseases.

Effectiveness of Physical Activity and Finger Millet-Based Food Supplement on Biochemical Parameters and Bone Mineral Density among Premenopausal Women.

The effectiveness of physical activity and finger millet-based food supplement on biochemical parameters and bone mineral density (BMD) among premenopausal women were studied. Serum calcium, phosphorus, alkaline phosphatase, and BMD of 720 women (30-40 years) were analyzed. From them, 150 women with low BMD (t-score, -1 to -2.5) and low calcium (<9.0 mg/dL) were randomized to control and experimental groups, equally. The experimental group was given 5 days per week physical activity, for 3 months, and a diet supplement of finger millet-based sweet balls (ragi laddu), 3 days per week for 3 months. The above parameters were measured as the posttest. Physical activity was assessed by the General Practice Physical Activity Questionnaire. A 24 h recall assessment was carried out for the diet supplement, and self-reported activity checklist was maintained for physical activity. Among 720 women, 163 (22.6%) showed BMD, t-score < -1.0, and calcium <9.0 mg/dL (p < 0.001). The serum phosphorus and alkaline phosphatase were also low (p < 0.001). After the supplementation to the experimental group, all the biochemical parameters, BMD, and physical activity score showed significant improvement in the posttest (p < 0.001). This study showed significantly low BMD and calcium among premenopausal women. Physical activity and finger millet supplement improved the calcium level and BMD.

Overexpression of the adeB Efflux Pump Gene in Tigecycline-Resistant Acinetobacter baumannii Clinical Isolates and Its Inhibition by (+)Usnic Acid as an Adjuvant.

Acinetobacter species are among the most life-threatening Gram-negative bacilli, causing hospital-acquired infections, and they are associated with high morbidity and mortality. They show multidrug resistance that acts via various mechanisms. In Acinetobacter baumannii, efflux pump-mediated resistance to many antimicrobial compounds, including tigecycline, has been widely reported. Natural compounds have been used for their various pharmacological properties, including anti-efflux pump activity. The present study aimed to evaluate the efflux pump-mediated resistance mechanism of Acinetobacter baumannii and the effect of (+)Usnic acid as an efflux pump inhibitor with tigecycline. For detecting the efflux pump activity of tigecycline-resistant Acinetobacter baumannii isolates, microbroth dilution method and real-time quantitative reverse transcription-polymerase chain reaction was used. (+)Usnic acid was added to tigecycline and tested by the checkerboard method to evaluate its efficacy as an efflux pump inhibitor. qRT-PCR analysis was carried out to show the downregulation of the efflux pump in the isolates. Out of 42 tigecycline-resistant Acinetobacter baumannii isolates, 19 showed efflux pump activity. All 19 strains expressed the adeB gene. (+)Usnic acid as an adjuvant showed better efficacy in lowering the minimum inhibitory concentration compared with the conventional efflux pump inhibitor, carbonyl cyanide phenylhydrazone.

Combination therapy of N-acetyl-L-cysteine and S-2(2-aminoethylamino) ethylphenyl sulfide for sulfur mustard induced oxidative stress in mice.

INTRODUCTION: Sulfur mustard (SM) is chemically, bis(2-chloroethyl) sulfide and a strong alkylating agent that causes cytotoxicity and blisters on skin. In laboratory animal models, SM is extremely lethal. Since no specific antidote has been proposed, decontamination upon contact is the recommended procedure. Several antidotes have been screened for SM, and in that sulfanyl compounds, N-acetyl-l-cysteine (NAC) and S-2(2-aminoethylamino) ethylphenyl sulfide (DRDE-07) showed good protection. Since they showed protection at high doses, the aim of this study was to evaluate the efficacy in combination at low dose, for percutaneously administered SM in mice. MATERIAL AND METHODS: 4 LD50 of SM (32.4 mg/kg) was administered, and NAC (50 mg/kg), DRDE-07 (25 and 50 mg/kg) and their combinations were evaluated as 30 min pre-treatment by single oral administration. RESULT: After 72 h of SM exposure, significant decrease in body weight, decrease in hepatic reduced glutathione, and increase in hepatic malondialdehyde were observed (P < 0.001), showing oxidative stress. The combination of NAC (100 mg/kg) and DRDE-07 (50 mg/kg) showed significant protection (P < 0.01). The severe histopathological lesions induced by SM in liver, spleen and skin were also considerably reduced by the combination. CONCLUSION: The combination of NAC and DRDE-07 having sulfanyl groups, will be promising antioxidants and an effective antidote for SM toxicity.

Effect of dibenz(b,f)-1,4-oxazepine aerosol on the breathing pattern and respiratory variables by continuous recording and analysis in unanaesthetised mice.

A riot control agent has to be a sensory irritant of a reversible type without pulmonary irritation as the later can cause lung injury. The aim of the present study is to continuously record and analyse breathing pattern and respiratory variables of dibenz (b,f)-1,4-oxazepine (CR) in unanaesthetised mice during and after exposure. The lowest concentration of 0.65 mg/m3 did not produce any effect on the breathing pattern. As high as 500 fold increase (315.9 mg/m3) in the concentration was used and no mortality was observed. CR produced a concentration dependent sensory irritation, without pulmonary irritation or airflow obstruction, showing that it may not cause any lung injury. The sensory irritation was initiated within 5 min of exposure due to the activation of TRPA1 receptors of the upper respiratory tract. Immediate recovery of normal breath without sensory irritation was observed in all the concentrations except the highest concentration of 315.9 mg/m3. Corresponding to the sensory irritation there was concentration dependent respiratory depression. The 50 percent respiratory depression (RD50) in this experiment was 152 mg/m3 and the estimated threshold limit value for occupational exposure was 4.56 mg/m3. The present study shows that CR causes sensory irritation only which is completely recoverable.

Autoinjector device for rapid administration of drugs and antidotes in emergency situations and in mass casualty management.

There are several situations such as medical emergencies and incidents involving mass casualties where drugs and antidotes have to be administered immediately along with other first aid at the site of the event. Self-administration by the affected person or by a companion is required as a life-saving measure. Autoinjector devices (AIDs) are useful for the rapid administration of drugs and antidotes and they can also be used by those who have not been medically trained. This makes them very convenient for emergency and mass casualty management. An AID has a drug cartridge with an embedded needle for subcutaneous or intramuscular injection, which is usually painless. The drugs are delivered slowly by the AID across a large area in the muscle, which increases the absorption and the drug effects are equal to that of intravenous administration. A variety of AIDs are available, such as atropine and pralidoxime for nerve agent poisoning, epinephrine for anaphylactic shock and allergy, diazepam for seizures, sumatriptan for migraine, amikacin for antibacterial treatment, buprenorphine for pain relief and monoclonal antibodies for a variety of diseases. This review describes the published peer-reviewed literature identified by online searches of journal databases.

HPLC characterization, acute and sub-acute toxicity evaluation of bark extract of Rhizophora mucronata in Swiss Albino mice.

AIM: Rhizophora mucronata, commonly called as 'red mangrove' grows in the tropical and sub-tropical regions and on the sheltered shores. The bioactive compounds from the plant have been used in the treatment of wide range of diseases. Though the beneficial effects have been reported, the safety and toxicological studies are not carried out. Hence, major bioactives have been identified by HPLC and then acute and sub-acute toxicity studies of (BERM) in Swiss Albino mice have been carried out. MAIN METHODS: HPLC fingerprinting was carried out of BERM for the characterization of bioactives. BERM as a single dose was given orally at 800, 1600 mg/kg and 3200 mg/kg by a stainless steel cannula to the mice. Then the mice were observed for 14 days for mortality and behavioural changes. Food, water intake and body weight changes were also observed throughout the study period. On the fifteenth day, the mice were anesthetized with isofluorane and blood was withdrawn for haematological and biochemical analysis. The animals were sacrificed by overdose of isofluorane and organs such as liver, kidney, lungs and spleen were dissected out for histopathological analysis. There was no mortality of the mice even in 3200 mg/kg dose, stating that the oral LD50 of BERM is more than 5000 mg/kg. In terms of Sub-acute toxicity, for a period of 28 days repeated dose of 400 mg/kg and 800 mg/kg as an optimum dose and a control group was kept with only distilled water at 5 ml/kg against the treated groups. On 29th day, the mice from all groups were sacrificed and blood was withdrawn and organs such as liver, kidney, lungs and spleen were dissected out for the assessment of internal tissues, wherein no abnormalities were observed in the treatment groups as compared to the control. The blood parameters, biochemical analysis of the treated groups were well within the range, histopathological confirmed the findings wherein the organs viz, liver, kidneys, lungs and spleen possessed normal architecture. KEY FINDINGS: Based on HPLC results, prominent 5 major compounds viz: Diadzein, Epicatechin, Hesperidin, Diosmin and Quercitrin respectively were identified. Isolated changes observed in the haematological, biochemical and histopathological studies were not dose related and showed the safety of the bark extract. Similarly, the sub-acute toxicity of BERM has been conducted for 28 days, wherein repeated dose of 400 mg/kg and 800 mg/kg and control group was given orally. There were no abnormalities found both in external and internal parameters. SIGNIFICANCE: Based on the study it is concluded that the bark extract of Rhizophora mucronata (BERM) is safe at 1000 mg/kg or less on repeated dosage can be considered as a safe dose for pharmacological efficacy studies.

Electrical vestibular nerve stimulation as an adjunctive therapy in the management of type 2 diabetes.

OBJECTIVES: Vestibular nerve stimulation using the portable battery-operated vestibular nerve stimulator is a sophisticated method noninvasive, safe, and easy to operate. It was hypothesized that vestibular nerve stimulation is effective in the management of type 2 diabetes. Hence, the present study was undertaken to determine the effectiveness of vestibular nerve stimulation using portable battery-operated vestibular nerve stimulator in the management of diabetes. METHODS: The present study was a double-blind randomized controlled trial with 1:1 split between the control and experimental groups. A total of 30 participants with type 2 diabetes were part of the study after obtaining the written informed consent. After recording the baseline values, the vestibular nerve stimulation was administered to the participants in the intervention group for 90 days. Sham stimulation was administered to the control group for 90 days. Outcome measures were recorded after 30 days and after 90 days of the intervention in both the groups. RESULTS: There was significant decrease in the total body weight, fasting, postprandial blood glucose, glycosylated hemoglobin levels, leptin, very low density lipoproteins levels followed by the intervention. There was significant improvement in both spatial and verbal memory scores. Depression and stress scores and systolic blood pressure decreased and remained in normal limits. CONCLUSIONS: The study results have proven multimodal action of vestibular stimulation. It not only acts on regulation of the glucose metabolism but also can regulate the autonomic activity and improve cognition and relieve stress. This is the interesting finding of our study, which needs detailed further research to support implementation of vestibular nerve stimulation as an adjunctive therapy in the management of diabetes.