Approaches to Improve the Translation of Safety, Pharmacokinetics and Therapeutic Index of ADCs.

Antibody-drug conjugates (ADCs) are an important class of cancer therapies. They are complex molecules, comprising an antibody, a cytotoxic payload, and a linker. ADCs intend to confer high specificity by targeting a unique antigen expressed predominately on the surface of the tumor cells than on the normal cells and by releasing the potent cytotoxic drug inside the tumor causing cytotoxic cell death. Despite high specificity to tumor antigens, many ADCs are associated with off-target and on-target off-tumor toxicities, often leading to safety concerns before achieving the desirable clinical efficacy. Therefore, it is crucial to improve the therapeutic index (TI) of ADCs to enable the full potential of this important therapeutic modality.The review summarizes current approaches to improve the translation of safety, pharmacokinetics, and TI of ADCs. Common safety findings of ADCs resulting from off-target and on-target toxicities and nonclinical approaches to de-risk ADC safety will be discussed; multiple approaches of using preclinical and clinical dose and exposure data to calculate TI to guide clinical dosing will be elaborated; different approaches to improve TI of ADCs, including selecting the right target, right payload-linker and patients, optimizing physicochemical properties, and using fractionation dosing, will also be discussed.

Increased Serum Levels of Matrix-metalloproteinase-9, Cyclo-oxygenase-2 and Prostaglandin E-2 in Patients with Chronic Obstructive Pulmonary Disease (COPD).

Chronic obstructive pulmonary disease (COPD), a heterogeneous lung disorder that is characterized by airflow obstruction and the third leading cause of death, globally. COPD is influenced by environmental and genetic factors. Here, we measured the serum level of matrix metalloproteinase-9 (MMP-9), cyclooxygenase-2 (COX-2) and prostaglandin E-2 (PGE-2) and reveal the correlation between their levels in COPD subjects. In this study, we included a total of 79 COPD and 79 healthy controls. We assessed demographic profile, risk factors, respiratory symptoms, clinical history, COPD Assessment Test (CAT) score and spirometry. Further, we determined the serum levels of MMP-9, COX-2 and PGE-2 by enzyme-linked immunosorbent assay (ELISA). The correlation between their serum levels was also determined. Among the studied population age, gender, body mass index and socioeconomic status were comparable. Serum levels of MMP-9, COX-2 and PGE-2 were significantly increased in the COPD group than in healthy controls (P < 0.0001). Moreover, MMP-9, COX-2 and PGE-2 levels were increased with the GOLD grades and CAT score (> 10). Serum levels of MMP-9, COX-2 and PGE-2 was enhanced in patients with larger clinical history (> 20 years) than those with lower clinical history (< 10 years). Serum levels of MMP-9 and COX-2; MMP-9 and PGE-2; COX-2 and PGE-2 showed a positive correlation (P < 0.0001) with the COPD group. Our data demonstrate that serum levels of MMP-9, COX-2 and PGE-2 were correlated with the GOLD grade, CAT score and clinical history of the COPD group, pointing that they can be used as a indicators to understand the disease progression. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-021-00973-2.

Recent advances in trophoblast cell-surface antigen 2 targeted therapy for solid tumors.

Trophoblast cell-surface antigen 2 (Trop 2) is a transmembrane glycoprotein that is highly expressed in various cancer types with relatively low or no baseline expression in most normal tissues. Its overexpression is associated with tumor growth and poor prognosis; Trop 2 is, therefore, an ideal therapeutic target for epithelial cancers. Several Trop 2 targeted therapeutics have recently been developed for the treatment of cancers, such as anti-Trop 2 antibodies and antibody-drug conjugates (ADCs), as well as Trop 2-specific cell therapy. In particular, the safety and clinical benefit of Trop 2-based ADCs have been demonstrated in clinical trials across multiple tumor types, including those with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial cancer, and heavily pretreated non-small cell lung cancer. In this review, we elaborate on recent advances in Trop 2 targeted modalities and provide an overview of novel insights for future developments in this field.

Beneficial effects of n-hexane bark extract of Onosma echioides L. on diabetic peripheral neuropathy.

Onosma echioides Linn (Boraginaceae) is the most frequently used curative herb widely used for kidney obstruction, sciatic pain, and gout. The present study was designed to investigate the therapeutic effects of n-hexane bark extract of O. echioides (OE) L. root in vivo against Streptozotocin-induced diabetic neuropathy in SD rats. For in vivo activity, the experiment was categorized into five different groups (n = 5). Group-I was considered as nondiabetic/normal control (NC) treated with 0.5% carboxymethyl cellulose (CMC), Group II as diabetic control, Group-III, IV, and V served as diabetic treated with OE 50, OE 100, and pregabalin at a dose of 50, 100, and 10 mg/kg body weight, orally, respectively. Body weight, blood glucose, oral glucose tolerance test, behavioral studies (motor coordination test, thermal hyperalgesia, cold allodynia, locomotor activity, oxidative biomarkers (thio barbituric acid reactive substances [TBARS], superoxide dismutase [SOD], glutathione [GSH], and catalase), and histopathology of the sciatic nerve were performed. Treatment with OE showed a dose-dependent increase in neuroprotective activity by improving the myelination and decreasing the axonal swelling of nerve fibers. The verdicts of behavioral activities showed a remarkable effect on animals after the treatment of extract and standard drug pregabalin. In conclusion, our findings supported the traditional application of OE and explored its importance in the management of diabetic neuropathy. Additional clinical experiments may provide novel therapeutic drugs for diabetes and its complications.

Omega-3 fatty acid attenuates oxidative stress in cerebral cortex, cerebellum, and hippocampus tissue and improves neurobehavioral activity in chronic lead-induced neurotoxicity.

Objectives: In view of the increasing risk of lead on human health, the present study has been carried out to investigate the neuroprotective effect of omega-3 fatty acid on chronic lead-induced neurotoxicity and behavioral impairment in rats. Methods: Different neurobehavioral parameters, biochemical assays, and histopathological analyses in brain regions of rats were conducted. Results: Rats exposed to different doses of lead (lead acetate 2.5, 5.0, 7.5 mg/kg body weight p.o. for 90 days) caused a significant decrease in body weight, brain weight, and behavioral changes as compared to controls. Abnormal histopathological and increased levels of lead in blood and brain regions increased the levels of ROS, LPO, PCC and decreased the levels of GSH with concomitant reduction in SOD, CAT, and GPx activities in the brain region of rats treated with different doses of lead as compared to controls. Co-treatment of lead with omega-3 fatty acid (500 mg/kg body weight p.o. for 90 days) decreased the levels of ROS, LPO, PCC, and increased the level of GSH, also increased SOD, CAT, and GPx activity and showed improvements in behavioral as well as histopathological changes as compared to lead-treated groups. Discussion: Our results proved that omega-3 fatty acid improved behavioral deficits, altered histopathological and oxidative stress in lead-intoxicated rats. Among three different doses, 2.5 mg/kg b.wt. of lead along with omega-3 fatty acid was the most preventive dose for the neurotoxicity. This work reveals the potential of omega-fatty acid as a protective drug for lead neurotoxicity.

Monoclonal antibody targeting of fibroblast growth factor receptor 1c causes cardiac valvulopathy in rats.

Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) have been proposed as potential drug targets for the treatment of obesity. The aim of this study was to assess the potential toxicity in rats of three anti-FGFR1c mAbs with differential binding activity prior to clinical development. Groups of male rats received weekly injections of either one of two FGFR1c-specific mAbs or an FGFR1c/FGFR4-specific mAb at 10 mg/kg for up to 4 weeks. All three mAbs caused significant reductions in food intake and weight loss leading to some animals being euthanized early for welfare reasons. In all three groups given these mAbs, microscopic changes were seen in the bones and heart valves. In the bones of the femoro-tibial joint, thickening of the diaphyseal cortex of long bones, due to deposition of well organized new lamellar bone, indicated that an osteogenic effect was observed. In the heart, valvulopathy described as an endocardial myxomatous change affecting the mitral, pulmonary, tricuspid and aortic valves was observed in all mAb-treated animals. The presence of FGFR1 mRNA expression in the heart valves was confirmed using in situ hybridization. Targeting the FGF-FGFR1c pathway with anti-FGFR1c mAbs leads to drug induced valvulopathy in rats. In effect, this precluded the development of these mAbs as potential anti-obesity drugs. The valvulopathy observed was similar to that described for fenfluramine and dexafenfluramine. The pathogenesis of the drug-induced valvulopathy is considered FGFR1c-mediated, based on the specificity of the mAbs and FGFR1 mRNA expression in the heart valves.

Nonclinical safety and pharmacokinetics of Miglyol 812: A medium chain triglyceride in exenatide once weekly suspension.

Exenatide, a glucagon-like peptide-1 receptor agonist was originally developed as either a twice daily or once weekly injectable therapeutic for patients with type 2 diabetes. Exenatide QW suspension was developed for use with an autoinjector device, in which the microspheres are suspended in Miglyol 812, a mixture of medium chain triglycerides (MCTs). MCTs are a class of lipids whose fatty acid chains contain from six to 12 carbon atoms (medium chain fatty acids or MCFAs). While MCTs are edible oils present in many foods, including foodstuffs containing coconut and palm kernel oils, limited information is available regarding the oral and subcutaneous bioavailability of MCTs as well as safety following subcutaneous injection. These studies were designed to investigate the non-clinical pharmacokinetics and safety of MCTs. In a single dose pharmacokinetic study, MCFAs were rapidly detected in the plasma of rats following oral administration of either Miglyol 812 or tricaprylin at doses of 10 or 9.48 g kg-1 , respectively. Following subcutaneous dosing with Miglyol 812, MCFAs were rapidly absorbed with a similar profile to that following oral dosing. Furthermore, the toxicity of Miglyol 812 alone was evaluated in a 3 month repeat dose toxicology studies in cynomolgus monkeys. In this study, weekly subcutaneous doses of 0.15 g kg-1 did not elicit any treatment-related effects in cynomolgus monkeys. In conclusion, these studies alongside the available literature data show that Miglyol 812 is a safe excipient for use in subcutaneously administered therapeutics.

Attenuation of lead neurotoxicity by supplementation of polyunsaturated fatty acid in Wistar rats.

BACKGROUND: Among various types of polyunsaturated fatty acid (PUFA), omega-3 fatty acids play a crucial role in development and function of the brain. This study was undertaken to investigate the possible neuroprotective efficacy of omega-3 fatty acid on lead-induced neurotoxicity in rats. MATERIAL AND METHODS: The experiment was carried out on 32 male Wistar rats divided into four groups. The first group (control) was treated with distilled water and second group with lead acetate at the doses of 3 mg/kg b.wt. (body weight)/oral, whereas third and fourth groups were simultaneously treated with lead acetate (3 mg/kg b.wt.) plus omega-3 fatty acid (300 mg/kg b.wt./oral) and lead acetate (3 mg/kg b.wt.) plus vitamin E (100 mg/kg b.wt./oral), respectively, for a period of 90 days. Their biochemical and histopathological investigations have been carried out. RESULTS: The level of lead was markedly elevated in brain (4.71-fold) and blood (5.65-fold), also increased levels of ROS, GSH, LPO with concomitant reduction in the activities of delta-ALAD, CAT, SOD, and GPx. In addition, lead-induced brain damage was indicated by histopathological changes. Omega-3 fatty acid resulted in marked improvement in most of the biochemical parameters as well as histopathological changes in rats. The results obtained were compared with vitamin E as the standard antioxidant agents. DISCUSSION: Omega-3 fatty acid significantly (P < 0.05) decreased the effect of lead-induced brain damage as well as biochemical changes similar to that of standard drug, vitamin E. So, our result suggested that omega-3 fatty acid may play a protective role in lead-induced neurotoxicity and associated human health risk.

Choice of Starting Dose for Biopharmaceuticals in First-in-Human Phase I Cancer Clinical Trials.

BACKGROUND: First-in-human (FIH) trials of low-molecular-weight anticancer agents conventionally derive a safe start dose (SD) from one-tenth the severely toxic dose in 10% of rodents or one-sixth the highest nonseverely toxic dose (HNSTD) in nonrodent species. No consensus has been reached on whether this paradigm can be safely applied to biotechnology-derived products (BDPs). MATERIALS AND METHODS: A comprehensive search was conducted to identify all BDPs (excluding immune checkpoint inhibitors and antibody drug conjugates) with sufficient nonclinical and clinical data to assess the safety of hypothetical use of one-sixth HNSTD in an advanced cancer FIH trial. RESULTS: The search identified 23 BDPs, of which 21 were monoclonal antibodies. The median ratio of the maximum tolerated or maximum administered dose (MTD or MAD) to the actual FIH SD was 36 (range, 8-500). Only 2 BDPs reached the MTD. Hypothetical use of one-sixth HNSTD (allometrically scaled to humans) would not have exceeded the MTD or MAD for all 23 BDPs and would have reduced the median ratio of the MTD or MAD to a SD to 6.1 (range, 3.5-55.3). Pharmacodynamic (PD) markers were included in some animal toxicology studies and were useful to confirm the hypothetical SD of one-sixth HNSTD. CONCLUSION: One-sixth HNSTD would not have resulted in unacceptable toxicities in the data available. Supporting its use could reduce the number of dose escalations needed to reach the recommended dose. A low incidence of toxicities in animals and humans underscores the need to identify the pharmacokinetic and PD parameters to guide SD selection of BDPs for FIH cancer trials. IMPLICATIONS FOR PRACTICE: Start dose (SD) for biotechnology-derived products (BDPs) can be safely derived from one-sixth the highest nonseverely toxic dose in nonrodent species and may reduce the number of dose escalations needed to reach the recommended dose in first-in-human studies while limiting unnecessary exposure to high drug levels in humans. The use of this type of SD could improve the design of phase I studies of BDPs by making them more efficient. The role of preclinical pharmacodynamic markers was useful in confirming the hypothetical SD, and attempts should be explored in future animal studies to identify such parameters.

Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: relevance for human safety.

Mavrilimumab (CAM-3001) is an investigational human IgG4 monoclonal antibody (MAb) targeting GM-CSF receptor alpha which is currently being developed for the treatment of RA. GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through the activation, differentiation, and survival of macrophages and neutrophils. To support clinical development, the nonclinical safety of mavrilimumab was evaluated in several studies with cynomolgus monkeys as the pharmacologically relevant species. Comprehensive toxicity parameters were assessed in each study, and treatment duration ranged from 4 to 26weeks. Mavrilimumab has an acceptable safety profile in monkeys with no changes in any parameters other than microscopic findings in lung. In several studies, minimal accumulation of foamy alveolar macrophages was observed. This finding was only seen in studies of at least 11weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥30mg/kg/week), in a 26-week repeat-IV dose study, the presence of lung foreign material, cholesterol clefts, and granulomatous inflammation was also observed in a few animals and was considered adverse. The dose- and time-related accumulation of foamy macrophages in lung following exposure to mavrilimumab observed in several NHP studies was expected based upon the known role of GM-CSFRα signaling in the function of alveolar macrophages. Overall, a clean no-observed-adverse-effect-level (NOAEL) without any effects in lung was established and provided adequate clinical safety margins. In clinical studies in RA patients, mavrilimumab has demonstrated good clinical activity with adequate safety to support further clinical development. A Phase 2b study of mavrilimumab in subjects with RA is in progress.

The severity of non-smoking chronic obstructive pulmonary disease is correlated with biomass fuel exposure and COPD assessment test score.

BACKGROUND AND OBJECTIVE: Tobacco smoking is an established risk factor for chronic obstructive pulmonary disease (COPD). Current evidence suggests that non-tobacco-related risk factors vary geographically and are less understood than smoking. This study aims to compare the risk factors, symptoms, and clinical features of smoking (S-COPD) and non-smoking (NS-COPD) in a COPD population. MATERIALS AND METHODS: In this retrospective cross-sectional study, 489 COPD patients were screened. Data on socio-demographics, smoking and medical history, other risk factors, symptoms, and clinical characteristics including COPD Assessment Test (CAT) score, and Modified Medical Research Council (mMRC) Dyspnea Scale were examined. RESULTS: Of the total selected 416 COPD patients, 35.34% were NS-COPD while 64.66% were S-COPD. S-COPD was predominant in males, whereas NS-COPD was predominant in females (P < 0.0001). In NS-COPD, biomass fuel exposure was a major risk factor (P < 0.0001), and 61% of subjects had a biomass fuel exposure index of >60. In bivariate and multivariate analyses, no risk factors were correlated with forced expiratory volume in 1 second (FEV1)% predicted, while among clinical features, duration of illness (P = 0.001) was correlated with lower values of FEV1 in the multivariate table of S-COPD. In the multivariate analysis, biomass fuel exposure (P = 0.039) and CAT score (P < 0.0001) were correlated with FEV1(%) in NS-COPD. CONCLUSION: Biomass fuel exposure is a substantial risk factor for NS-COPD and was correlated with FEV1(%) predicted. In addition, the CAT score correlated with disease severity in patients with NS-COPD. The development of COPD in non-smokers is being recognized as a separate phenotype and it should be managed according to risk factors.

Effect of Curcumin and Coenzyme Q10 Alone and in Combination on Learning and Memory in an Animal Model of Alzheimer's Disease.

The most frequent neurodegenerative illness among senior people and the main cause of dementia is Alzheimer's disease. The present dementia medications available only help with the symptoms of cognitive deficits and have several negative effects. The current study's goal is to assess the effects of curcumin and coenzyme Q10, two herbal medicines, both separately and in combination, on learning and memory before comparing them to the industry standard drug. A total of 42 adult healthy Wistar rats were used in our study. In this experiment, rats were given daily doses of 2.5 mg/kg of body weight of scopolamine hydrobromide for 7 days to induce Alzheimer's disease. On the eighth day, behavioural testing was conducted. Following testing, scopolamine and the test medications were given daily for the following 21 days. On days 29 and 30, behavioural testing was conducted once more, and then animals were slaughtered. Brain homogenate was produced for the estimation of molecular and biochemical markers. Curcumin has demonstrated a dose-response relationship, with a higher dose (200 mg/kg b.w. p.o.) being more effective than a lower dose (100 mg/kg b.w. p.o.). Similar to the greater dose of curcumin, coenzyme Q10 (200 mg/kg b.w. p.o.) has also been found to improve memory and learning. Higher doses of curcumin and coenzyme Q10 had more pronounced and meaningful effects. Acetylcholinesterase and TNF levels increased in scopolamine-induced memory impairment, but these effects were restored by the test medications, and improved by the combined therapy. These outcomes are comparable to those of the common medication memantine. As a result, we may infer from our results that curcumin at higher doses and its combination with coenzyme Q10 (200 mg/kg b.w. p.o.) have a significant impact on cognitive impairment in animal models of Alzheimer's disease and can be utilised alone or as an add-on therapy for the condition.

The Relationship Between Clinical Phenotypes and Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stages/Groups in Patients With Chronic Obstructive Pulmonary Disease.

Background Chronic obstructive pulmonary disease (COPD) cannot be properly characterised by a single metric, forced expiratory volume in the first second (FEV1), due to its complexity and heterogeneity. The GOLD 2017 report contained the ABCD evaluation method to measure airflow limitation, symptoms, and/or exacerbation risk. Objective The purpose of this study was to explore the relationship between clinical characteristics and GOLD groups or stages in patients with COPD. Methods This cross-sectional observational study was conducted at the department of respiratory medicine, King George's Medical University, Lucknow, Uttar Pradesh, India, between 2019 and 2022. Here, stable COPD patients' demographics, clinical characteristics, and the number of exacerbations were compared between the groups following the GOLD 2022 report. An unpaired t-test with Welch's correction, chi-square test, Fisher's exact test, one-way ANOVA, and Kruskal-Wallis test were used for statistical significance. Results In this study, 349 stable COPD patients (256 males and 93 females) were selected. The GOLD 2017 categorization placed 78 (22.4%) patients in group A, 158 (45.3%) in B, 44 (12.6%) in C, and 69 (19.8%) in D. Further, we used GOLD 2017 to classify COPD patients into 16 subgroups (1A-4D). FEV1 (% predicted) decreased across groups A to D (p<0.0001). Groups C and D had a longer duration of illness, higher COPD assessment test (CAT) score, higher Modified Medical Research Council (mMRC) dyspnea scale, longer exacerbation history, and more COPD hospitalizations in the previous year than groups A and B. More symptomatic patients (B and D) exhibited lower FEV1 (% predicted) and more severe airflow limitation than less symptomatic patients (A and C) (p=0.0002). Symptomatic individuals exhibited higher CAT and mMRC dyspnea scores (p<0.0001). Groups C and D comprised older patients and those with longer disease duration, higher mMRC dyspnea scale and CAT, lower FEV1, and more severe airflow limitation (A and B). Conclusion The present study demonstrates the distribution of COPD patients' clinical phenotypes in an Indian population. We conclude that the combined COPD assessment according to the GOLD 2022 guideline provides a better understanding of COPD.

Correction: Shoaib et al. Neuroprotective Effects of Dried Tubers of Aconitum napellus. Plants 2020, 9, 356.

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Nasal turbinate enlargement due to cartilage and bone proliferation: a normal developmental finding in young ferrets.

Toxicity studies of intranasally administered, live attenuated influenza virus vaccine candidates conducted in male and female ferrets led to the microscopic observation of individual differences in the size of nasal turbinates, especially in the dorsal aspect of the nasal cavity. The association of these enlarged turbinates with acute to subacute inflammation, which is sometimes common in ferrets given live attenuated influenza virus vaccine candidates, led to this detailed microscopic evaluation of turbinate enlargement (cartilaginous and osseous thickening, or COT) in control animals dosed intranasally with saline. Results of this evaluation led to the conclusion that COT is a normal developmental feature of growing ferrets, irrespective of inflammation in nasal tissues or inflammatory exudate in the nasal cavity.

Evaluation of Noxious Consequence of Bark Extract of Onosma echioides Linn Root: Hematology, Biochemistry, and Histopathological Findings.

Onosma echioides is a perennial herb widely used for the treatment of various ailments such as sciatica, gout, and rheumatism. This study focused on toxicological assessment of bark extract of O. echioides root. In subacute toxicity study, 20 Sprague Dawley rats (140 ± 10 g body weight) were randomly grouped into two groups of 10 rats each (5 male and 5 female). Effect of the n-hexane extract of O. echioides (100 mg/kg body weight/day) was studied for a period of 28 days using control and treated groups. Effects of the extract on body weight, food consumption, water intake, serum glucose, and hematology, biochemistry, and histopathology were evaluated. The histopathology was carried out to evaluate the degenerative changes in liver, heart, and kidney. Result of acute toxicity study showed dose-dependent increase in mortality. LD50 was found to be 1,000 mg/kg body weight. The subacute toxicity data showed that the treated group did not show any change in behavior and urinalysis whereas an increase in body weight was observed in the male treated group. A significant but nontoxic effect was observed on food and water consumption. Significant increases in RBC (female treated group; **p < .01), neutrophil (both male and female treated group; **p < .01), MCV (female treated group, **p < .01), MCH (both male and female treated groups; **p < .01), and MCHC (both male and female treated groups; *p < .05) levels were observed; a significant changes were observed in total bilirubin (*p < .05), BUN (**p < .01), potassium (*p < .05), and ALT (**p < .01) levels. The relative organ weights of vital organs at this dose did not show any significant change. In conclusion, the toxicity data showed that the bark extract of O. echioides root does not possess any adverse effect at a fixed dose, which provides a support for its further safety study and biocompatibility application.

QSAR modeling and docking analysis of D2 receptor with known olanzapine derivatives.

Dopamine (D2) receptors are known drug targets for various antipsychotics used in Schizophrenia. Therefore, it is of interest to analyze the binding features of D2 receptors with known olanzapine derivatives for further consideration using molecular docking and QSAR analysis. A 2D QSAR model was built using energy-based descriptors generated by docking as independent variable and known Ki value of Olanzapine derivatives with D2 Receptor as dependent variable. QSAR model provided coefficient of determination of r2 of 0.7 in multiple linear regression analysis. The predictive performance of QSAR model was assessed using different cross-validation procedures. Thus, data shows that a ligand-receptor binding interaction for D2 Receptor using a QSAR model is promising approach to design novel and potent inhibitors of D2 Receptor.

Antidiabetic activity of standardized dried tubers extract of Aconitum napellus in streptozotocin-induced diabetic rats.

India has got rich cultural inheritage in the forms of Ayurveda texts which are a rich and ample source of herbs, shrubs, trees and affluent in medicinally active phytoconstituents. Aconitum napellus is used for the cure of many ailments including rheumatoid arthritis, sciatica and gout. The present work attempts to evaluate the physicochemical and preliminary phytochemical studies on the tubers of Aconitum napellus along with its antidiabetic activity. The herbal standardization was carried out on the basis of organoleptic properties, physical characteristics and physicochemical properties. The body weight of ACON-I (1.25 mg/kg) and ACON-II (2.5 mg/kg) was recorded as 190.40 and 209.40 g, respectively, compared with 163.00 g in diabetic rats at day 28. The body weight of ACON-I and ACON-II was significantly increased compared with diabetic rats (p < 0.01). However, the body weight of ACON-I and ACON-II was decreased significantly (p < 0.01) compared with normal group (222.60 g). The blood glucose levels of diabetic rats and ACON-I group were recorded as 277.800 and 152.400 mg/dl, respectively, compared with 83.600 mg/dl in normal rats (p < 0.01). However, the HbA1c levels of diabetic rats and ACON-I group were recorded as 11.306 and 6.936% Hb, respectively, compared with 4.539% Hb in normal rats. The glucose and HbA1c levels of diabetic and ACON-I groups were significant compared with normal group (p < 0.01). The results of antidiabetic activity showed that the plant can be used as a potent source for the treatment of diabetes and its complications. The results of this work provided the referential information for the identification and standardization of Aconitum napellus along with its role as a hypoglycemic agent.

Neuroprotective Effects of Dried Tubers of Aconitum napellus.

The present study was designed to explore the neuroprotective properties of Aconitum napellus (Ranunculaceae). The plant detoxification was done using either water, or cow or goat milk as per the Ayurvedic shodhana method. The evaluation of the neuroprotective role of A. napellus was performed on diabetic neuropathy induced by streptozotocin in Sprague Dawley (SD) rats. Body mass, blood sugar level, oral glucose tolerance test, hyperalgesia, cold allodynia, motor co-ordination test, and locomotor activity, oxidative biomarkers (TBARS, reduced glutathione, catalase and superoxide dismutase) and sciatic nerve histomorphology were assessed. The in vitro studies were done on human neuroblastoma cell line SHSY-5Y and used an MTT assay to assess the antiproliferative activity of different extracts. Results suggest that the goat milk treated chloroform extract has less percentage of aconitine. After administration of the detoxified chloroform extract to the diabetic animals, there was a significant improvement in the myelination and degenerative changes of the nerve fibers along with behavioral changes (p < 0.05 as compared with diabetic control group). The findings of the in vitro research show an effective neuroprotective role of A. napellus. This suggests that A. napellus should be further investigated for its effect in diabetic pathology.