Antiepileptic Drug Targets: An Update on Ion Channels

Different mechanisms of action have been proposed to explain the effects of antiepileptic drugs (AEDs) including modulation of voltage‐dependent sodium calcium and potassium channels, enhancement of γ‐aminobutyric acid (GABA)‐mediated neuronal inhibition, and reduction in glutamate‐mediated excitatory transmission. Recent advances in understanding the physiology of ion channels and genetics basis of epilepsies have given insight into various molecular targets for AEDs. Conventional AEDs predominantly target voltage‐ and ligand‐gated ion channels including the α subunits of voltage‐gated Na+ channels, T‐type, and α2‐δ subunits of the voltage‐gated Ca2+ channels, A‐ or M‐type voltage‐gated K+ channels, the γ‐aminobutyric acid (GABA) receptor channel complex, and ionotropic glutamatergic receptors. Molecular cloning of ion channel subunit proteins and studies in epilepsy models suggest additional targets including hyperpolarization‐activated cyclic nucleotide‐gated cation (HCN) channel subunits, responsible for hyperpolarization‐activated current (Ih), voltage‐gated chloride channels, and acid‐sensing ion channels. This chapter gives an update on voltage‐ and ligand‐gated ion channels, discussing their structures, functions, and relevance as potential targets for AEDs

Maerua angolensis DC: evaluation of the oral acute and sub-chronic toxicity profile of its freeze-dried leaves infusion extract

Maerua angolensis is a shrub/small tree that grows up to about 10 m tall. The plant is widely distributed in tropical Africa and used in various ethnomedicinal applications across the region. The objective of this study is to investigate the oral safety profile of the infusion extract of Maerua angolensis (IEMa) in laboratory animals. Hippocratic screening was adopted to evaluate the acute toxicity profile using 2000 mg/kg of IEMa, p.o. in mice. The sub-chronic toxicity was performed by daily oral administration of IEMa (800 mg/kg) in Wistar rats for 28 days and clinical observations and toxicological related parameters were recorded. After the treatment period, blood was collected for hematological and biochemical analysis, and organs were removed for macroscopic analysis. The agent exhibited mild symptoms and no mortality recorded in the Hippocratic screening. In the sub-chronic test, few changes in urine output, platelets counts and alkaline phosphatase were observed, but are within the physiological ranges for this animal specie. The results shows that IEMa does not present oral toxicity thereby displaying a wide safety margin for therapeutic use

Adverse event following vaccine surveillance in Kaduna State, Northwestern Nigeria (January 2018 - June 2019): analysis of health facility´s records

Introduction: Adverse Events Following Immunization (AEFI) are one of the main reasons for inadequate immunization coverage in Kaduna State, and AEFI underreporting serves as a barrier to achieving goals of global pharmaco-vigilance for vaccine. The purpose of this study is to estimate the completeness of variables in the AEFI line-listing forms, calculate AEFI reporting rates by local government Areas & vaccine type and profile the reported cases according to their reactions. Methods: we conducted a descriptive, cross-sectional, retrospective study of primary surveillance records. We calculated AEFI reporting rates in the State and local government areas and AEFI Vaccine reaction rates to the various antigens. We used Binary logistic regression to determine the association between gender and vaccine reactions. Results: seven thousand eight hundred and twenty-four (7,824) AEFI cases were reported. The completeness of variables on the filled AEFI line-list varied from 21% to 100%. The State had a high AEFI reporting rate of 9.09 per 10,000 administered doses. Fever (<38oC) was the main AEFI reaction. Severe AEFI cases accounted for only 0.89% of the total reported cases. Pentavalent vaccine was the suspect antigen responsible for the highest number of AEFI cases, with a vaccine reaction rate of 44.77 per 10,000 doses. The Zaria Local Government area had the highest AEFI reporting rate, while the Sanga Local Government area had the lowest AEFI reporting rate in the State. The difference between genders in the number of reported AEFI cases was not statistically significant (p>0.05). There were 35% higher odds of occurrence of bleeding among males than among females (aOR:1.354; P-value: p=.012; 95% CI: 1.070-1.715; Nagelkerke-R2-: 0.003). The other reactions were not significantly related to gender. Conclusion: our study shows a higher occurrence of severe AEFI in subjects undergoing pentavalent vaccine. Thiscaused the highest incidence of AEFI. There was no significant association between gender and AEFI reactions

Antidiabetic phytodrug from Maerua angolensis DC: Formulation, standardization, in vitro and in vivo evaluations

Maerua angolensis is a shrub or small tree widely distributed in tropical Africa. The plant materials are used for various ethnomedicinal applications across the region, including the prevention and treatment of diabetes. This study was aimed to evaluate the antidiabetic potential of formulated freeze-dried aqueous extract of Maerua angolensis leaves using standard in vitro and in vivo experimental models. Infusion extract of the plant's powdered dried leaves was prepared, the resultant extract was freeze-dried and formulated (denoted FIEMa). The physicochemical, quantitative and qualitative phytochemical constituents of FIEMa were determined using analytical techniques (UV-visible and HPLC). The antidiabetic activity of the reconstituted formulation was investigated using in vitro and in vivo models. The in vitro activity was assessed using Phosphomolybdenum assay and DPPH (2,2-Diphenyl-1-picrylhydrazyl) radical scavenging activity for antioxidant effect, and α-amylase inhibition and α- glycosidase inhibition assays. The assays of the normoglycemic, oral glucose load tolerance, and single-dose alloxan (150 mg/kg) induced diabetes in rats were used for in vivo antidiabetic activity. The results show that FIEMa contains valuable phytochemicals. It exhibited antioxidant effect, α-amylase and α- glucosidase inhibition activities. FIEMa did not significantly reduce blood glucose levels (BGL) in normoglycemic mice but produced a significant reduction of BGL in the oral glucose tolerance test. In alloxan-induced diabetic rats, significant reductions of BGL were observed in groups treated with high doses of FIEMa in the single-dose study and from the second week onwards in the repeated dose study. It also exhibited less reduction in body weight compared to the control group. The findings indicate that FIEMa has an antidiabetic activity, low risk of hypoglycemia, and body weight loss. The valuable phytochemicals plausibly mediate this effect, especially the dominant betulinic acid detected in FIEMa, most likely acting in synergy

Simulation of metabolism-based herb-drug interaction: towards safe and efficacious use of NIPRD-AM1

Objective: To evaluate the effect of NIPRD-AM1 on CYP3A4 in order to generate clinically significant data for its safe and efficacious use. Materials and Methods: NIPRD-AM1 is a phytomedicine developed from aqueous root extracts of Nauclea latifolia Smith (Rubiaceae) for the treatment of uncomplicated malaria. The effect of NIPRD-AM1 on CYP3A4 was measured with and without the addition of NIPRD-AM1, by testing different concentrations of the product at 37 °C in reactive mixtures with ketoconazole (2.5 µM) as the positive control. Results: Results showed a very low IC50 value of 0.01 mg/ml similar to that of ketoconazole (0.016 mg/ml). Conclusion: Metabolic processes of NIPRD-AM1 are likely to inhibit CYP3A4, with potential implication on drugs that are CYP3A4 substrates. This is a promising approach for guidance towards the safe and efficacious use of NIPRD-AM1

Evaluation of the toxic effects of the aqueous extract of Niprineem tea in mice and rats

Azadirachta indica is an important plant in traditional complementary and alternative medicine with decoctions (tea) being a common mode of administration. Herbal teas are frequently self-administered thus the need to prepare a standardized dosage form for the administration of such decoctions. The leaf of Azadirachta indica was formulated for administration as tea; thus, this study was designed to determine the safety profile of Niprineem tea. Oral acute and sub-chronic toxicity studies of the aqueous extract of Niprineem tea (NTE) were evaluated. The OECD (No 423) limit test was followed to determine the LD50 in Swiss albino mice, while OECD 407 guideline was used for the sub-chronic toxicity studies in Wistar rats. Acute administration of NTE did not cause detectable signs of toxicity in treated animals and no mortality was recorded. In the 28-day toxicity tests, there were no significant (p<0.05) changes in food and water intake, or urine and faecal output. Haematological analysis did not show deleterious effects in treated rats. Biochemical evaluation of indicators for renal and hepatic functions did not show significant changes after treatment with NTE. Likewise, histological tests did not result in structural changes in cells of the tissues of major organs. The results obtained suggest that Niprineem tea is relatively non-toxic and safe at the tested dose

Structural Characterization of ZS – 2A: An Antiplasmodial Compound Isolated from Zizyphus spina-christi Root Bark

Zizyphus spina-christi (Rhamnaceae) is a popular medicinal plant that grows wildly in Asia and Tropical Africa. The plant is widely used in ethnomedical practice for the treatment of fever. As a step towards the isolation of biologically active constituents of this plant, we carried out a bioassay guided extraction of the root bark using solvents of varying polarity including, hexane, chloroform, ethylacetate and methanol. An antiplasmodial compound, designated as ZS-2A, was isolated from the chloroform extract and the chemical structure of the compound was characterized using UVvisible, IR, 13C and 1H NMR and thermo-analytical techniques. Our analysis established ZS – 2A as a betulinic acid

Phytochemical and Antidiabetic Evaluation of the Methanolic Stem Bark Extract of Spathodea campanulata (P. Beauv.) Bignoniaceae

ABSTRACT Background: Spathodea campanulata (P. Beauv.) Bignoniaceae extract (SCE) is one of many herbal medicines used widely in Ugandan traditional medicine for various ailments. Generally most of these herbal medicines are yet to be standardized or have their phytochemical content characterized. Method: This study identified the secondary metabolites in the stem bark methanolic extract and quantified them. The same extract was subjected to serial solvent fractionation, TLC characterization and antidiabetic testing

Evaluation of the Acute and Subactue chronic Toxicities of the Methanolic Stem Bark Extract of Spathodea campanulata (P.Beauv.) Bignoniaceae

status: publishe