Several generations of antiepileptic drugs (AEDs) are available in the market for the treatment of seizures, but these are amalgamated with acute to chronic side effects. The most common side effects ...of AEDs are dose-related, but some are idiosyncratic adverse drug reactions (ADRs) that transpire due to the formation of reactive metabolite (RM) after the bioactivation process. Because of the adverse reactions patients usually discontinue the medication in between the treatment. The AEDs such as valproic acid, lamotrigine, phenytoin etc., can be categorized under such types because they form the RM which may prevail with life-threatening adverse effects or immune-mediated reactions. Hepatotoxicity, teratogenicity, cutaneous hypersensitivity, dizziness, addiction, serum sickness reaction, renal calculi, metabolic acidosis are associated with the metabolites of drugs such as arene oxide, N-desmethyldiazepam, 2-(1-hydroxyethyl)-2-methylsuccinimide, 2-(sulphamoy1acetyl)-phenol, E−2-en-VPA and 4-en-VPA and carbamazepine-10,11-epoxide, etc. The major toxicities are associated with the moieties that are either capable of forming RM or the functional groups may itself be too reactive prior to the metabolism. These functional groups or fragment structures are typically known as structural alerts or toxicophores. Therefore, minimizing the bioactivation potential of lead structures in the early phases of drug discovery by a modification to low-risk drug molecules is a priority for the pharmaceutical companies. Additionally, excellent potency and pharmacokinetic (PK) behaviour help in ensuring that appropriate (low dose) candidate drugs progress into the development phase. The current review discusses about RMs in the anticonvulsant drugs along with their mechanism vis-a-vis research efforts that have been taken to minimize the toxic effects of AEDs therapy.
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•Reactive metabolites of established antiepileptic drugs (AEDs) with their acute/chronic side-effects are reported.•Various synthetic strategies to minimize the toxicity under each category of AEDs are discussed.•Preclinical data for the synthesized derivatives is represented as compared to standard AEDs.•Structural activity relationship has been discussed for various synthesized derivatives.
The radionuclide .sup.117m Sn (tin-117m) embedded in a homogeneous colloid is a novel radiosynoviorthesis (RSO) device for intra-articular (IA) administration to treat synovial inflammation and ...mitigate osteoarthritis (OA) in dogs. A study to evaluate tin-117m colloid treatment response in dogs with OA was conducted at two centers, the School of Veterinary Medicine at Louisiana State University, and at a referral practice in Houston, Texas. The tin-117m colloid was administered per-protocol to 14 client-owned dogs with radiographically confirmed, grade 3 OA in one or both elbow joints. Dog owners and attending clinicians assessed the level of pain at baseline (BL) and the post-treatment pain response at 90-day intervals for one year. Owners assessed treatment response according to a pain severity score (PSS) and a pain interference score (PIS) as defined by the Canine Brief Pain Inventory. Clinicians reported a lameness score using a 0-5 scale, from no lameness to continuous non-weight bearing lameness, when observing dogs at a walk and a trot. The rate of treatment success as determined by improved mean PSS and PIS scores reported by dog owners was >70% at all time points. Clinicians reported an improved mean pain score from BL at post-treatment Days 90 (p0.05) at Day 90 and Day 180 time points. Results indicated that a single IA dose of tin-117m colloid provided a significant reduction in pain and lameness and improved functionality for up to a full year, with no adverse treatment related effects, in a high percentage of dogs with advanced, clinical OA of the elbow joint.
The radionuclide .sup.117m Sn (tin-117m) embedded in a homogeneous colloid is a novel radiosynoviorthesis (RSO) device for intra-articular (IA) administration to treat synovial inflammation and ...mitigate osteoarthritis (OA) in dogs. A study to evaluate tin-117m colloid treatment response in dogs with OA was conducted at two centers, the School of Veterinary Medicine at Louisiana State University, and at a referral practice in Houston, Texas. The tin-117m colloid was administered per-protocol to 14 client-owned dogs with radiographically confirmed, grade 3 OA in one or both elbow joints. Dog owners and attending clinicians assessed the level of pain at baseline (BL) and the post-treatment pain response at 90-day intervals for one year. Owners assessed treatment response according to a pain severity score (PSS) and a pain interference score (PIS) as defined by the Canine Brief Pain Inventory. Clinicians reported a lameness score using a 0-5 scale, from no lameness to continuous non-weight bearing lameness, when observing dogs at a walk and a trot. The rate of treatment success as determined by improved mean PSS and PIS scores reported by dog owners was >70% at all time points. Clinicians reported an improved mean pain score from BL at post-treatment Days 90 (p0.05) at Day 90 and Day 180 time points. Results indicated that a single IA dose of tin-117m colloid provided a significant reduction in pain and lameness and improved functionality for up to a full year, with no adverse treatment related effects, in a high percentage of dogs with advanced, clinical OA of the elbow joint.
The sodium dependent SLC13 family transporters comprise of five genes SLC13A1, SLC13A2 (NaDC1), SLC13A3 (NaDC3), SLC13A4 and SLC13A5 (NaCT). Among them, NaDC1, NaDC3 and NaCT are sodium dependent ...transporters belonging to family of dicarboxylates (succinate, malate,
α
-ketoglutarate) and tricarboxylates (citrate). The mouse and the human NaCT structures have still not been crystallized, therefore structural information is taken from the related bacterial transporter of VcINDY. Citrate in the cytosol works as a precursor for the fatty acid synthesis, cholesterol, and low-density lipoproteins. The excess citrate from the matrix is translocated to the cytosol for fatty acid synthesis through these transporters and thus controls the energy balance by downregulating the glycolysis, tricarboxylic acid (TCA), and fatty acid breakdown. These transporters play an important role in regulating various metabolic diseases including cancer, diabetes, obesity, fatty liver diseases and CNS disorders. These di and tricarboxylate transporters are emerging as new targets for metabolic disorders such as obesity and diabetes. The mutation in the function of the NaCT causes several neurological diseases including neonatal epilepsy and impaired brain development whereas mutation of genes coding for citrate transport present in the liver may provide positive effect. Therefore, continued efforts from the earlier work on citrate transporters are required for the development of citrate inhibitors. This review discusses the structure, function, and regulation of the NaCT transporter. The review also highlights citrate role in diagnosing diseases such as cancer, diabetes, fatty liver, and diabetes. The therapeutic perspective of synthetic inhibitors against NaCT transporters is succinctly summarized.
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Fungal infections are posing serious threat to healthcare system due to emerging resistance among available antifungal agents. Among available antifungal agents in clinical practice, azoles (diazole, ...1,2,4‐triazole and tetrazole) remained most effective and widely prescribed antifungal agents. Now their associated side effects and emerging resistance pattern raised a need of new and potent antifungal agents. Lanosterol 14α‐demethylase (CYP51) is responsible for the oxidative removal of 14α‐methyl group of sterol precursors lanosterol and 24(28)‐methylene‐24,25‐dihydrolanosterol in ergosterol biosynthesis hence an essential component of fungal life cycle and prominent target for antifungal drug development. This review will shed light on various azole‐ as well as non‐azoles‐based derivatives as potential antifungal agents that target fungal CYP51. Review will provide deep insight about structure activity relationship, pharmacological outcomes, and interactions of derivatives with CYP51 at molecular level. It will help medicinal chemists working on antifungal development in designing more rational, potent, and safer antifungal agents by targeting fungal CYP51 for tackling emerging antifungal drug resistance.
Lanosterol 14α‐demethylase (CYP51) responsible for oxidative removal of 14α‐methyl group of sterol precursors, lanosterol, and 24(28)‐methylene‐24,25‐dihydrolanosterol in ergosterol biosynthesis; essential component of fungal life cycle and prominent target for antifungal drug development. This review addresses various azole‐ and non‐azoles‐based derivatives as potential antifungal agents that target fungal CYP51.
In this work, Al
2
O
3
coatings were produced by plasma electrolytic oxidation (PEO) of AA6063 substrates using KOH–Na
2
SiO
3
electrolyte. The influence of the pulse duty cycle (25%, 60% at
J
= 0.2 ...A/cm
2
) on the morphology, nanoindentation, and tribology of PEO coatings was studied. The results indicate that a higher pulse duty cycle resulted in thicker and more porous coatings. Initially, the γ-Al
2
O
3
phase was dominant with the additional presence of mullite and α-Al
2
O
3
phases. The nanomechanical and wear results demonstrated that the microhardness, elastic recovery, and strength of PEO coatings can be controlled according to the pulse duty cycle applied.
Graphical abstract
Estrogen acting through estrogen receptor beta (ERbeta) has been shown to oppose the stimulation of cardiac myocytes and cardiac fibroblasts that results in cardiac hypertrophy and fibrosis. Previous ...work has implicated signal transduction from ERbeta as being important to the function of estrogen in this regard. Here we address whether membrane ERbeta is sufficient to oppose key mechanisms by which angiotensin II (AngII) stimulates cardiac cell pathology. To do this we first defined essential structural elements within ERbeta that are necessary for membrane or nuclear localization in cells. We previously determined that cysteine 418 is the site of palmitoylation of ERbeta that is required and sufficient for cell membrane localization in mice and is the same site in humans. Here we determined in Chinese hamster ovarian (CHO) cells, and mouse and rat myocytes and cardiac fibroblasts, the effect on multiple aspects of signal transduction by expressing wild-type (WT) or a C418A-mutant ERbeta. To test the importance of the nuclear receptor, we determined a 4-amino acid deletion in the E domain of ERbeta that strongly blocked nuclear localization. Using these tools, we expressed WT and mutant ERbeta constructs into cardiomyocytes and cardiac fibroblasts from ERbeta-deleted mice. We determined the ability of estrogen to mitigate cell pathology stimulated by AngII and whether the membrane ERbeta is necessary and sufficient. Key Words: estrogen receptor, signal transduction, cardiac myocytes, cardiac fibroblasts Abbreviations: AKT, protein kinase B; AngII, angiotensin II; BSA, bovine serum albumin; cDNA, complementary DNA; CHO, Chinese hamster ovarian; DMEM, Dulbecco's modified Eagle's medium; E2, 17-beta estradiol; ERbeta, estrogen receptor beta; Erk, extracellularly regulated kinase; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HDAC, histone deacetylase; KO, knockdown; mRNA, messenger RNA; NLSD, nuclear localization sequence deleted; PDL, poly-D lysine; qPCR, quantitative polymerase chain reaction; RT, reverse transcription; siRNA, small interfering RNA; SMAalpha, smooth muscle actin alpha; WT, wild-type.