- Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes. [Journal Article]
- JCIJ Clin Invest 2018 Feb 13
- Major histocompatibility (MHC) class II molecules are strongly associated with many autoimmune disorders. In type 1 diabetes, the DQ8 molecule is common, confers significant disease risk and is invol...
Major histocompatibility (MHC) class II molecules are strongly associated with many autoimmune disorders. In type 1 diabetes, the DQ8 molecule is common, confers significant disease risk and is involved in disease pathogenesis. We hypothesized blocking DQ8 antigen presentation would provide therapeutic benefit by preventing recognition of self-peptides by pathogenic T cells. We used the crystal structure of DQ8 to select drug-like small molecules predicted to bind structural pockets in the MHC antigen-binding cleft. A limited number of the predicted compounds inhibited DQ8 antigen presentation in vitro with one compound preventing insulin autoantibody production and delaying diabetes onset in an animal model of spontaneous autoimmune diabetes. An existing drug of similar structure, methyldopa, specifically blocked DQ8 in recent-onset patients with type 1 diabetes along with reducing inflammatory T cell responses toward insulin, highlighting the relevance of blocking disease-specific MHC class II antigen presentation to treat autoimmunity.
- Non-antipsychotic catecholaminergic drugs for antipsychotic-induced tardive dyskinesia. [Review]
- CDCochrane Database Syst Rev 2018 01 18; 1:CD000458
- CONCLUSIONS: Although there has been a large amount of research in this area, many studies were excluded due to inherent problems in the nature of their cross-over designs. Usually data are not reported before the cross-over and the nature of TD and its likely response to treatments make it imprudent to use this data. The review provides little usable information for service users or providers and more well-designed and well-reported studies are indicated.
- Clinical Value of 18F-FDOPA PET/CT With Contrast Enhancement and Without Carbidopa Premedication in Patients with Insulinoma. [Journal Article]
- ARAnticancer Res 2018; 38(1):353-358
- CONCLUSIONS: Based on our data, 18F-DOPA PET/CT, with contrast enhancement and without carbidopa premedication, as a 'one-stop' diagnostic modality is a viable option for insulinoma detection.
- Lisdexamfetamine: chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy, safety, and tolerability in the treatment of binge eating disorder. [Review]
- EOExpert Opin Drug Metab Toxicol 2018; 14(2):229-238
- The indications for lisdexamfetamine (LDX), a central nervous system stimulant, were recently expanded to include treatment of moderate to severe binge eating disorder (BED). Areas covered: This revi...
The indications for lisdexamfetamine (LDX), a central nervous system stimulant, were recently expanded to include treatment of moderate to severe binge eating disorder (BED). Areas covered: This review aims to describe the chemistry and pharmacology of LDX, as well as the clinical trials investigating the efficacy and safety of this medication for the management of BED. Expert opinion: LDX is the first medication with United States Food and Drug Administration approval for the treatment of BED. It is an inactive prodrug of d-amphetamine that extends the half-life of d-amphetamine to allow for once daily dosing. D-amphetamine acts primarily to increase the concentrations of synaptic dopamine and norepinephrine. Metabolism of LDX to d-amphetamine occurs when peptidases in red blood cells cleave the covalent bond between d-amphetamine and l-lysine. D-amphetamine is then further metabolized by CYP2D6. Excretion is primarily through renal mechanisms. In clinical trials, LDX demonstrated statistical and clinical superiority over placebo in reducing binge eating days per week at doses of 50 and 70 mg daily. Commonly reported side effects of LDX include dry mouth, insomnia, weight loss, and headache, and its use should be avoided in patients with known structural cardiac abnormalities, cardiomyopathy, serious heart arrhythmia or coronary artery disease. As with all CNS stimulants, risk of abuse needs to be assessed prior to prescribing.
- Patient Preferences for Device-Aided Treatments Indicated for Advanced Parkinson Disease. [Journal Article]
- VHValue Health 2017; 20(10):1383-1393
- CONCLUSIONS: This study clarifies the patient perspective in therapeutic choices for advanced PD. These findings may help improve communication between patients and providers and also provide evidence on patient preferences to inform regulatory and access decisions.
- Case 38-2017. A 20-Year-Old Woman with Seizures and Progressive Dystonia. [Case Reports]
- NEJMN Engl J Med 2017 Dec 14; 377(24):2376-2385
- Voltammetric Determination of Penicillamine Using a Carbon Paste Electrode Modified with Multiwall Carbon Nanotubes In the Presence of Methyldopa as a Mediator. [Journal Article]
- IJIran J Pharm Res 2017; 16(3):1019-1029
- A multiwall carbon nanotubes-modified carbon paste electrode (MWCNTs/MCPE) was fabricated and used to study the electrooxidation of penicillamine (PA) by electrochemical methods in the presence of me...
A multiwall carbon nanotubes-modified carbon paste electrode (MWCNTs/MCPE) was fabricated and used to study the electrooxidation of penicillamine (PA) by electrochemical methods in the presence of methyldopa (MDOP) as a homogeneous mediator. The electrochemical oxidation of PA on the new sensor has been carefully studied. The kinetic parameters such as electron transfer coefficient, α, and catalytic reaction rate constant, K/h, were also determined using electrochemical approaches. The electrocatalytic oxidation peak current of PA showed a linear dependent on the PA concentrations and linear calibration curves were obtained in the ranges of 0.2-250.0 µM of PA concentration with square wave voltammetry (SWV) method. The detection limit (3σ) was determined as 0.1 µM. This sensor was also examined as a fast, selective, simple and precise new sensor for voltammetric determination of PA in real samples such as drug and urine.
- Adverse drug reactions in high-risk pregnant women: A prospective study. [Journal Article]
- SPSaudi Pharm J 2017; 25(7):1073-1077
- CONCLUSIONS: Overall, ADRs were not common events among high-risk pregnant women and no adverse pregnancy outcomes following these events were observed.
- Carbidopa: a selective Ah receptor modulator (SAhRM). [Journal Article]
- BJBiochem J 2017 Nov 06; 474(22):3763-3765
- The aryl hydrocarbon receptor (AhR) was discovered as the intracellular receptor that bound with high affinity to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and the AhR is...
The aryl hydrocarbon receptor (AhR) was discovered as the intracellular receptor that bound with high affinity to the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and the AhR is required for mediating the toxicity induced by TCDD. Subsequent studies show that the AhR binds structurally diverse chemicals including plant-derived compounds that promote health and several AhR-active pharmaceuticals that exhibit anticancer activity. In this issue, there is a report that carbidopa, a drug used for treating Parkinson's disease, is also an AhR ligand, and this compound inhibits pancreatic cancer cell and tumor growth. These results are consistent with activities of other AhR-active compounds that inhibit carcinogenesis. Like carbidopa, these chemicals are selective AhR modulators with potential clinical applications that are AhR-dependent.
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- Carbidopa is an activator of aryl hydrocarbon receptor with potential for cancer therapy. [Journal Article]
- BJBiochem J 2017 Sep 28; 474(20):3391-3402
- Carbidopa is used with l-DOPA (l-3,4-dihydroxyphenylalanine) to treat Parkinson's disease (PD). PD patients exhibit lower incidence of most cancers including pancreatic cancer, but with the notable e...
Carbidopa is used with l-DOPA (l-3,4-dihydroxyphenylalanine) to treat Parkinson's disease (PD). PD patients exhibit lower incidence of most cancers including pancreatic cancer, but with the notable exception of melanoma. The decreased cancer incidence is not due to l-DOPA; however, the relevance of Carbidopa to this phenomenon has not been investigated. Here, we tested the hypothesis that Carbidopa, independent of l-DOPA, might elicit an anticancer effect. Carbidopa inhibited pancreatic cancer cell proliferation both in vitro and in vivo Based on structural similarity with phenylhydrazine, an inhibitor of indoleamine-2,3-dioxygenase-1 (IDO1), we predicted that Carbidopa might also inhibit IDO1, thus providing a molecular basis for its anticancer effect. The inhibitory effect was confirmed using human recombinant IDO1. To demonstrate the inhibition in intact cells, AhR (aryl hydrocarbon receptor) activity was monitored as readout for IDO1-mediated generation of the endogenous AhR agonist kynurenine in pancreatic and liver cancer cells. Surprisingly, Carbidopa did not inhibit but instead potentiated AhR signaling, evident from increased CYP1A1 (cytochrome P450 family 1 subfamily A member 1), CYP1A2, and CYP1B1 expression. In pancreatic and liver cancer cells, Carbidopa promoted AhR nuclear localization. AhR antagonists blocked Carbidopa-dependent activation of AhR signaling. The inhibitory effect on pancreatic cancer cells in vitro and in vivo and the activation of AhR occurred at therapeutic concentrations of Carbidopa. Chromatin immunoprecipitation assay further confirmed that Carbidopa promoted AhR binding to its target gene CYP1A1 leading to its induction. We conclude that Carbidopa is an AhR agonist and suppresses pancreatic cancer. Hence, Carbidopa could potentially be re-purposed to treat pancreatic cancer and possibly other cancers as well.