Methyldopa for primary hypertension

Mah, Greg T; Tejani, Aaron M; Musini, Vijaya M

doi:10.1002/14651858.cd003893.pub3

Cited by 42 publications

(35 citation statements)

References 40 publications

(14 reference statements)

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“…Using the approach outlined in figure 1, we performed molecular modeling and docking of FDA approved drugs to bind within pockets in the DQ8 peptide-binding groove (31). By screening the top 'hits', we discovered methyldopa (Aldomet), a clinically wellestablished oral antihypertensive drug used to treat both children and adults (34), specifically blocked DQ8. Further testing revealed methyldopa bound DQ8 in the middle of the peptidebinding groove with a dissociation constant, K D ≈ 26 μM ( Fig.…”

Section: Methyldopa As a Specific Dq8 Blockermentioning

confidence: 99%

Rationally designed small molecules to prevent type 1 diabetes

Ostrov

Gottlieb

Michels

2019

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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Purpose of review: To review the recent findings that small 'drug-like' compounds block disease-specific HLA molecules in type 1 diabetes (T1D). Recent findings: The predominant genetic risk for developing T1D, the immune mediated form of diabetes, is conferred through human leukocyte antigen (HLA) genes. One such gene, termed HLA-DQ8, is present in 50-60% of patients with T1D and those at-risk. DQ8 presents diseaserelevant peptides to T cells, which mediate tissue specific destruction of pancreatic islets. Using a structure-based approach to evaluate the 'druggability' of the DQ8 molecule, methyldopa, a clinically well-established oral anti-hypertensive agent, was discovered to bind DQ8. Methyldopa blocked the activation of DQ8 specific T cells responding to self-antigens such as insulin but not influenza. In a proof-of-concept clinical trial (NCT01883804), methyldopa was administered to recent-onset T1D patients with the DQ8 gene that confirmed the mechanism of action and diminished inflammatory T cell responses towards insulin. Summary: Methyldopa blocks the diabetes-specific function of HLA-DQ8, which represents a personalized medicine approach to treat the underlying autoimmunity in T1D. Clinical trials are warranted and underway to evaluate methyldopa in potentially preserving residual beta-cell function in those with new-onset and at-risk for T1D.

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Section: Methyldopa As a Specific Dq8 Blockermentioning

confidence: 99%

Rationally designed small molecules to prevent type 1 diabetes

Ostrov

Gottlieb

Michels

2019

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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“…One of these, methyldopa (Aldomet; Figure 3A) inhibited T cell responsiveness in vitro. Methyldopa is a clinically well-established oral drug used for over 50 years to treat hypertension in both children and adults (33), which provides an opportunity to repurpose methyldopa for immune-mediated treatment of T1D.…”

Section: 0mentioning

confidence: 99%

Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes

Ostrov

Alkanani²,

McDaniel³

et al. 2018

Journal of Clinical Investigation

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Authorship note: PAG and AWM contributed equally to this work. Conflict of interest: AWM and DAO are inventors on a patent titled "Compounds that modulate autoimmunity and methods of using the same, " licensed to ImmunoMolecular Therapeutics (US patent number 9,629,848). AWM and PAG are scientific cofounders of ImmunoMolecular Therapeutics and own shares in the company. KJS and BP are former employees of Novartis.

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“…However, none of these studies reported on useful clinical outcomes such as the reduction in stroke with methyldopa treatment versus placebo. 28 Recent UK guidelines for managing hypertension in pregnancy have relegated methyldopa to a second-line treatment. It retains a more prominent role in the guidelines of Canada and Australia and New Zealand where it is included as a first-line treatment.…”

Section: Clinical Use Of Methyldopamentioning

confidence: 99%

Hypertension in pregnancy: a review of therapeutic options

2012

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Summary: Hypertensive disorders in pregnancy are common and can occur as a result of pre-existing hypertension or as new onset hypertension usually in the second half of pregnancy. In either situation there is potential for considerable perinatal and maternal morbidity and mortality. This review article aims to compare therapeutic options outlined in a selection of national guidelines and to look in more detail at the most commonly prescribed drugs -labetalol, methyldopa and nifedipine -with respect to their pharmacology and the evidence for their use in pregnancy. We will also consider the rationale for identifying and treating hypertension in pregnancy and the effect this can have on short-and long-term maternal and neonatal outcomes.

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Methyldopa for primary hypertension

Abstract: Methyldopa lowers blood pressure to varying degrees compared to placebo for patients with primary hypertension. Its effect on clinical outcomes, however, remains uncertain.

Cited by 42 publications

References 40 publications

Rationally designed small molecules to prevent type 1 diabetes

Rationally designed small molecules to prevent type 1 diabetes

Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes

Hypertension in pregnancy: a review of therapeutic options

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