Methyldopa

Differentiation of Central vs. Peripheral Actions

The antihypertensive effects of methyldopa are largely mediated by its actions within the central nervous system (CNS) drugbank.comnih.govpatsnap.compatsnap.com. This compound crosses the blood-brain barrier and is metabolized to alpha-methylnorepinephrine within adrenergic neurons in the CNS nih.govpatsnap.com. Alpha-methylnorepinephrine stimulates central alpha-2 adrenergic receptors, particularly in the brainstem, such as those in the rostral ventrolateral medulla drugbank.comnih.govpatsnap.com. This stimulation inhibits adrenergic neuronal outflow, leading to a decrease in sympathetic tone and a reduction in vasoconstrictor adrenergic signals sent to the periphery drugbank.comnih.govpatsnap.compatsnap.com. This reduced sympathetic outflow results in decreased peripheral vascular resistance and consequently lowers blood pressure nih.govpatsnap.combiolife-publisher.it.

While the central action is considered predominant, the potential for peripheral effects has also been investigated biolife-publisher.it. This compound is metabolized to alpha-methylnorepinephrine via dopamine beta-hydroxylase activity, and further to alpha-methylepinephrine via phenylethanolamine-N-methyltransferase activity drugbank.com. These active metabolites are agonists at presynaptic alpha-2 adrenergic receptors drugbank.com. The "false neurotransmitter" hypothesis proposed that alpha-methylnorepinephrine, synthesized from this compound, is released from peripheral adrenergic neurons and exerts a weaker effect on peripheral receptors compared to norepinephrine, thus reducing sympathetic vasoconstriction biolife-publisher.it. However, some studies in experimental animals have suggested that this compound can suppress vascular resistance and reduce blood pressure without affecting post-ganglionic sympathetic activity, making the "false neurotransmitter" hypothesis in the periphery less clear-cut biolife-publisher.it.

Studies using peripheral inhibitors of Dopa-decarboxylase, an enzyme involved in the metabolism of this compound, have provided further insight. When the formation of methylnorepinephrine is blocked in the peripheral sympathetic system but not in the central adrenergic pathways, a drop in peripheral vascular resistance is still observed biolife-publisher.it. This supports the notion that a significant part of the drug's mechanism of action is mediated through a decrease in central adrenergic activity biolife-publisher.it.

Decreased Plasma Renin Activity

Treatment with this compound has been shown to substantially reduce plasma renin activity (PRA) in both laboratory animals and hypertensive subjects biolife-publisher.itahajournals.org. This effect is in contrast to some other antihypertensive drugs, such as reserpine, chlorothiazide, and hydralazine, which can increase PRA biolife-publisher.it.

In studies involving dogs, intravenous administration of this compound for 7 to 10 days resulted in a decrease in PRA biolife-publisher.it. For example, PRA levels decreased from 13 mg/ml to 7 mg/ml of produced angiotensin II in one study biolife-publisher.it. This compound also blocked the increase in renin production induced by sympathetic stimulation of the kidney in dogs, without preventing the vasoconstrictor effect of the stimulation itself biolife-publisher.it.

Clinical studies in humans have also demonstrated that this compound decreases PRA in both normotensive subjects and hypertensive patients, including those with renal failure biolife-publisher.itahajournals.orgahajournals.org. In one study involving normotensive and hypertensive volunteers, this compound reduced PRA in both supine and tilted positions, despite a simultaneous reduction in mean arterial pressure ahajournals.orgahajournals.org. The percentage reduction in PRA during this compound treatment was approximately 40.0 ± 8.0% in the supine position and 45.3 ± 7.9% in the tilted position ahajournals.org.

The depressant action of this compound on the renin system does not appear to be mediated by modifications in electrolyte balance or aldosterone secretion, as these parameters were not modified in hypertensive subjects after drug administration biolife-publisher.it. It has been suggested that the "false neurotransmitter" alpha-methylnorepinephrine, synthesized from this compound, is less active than norepinephrine in stimulating renin secretion, potentially contributing to the reduction in PRA biolife-publisher.it.

The following table summarizes the effect of this compound on plasma renin activity in a study involving human volunteers:

*Data derived from a study on human volunteers ahajournals.org.

Renoprotective Effects (General Research Area, No Specific Mechanisms Provided)

Research suggests that this compound may have renoprotective effects biolife-publisher.itpnas.org. While specific mechanisms for these effects were not detailed in the provided information, studies have indicated that this compound does not significantly affect glomerular filtration rate, renal blood flow, or filtration fraction drugbank.comnih.gov. Some animal studies have suggested that this compound might induce a selective reduction in renal circulation resistance, leading to an increase in glomerular flow biolife-publisher.it. Furthermore, research in rats with L-NAME-induced hypertension in pregnancy suggested that this compound treatment could be associated with an increase in nitric oxide concentration, potentially contributing to an improvement in renal function researchgate.net.

Patient Populations with Specific Considerations

Hypertension in Pregnancy

Hypertensive disorders complicate approximately 5-10% of pregnancies and are a leading cause of maternal, fetal, and neonatal morbidity and mortality. ginekologiaipoloznictwo.comijbcp.compgcardiologiausp.com.br Methyldopa has a long history of use in managing hypertension during pregnancy and is considered a first-line treatment in many countries. ginekologiaipoloznictwo.comahajournals.orguktis.org Its safety profile in pregnancy has been extensively studied. ginekologiaipoloznictwo.comahajournals.orgnih.gov

Pre-eclampsia, a specific hypertensive disorder of pregnancy, is characterized by an imbalance of angiogenic and anti-angiogenic factors. plos.orgunair.ac.idmdpi.com Studies have investigated the effect of this compound on these factors. Research suggests that this compound may have a specific effect on placental and/or endothelial cell function in patients with pre-eclampsia, potentially altering angiogenic proteins. plos.orgnih.gov

One study evaluated the impact of this compound therapy on maternal circulating levels and placental production of soluble fms-like tyrosine kinase 1 (sFlt-1), soluble endoglin (sEng), vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) in hypertensive disorders of pregnancy. plos.orgnih.gov The study found that antihypertensive treatment with this compound was associated with a significant fall in serum concentrations of both sFlt-1 and sEng in women with pre-eclampsia (both early and late onset). plos.orgnih.gov This effect was not observed in women with gestational hypertension. plos.org Consistent with the maternal serum findings, this compound treatment was also associated with significantly lower placental concentrations of sFlt-1 and sEng in pre-eclampsia, but not in gestational hypertension. plos.org this compound treatment did not affect placental levels of PlGF or VEGF in this study. plos.org

Another study specifically analyzed the effects of this compound on VEGF maternal circulating levels in severe pre-eclampsia. unair.ac.idresearchgate.net The results indicated that this compound could decrease VEGF levels in severe pre-eclampsia patients, with a notable decrease observed after treatment. unair.ac.idresearchgate.net

Comparative studies have evaluated maternal and fetal outcomes when using this compound versus other antihypertensive medications in pregnancy. A retrospective cohort study comparing this compound, labetalol, and nifedipine found that the risk of the infant being small for gestational age (birthweight < 10th percentile) was lower with this compound than with labetalol. plos.org For birthweight < 3rd percentile, the association was even stronger with this compound. plos.org The risk of preterm delivery was similar for this compound and labetalol in this study. plos.org Neonatal intensive care unit (NICU) admission was not elevated with this compound compared to labetalol. plos.org

A randomized controlled trial comparing labetalol and this compound in pregnancy-induced hypertension in an Indian population found no significant difference between the groups for most fetal and neonatal outcomes, including stillbirth, death in the first week, birth weight, pre-term delivery, Apgar score, need for intensive neonatal care, and jaundice. researchgate.net However, some observational data from this study suggested a higher incidence of Intra Uterine Growth Retardation (IUGR), NICU admissions, and small for gestational age babies with this compound compared to labetalol, although the difference was not statistically significant. ijbcp.comresearchgate.net

An earlier controlled trial of this compound for moderate hypertension in pregnancy reported a significantly improved fetal outcome with active treatment, partly attributed to a reduced number of mid-pregnancy abortions. nih.gov Birthweight and maturity of viable infants were similar in treated and control groups. nih.gov

A randomized controlled trial comparing this compound, labetalol, and nifedipine in pre-eclamptic women found no significant difference in mode of delivery, gestational age at delivery, preterm delivery, postpartum hemorrhage, HELLP syndrome, placental abruption, admission to NICU, neonatal death, and neonatal birth weight between the groups. ekb.eg However, Labetalol and Nifedipine showed better efficacy regarding Doppler indices (Pulsatility Index and Resistive Index of the umbilical and middle cerebral arteries) compared to this compound. ekb.eg

Here is a table summarizing some of the comparative outcomes:

Postpartum hypertension is common, with blood pressure typically peaking around days 3-6 after birth. scot.nhs.uknih.gov While this compound may be used in the postpartum period, some guidelines recommend discontinuing it within two days of delivery and initiating an alternative antihypertensive treatment. uktis.orgscot.nhs.uk This recommendation is often based on an increased risk of postnatal depression associated with this compound use. uktis.orgscot.nhs.uknih.gov However, some healthcare services continue this compound in the postpartum period, particularly if a future pregnancy is anticipated. pgcardiologiausp.com.br A randomized controlled trial comparing the continuation of this compound with switching to captopril in the immediate postpartum period in hypertensive women who had used this compound during pregnancy found similar results regarding blood pressure control, side effects, and postpartum depression in the first 48 hours. pgcardiologiausp.com.br

First Trimester Exposure and Pregnancy Outcomes

Patients with Renal Insufficiency

This compound is considered useful in hypertensive patients with renal insufficiency. drugbank.comwileymicrositebuilder.comnih.gov Its mechanism of action, which involves decreasing adrenergic outflow from the central nervous system, does not typically affect cardiac output or renal blood flow. wileymicrositebuilder.comnih.gov This relative freedom from adverse effects on kidney function makes it beneficial for controlling high blood pressure even in the presence of renal impairment. medsafe.govt.nzmedsafe.govt.nz It may potentially help to arrest or slow the progression of renal function impairment and damage caused by sustained high blood pressure. medsafe.govt.nzmedsafe.govt.nz

However, this compound is largely excreted by the kidney, and its excretion is slow in patients with renal failure, leading to the accumulation of the drug and its metabolites, particularly this compound-O-sulphate. drugbank.comnih.govtandfonline.comtandfonline.com Studies have shown that the rate of conjugation of this compound is decreased in renal insufficiency compared to patients with normal kidney function. tandfonline.comtandfonline.com The increased sensitivity to the hypotensive effect sometimes observed in renal failure patients is not due to increased plasma levels of the unconjugated drug but rather to the accumulation of this compound-O-sulphate. tandfonline.comtandfonline.com Despite the potential for accumulation, this compound can be used in patients with renal impairment, although dosage adjustments may be necessary. medsafe.govt.nzmedscape.commedicines.org.uk

Elderly Patients

This compound has been considered an effective antihypertensive agent in elderly patients. wileymicrositebuilder.com Studies have investigated its use and effects in this population. An open-label study evaluating this compound in older patients (mean age 67 years) with isolated systolic hypertension found that therapy controlled hypertension without orthostatic hypotension or adverse reactions. nih.gov Significant reductions in mean sitting and standing systolic blood pressures were observed. nih.gov

In the elderly, dizziness or lightheadedness and drowsiness may be more likely to occur due to increased sensitivity to this compound's effects. mayoclinic.org Syncope in older patients may be related to increased sensitivity and advanced arteriosclerotic vascular disease, which might be avoided with lower doses. medsafe.govt.nzmedicines.org.uk

A study on the antiadrenergic treatment with this compound in elderly patients with essential hypertension observed that the fall in arterial pressure was associated with a significant decrease in cardiac output and heart rate in patients over 60 years of age, with no change in total peripheral resistance. ahajournals.org In younger patients, a non-significant fall in resistance occurred. ahajournals.org Renal blood flow and plasma/total blood volume did not change in either group with this compound treatment. ahajournals.org The study concluded that this compound lowers arterial pressure in the elderly by decreasing circulating norepinephrine levels, with the antihypertensive effect associated with a decrease in cardiac output in older patients and not compromising renal blood flow or cardiac reflexive responses. ahajournals.org

An older randomized controlled trial in elderly residents with diastolic blood pressure of 100 mmHg or more allocated participants to observation or treatment with this compound. nih.govbmj.com Over a 5-year period, there was a significantly greater reduction in sitting blood pressure in the actively treated group. nih.gov

Here is a table summarizing some findings in elderly patients:

Patients with Diabetes (Limited Data)

The clinical data regarding the use of this compound specifically in patients with diabetes is limited, primarily consisting of small observational studies wileymicrositebuilder.com. While this compound has been successfully used in pregnancies complicated by diabetes, there are no large-scale randomized controlled trials assessing its clinical impact on endpoints such as mortality, stroke, cardiovascular disease, or heart failure in diabetic patients wileymicrositebuilder.com. This compound does not appear to significantly alter glucose tolerance and is not anticipated to have adverse interactions with diabetes management wileymicrositebuilder.com. However, it has been suggested that it might potentially elevate triglycerides wileymicrositebuilder.com.

Autoimmune Diabetes (Type 1 Diabetes)

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing beta cells in the pancreas. The human leukocyte antigen (HLA) genes play a significant role in predisposing individuals to T1D, with the HLA-DQ8 gene being a major risk factor present in 50-60% of patients nih.govimtherapeutics.comdiabetes.co.uk. The protein product of the DQ8 gene, a Major Histocompatibility Complex (MHC) class II molecule, can abnormally bind and present certain self-peptides, such as insulin, to autoreactive T cells, initiating the autoimmune cascade that leads to beta-cell destruction imtherapeutics.comnih.gov.

Mechanism of MHC Class II (HLA-DQ8) Binding

Research has indicated that this compound can directly bind to the HLA-DQ8 molecule. This binding occurs within the peptide-binding groove of the DQ8 molecule on the surface of antigen-presenting cells imtherapeutics.comdrugdiscoverynews.comnih.gov. By occupying this site, this compound can interfere with the abnormal binding and presentation of self-antigen peptides to T cells imtherapeutics.comdrugdiscoverynews.comnih.gov. This mechanism is specific to DQ8, and this compound has been shown not to alter T cell responses restricted by other MHC class II molecules like DR4 nih.govjci.org.

Molecular docking studies, using the crystal structure of DQ8, predicted that this compound could bind to structural pockets within the antigen-binding cleft nih.govnih.govuspharmacist.com. In vitro experiments have validated this binding mechanism imtherapeutics.comnih.govdrugdiscoverynews.com.

Inhibition of Antigen Presentation and T-cell Responses

The binding of this compound to HLA-DQ8 has been shown to block antigen presentation in vitro and in vivo nih.govnih.gov. In vitro studies demonstrated that this compound blocked DQ8-restricted T cell responses to insulin peptides and deamidated α-gliadin in a dose-dependent manner nih.govjci.org. The effectiveness of this compound in blocking peptides appeared to be greater for those with lower affinity for DQ8 nih.gov. Importantly, this compound specifically inhibited DQ8-restricted T cell responses without affecting responses restricted by DR4 nih.govjci.org.

Studies in DQ8-transgenic mice also showed that this compound treatment blocked DQ8 antigen presentation in vivo nih.gov. This inhibition of antigen presentation is hypothesized to prevent the recognition of self-peptides by pathogenic T cells, thereby potentially blocking the autoimmune response in T1D nih.govimtherapeutics.comdrugdiscoverynews.com.

Preclinical and Phase Ib Clinical Trial Findings

Preclinical studies in the non-obese diabetic (NOD) mouse model, a model of spontaneous autoimmune diabetes, demonstrated that a small molecule with a structure similar to this compound delayed the onset of diabetes and prevented the disease in a portion of the treated mice nih.govdrugdiscoverynews.comnih.gov. This treatment also prevented insulin autoantibody production and preserved glucose tolerance nih.gov.

These preclinical findings led to the translation of this approach to human T1D in a single-arm, open-label Phase Ib dose-escalation study (NCT01883804) imtherapeutics.comdrugdiscoverynews.comnih.govmedscape.com. The trial evaluated this compound treatment in 20 DQ8-positive T1D participants with recent-onset diabetes and residual beta-cell function nih.govmedscape.com.

The study results indicated that DQ8 presentation was inhibited compared to baseline levels, with a significant percentage of patients showing a response drugdiscoverynews.commedscape.com. A subset of patients also exhibited reduced inflammatory T cell responses towards insulin drugdiscoverynews.comnih.govmedscape.com. While this was a short-term, proof-of-concept trial, the results suggested that this compound treatment might limit beta-cell destruction and preserve function medscape.com.

Data from the Phase Ib trial showed that DQ8 presentation was inhibited by approximately 40% compared to baseline levels, with 17 out of 20 patients showing a response imtherapeutics.commedscape.com. Reductions in insulin-specific CD4 T-cell responses in the peripheral circulation were also associated with this compound treatment medscape.com.

Table: Summary of Phase Ib Clinical Trial Findings (NCT01883804)

These findings highlight the potential of targeting disease-specific MHC class II antigen presentation as a therapeutic strategy for autoimmune diseases like T1D nih.govnih.gov. Further clinical trials are warranted and underway to evaluate this compound's potential in preserving residual beta-cell function in individuals with new-onset and at-risk T1D nih.gov. IM Therapeutics is developing IMT-002 (D-methyldopa), an oral small-molecule drug specifically designed as a selective HLA-DQ8 blocker for T1D, which has shown effective inhibition of DQ8 activity in new onset T1D patients with the DQ8 variant in a Phase 1b study imtherapeutics.comdrugdiscoverynews.combusinesswire.comdrug-dev.com.

Autoantibody Production

One of the well-documented immunological effects of this compound is the induction of autoantibodies. viamedica.plnih.gov It is estimated that approximately 10-20% of patients treated with this compound develop autoantibodies against red blood cells. viamedica.plnih.govdrugs.com These autoantibodies are typically drug-independent, meaning they react with red blood cells even in the absence of the drug in vitro. viamedica.plnih.govresearchgate.net

The exact mechanisms by which this compound induces autoantibody production are not fully understood, but several hypotheses exist. These include molecular mimicry, where the drug or its metabolites resemble host antigens; drug adsorption onto erythrocyte membranes, altering their antigenic properties; and dysregulation of the immune system. viamedica.plnih.govresearchgate.net Some research suggests that this compound may alter the immune system by causing a persistent increase in lymphocyte cyclic AMP, which could inhibit suppressor T-cell function, leading to unregulated autoantibody production by B cells. researchgate.net this compound has also been shown to inhibit T-lymphocyte suppression of IgG production in vitro. researchgate.net

Drug-induced Immune Hemolytic Anemia

In a subset of patients who develop autoantibodies, this compound can lead to drug-induced immune hemolytic anemia (DIIHA). viamedica.plnih.govdrugs.com This complication is estimated to occur in about 0.5% to 1% of patients treated with the drug. viamedica.plnih.gov this compound-induced hemolytic anemia is characterized by extravascular hemolysis mediated by IgG antibodies. viamedica.plnih.gov Serologically, it often presents similarly to warm-type autoimmune hemolytic anemia (AIHA), with a positive direct antiglobulin test (DAT), positive indirect antiglobulin test (IAT), and a reactive eluate from tested red blood cells. viamedica.plnih.gov The mechanism is categorized as true autoimmune and drug-independent antibody-mediated. nih.gov

The onset of this compound-induced autoantibodies and subsequent hemolytic anemia typically occurs between 4 months and 1 year after initiating therapy, although it can sometimes occur earlier. viamedica.plnih.gov Discontinuation of this compound generally leads to the resolution of hemolysis. viamedica.pl

Hypersensitivity Reactions

Beyond autoantibody production and hemolytic anemia, this compound can also cause various hypersensitivity reactions. These are considered immune-mediated responses to the drug. Reported hypersensitivity reactions include vasculitis, rash, drug fever, and anaphylactoid-like reactions. drugs.com

Hepatotoxicity associated with this compound is also believed to involve a delayed hypersensitivity mechanism, although direct hepatotoxicity from accumulated metabolites is also speculated in some late-onset cases. drugs.comjcgo.org Cases of this compound hypersensitivity syndrome, characterized by symptoms such as extensive skin eruption, fever, lymphadenopathy, and eosinophilia, have been reported, with in vitro tests suggesting an immunological, allergic mechanism. drugs.comnih.gov Myocarditis and pericarditis have also been associated with this compound hypersensitivity. wikipedia.org

This compound's interaction with the immune system, particularly its ability to induce autoantibodies and trigger hypersensitivity reactions, highlights the complex interplay between the drug and host immune responses.

Spectrophotometric Methods

Spectrophotometric methods are widely used for the determination of this compound due to their simplicity, cost-effectiveness, and rapid analysis time. These methods typically involve reactions that produce a colored product which can be measured by UV-Vis spectrophotometry. UV-Vis spectrophotometric approaches are inexpensive, simple to use, and rapid for detecting active chemicals in pharmaceutical formulations. chemmethod.com

Several spectrophotometric methods have been developed for this compound analysis. One approach involves an oxidative coupling reaction with a new organic reagent in acidic medium in the presence of potassium periodate, producing a stable, water-soluble orange complex with maximum absorption at 481 nm. chemmethod.com This method follows Beer's law in the range of 5.0-40 µg/mL. chemmethod.com Another method is based on the oxidation of this compound with N-Bromosuccinimide (NBS) followed by reduction with 3,3-Diaminobenzidine (DAB), yielding a magenta-colored product with maximum absorbance at 513 nm. moca.net.ua This method shows linearity in the range of 0.5 to 10 mg L−1 and 0.5 to 15 mg L−1 for different spectroscopy methods, with detection limits of 0.171 and 0.180 µg mL-1 respectively. moca.net.ua Another reported spectrophotometric technique involves the reaction of this compound with metoclopramide and NaNO2 in hydrochloric acid to form a diazonium salt, which then reacts with this compound to produce a yellow azo dye with a maximum wavelength at 458 nm. ekb.eg Additionally, a method based on the complexation reaction of this compound with molybdate ions produces a yellow colored product with maximum absorbance at 410 nm, obeying Beer's Law in the range of 50 – 200 µg ml-1. redalyc.org

Here is a summary of some spectrophotometric methods for this compound determination:

Chromatographic Techniques (e.g., HPLC, Liquid Chromatography)

Chromatographic techniques, particularly High-Performance Liquid Chromatography (HPLC) and other liquid chromatography methods, are widely utilized for the separation and quantification of this compound in complex matrices due to their high selectivity and sensitivity. chemmethod.com HPLC methods for this compound analysis often involve reversed-phase columns and various detection methods, including UV-Vis and fluorescence detection. nih.govnih.gov

A reversed-phase HPLC method for determining free this compound in human urine uses a reversed-phase column (octadecyl-bonded silica) with dilute acetate buffer as the mobile phase and UV detection at 280 nm. nih.gov This method can quantify 8.0 mg of this compound per liter in a 30 ml sample, with a lower limit of detection of 25 ng. nih.gov Analytical recovery ranged from 95 to 102%. nih.gov Another RP-HPLC method for simultaneous estimation of this compound and hydrochlorothiazide in tablets uses a Hypersil BDS C8 column with a mobile phase of mixed phosphate buffer and acetonitrile, detected at 287 nm. japer.in This method showed linearity for this compound in the range of 62.5-375.0 μg/ml. japer.in

HPLC coupled with more sensitive detectors like mass spectrometry (LC-MS/MS) is employed for the quantification of this compound in biological fluids like plasma, offering high sensitivity and specificity. researchgate.netnih.gov An LC-MS/MS method for this compound in human plasma using dopa-phenyl-D3 as an internal standard has a chromatographic run time of 5.5 minutes and is linear in the range of 20-5000 ng/ml. researchgate.netnih.gov The limit of quantitation for this method is 20 ng/ml. researchgate.netnih.gov A sensitive reversed-phase gradient elution HPLC method with fluorescence detection has also been developed for this compound in human plasma, with a limit of quantitation of 10 ng/ml. nih.gov

Direct injection HPLC methods have also been developed for this compound determination in serum, utilizing protein-coated columns that function in both size-exclusion and reversed-phase modes. oup.com This allows for simultaneous cleanup and separation of this compound from serum proteins. oup.com

Electroanalytical Methods

Electroanalytical methods, such as voltammetry, offer sensitive and rapid approaches for this compound determination, often without the need for extensive sample preparation. turkjps.org These methods exploit the electrochemical activity of this compound, which is a catechol derivative. rhhz.net

Electrochemical methods are used for the determination of this compound in addition to chromatographic and spectrophotometric methods. Modified electrodes are often used to increase the sensitivity of the analysis. For example, a glassy carbon electrode (GCE) modified with poly(p-aminobenzene sulfonic acid) has been used for this compound determination using differential pulse voltammetry (DPV). This method showed linearity in the range of 0.020-2.500 µM for the modified GCE, with a limit of detection of 0.006 µM. Another study using a poly (p-ABSA) modified GCE reported linear ranges of 1.0-30.0 µM and 30.0-300.0 µM with a limit of detection of 5.0 nM. turkjps.org Electrochemical biosensors utilizing enzymes like polyphenol oxidase from Genipa americana L. have also been developed for this compound determination in pharmaceutical samples, showing good analytical features and low detection limits (8 μmol L-1). nih.gov

Titrimetric Methods

Titrimetric methods, while perhaps less common for routine analysis compared to spectroscopic or chromatographic techniques, have also been applied for the determination of this compound. These methods often involve redox reactions. nih.govscielo.br The official method reported in some pharmacopoeias describes a nonaqueous titration for the assay of this compound. scielo.br Titrimetric methods based on reduction reactions have been reported, although they can suffer from interferences from unsaturated organic compounds. scielo.br Oxidimetric titrants such as bromamine T, dibromohydantoin, N-bromophthalimide, and N-bromosuccinimide have been applied to the determination of this compound using direct potentiometric and visual indicator titration methods, as well as back-titration procedures. nih.gov this compound can act as a self-indicator in some titrations, with solutions changing color from colorless to red. nih.gov

Randomized Controlled Trials

Randomized Controlled Trials (RCTs) are considered the gold standard for evaluating the effectiveness of interventions, including pharmacological treatments like this compound. In RCTs, participants are randomly assigned to receive either the intervention (this compound) or a control (e.g., placebo, another antihypertensive drug, or standard care). This randomization helps to minimize bias and ensure that the groups are comparable at the start of the study.

RCTs have been conducted to compare this compound with other antihypertensive agents or placebo in various hypertensive populations. For instance, a single-blind, randomized clinical trial involving postpartum women with hypertension who used this compound during pregnancy compared the continuation of this compound with switching to captopril. pgcardiologiausp.com.brnih.gov Patients were randomized to either continue this compound (n=88) or switch to captopril (n=84). pgcardiologiausp.com.brnih.gov The study evaluated blood pressure control in the first 48 hours postpartum. pgcardiologiausp.com.brnih.gov

Another randomized controlled trial compared this compound and labetalol in the management of pregnancy-induced hypertension. theprofesional.com Patients were randomly assigned to either the labetalol group or the this compound group, with each group including 157 patients. theprofesional.com Blood pressure was recorded regularly to assess the efficacy of the treatments. theprofesional.com A multicenter randomized clinical study in pregnant women with mild to moderate chronic hypertension randomized participants into three groups: this compound, labetalol, and a control group (no medication). researchgate.net 486 pregnant women were randomized, with 164 in the this compound group, 160 in the labetalol group, and 162 in the control group. researchgate.net The study followed these women from the beginning of pregnancy until the end of the puerperium to record maternal and fetal outcomes. researchgate.net

A double-blind crossover study in patients with previously well-controlled hypertension compared the antihypertensive efficacy of a single bedtime dose of this compound with the same total dose given three times daily. nih.gov Patients received their usual effective daily dose of this compound (0.37 gm, 0.75 gm, or 1.5 gm) in either dosing regimen for 12 weeks each. nih.gov Blood pressure was recorded multiple times daily throughout the study. nih.gov

RCTs involving this compound have also been included in systematic reviews and meta-analyses to synthesize evidence on its effects. A review of this compound for primary hypertension included 12 RCTs (N=595) comparing this compound to placebo. nih.govresearchgate.net These trials varied in design, including randomized controlled parallel trials and randomized crossover trials. researchgate.net The duration of this compound treatment in these studies ranged from three to 52 weeks, with most studies evaluating effects over four to six weeks. researchgate.net While these studies evaluated blood pressure lowering effects, none assessed mortality and morbidity outcomes. researchgate.net A meta-analysis of data from six of these trials (N=231) showed that this compound at doses ranging from 500-2250 mg daily lowered systolic and diastolic blood pressure by a mean of 13/8 mmHg compared to placebo. researchgate.net

The CHAP trial, a randomized, parallel, open-label study, randomized pregnant individuals with mild chronic hypertension to a blood pressure goal of <140/90 mm Hg (active treatment) or a control group where antihypertensive therapy was withheld unless blood pressure was ≥160/105 mm Hg. acc.org While standard first-line agents were labetalol or extended-release nifedipine, this compound or amlodipine could also be used in the active treatment group if needed. acc.org The study included 2,408 enrollees. acc.org

Table summarizing data from selected Randomized Controlled Trials involving this compound:

Prospective Cohort Studies

Prospective cohort studies have been utilized to investigate the outcomes associated with this compound use in specific patient populations. One notable area of focus has been the use of this compound during pregnancy. A prospective observational cohort study evaluated outcomes in pregnancies with first-trimester exposure to this compound compared to pregnancies without chronic hypertension. ahajournals.orgresearchgate.net This study, which included outcomes of 261 pregnancies exposed to this compound and 526 comparison pregnancies, aimed to analyze the rates of major birth defects and spontaneous abortions. ahajournals.orgresearchgate.net The study reported that the rate of major birth defects in the this compound-exposed cohort was not significantly increased compared to the comparison cohort (3.7% versus 2.5%; adjusted odds ratio, 1.24; 95% confidence interval, 0.4–4.0). ahajournals.orgresearchgate.net However, there was a tendency towards a higher rate of spontaneous abortions in exposed women, and the risk of preterm birth was significantly higher, with adjusted birth weight scores significantly lower in the this compound group. ahajournals.orgresearchgate.net Head circumferences were also significantly reduced in exposed boys only. ahajournals.orgresearchgate.net Another observational prospective cohort study explored the usefulness of oral labetalol combined with oral this compound in treating hypertension in pregnant women. ginekologiaipoloznictwo.com This study included 60 pregnant women, divided into two groups, one receiving labetalol and the other this compound. ginekologiaipoloznictwo.com

Meta-analyses and Systematic Reviews

Meta-analyses and systematic reviews have been conducted to synthesize findings from multiple studies on this compound, providing a broader perspective on its effects and comparisons with other treatments. A meta-analysis assessing the efficacy and safety of this compound versus labetalol in pregnancy-induced hypertension included data from 10 randomized controlled trials involving 1,200 patients. researchgate.netajol.info The analysis found that both drugs statistically significantly decreased mean arterial pressure (MAP). researchgate.netajol.info While both were effective, the difference in the reduction of MAP was higher in the labetalol group compared to the this compound group in the majority of studies included in this meta-analysis. researchgate.netajol.info

Here is a summary of blood pressure reduction findings from a meta-analysis: