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International Journal of Molecular... Oct 2023Antihypertensive therapy is an essential part of management of patients with preeclampsia (PE). Methyldopa (Dopegyt) and nifedipine (Cordaflex) are basic medications of...
Features and Comparative Characteristics of Fucosylated Glycans Expression in Endothelial Glycocalyx of Placental Terminal Villi in Patients with Preeclampsia Treated with Different Antihypertensive Regimens.
Antihypertensive therapy is an essential part of management of patients with preeclampsia (PE). Methyldopa (Dopegyt) and nifedipine (Cordaflex) are basic medications of therapy since they stabilize blood pressure without affecting the fetus. Their effect on the endothelium of placental vessels has not yet been studied. In this study, we analyzed the effect of antihypertensive therapy on the expression of fucosylated glycans in fetal capillaries of placental terminal villi in patients with early-onset PE (EOPE) and late-onset PE (LOPE), and determined correlation between their expression and mother's hemodynamic parameters, fetoplacental system, factors reflecting inflammatory response, and destructive processes in the endothelial glycocalyx (eGC). A total of 76 women were enrolled in the study: the comparison group consisted of 15 women with healthy pregnancy, and the main group comprised 61 women with early-onset and late-onset PE, who received one-component or two-component antihypertensive therapy. Hemodynamic status was assessed by daily blood pressure monitoring, dopplerometry of maternal placental and fetoplacental blood flows, and the levels of IL-18, IL-6, TNFα, galectin-3, endocan-1, syndecan-1, and hyaluronan in the blood of the mother. Expression of fucosylated glycans was assessed by staining placental sections with AAL, UEA-I, LTL lectins, and anti-Le MAbs. It was found that (i) expression patterns of fucosylated glycans in eGC capillaries of placental terminal villi in EOPE and LOPE are characterized by predominant expression of structures with a type 2 core and have a similar pattern of quantitative changes, which seems to be due to the impact of one-component and two-component antihypertensive therapy on their expression; (ii) correlation patterns indicate interrelated changes in the molecular composition of eGC fucoglycans and indicators reflecting changes in maternal hemodynamics, fetoplacental hemodynamics, and humoral factors associated with eGC damage. The presented study is the first to demonstrate the features of placental eGC in women with PE treated with antihypertensive therapy. This study also considers placental fucoglycans as a functional part of the eGC, which affects hemodynamics in the mother-placenta-fetus system.
Topics: Humans; Pregnancy; Female; Placenta; Pre-Eclampsia; Antihypertensive Agents; Glycocalyx; Methyldopa; Polysaccharides
PubMed: 37958597
DOI: 10.3390/ijms242115611 -
Molecular Neurobiology May 2024Aromatic l-amino acid decarboxylase deficiency (AADC-DY) is caused by one or more mutations in the DDC gene, resulting in the deficit in catecholamines and serotonin... (Review)
Review
Aromatic l-amino acid decarboxylase deficiency (AADC-DY) is caused by one or more mutations in the DDC gene, resulting in the deficit in catecholamines and serotonin neurotransmitters. The disease has limited therapeutic options with relatively poor clinical outcomes. Accumulated evidence suggests the involvement of neurodegenerative mechanisms in the etiology of AADC-DY. In the absence of neurotransmitters' neuroprotective effects, the accumulation and the chronic presence of several neurotoxic metabolites including 4-dihydroxy-L-phenylalanine, 3-methyldopa, and homocysteine, in the brain of subjects with AADC-DY, promote oxidative stress and reduce the cellular antioxidant and methylation capacities, leading to glial activation and mitochondrial dysfunction, culminating to neuronal injury and death. These pathophysiological processes have the potential to hinder the clinical efficacy of treatments aimed at increasing neurotransmitters' synthesis and or function. This review describes in detail the mechanisms involved in AADC-DY neurodegenerative etiology, highlighting the close similarities with those involved in other neurodegenerative diseases. We then offer novel strategies for the treatment of the disease with the objective to either reduce the level of the metabolites or counteract their prooxidant and neurotoxic effects. These treatment modalities used singly or in combination, early in the course of the disease, will minimize neuronal injury, preserving the functional integrity of neurons, hence improving the clinical outcomes of both conventional and unconventional interventions in AADC-DY. These modalities may not be limited to AADC-DY but also to other metabolic disorders where a specific mutation leads to the accumulation of prooxidant and neurotoxic metabolites.
Topics: Humans; Aromatic-L-Amino-Acid Decarboxylases; Amino Acid Metabolism, Inborn Errors; Animals; Neurodegenerative Diseases
PubMed: 37953352
DOI: 10.1007/s12035-023-03684-2 -
Journal of Neural Transmission (Vienna,... Nov 2023The standard of care is a term that refers to the level of care, skill, and treatment that a healthcare provider should offer to a patient based on the current... (Review)
Review
The standard of care is a term that refers to the level of care, skill, and treatment that a healthcare provider should offer to a patient based on the current scientific evidence and the level of medical knowledge available in the field. For Parkinson's disease (PD), the standard care is mostly considered to be oral treatment with dopaminergic drugs, particularly levodopa which remains the 'gold standard'. However, effective management with levodopa during the later stages of the disease becomes increasingly challenging due to the ongoing neurodegenerative process, the consequences of its pulsatile dopaminergic stimulation, and the gastrointestinal barriers to effective drug absorption. As a result, the concept of applying continuous dopaminergic stimulation has emerged with infusion therapies (continuous subcutaneous apomorphine, levodopa-carbidopa intestinal gel, and levodopa-entacapone-carbidopa intestinal gel infusion). These therapies seek to provide continuous stimulation of striatal dopamine receptors that is efficient not only in alleviating clinical symptoms, but also in delaying, reducing, and possibly preventing the onset of levodopa-related motor (fluctuations, dyskinesia) and non-motor complications; and they are also associated with clinically relevant side effects. Clinical studies and real-life experience support the notion that infusion therapies should be accepted as part of the standard of care for patients with advanced PD who have refractory, severe, and disabling motor complications that affect their quality of life. However, they should be considered based on the needs of individualized patients and the access to these advanced therapies needs to be made more accessible to the general PD population.
Topics: Humans; Levodopa; Carbidopa; Parkinson Disease; Quality of Life; Standard of Care; Antiparkinson Agents
PubMed: 37930456
DOI: 10.1007/s00702-023-02708-4 -
Neurological Sciences : Official... Apr 2024Levodopa-carbidopa intestinal gel infusion (LCIG) is a therapeutic option for advanced Parkinson disease (PD) patients with troublesome motor complications, unresponsive...
BACKGROUND
Levodopa-carbidopa intestinal gel infusion (LCIG) is a therapeutic option for advanced Parkinson disease (PD) patients with troublesome motor complications, unresponsive to conventional oral treatment. There is some evidence to suggest that the genetic background may influence the clinical presentation and rate of progression of PD. Whether the genetic background influences the outcome of device-assisted therapies is currently debated. Some studies have investigated the effectiveness of deep brain stimulation (DBS) in PD patients with different genetic background, while evidence is lacking regarding LCIG.
METHODS
A cohort of LCIG patients underwent genetic testing. The motor and neuropsychological outcomes of LCIG were retrospectively analyzed.
RESULTS
Fifty-six patients were analyzed, nine of them (15%) had at least one mutation/variant in a PD-associated gene: five GBA1, two SNCA, one LRRK2, one PRKN; 13 (23%) carried the BDNF Val66Met polymorphism. The mean duration of follow-up was 4.9 ± 2.6 years. There were no significant differences in motor or neuropsychological outcomes between patients with and without these gene mutations/variants. No cognitive worsening was observed at follow-up among GBA-PD patients, and they responded well to LCIG in terms of motor symptoms.
CONCLUSIONS
Overall, we observed a significant benefit in terms of motor complications in our cohort, including patients carrying genetic mutations/variants. Due to the small sample and limited number of patients carrying genetic mutations/variants, no definitive conclusions can be drawn yet on the genotype impact on LCIG outcome. A careful selection of patients, regardless of the genetic background, is pivotal for an optimal outcome of LCIG.
Topics: Humans; Carbidopa; Levodopa; Parkinson Disease; Antiparkinson Agents; Retrospective Studies; Gels; Drug Combinations; Mutation
PubMed: 37926749
DOI: 10.1007/s10072-023-07173-1 -
Neurology Nov 2023Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG])...
BACKGROUND AND OBJECTIVES
Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications.
METHODS
Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT.
RESULTS
A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [ < 0.001], of MDS-UPDRS Part IV 6.0 points [ < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [ < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS.
DISCUSSION
Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.
Topics: Humans; Parkinson Disease; Antiparkinson Agents; Retrospective Studies; Prospective Studies; Carbidopa; Levodopa; Infusions, Subcutaneous; Drug Combinations; Gels
PubMed: 37914414
DOI: 10.1212/WNL.0000000000207858 -
Pharmaceutics Sep 2023The present study aimed to evaluate the stability of active pharmaceutical ingredients (APIs) from different pharmacological classes in a compounded oral suspending...
The present study aimed to evaluate the stability of active pharmaceutical ingredients (APIs) from different pharmacological classes in a compounded oral suspending vehicle. Oral suspensions of amoxicillin trihydrate (50 mg/mL), clozapine (25 mg/mL), indomethacin (5.0 mg/mL), levodopa/carbidopa (10.0/2.5 mg/mL), levothyroxine sodium (T4, 25 µg/mL), lomustine (4.0 and 10.0 mg/mL), methyldopa (25 mg/mL) and procarbazine (10.0 mg/mL) were formulated in SyrSpend SF PH4 and the stability was monitored for up to 90 days, except for amoxicillin trihydrate, which was evaluated for 30 days only. The APIs' stability was determined by measuring percent recovery using stability-indicating high-performance liquid chromatography (HPLC or UHPLC) or titration (amoxicillin trihydrate only). The stability of amoxicillin trihydrate, clozapine, indomethacin and levodopa/carbidopa were studied at both refrigerated (2-8 °C) and room temperature (20-25 °C). Lomustine, procarbazine, and methyldopa were studied at refrigerated temperature only. Our data demonstrated promising stability for the compounded suspensions containing various APIs, investigated in SyrSpend SF PH4, as all APIs exhibited stability throughout the study duration and met content uniformity criteria. These findings lead to the conclusion that the tested compounded oral suspensions present a viable approach for creating personalized, age-appropriate formulations. The capacity to ensure dose consistency and stability using APIs from diverse pharmacological classes renders them suitable choices for both pediatric and geriatric patients.
PubMed: 37896148
DOI: 10.3390/pharmaceutics15102388 -
Journal of Trace Elements in Medicine... Jan 2024the antihypertensive drug α-methyldopa (MD) stands as one of the extensively used medications for managing hypertension during pregnancy. Zinc deprivation has been...
BACKGROUND
the antihypertensive drug α-methyldopa (MD) stands as one of the extensively used medications for managing hypertension during pregnancy. Zinc deprivation has been associated with many diseases. In this context, the synthesis of a Zn coordination complex [Zn(MD)(OH)(HO)]·HO (ZnMD) provide a promising alternative pathway to improve the biological properties of MD.
METHODS
ZnMD was synthesized and physicochemically characterized. Fluorescence spectral studies were conducted to examine the binding of both, the ligand and the metal with bovine serum albumin (BSA). MD, ZnMD, and ZnCl were administered to spontaneous hypertensive rats (SHR) rats during 8 weeks and blood pressure and echocardiographic parameters were determined. Ex vivo assays were conducted to evaluate levels of reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), and nitric oxide (NO). Cross-sectional area (CSA) and collagen levels of left ventricular cardiomyocytes were also assessed. Furthermore, the expression of NAD(P)H oxidase subunits (gp91 and p47) and Superoxide Dismutase 1 (SOD1) was quantified through western blot analysis.
RESULTS
The complex exhibited a moderate affinity for binding with BSA showing a spontaneous interaction (indicated by negative ΔG values) and moderate affinity (determined by affinity constant values). The binding process involved the formation of Van der Waals forces and hydrogen bonds. Upon treatment with MD and ZnMD, a reduction in the systolic blood pressure in SHR was observed, being ZnMD more effective than MD (122 ± 8.1 mmHg and 145 ± 5.6 mmHg, at 8th week of treatment, respectively). The ZnMD treatment prevented myocardial hypertrophy, improved the heart function and reduced the cardiac fibrosis, as evidenced by parameters such as left ventricular mass, fractional shortening, and histological studies. In contrast, MD did not show noticeable differences in these parameters. ZnMD regulates negatively the oxidative damage by reducing levels of ROS and lipid peroxidation, as well as the cardiac NAD(P)H oxidase, and increasing SOD1 expression, while MD did not show significant effect. Moreover, cardiac nitric oxide levels were greater in the ZnMD therapy compared to MD treatment.
CONCLUSION
Both MD and ZnMD have the potential to be transported by albumin. Our findings provide important evidence suggesting that this complex could be a potential therapeutic drug for the treatment of hypertension and cardiac hypertrophy and dysfunction.
Topics: Rats; Animals; Antihypertensive Agents; Methyldopa; Reactive Oxygen Species; Superoxide Dismutase-1; Nitric Oxide; Hypertension; Blood Pressure; Rats, Inbred SHR; Myocytes, Cardiac; Cardiomegaly; NADPH Oxidases; Zinc
PubMed: 37890445
DOI: 10.1016/j.jtemb.2023.127327 -
Movement Disorders : Official Journal... Dec 2023Carbidopa/levodopa enteral suspension (CLES) is indicated for the treatment of advanced Parkinson's disease (aPD) with severe motor fluctuations.
BACKGROUND
Carbidopa/levodopa enteral suspension (CLES) is indicated for the treatment of advanced Parkinson's disease (aPD) with severe motor fluctuations.
OBJECTIVE
To determine the cost, quality-adjusted life years (QALY), and cost-effectiveness of CLES compared to the standard-of-care (SoC) for aPD patients in the United States (US), using real-world data.
METHODS
A published Markov model, comprising of 25 health states and a death state, (defined by a combination of the Hoehn and Yahr scale and waking time spent in OFF-time) was adapted to estimate the benefits for CLES versus oral SoC over a patient's lifetime in the US healthcare setting. Clinical inputs were based on a clinical trial and a registry study; utility inputs were sourced from the Adelphi-Disease Specific Programmes.
RESULTS
CLES compared to SoC was associated with incremental costs ($1,031,791 vs. $1,025,180) and QALY gain (4.61 vs. 3.76), resulting in an incremental cost-effectiveness ratio of $7711/QALY.
CONCLUSION
CLES is a cost-effective treatment for aPD patients with medication resistant motor fluctuations. © 2023 AbbVie, Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; United States; Levodopa; Carbidopa; Parkinson Disease; Antiparkinson Agents; Cost-Benefit Analysis; Drug Combinations; Gels
PubMed: 37877478
DOI: 10.1002/mds.29624 -
Pakistan Journal of Pharmaceutical... Sep 2023Carbidopa levodopa is widely used to ameliorate motor symptoms of Parkinson's disease (PD) patients. Pain is one of common symptoms of PD. The aim of this experiment is...
Carbidopa levodopa is widely used to ameliorate motor symptoms of Parkinson's disease (PD) patients. Pain is one of common symptoms of PD. The aim of this experiment is to study antinociceptive effects of carbidopa levodopa on normal rats and PD mice. Rats were intragastrically treated with carbidopa levodopa and the hind paw withdrawal latency (HWL) was investigated. PD mouse model was prepared with MPTP and then the antinociceptive effects of carbidopa levodopa on PD mice were evaluated. In normal rats, the HWL to thermal stimulus was augmented after carbidopa levodopa administration (p<0.05 or p<0.01) and carbidopa levodopa increased the HWL (p<0.05 or p<0.01) to mechanical stimulus. In PD mice, carbidopa levodopa elevated the HWL of the thermal stimulus in PD mice (p<0.05). Furthermore, the HWL in the inflammatory pain of PD mice was also increased by carbidopa levodopa treatmet (p<0.01). The current findings indicate that carbidopa levodopa has an antinociceptive effects in normal rats and PD mice. The analgesic effect of carbidopa levodopa on patients with or without PD is worth studying in further research.
Topics: Humans; Rats; Mice; Animals; Levodopa; Carbidopa; Parkinson Disease; Antiparkinson Agents; Drug Combinations; Pain; Analgesics
PubMed: 37869925
DOI: No ID Found -
Pregnancy Hypertension Dec 2023Consensus on the relative efficacy of available antihypertensive agents used in pregnancy is lacking. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Consensus on the relative efficacy of available antihypertensive agents used in pregnancy is lacking.
OBJECTIVE
To compare treatment success with antihypertensives and categorize by route of administration.
SEARCH STRATEGY
MEDLINE, Embase, PubMed, Web of Science, Scopus, CINAHL, and clinicaltrials.gov were searched without date restriction.
DATA COLLECTION
Peer-reviewed randomized controlled trials (RCTs) comparing pharmacologic agents used to treat hypertension in parturients were included. Evaluated treatment groups included IV-labetalol (BBIV), IV-hydralazine (DIV), oral-nifedipine (CCBPO), sublingual nifedipine (CCBSL), IV-calcium channel blocker (nonspecific)(CCBIV), IV-nitroglycerine (NTG), epoprostenol infusion (PRO), IV-ketanserin (5HT2B), IV-diazoxide (BZO), oral-nifedipine + methyldopa (CCBAG), oral-methyl-dopa (AAG), and oral prazosin (ABPO).
ANALYSIS
Seventy-four studies (8324 patients) were eligible post PRISMA guidelines screening. Results were pooled using a Bayesian-approach for success of treatment (study defined target blood pressure), time to achieve target pressure, and neonatal intensive-care admissions.
RESULTS
Treatment success (primary outcome, 55 trials with 5518 patients) was analyzed. Surface under the cumulative ranking curve (SUCRA) was categorized for 13 drugs, CCBPO (0.84) followed by CCBSL (0.78) were most likely to be effective in achieving target blood pressure. After sub-grouping by presence/absence of preeclampsia, CCB-PO ranked highest for both [(0.82) vs. (0.77), respectively]. Serotonin antagonists (0.99) and nitroglycerin (0.88) ranked highest for time to target pressure. NICU admissions were lowest for alpha-2 agonists (0.89), followed by BB PO (0.82) and hydralazine IV (0.49).
CONCLUSION
Oral calcium-channel blockers ranked highest for treatment success. Ketanserin achieved target blood pressure fastest, warranting additional research. The results should be interpreted with caution as SUCRA values may not indicate whether the differences between interventions have clinically meaningful effect sizes.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Antihypertensive Agents; Calcium Channel Blockers; Hydralazine; Hypertension; Ketanserin; Methyldopa; Network Meta-Analysis; Nifedipine; Pre-Eclampsia; Randomized Controlled Trials as Topic
PubMed: 37857042
DOI: 10.1016/j.preghy.2023.10.005