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Molecular Genetics and Metabolism 2023Aromatic L-amino-acid decarboxylase (AADC) deficiency diagnosis is often delayed by low disease awareness and specific laboratory examinations. We demonstrated that an...
BACKGROUND
Aromatic L-amino-acid decarboxylase (AADC) deficiency diagnosis is often delayed by low disease awareness and specific laboratory examinations. We demonstrated that an elevated concentration of L-dopa metabolite 3-O-methyldopa (3-OMD) in dried blood spots could be integrated into a newborn screening program to detect AADC deficiency.
METHODS
DBS samples for amino acid and acylcarnitine analysis using NeoBase™2 reagents were also analyzed for the 3-OMD concentration using C-phenylalanine as an internal standard. For samples exceeding the pre-defined cutoffs, an additional spot was punched from the original filter paper for second-tier 3-OMD measurement by high performance liquid chromatography (HPLC)-MS/MS assay. Newborns with a 3-OMD concentration exceeding 500 ng/mL were referred for confirmatory testing.
RESULTS
From Feb. 2020 to Dec. 2022, 157,371 newborns were screened for AADC deficiency. Eight newborns exhibited an elevated 3-OMD concentration (839-5170 ng/mL). Among them, six newborns were confirmed to carry two pathogenic DDC variants, indicating an incidence of AADC deficiency of ∼1:26,000 (95% confidence interval: 1 in 12,021 to 1 in 57,228). During the follow-up period, all six patients developed typical symptoms of AADC deficiency.
CONCLUSION
The screening for 3-OMD, a target for AADC deficiency, could be easily integrated into the existing newborn screening programs and facilitate the future application for early diagnosis and effective treatment.
Topics: Humans; Infant, Newborn; Tandem Mass Spectrometry; Prospective Studies; Tyrosine; Aromatic-L-Amino-Acid Decarboxylases; Amino Acid Metabolism, Inborn Errors
PubMed: 37635029
DOI: 10.1016/j.ymgme.2023.107687 -
Expert Opinion on Drug Delivery 2023Parkinson's disease (PD) is the second most common neurodegenerative disease and is growing in prevalence and disability. The standard treatment for PD is oral levo-dopa... (Review)
Review
INTRODUCTION
Parkinson's disease (PD) is the second most common neurodegenerative disease and is growing in prevalence and disability. The standard treatment for PD is oral levo-dopa (LD) with carbidopa (CD). As PD progresses, despite higher doses of LD/CD, plasma levels of LD fluctuate, and may be associated with motor fluctuations and dyskinesia.
AREAS COVERED
The development of two new subcutaneous preparations of LD/CD (ND0612 and ABBV-951) for the treatment of motor fluctuations in PD is described in detail. Both reduce motor fluctuations and dyskinesia with minor infusion site adverse events. A third subcutaneous preparation, DIZ102, is in early-stage development.
EXPERT OPINION
The premise for using continuous release LD in advanced PD is that steady state levels of LD will prevent motor fluctuations/dyskinesia, but this is not the whole story, and will limit the benefits of subcutaneous continuous release LD. With its present pump system ND0612 cannot be used as monotherapy, whereas ABBV-951 can be. Having to combine with oral LD/CD will complicate the use of ND0612. Both ND0612 and ABBV-951 only cause modest reductions in OFF time. It is not clear whether these subcutaneous preparations will have more benefits than the intestinal gel, which also reduces OFF time and dyskinesia.
Topics: Humans; Carbidopa; Levodopa; Parkinson Disease; Neurodegenerative Diseases; Drug Combinations; Dyskinesias; Antiparkinson Agents
PubMed: 37634938
DOI: 10.1080/17425247.2023.2253146 -
Electrochemical sensor based on bio-inspired molecularly imprinted polymer for sofosbuvir detection.RSC Advances Aug 2023The electropolymerized molecularly imprinted polymers (MIP) have enabled the utilization of various functional monomers with superior selective recognition of the target...
The electropolymerized molecularly imprinted polymers (MIP) have enabled the utilization of various functional monomers with superior selective recognition of the target analyte template. Methyldopa is an attractive synthetic dopamine analogue which has phenolic, carboxylic, and aminic functional groups. In this research, methyldopa was exploited to fabricate selective MIPs, for the detection of sofosbuvir (SFB), by a simple electropolymerization step onto a disposable pencil graphite electrode (PGE) substrate. The interaction between methyldopa, as a functional monomer, and a template has been investigated experimentally by UV spectroscopy. A polymethyldopa (PMD) polymer was electrografted onto PGE in the presence of SFB as a template. X-ray photoelectron spectroscopy (XPS), electrochemical impedance spectroscopy (ESI), and cyclic voltammetry (CV) were used for the characterization of the fabricated sensor. Differential pulse voltammetry (DPV) of a ferrocyanide/ferricyanide redox probe was employed to indirectly detect the SFB binding to the MIP cavities. The sensor shows a reproducible and linear response over a dynamic linear range from 1.0 × 10 M to 1.0 × 10 M of SFB with a limit of detection of 3.1 × 10 M. The sensor showed high selectivity for the target drug over structurally similar and co-administered interfering drugs, and this enabled its application to detect SFB in its pharmaceutical dosage form and in spiked human plasma samples.
PubMed: 37614794
DOI: 10.1039/d3ra03870j -
Ghana Medical Journal Jan 2023To identify the determinants of systolic blood pressure variability (SBPV) among Ghanaians.
OBJECTIVE
To identify the determinants of systolic blood pressure variability (SBPV) among Ghanaians.
DESIGN
We undertook a secondary analysis of data collected in a prospective study.
SETTING
The study involved patients with hypertension and or diabetes receiving care in five hospitals in Ghana.
MAIN OUTCOME MEASURES
We assessed determinants of SBPV among 2,785 Ghanaian patients. We calculated the standard deviation (SD) of systolic BP recordings of 3 to 10 visits per patient over 18 months as a measure of SBPV. A multivariate linear regression analysis was fitted to identify factors independently associated with risk visit-to-visit SBP standard deviation.
RESULTS
The mean SD of individual patient visit-to-visit SBP overall was 14.8± 6.3 mm Hg. Those with hypertension and diabetes had the highest SD of 15.4 ±6.2 mm Hg followed by 15.2 ±6.5 mm Hg among those with hypertension only and then 12.0 ± 5.2 mm Hg among those with diabetes only, p<0.0001. Factors independently associated with SBPV with adjusted β coefficients (95% CI) included age: 0.06 (0.03 - 0.08) for each year rise in age, eGFR -0.03 (-0.05 - -0.02) for each ml/min rise, low monthly income of <210 Ghana cedis 1.45 (0.43-2.46), and secondary level of education -1.10 (-1.69, -0.50). Antihypertensive classes were associated with SBPV, the strongest associations being hydralazine 2.35 (0.03 - 4.68) and Methyldopa 3.08 (2.39 - 3.77).
CONCLUSION
Several socio-demographic and clinical factors are associated with SBPV. Future studies should assess the contribution of SBPV to CVD outcomes among indigenous Africans and identify actionable targets.
FUNDING
Funding for this study was provided by MSD, Novartis, Pfizer, Sanofi (each a Participant Company) and the Bill and Melinda Gates Foundation (collectively, the Funders) through the New Venture Fund (NVF). FSS and BO are also supported by funding from the National Heart, Lung, and Blood Institute (R01HL152188).
Topics: Humans; Infant, Newborn; Blood Pressure; Ghana; Prospective Studies; Hypertension; Diabetes Mellitus; Risk Factors
PubMed: 37576371
DOI: 10.4314/gmj.v57i1.5 -
Medical Science Monitor : International... Aug 2023BACKGROUND Parkinson's disease (PD) is a neurodegenerative disorder that often requires long-term management of motor symptoms. Continuous infusion of levodopa-carbidopa...
BACKGROUND Parkinson's disease (PD) is a neurodegenerative disorder that often requires long-term management of motor symptoms. Continuous infusion of levodopa-carbidopa intestinal gel (LCIG) has shown promising results in alleviating motor fluctuations and improving quality of life. This study aimed to evaluate the efficacy and safety of transgastric jejunostomy (PEG-J) as a delivery method for LCIG in a cohort of 43 PD patients. MATERIAL AND METHODS Forty-three PD patients who were candidates for LCIG therapy underwent transgastric jejunostomy to facilitate continuous infusion of LCIG. The primary outcomes assessed were motor symptom improvement, reduction in motor fluctuations, and medication-related adverse events. Secondary outcomes included changes in quality of life, dyskinesia severity, and healthcare resource utilization. RESULTS The results of this study demonstrated significant improvements in motor symptoms, reduction in motor fluctuations, and enhanced quality of life following PEG-J for LCIG infusion. The treatment was generally well-tolerated, with a low incidence of procedure-related complications. Notably, the use of PEG-J allowed for precise and continuous delivery of LCIG, minimizing variations in drug absorption and ensuring consistent therapeutic levels. CONCLUSIONS Transgastric jejunostomy (PEG-J) offers an effective approach for the continuous infusion of LCIG in Parkinson's disease treatment. This method provides a stable and reliable delivery system, leading to improved symptom control and enhanced quality of life for PD patients.
Topics: Humans; Carbidopa; Levodopa; Parkinson Disease; Antiparkinson Agents; Jejunostomy; Quality of Life; Drug Combinations; Gels
PubMed: 37571821
DOI: 10.12659/MSM.941285 -
Parkinsonism & Related Disorders Sep 2023It is known that the pharmacokinetics (PK) of levodopa (LD) varies considerably. Difference in PK shapes is expected to affect drug efficacy and development of...
BACKGROUND
It is known that the pharmacokinetics (PK) of levodopa (LD) varies considerably. Difference in PK shapes is expected to affect drug efficacy and development of dyskinesia. In this study, the authors aimed to explore correlations between PK series data of LD and clinical characteristics and dyskinesia in patients with Parkinson's disease (PD).
METHODS
We studied 270 PD patients who underwent PK assessment after administration of LD/carbidopa (100/10 mg) in non-compartmental analysis. The patients were grouped according to similarities in time series data of blood LD concentration. Each group was analyzed with respect to clinical characteristics and PK parameters. We created a model to predict PK patterns based on these findings.
RESULTS
PD patients were divided into three groups by clustering analysis: blood LD concentration of the patients in Groups 1 (n = 129), 3 (n = 44) and 2 (n = 97) rose rapidly, relatively slowly and at an intermediate rate, respectively. There were no statistically significant differences in patient characteristics except age among the three groups (one-way ANOVA). Multivariate analysis showed that frequency of dyskinesias in Group 1 was significantly higher than that in Group 2. We successfully created a PK pattern prediction model based on body weight and blood LD concentration at 15 and 30 min after administration.
CONCLUSIONS
The PK series data of LD was classified into three patterns. The rapid absorption was associated with dyskinesias. Patients' PK patterns were successfully predicted based on their body weight and two-point LD concentration.
Topics: Humans; Levodopa; Antiparkinson Agents; Carbidopa; Parkinson Disease; Dyskinesias; Drug Combinations
PubMed: 37556972
DOI: 10.1016/j.parkreldis.2023.105798 -
Annals of Medicine and Surgery (2012) Aug 2023Wunderlich syndrome is a rare and life-threatening condition that is characterized by spontaneous renal hemorrhage into the subcapsular and perinephric regions. This...
UNLABELLED
Wunderlich syndrome is a rare and life-threatening condition that is characterized by spontaneous renal hemorrhage into the subcapsular and perinephric regions. This case report describes the diagnosis and management of bilateral Wunderlich syndrome during pregnancy, resulting in Page kidney.
CASE PRESENTATION
The patient presented with complaints of left flank pain and breathlessness. After stabilization, an emergency lower cesarean delivery was performed, and a percutaneous drainage procedure was carried out to alleviate the compression on the left kidney. The patient was treated with blood transfusion, methyldopa, and perindopril. Follow-up examinations performed 3 months later revealed a significant decrease in fluid volume surrounding the left kidney.
CLINICAL DISCUSSION
Lenk's triad provides the primary description of the classical manifestations of this syndrome. Some instances have been connected to the Page kidney phenomenon. The relationship between pregnancy and Wunderlich syndrome has not been extensively studied, primarily because the symptoms can resemble other complications related to pregnancy. Due to the scarcity of evidence in the literature, there is no definitive guideline for managing Wunderlich syndrome during pregnancy. Consequently, each patient is treated on an individual basis. Conservative treatment is recommended once malignancy has been ruled out.
CONCLUSION
The case highlights the importance of considering Wunderlich syndrome as a differential diagnosis in pregnant patients with abdominal or flank pain, a palpable mass, and hypovolemia. Furthermore, the case illustrates the successful management of Wunderlich syndrome during pregnancy.
PubMed: 37554856
DOI: 10.1097/MS9.0000000000001062 -
Journal of Neural Transmission (Vienna,... Nov 2023In the advanced Parkinson's disease, motor and non-motor symptoms become more severe and more difficult to treat. Oral therapy may become insufficient in controlling a...
In the advanced Parkinson's disease, motor and non-motor symptoms become more severe and more difficult to treat. Oral therapy may become insufficient in controlling a patient´s motor complications, which results in a substantial deterioration of the patient's quality of life, ability to work and self-reliance. This is when device-aided treatments should be considered and offered, if suitable for a given patient. They include subcutaneous and intestinal infusion therapies, deep brain stimulation and, more recently, MRI-guided focussed ultrasound. Device-aided treatments should be offered in accordance with guidelines and treatment standardization. Also there is a need to ensure availability of treatment and education of patients and physicians.
Topics: Humans; Parkinson Disease; Antiparkinson Agents; Levodopa; Carbidopa; Quality of Life; Deep Brain Stimulation; Drug Combinations
PubMed: 37526767
DOI: 10.1007/s00702-023-02680-z -
Kidney360 Oct 2023Hypertensive disorders of pregnancy complicate up to 10% of pregnancies and remain the major cause of maternal and neonatal morbidity and mortality. Hypertensive... (Review)
Review
Hypertensive disorders of pregnancy complicate up to 10% of pregnancies and remain the major cause of maternal and neonatal morbidity and mortality. Hypertensive disorders of pregnancy can be classified into four groups depending on the onset of hypertension and the presence of target organ involvement: chronic hypertension, preeclampsia, gestational hypertension, and superimposed preeclampsia on chronic hypertension. Hypertension during pregnancy is associated with a higher risk of cardiovascular disease and kidney failure. Early diagnosis and proper treatment for pregnant women with hypertension remain a priority since this leads to improved maternal and fetal outcomes. Labetalol, nifedipine, methyldopa, and hydralazine are the preferred medications to treat hypertension during pregnancy. In this comprehensive review, we discuss the diagnostic criteria, evaluation, and management of pregnant women with hypertension.
Topics: Infant, Newborn; Female; Pregnancy; Humans; Hypertension, Pregnancy-Induced; Pre-Eclampsia; Antihypertensive Agents; Labetalol; Nifedipine
PubMed: 37526641
DOI: 10.34067/KID.0000000000000228