Levodopa (L-DOPA) is the most effective drug for Parkinson's disease; however, various side effects occur during therapy. L-DOPA metabolites and the high cumulative dose of L-DOPA were responsible for its side effects. It is necessary to monitor the concentration of L-DOPA and its metabolites for individualized therapy. This review focuses on L-DOPA analysis by chromatography-based methods in biological matrices. Literature published up to September 2021 was collected in the PubMed, Web of Science, and Embase by using search strategy ("levodopa" OR "L-DOPA") AND ("chromatography"). A total of 1249 articles were identified and 32 articles were included. The contents for method development and validation were summarized and analyzed. Due to the instability of catecholamines (L-DOPA, dopamine, and 3-O-methyldopa) and carbidopa, antioxidation (0.5 mg sodium metabisulfite for 100 μL sample) and environment temperature control were used alone or in combination to enhance stability. Sample was mainly pretreated by protein precipitation (0.4-0.7 M perchloric acid). Separation was usually achieved using methanol or acetonitrile:water (with formic acid) on C18 columns. Mass spectrometry, electrochemical detector, ultraviolet-visible detector and fluorescence detector were used for detection. For L-DOPA, the calibration range was 2.5-10,000 ng/mL, the matrix effect and its coefficient of variation was 85-115 and -9.0-8.5%, and the recovery was 66.8-127.0%. Without stabilization strategy, L-DOPA was stable in plasma at room temperature for 1-7 h (4-6 h for most studies), at - 70 °C to - 80 °C for 10-20 days and after 3-5 freeze-thaw cycles. With stabilization strategies, the stability of L-DOPA in plasma was significantly improved. Metabolites of L-DOPA and enzyme inhibitors (carbidopa, entacapone, tolcapone and benserazide) were all stable in biological matrix. This study might be useful for researchers to develop their methods for individualized therapy of patients with Parkinson.

Hypertensive disorders of pregnancy cause maternal organ damage. Therefore, appropriate management with antihypertensive medication is required from the first trimester. We aimed to clarify the antihypertensive drug prescription trends in pregnant women with hypertension in Japan. The administrative data of pregnant outpatients aged 16-49 years who visited acute hospitals between 2013 and 2020 were included. The annual antihypertensive drug prescription trends were evaluated based on their prescription proportions. The most prescribed drug in 2020 was nifedipine, followed by methyldopa and amlodipine. The proportion of nifedipine prescriptions significantly increased from 33.5 to 40.8% during the study period, whereas that of methyldopa significantly decreased from 16.6 to 11.6%. There was no change in the prescription trend of amlodipine. Dihydropyridine calcium channel blockers were the most commonly prescribed drug for pregnant women with hypertension.

Nitrofurantoin, minocycline, methyldopa and infliximab, have been found to induce autoimmune-like hepatitis (DI-AILH). Evidence for other drugs and herbal and dietary supplements (HDS) is unclear. The aims of the study were to establish criteria to define and review the published evidence of suspected DI-AILH. Search was undertaken in Pubmed using search terms "drug-induced liver injury," "autoimmune hepatitis," and "drug-induced autoimmune hepatitis." DI-AILH was defined as (1) drug as a potential trigger of liver injury with autoimmune features and histological findings compatible with AIH; (2) no or incomplete recovery or worsening of liver tests after discontinuation of the drug; (3) corticosteroids requirement or spontaneous recovery; (4) follow-up without immunosuppression (IS) and no relapse of AIH at least 6 months after discontinuation of IS; and (5) drugs potentially inducing AILH with a chronic course. Cases fulfilling the first four criteria were considered probable DI-AILH with three possible DI-AILH. A total of 186 case reports were identified for conventional drugs (n = 148; females 79%; latency 2.6 months) and HDS (n = 38; females 50%). The most commonly reported agents of DI-AILH were interferons (n = 37), statins (n = 24), methylprednisolone (MPS) (n = 16), adalimumab (n = 10), imatinib (n = 8), and diclofenac (n = 7). Tinospora cordifolia and Khat were the only HDS with probable DI-AILH cases. No relapses of AIH were observed when IS was stopped after interferons, imatinib, diclofenac, and methylprednisolone. Conclusion: Beyond well-recognized nitrofurantoin, methyldopa, hydralazine, minocycline, and infliximab as causes of DI-AILH, interferons, imatinib, adalimumab, and MPS were the best-documented agents leading to probable DI-AILH. Khat and Tinospora cordifolia were the only HDS found to be able to induce DI-AILH. Long-term immunosuppression appears to be rarely required in patients with DI-AILH due to these drugs.

The catechol-O-methyltransferase inhibitors entacapone and opicapone prolong the efficacy of conventional oral levodopa/dopa decarboxylase inhibitor formulations through an increase in levodopa plasma bioavailability. Catechol-O-methyltransferase inhibitors influence the homocysteine metabolism associated with levodopa/dopa decarboxylase application. The objectives of this study were to compare the impact of additional single-day entacapone or opicapone intake on the pharmacokinetic plasma behaviour of levodopa, 3-O-methyldopa and total homocysteine in 15 Parkinson's disease patients, with concomitant scoring of motor symptoms, under standardized conditions. The patients received opicapone plus two doses of 100 mg levodopa/carbidopa and, one week later, two doses of levodopa/carbidopa/entacapone or vice versa. Levodopa, 3-O-methyldopa and total homocysteine were determined with reversed-phase high-performance liquid chromatography. Levodopa bioavailability and its maximum concentration were higher with opicapone. The computed peak-to-trough difference was lower after the second levodopa administration with entacapone. The fluctuation index of levodopa did not differ between both conditions. 3-O-methyldopa decreased on both days. Homocysteine levels did not significantly vary between both conditions. A significant homocysteine decrease occurred with entacapone, but not with opicapone. Motor behaviour improved with entacapone, but not with opicapone. Opicapone baseline scores were significantly better, and thus the potential for the improvement in motor symptoms was lower compared with the entacapone condition. The higher levodopa bioavailability with opicapone suggests that it is more efficacious than entacapone for the amelioration of "off" phenomena in fluctuating patients when co-administered with a levodopa/dopa decarboxylase inhibitor regimen. Both compounds prevented an increase in homocysteine, which is a metabolic marker for an impaired capacity in the performance of methylation processes.

Compounds that induce 5-aminolevulinic acid [ALA] synthase-1 and/or cytochromes P-450 may induce acute porphyric attacks in patients with the acute hepatic porphyrias [AHPs]. Currently, there is no simple, robust model used to assess and predict the porphyrogenicity of drugs and chemicals. Our aim was to develop a fluorescence-based in vitro assay for this purpose. We studied four different hepatic cell culture models: HepG2 cells, LMH cells, 3D HepG2 organoids, and 3D organoids of primary liver cells from people without known disease [normal human controls]. We took advantage of the fluorescent properties of protoporphyrin IX [PP], the last intermediate of the heme biosynthesis pathway, performing fluorescence spectrometry to measure the intensity of fluorescence emitted by these cells treated with selected compounds of importance to patients with AHPs. Among the four cell culture models, the LMH cells produced the highest fluorescence readings, suggesting that these cells retain more robust heme biosynthesis enzymes or that the other cell models may have lost their inducibility of ALA synthase-1 [ALAS-1]. Allyl isopropyl acetamide [AIA], a known potent porphyrogen and inducer of ALAS-1, was used as a positive control to help predict porphyrogenicity for tested compounds. Among the tested compounds (acetaminophen, acetylsalicylic acid, β-estradiol, hydroxychloroquine sulfate, alpha-methyldopa, D (-) norgestrel, phenobarbital, phenytoin, sulfamethoxazole, sulfisoxazole, sodium valproate, and valsartan), concentrations greater than 0.314 mM for norgestrel, phenobarbital, phenytoin, and sodium valproate produced fluorescence readings higher than the reading produced by the positive AIA control. Porphyrin accumulation was also measured by HPLC to confirm the validity of the assay. We conclude that LMH cell cultures in multi-well plates are an inexpensive, robust, and simple system to predict the porphyrogenicity of existing or novel compounds that may exacerbate the AHPs.

The MANAGE-PD tool may help general neurologists in deciding whether a patient with advanced Parkinson's disease should be referred for an advanced therapy. Although the development and clinical validation of MANAGE-PD would appear to serve an important need, we urge the reader to be aware of several methodological concerns.

A 68-year-old woman with Parkinson's disease, who had previously undergone Roux-en-Y gastrojejunostomy for early gastric cancer, complained of wearing-off and troublesome dyskinesia that had progressed over 7-years. After the introduction of levodopa-carbidopa intestinal gel therapy (LCIG) by nasojejunal tube, she had a good clinical response. Percutaneous endoscopic gastrostomy with a jejunal extension tube was difficult in this case, due to lack of gastrostomy site and fibrous postoperative adhesion. We introduced LCIG by direct percutaneous endoscopic jejunostomy (D-PEJ) which offers a less invasive procedure to operative tube placement. The factors affecting the success of D-PEJ could interfere with transillumination, abdominal thickness and the location of other organs. We determined the optimum site of catheter insertion with the assistance of real-time 3D reconstruction CT-jejunography. She was discharged home on postoperative day 14 without any procedure-related complications. Real-time 3D reconstructive CT-jejunography guided D-PEJ is a useful method for a patient who benefit from LCIG with prior gastrojejunostomy.

Oleh Hornykiewicz was born on November 17, 1926 in Lamberg, Ukraine. After completing his studies in July 1951, he moved to the "Pharmacological Institute of the University of Vienna". In 1958, he started his research on centrally acting drugs at the same institute and came up with the idea of linking laboratory observations with animals with the basal ganglia of the human brain. Soon, Hornykiewicz initiated a new question: L-DOPA as a therapy for Parkinson's disease? Fortunately, after administration of this new drug, patients were able to perform motor activities which could not be prompted to any comparable degree by any known drug. In the following decades, initial fiction became an unavoidable fact. Dopamine, adapted and combined with carbidopa or benzerazide, has evolved into a drug that no longer recognizes the borders of countries and continents. Distinguished emeritus prof. Oleh Hornykiewicz died on May 26, 2020 at the age of 93 in Vienna, Austria. Unfortunately, despite everything he has done and deserved, the Nobel Prize was not received.

Paraganglioma is a catecholamine-secreting tumor (CST) in extra-adrenal autonomic ganglia and a rare cause of hypertension during pregnancy. If not properly treated, it can lead to disastrous outcomes for both the mother and fetus. This report describes the successful anesthetic management of a paraganglioma diagnosed during pregnancy. A pregnant woman, with 32 weeks of gestational age, presented with severe paroxysmal hypertension, refractory to methyldopa and nifedipine at maximum dosages, headache, sweating, and palpitations. Diagnostic work-up was positive for elevated serum and urinary normetanephrines, and magnetic resonance showed a solid nodule above the hilum of the right kidney, suggestive of paraganglioma. Optimal alpha-blockade was achieved with doxazosin, and given the advanced gestational age, tumor resection was postponed until after delivery. Cesarean delivery was scheduled at 34 weeks, under combined spinal-epidural anesthesia and continuous blood pressure monitoring. Antihypertensive drugs were prepared for immediate administration as needed. Intraoperative and postoperative periods went uneventfully for both the mother and newborn, both under intensive care observation for 24 h.

Diltiazem (DTZ) is one of the most important drugs in blood pressure that is used to treat cardiovascular diseases. With this overuse of this drug and its use for suicide, swelling and neck cramps and fever has made it important to measure it. So, this paper will give an account of modification of carbon paste electrode with the ternary-nanocomposite including reduced-graphene oxide (rGO), cadmium oxide and 1-ethyl 3- methyl imidazole chloride as ionic liquid for using the determination of DTZ in blood serum samples. Characterization of the synthesized rGO, cadmium oxide, and modified electrodes and their electrochemical performance were studied by, scanning electron microscopy, and X-ray diffraction, electrochemical impedance spectroscopy, and voltammetry technique. The improvement of the DTZ oxidation current by modified electrode originated from the increased electrode surface area. The optimized method was validated and the results showed that LOD = 3 nM and good linearity. Also, a linear concentration range of 0.01-150 μM with a LOD of 0.03 μM in presence methyldopa were achieved based on the electrochemical investigations. The prepared sensor showed good repeatability (RSD = 2.26%) and selectivity for DTZ determination in the real samples (relative recovery of 93-102%).

Pre-eclampsia complicated by pulmonary oedema, severe hypertension, tachycardia and desaturation is a devastating condition. A comprehensive understanding of the aetiopathogenesis during such an emergency is challenging in the absence of functional and responsive point-of-care imaging, and laboratory and other critical-care services. An unbooked 26-year-old gravida 3 para 1+1 presented to a primary healthcare clinic with features of pre-eclampsia, severe hypertension and pulmonary oedema. The only available antihypertensive drug, methyldopa, was administered. The patient was transferred to a district hospital and subsequently referred to a tertiary hospital. On arrival, she was booked for caesarean delivery and in the maternity ward a central venous pressure (CVP) line was inserted. The patient developed pneumothorax and died in the intensive care unit undelivered. This case highlights many lessons, which are discussed. If CVP monitoring is indicated before caesarean delivery, consideration must be given to line insertion in the operating room to facilitate rapid delivery should the patient's condition deteriorate.

The aim of this study is to evaluate and present the evidence so far, regarding fetal outcomes after in utero exposure to antihypertensive medication. Hypertensive disorders during pregnancy constitute a significant risk factor for maternal and fetal outcomes, necessitating antihypertensive treatment. However, current data concerning the safety of in utero exposure to antihypertensive medication are controversial. While some studies recommend the administration of certain agents, others underline the possible adverse effects on fetal development. This review aims to summarize the outcomes of studies published during the last decade, referring to first trimester in utero exposure to antihypertensive agents. In general, a-methyldopa, β-blockers and calcium channel blockers are the first or second treatment line for hypertension during pregnancy. However, ACEIs, ARBs and diuretics are mostly contraindicated, as the potential risk outweighs the benefits of their administration. Additionally, several drugs should be avoided, due to the lack of data regarding their safety. CONCLUSION: As current studies are restricted for ethical reasons, there is a significant lack of evidence concerning diverse antihypertensive agent use. In utero exposure to antihypertensive medication needs to be carefully evaluated and supported by further research.

An exome sequencing result on a child with atypical gait was reported as negative; follow-up biochemical evaluation and reanalysis led to diagnosis of treatable DOPA-responsive dystonia.

Gestational diabetes mellitus (GDM) is associated with hypertensive disorders in pregnancy. Alpha-methyl-DOPA (αMD) is a commonly used medication for hypertension in pregnant women. This medication may be associated with alteration in insulin resistance and glucose homeostasis. The aim of the present study was to investigate in 152 pregnant women whether the demands of exogenous insulin in glucocorticoid-treated women during pregnancy are different between those with GDM and hypertension treated with αMD and those without hypertension. In the group of women with GDM under insulin treatment, who received αMD for hypertension, the increase in insulin needs was relatively lower by at least 30% of the pre-admission insulin dose compared to all of the remaining women not receiving αMD in the same group (9 women vs. 50 women, p = 0.035). Our work raises the hypothesis that αMD can favorably modulate insulin sensitivity in the third trimester of pregnancy in previously insulin-treated women with gestational diabetes who receive glucocorticoids.

Purpose: To determine the clinical effectiveness of combination therapy with intravitreal injection of triamcinolone acetonide (IVITA) and oral levodopa in eyes affected by nonarteritic anterior ischemic optic neuropathy (NAION). Methods: Longitudinal study involving 45 eyes of 45 patients with NAION who were evaluated within 14 days of NAION onset. The treatment group received an IVITA 4 mg/0.1 mL followed by 25 mg carbidopa/100 mg levodopa (Sinemet 25-100) 3 times daily for 12 weeks and the control group was untreated. Best-corrected visual acuity (BCVA) converted to logarithmic minimum angle of resolution (logMAR), visual field (VF) grades based on automated or Goldman perimetry, and mean retinal nerve fiber layer (RNFL) thickness measured on optical coherence tomography were assessed at the initial visit, 1, 3, and 6 months after NAION attack. Results: At the first visit and 6 months after NAION onset, the mean logMAR BCVA in the treatment group was significantly better than the control group (P < 0.05). BCVA was not significantly different between onset and the 6-month visit for both the control and the treatment group; however, the change in BCVA after 6 months was significantly greater in the treatment group compared with the control group (P = 0.007). Concomitant systemic disease, the changes in VF grades, and RNFL thickness from initial to 6 months after NAION onset were not significantly different between 2 groups. Conclusions: Combination therapy with IVITA and oral levodopa/carbidopa appears to be effective in the treatment of recent-onset NAION.

Transmission of HIV across the mucosal surface of the female reproductive tract to engage subepithelial CD4-positive T cells is not fully understood. Cervical epithelial cells express complement receptor 3 (CR3) (integrin αMβ2 or CD11b/CD18). In women, the bacterium Neisseria gonorrhoeae uses CR3 to invade the cervical epithelia to cause cervicitis. We hypothesized that HIV may also use CR3 to transcytose across the cervical epithelia. Here, we show that HIV-1 strains bound with high affinity to recombinant CR3 in biophysical assays. HIV-1 bound CR3 via the I-domain region of the CR3 alpha subunit, CD11b, and binding was dependent on HIV-1 N-linked glycans. Mannosylated glycans on the HIV surface were a high-affinity ligand for the I-domain. Man5 pentasaccharide, representative of HIV N-glycans, could compete with HIV-1 for CR3 binding. Using cellular assays, we show that HIV bound to CHO cells by a CR3-dependent mechanism. Antibodies to the CR3 I-domain or to the HIV-1 envelope glycoprotein blocked the binding of HIV-1 to primary human cervical epithelial (Pex) cells, indicating that CR3 was necessary and sufficient for HIV-1 adherence to Pex cells. Using Pex cells in a Transwell model system, we show that, following transcytosis across an intact Pex cell monolayer, HIV-1 is able to infect TZM-bl reporter cells. Targeting the HIV-CR3 interaction using antibodies, mannose-binding lectins, or CR3-binding small-molecule drugs blocked HIV transcytosis. These studies indicate that CR3/Pex may constitute an efficient pathway for HIV-1 transmission in women and also demonstrate strategies that may prevent transmission via this pathway. IMPORTANCE In women, the lower female reproductive tract is the primary site for HIV infection. How HIV traverses the epithelium to infect CD4 T cells in the submucosa is ill-defined. Cervical epithelial cells have a protein called CR3 on their surface. We show that HIV-1 binds to CR3 with high affinity and that this interaction is necessary and sufficient for HIV adherence to, and transcytosis across, polarized, human primary cervical epithelial cells. This suggests a unique role for CR3 on epithelial cells in dually facilitating HIV-1 attachment and entry. The HIV-CR3 interaction may constitute an efficient pathway for HIV delivery to subepithelial lymphocytes following virus transmission across an intact cervical epithelial barrier. Strategies with potential to prevent transmission via this pathway are presented.

Βeta oscillatory activity (human: 13-35 Hz; primate: 8-24 Hz) is pervasive within the cortex and basal ganglia. Studies in Parkinson's disease patients and animal models suggest that beta-power increases with dopamine depletion. However, the exact relationship between oscillatory power, frequency and dopamine tone remains unclear. We recorded neural activity in the cortex and basal ganglia of healthy non-human primates while acutely and chronically up- and down-modulating dopamine levels. We assessed changes in beta oscillations in patients with Parkinson's following acute and chronic changes in dopamine tone. Here we show beta oscillation frequency is strongly coupled with dopamine tone in both monkeys and humans. Power, coherence between single-units and local field potentials (LFP), spike-LFP phase-locking, and phase-amplitude coupling are not systematically regulated by dopamine levels. These results demonstrate that beta frequency is a key property of pathological oscillations in cortical and basal ganglia networks.