- A Case of Recurrent Thrombotic Microangiopathy Caused by Hypertensive Urgency. [Journal Article]
- CCureus 2018 Aug 30; 10(8):e3235
- A 26-year-old man presented to the emergency room with abdominal pain, nausea, and vomiting for four days. His medical history was significant for hypertension and end-stage renal disease managed wit...
A 26-year-old man presented to the emergency room with abdominal pain, nausea, and vomiting for four days. His medical history was significant for hypertension and end-stage renal disease managed with hemodialysis. He had been noncompliant with the antihypertensive regimen which included nifedipine, hydralazine, and spironolactone. At presentation, his blood pressure was 231/123 mmHg. Laboratory workup showed white blood count 17.3 × 109/L (normal range: 4.5 to 11.0 × 109/L), hemoglobin 7.8 gm/dL (normal range: 13.5 to 17.5 g/dL), platelet count 46 × 109/L (normal range: 150 to 400 × 109/L), reticulocyte count 7.8%, total bilirubin 1 mg/dL (normal range: 0.1 to 1.2 mg/dL), lactate dehydrogenase 1,235 U/L (normal range: 140 to 280 U/L), haptoglobin < 10 mg/dL, and a direct Coomb's test was negative. Numerous schistocytes were identified on the peripheral blood smear. The patient was diagnosed with thrombotic microangiopathy secondary to severe hypertension and was started on intravenous nicardipine. With appropriate blood pressure control, hematological parameters improved with normalization of the platelet count within 10 days. Notably, the patient had one similar episode of hypertension-induced thrombotic microangiopathy within a period of the last three months and ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motif 13) activity was normal on his previous admission.
- Review of Cardiovascular Drugs in Pregnancy. [Journal Article]
- JWJ Womens Health (Larchmt) 2018 Nov 08
- Cardiovascular disease is now the leading cause of pregnancy-related deaths in the United States. Increasing maternal mortality in the United States underscores the importance of proper cardiovascula...
Cardiovascular disease is now the leading cause of pregnancy-related deaths in the United States. Increasing maternal mortality in the United States underscores the importance of proper cardiovascular management. Significant physiological changes during pregnancy affect the heart's ability to respond to pathological processes such as hypertension and heart failure. These physiological changes further affect the pharmacokinetic and pharmacodynamic properties of cardiac medications. During pregnancy, these changes can significantly alter medication efficacy and metabolism. This article systematically reviews the literature on safety, efficacy, pharmacokinetics, and pharmacodynamics of cardiovascular drugs used for hypertension and heart failure during pregnancy and lactation. The 2017 American College of Cardiology/American Heart Association hypertension guidelines recommend transitioning pregnant patients to methyldopa, nifedipine, or labetalol. Heart failure medications, including beta-blockers, furosemide, and digoxin, are relatively safe and can be used effectively. Medications that block the renin angiotensin-aldosterone system have been shown to be beneficial in the general population; however, they are teratogenic and, therefore, contraindicated in pregnancy. Cardiovascular medications can also enter breast milk and, therefore, care must be taken when selecting drugs during the lactation period. A summary of the safety of drugs during pregnancy and lactation from an online resource, LactMed by the National Library of Medicine's TOXNET database, is included. High-risk pregnant patients with cardiovascular disease require a multispecialty team of doctors, including health care providers from obstetrics and gynecology, maternal fetal medicine, internal medicine, cardiovascular disease specialists, and specialized pharmacology expertise.
- Enhanced calcium entry via activation of NOX/PKC underlies increased vasoconstriction induced by methylglyoxal. [Journal Article]
- BBBiochem Biophys Res Commun 2018 Nov 04
- Advanced glycation end-products (AGEs) play a pivotal role in macro- and micro-vascular diabetic complications. We investigated the mechanism by which methylglyoxal (an endogenous generator of AGEs) ...
Advanced glycation end-products (AGEs) play a pivotal role in macro- and micro-vascular diabetic complications. We investigated the mechanism by which methylglyoxal (an endogenous generator of AGEs) affects vascular contractility using the isolated artery technique. Contractile responses to vasoconstrictors phenylephrine (PE), angiotensin II (Ang II), vasopressin (VP) and KCl were measured in the isolated rat aorta following one-our exposure to methylglyoxal (50-200 μM). The perfused rat kidney was employed to confirm the effect of methylglyoxal on microvessels. Methylglyoxal-induced changes in cytosolic calcium were measured in the smooth muscle layer of the aorta with the calcium-sensing fluorophore Fluo-4 AM. Methylglyoxal significantly increased maximal contraction of the rat aorta to PE, Ang II and VP. Similar results were seen in response to the depolarizing vasoconstrictor KCl in macro and micro vessels. The methylglyoxal-induced increases in aortic contraction mediated by the agonist and KCl were endothelium independent. Methylglyoxal-induced increases in KCl-dependent aortic contraction were abolished after the removal of extracellular calcium or in the presence of the calcium channel blocker nifedipine. Incubation with the antioxidant N-acetyl-l-cysteine (NAC), apocynin (a nonselective NADPH oxidase (NOX) inhibitor) or chelerythrine (a protein kinase C (PKC) inhibitor) prior to methylglyoxal pre-treatment reversed the methylglyoxal-induced increases in the rat aortic contractility. In conclusion, the formation of AGEs increases vasoconstriction of both macro- and micro-vessels by increasing the voltage-activated calcium entry in vascular smooth muscles in a NOX and PKC dependent manner.
- Extracellular calcium influx through L-type calcium channels, intracellular calcium currents and extracellular signal-regulated kinase signaling are involved in the abscisic acid-induced precognitive and anti-anxiety effects. [Journal Article]
- BPBiomed Pharmacother 2018 Nov 03; 109:582-588
- Abscisic acid (ABA), a critical phytohormone, is also produced in animal tissues. It has been reported that ABA has pro-cognitive and anti-anxiety effects in rats. However, its detailed mechanism has...
Abscisic acid (ABA), a critical phytohormone, is also produced in animal tissues. It has been reported that ABA has pro-cognitive and anti-anxiety effects in rats. However, its detailed mechanism has not yet been clarified. Here, the possible roles of extracellular and intracellular calcium store and ERK signaling were evaluated in pro-cognitive and anti-anxiety effects of ABA. Morris water maze (MWM) and plus maze tests were used to evaluate the learning and memory and anxiety-like behavior, respectively, in rats. The inhibitors of L- (nifedipine) and T-type (amiloride) calcium channels and endoplasmic reticulum Ca2+-ATPase (thapsigargin) were centrally (i.c.v.) injected 15 min before ABA. Hippocampal and prefrontal lobe levels of phosphorylated extracellular signal-regulated Kinase (p-ERK) were assessed by immunoblotting. The data showed that ABA has promoting effect on rat's performance in MWM task and induced anti-anxiety effect. In addition, nifedipine and thapsigargin significantly prevented while, amiloride had no effect on the mentioned effects of ABA. Furthermore, p-ERK levels were significantly increased in ABA-treated rats which were inhibited by nifedipine and thapsigargin pretreatment. It seems that the extracellular calcium influx through L-type calcium channels, intracellular calcium storage and ERK signaling are involved, at least in part, in the pro-cognitive and anti-anxiety effects of ABA.
- Effects of timolol on Ca2+ handling and viability in human prostate cancer cells. [Journal Article]
- TMToxicol Mech Methods 2018 Nov 05; :1-27
- Timolol is a medication used widely to treat glaucoma. Regarding Ca2+ signaling, timolol was shown to modulate Ca2+-related physiology in various cell types, however, the effect of timolol on Ca2+ ho...
Timolol is a medication used widely to treat glaucoma. Regarding Ca2+ signaling, timolol was shown to modulate Ca2+-related physiology in various cell types, however, the effect of timolol on Ca2+ homeostasis and cell viability has not been explored in human prostate cancer cells. The aim of this study was to explore the effect of timolol on intracellular Ca2+ concentrations ([Ca2+]i) and viability in PC3 human prostate cancer cells. Timolol at concentrations of 100-1000 μM induced [Ca2+]i rises. The Ca2+ signal in Ca2+-containing medium was reduced by removal of extracellular Ca2+ by approximately 75%. Timolol (1000 μM) induced Mn2+ influx suggesting of Ca2+ entry. Timolol-induced Ca2+ entry was partially inhibited by three inhibitors of store-operated Ca2+ channels: nifedipine, econoazole and SKF96365, and by a protein kinase C (PKC) activator (phorbol 12-myristate 13 acetate, PMA) or an inhibitor (GF109203X). In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin abolished timolol-evoked [Ca2+]i rises. Conversely, treatment with timolol abolished thapsigargin-evoked [Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 abolished timolol-induced [Ca2+]i rises. Timolol at concentrations between 200-600 μM killed cells in a concentration-dependent fashion. Chelation of cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/AM (BAPTA/AM) did not reverse cytotoxicity of timolol. Together, in PC3 cells, timolol induced [Ca2+]i rises by evoking Ca2+release from the endoplasmic reticulum in a PLC-dependent manner, and Ca2+ influx via PKC-regulated store-operated Ca2+ entry. Timolol also caused cell death that was not linked to preceding [Ca2+]i rises.
- State-of-the-Art Diagnosis and Treatment of Hypertension in Pregnancy. [Review]
- MCMayo Clin Proc 2018; 93(11):1664-1677
- Hypertension complicates up to 10% of pregnancies worldwide. Pregnancy hypertension is defined as systolic blood pressure (BP) equal to or greater than 140 mm Hg or diastolic BP equal to or greater t...
Hypertension complicates up to 10% of pregnancies worldwide. Pregnancy hypertension is defined as systolic blood pressure (BP) equal to or greater than 140 mm Hg or diastolic BP equal to or greater than 90 mm Hg, usually on the basis of measurements in office/clinic settings and using various BP devices. Hypertensive disorders of pregnancy are classified into (1) chronic hypertension diagnosed before pregnancy or before 20 weeks' gestation, (2) gestational hypertension diagnosed at equal to or greater than 20 weeks, or (3) preeclampsia, defined restrictively as gestational hypertension with proteinuria or broadly as gestational hypertension with proteinuria or an end-organ manifestation consistent with preeclampsia. Absolute BP values equal to or greater than 140/90 mm Hg are associated with increased maternal and perinatal risks, particularly with preeclampsia. This review focuses on antihypertensive therapy of hypertensive disorders of pregnancy as a specific management strategy. Underpinning this therapy is the need for accurate measurement of BP, agreed-upon classification of pregnancy hypertension, agreed-upon BP thresholds for enhanced surveillance and antihypertensive treatment, and collaborative teamwork in management. Challenges relate to the methodology of studies on which care is based, as well as aspects of the care itself, particularly the unregulated use of home BP monitoring. Pitfalls include the unsubstantiated belief that nifedipine and magnesium sulfate cannot be used together and the perception that severe hypertension and nonsevere hypertension are separate entities rather than lying along a spectrum of BP values. The following must be addressed by future research: guidance for nuanced care as women transition between severe and nonsevere hypertension, personalized antihypertensive therapy, and incorporation of women's values into research priorities and clinical practice when antihypertensive care is chosen.
- Study on the inhibitory effect of furafylline and troleandomycin in the 7-methoxyresorufin-O-demethylase and nifedipine oxidase activities in hepatic microsomes from four poultry species using high-performance liquid chromatography coupled with fluorescence and ultraviolet detection. [Journal Article]
- JPJ Pharm Biomed Anal 2018 Oct 22; 164:148-154
- The present study reports the in vitro studies with furafylline and troleandomycin (TAO) as specific inhibitors of activities 7-methoxyresorufin-O-demethylase (MROD) and nifedipine oxidase, catalyzed...
The present study reports the in vitro studies with furafylline and troleandomycin (TAO) as specific inhibitors of activities 7-methoxyresorufin-O-demethylase (MROD) and nifedipine oxidase, catalyzed by cytochrome P450 1 A2 (CYP1 A2) and 3A4 human enzymes, respectively, in hepatic microsomes of quail, duck, turkey and chicken. The results suggest that in chicken and quail the MROD activity is carried out by orthologs CYP1 A4 and 1 A5, meanwhile in duck and turkey by a CYP1 A5 ortholog. The nifedipine oxidase activity is carried out by orthologs of the CYP3A family in the four bird species. The use of furafylline and TAO significantly decreased these activities (P < 0.05) and suggested that the biotransformation of resorufin methyl ether (RME) may be related to more than one avian ortholog.
- Simultaneous prediction of intestinal absorption and metabolism using the mini-Ussing chamber system. [Journal Article]
- JPJ Pharm Sci 2018 Oct 30
- The purpose of this study was to investigate the possibility of simultaneous prediction of the intestinal absorption and metabolism in a mini-Ussing chamber equipped with rat intestinal tissues, base...
The purpose of this study was to investigate the possibility of simultaneous prediction of the intestinal absorption and metabolism in a mini-Ussing chamber equipped with rat intestinal tissues, based on the transport index (TI). TI value was defined as the sum of drug amounts, by mass balance method, transported to the basal-side component and drug amounts accumulated in the tissue, which are normalized by AUC of the drug in the apical compartment. Midazolam and nifedipine with high permeability, were used as typical P450 substrates to examine the possibility of simultaneous prediction of intestinal absorption and metabolism. The metabolite formation of both compounds was observed and ketoconazole strongly inhibited the metabolite formation of both compounds in rat intestinal tissues, leading to the improvement of the TI value to a statistically significant extent for both compounds. TI ratio of nifedipine between in the presence and absence of ketoconazole was larger than that of midazolam, which was consistent with the reported lower value of fraction absorbed multiplied by intestinal availability of nifedipine. Therefore, the mini-Ussing chamber, equipped with animal intestinal tissues, showed potential to predict the intestinal absorption and metabolism simultaneously.
- Constriction of Retinal Venules to Endothelin-1: Obligatory Roles of ETA Receptors, Extracellular Calcium Entry, and Rho Kinase. [Journal Article]
- IOInvest Ophthalmol Vis Sci 2018 Oct 01; 59(12):5167-5175
- CONCLUSIONS: Extracellular Ca2+ entry via L-VOCCs is essential for developing and maintaining basal tone of porcine retinal venules. ET-1 causes significant constriction of retinal venules by activating ETARs and extracellular Ca2+ entry independent of L-VOCCs. Activation of ROCK signaling, without involvement of PKC, appears to mediate venular constriction to ET-1 in the porcine retina.
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- Substrate selectivity of human aldehyde oxidase 1 in reduction of nitroaromatic drugs. [Journal Article]
- ABArch Biochem Biophys 2018 Dec 01; 659:85-92
- Human aldehyde oxidase 1 (AOX1) catalyzes the oxidation of various drugs and endogenous compounds. Recently, we found that AOX1 catalyzed the reduction of drugs such as nitrazepam and dantrolene. In ...
Human aldehyde oxidase 1 (AOX1) catalyzes the oxidation of various drugs and endogenous compounds. Recently, we found that AOX1 catalyzed the reduction of drugs such as nitrazepam and dantrolene. In this study, we aimed to clarify the substrate selectivity of human AOX1 for the reduction of nitroaromatic drugs to obtain helpful information for drug development. We investigated whether 11 nitroaromatic drugs were reduced by AOX1 using recombinant AOX1 and human liver cytosol (HLC) in the presence of N1-methylnicotinamide, an electron donor to AOX1. We found that clonazepam, flunitrazepam, flutamide, nilutamide, nimesulide, and nimetazepam were substantially reduced by recombinant AOX1 and HLC, whereas azelnidipine, nifedipine, and nimodipine were slightly reduced and metronidazole and tolcapone were not reduced. Via structural analysis, we observed that nitroaromatic drugs reduced by AOX1 possessed a relatively electron-deficient nitro group. Since the addition of NADPH to human liver microsomes (HLM) did not increase the reductase activities of the drugs that were reduced by recombinant AOX1, it was determined that NADPH-dependent enzymes in microsomes, such as cytochrome P450, were not involved in this process. Inhibition studies using known AOX1 inhibitors supported the role of AOX1 in the reduction of drugs in HLC. In conclusion, this provides new information related to the substrate selectivity of human AOX1 for the reduction of nitroaromatic drugs.