Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin I-converting enzyme (ACE) isoforms in urine from healthy and mildly hypertensive untreated patients have been described in the literature. Healthy subjects have high- and low-molecular-weight ACEs (170 and 65 kDa), whereas mildly hypertensive untreated patients have only low-molecular-weight ACEs (90 and 65 kDa), both of which resemble ACE from the N-terminal domain. Previous studies have shown that ACE is regulated during development, and renal tubules of premature human infants are not completely mature, given that nephrogenesis is not complete until the 36th week of gestation. The aim of the present study was to purify and characterize ACE isoforms from urine of premature and full-term infants and to detect the presence of the N-domain form of ACE during prenatal development. Urine from premature and full-term infants was concentrated in an Amicon concentrator, dialyzed in the same equipment against 50 mmol/L Tris-HCl buffer (pH 8.0) that contained 150 mmol/L NaCl, and submitted to gel filtration on an AcA-34 column equilibrated with the buffer described above. Two peaks (P1 and P2 for premature infants; TP1 and TP2 for full-term infants) with ACE activity on hippuryl-His-Leu (K(m), 3 mmol/L) were detected. All enzymes were Cl(-) dependent and inhibited by captopril and EDTA. The peptides angiotensin-(1-7) and N-acetyl-Ser-Asp-Lys-Pro, described as specific for N-domain ACE, were hydrolyzed by P2 and TP2, which suggests that both enzymes are N-domain ACE. In premature infants, P1 activity with hippuryl-His-Leu was 12-fold lower than P2 activity, but in full-term infants, the difference between TP1 and TP2 was 1.6-fold. Chromatography profiles of urine from premature infants were analyzed on days 1, 3, 7, 14, 21, and 30 after birth. The P1 of ACE was detected around the 21st and 30th days, whereas P2 was detected from day 1. These results suggest that ACE activity is related to renal development and that N-domain ACE as well as full-length ACE is present in urine from premature infants. This may indicate that healthy subjects produce and secrete the N-domain form of ACE even before term development.
Hypertension 2000 Jun
PMID:Angiotensin I-converting enzyme isoforms (high and low molecular weight) in urine of premature and full-term infants. 1085 78

Six healthy, awake, and pharmacologically restrained mature horses were studied in order to define the changes in cardiopulmonary function during and after exploratory thoracoscopy and to determine the presence of postoperative complications occurring 48 hours after thoracoscopy. In a randomised 3 x 3 latin square design with 2 replications, 18 procedures were performed: 6 right (RTH) and 6 left thoracoscopies (LTH) and 6 sham procedures (STH). Prior to each procedure a physical examination and a bronchoalveolar lavage fluid analysis were performed. During thoracoscopy and sham protocols, horses were sedated with a continual drip of detomidine HCl and data were collected at 6 time intervals: T1 (baseline), T2 (10 min detomidine administration), T3 (first 15 min pneumothorax), T4 (5 min recovery from pneumothorax), T5 (second 15 min pneumothorax), and T6 (10 min recovery from the second pneumothorax and detomidine). An endoscopic thoracic examination was conducted during the 2 pneumothorax periods. An identical protocol was followed for sham procedures without surgery or pneumothorax. Data were analysed by ANOVA with time and surgical procedure as main factors. Physical examinations, thoracic radiography and ultrasound, CBC and bronchoalveolar lavage fluid analysis were performed 48 h after thoracoscopy. Heart rate, respiratory rate, and cardiac output decreased following detomidine administration. There was a trend for cardiac output to be lower during thoracoscopy. Mild systemic hypertension was associated with thoracoscopy although there was no effect on pulmonary arterial pressure. Total and pulmonary vascular resistances were increased following detomidine administration. Thoracoscopy caused a further increase in systemic and pulmonary vascular resistances especially during the second pneumothorax. Arterial O2 tension decreased following detomidine administration and was further decreased during the second pneumothorax period. PaO2 values were lower when thoracoscopy was performed on the left rather than the right hemithorax. No significant complications were found during the 48 h follow-up evaluation. A subclinical postoperative pneumothorax occurred in 2 horses, one of which had sustained a lung laceration by the trocar. Thoracoscopy performed in healthy, awake, and pharmacologically restrained horses did not have detrimental cardiopulmonary effects and did not cause postoperative complications within the first 48 h period.
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PMID:Pleuropulmonary and cardiovascular consequences of thoracoscopy performed in healthy standing horses. 1095 75

The nucleoside triphosphate diphosphohydrolases (NTPDase; EC 3.6.1. 5) are a family of ectonucleotidases associated with vascular endothelial and smooth muscle cells. These ectonucleotidases are involved in the control of vascular tone by regulating the level of circulating ATP. Ca(2+)-channel blocking agents are currently used for the treatment of hypertension. Considering the external localization of the NTPDase catalytic site and its Ca(2+) requirement for enzyme activity, a possible interference of calcium antagonists (nifedipine, verapamil-HCl, and diltiazem-HCl and some of its metabolites) could be anticipated. To test that hypothesis, an NTPDase-enriched particulate fraction was used. Our results show that verapamil, diltiazem, and its metabolites all produced a concentration-dependent inhibition of NTPDase, at concentrations greater or equal to 0.1 mM with verapamil and to 0.5 mM with diltiazem and its metabolites, whereas no significant effect was observed with nifedipine. Kinetic studies, carried out to define the mode of action of these drugs, showed a mixed type of inhibition. Based on their respective K(i) values (in parentheses, in mM), inhibitory potencies of these molecules were in the following order: desacetyl-N-desmethyldiltiazem (M(2)-HCl; 0.6) > verapamil (0.76) > N-desmethyldiltiazem (M(A;) 0.9) > diltiazem (2.4) > desacetyl-O-desmethyldiltiazem (M(4)-HCl; 3.5) > desacetyl N, O-desmethyldiltiazem (M(6)-HCl; 3.9). Hence, these calcium antagonists can be considered as weak NTPDase inhibitors. Moreover, based on these K(i) values and the range of concentrations found in the blood, NTPDase would not be inhibited significantly in vivo.
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PMID:Ca(2+)-channel blockers and nucleoside triphosphate diphosphohydrolase (NTPDase) influence of diltiazem, nifedipine, and verapamil. 1110 13

Even though Mg is by far the least abundant serum electrolyte, it is extremely important for the metabolism of Ca, K, P, Zn, Cu, Fe, Na, Pb, Cd, HCl, acetylcholine, and nitric oxide (NO), for many enzymes, for the intracellular homeostasis and for activation of thiamine and therefore, for a very wide gamut of crucial body functions. Unfortunately, Mg absorption and elimination depend on a very large number of variables, at least one of which often goes awry, leading to a Mg deficiency that can present with many signs and symptoms. Mg absorption requires plenty of Mg in the diet, Se, parathyroid hormone (PTH) and vitamins B6 and D. Furthermore, it is hindered by excess fat. On the other hand, Mg levels are decreased by excess ethanol, salt, phosphoric acid (sodas) and coffee intake, by profuse sweating, by intense, prolonged stress, by excessive menstruation and vaginal flux, by diuretics and other drugs and by certain parasites (pinworms). The very small probability that all the variables affecting Mg levels will behave favorably, results in a high probability of a gradually intensifying Mg deficiency. It is highly regrettable that the deficiency of such an inexpensive, low-toxicity nutrient result in diseases that cause incalculable suffering and expense throughout the world. The range of pathologies associated with Mg deficiency is staggering: hypertension (cardiovascular disease, kidney and liver damage, etc.), peroxynitrite damage (migraine, multiple sclerosis, glaucoma, Alzheimer's disease, etc.), recurrent bacterial infection due to low levels of nitric oxide in the cavities (sinuses, vagina, middle ear, lungs, throat, etc.), fungal infections due to a depressed immune system, thiamine deactivation (low gastric acid, behavioral disorders, etc.), premenstrual syndrome, Ca deficiency (osteoporosis, hypertension, mood swings, etc.), tooth cavities, hearing loss, diabetes type II, cramps, muscle weakness, impotence (lack of NO), aggression (lack of NO), fibromas, K deficiency (arrhythmia, hypertension, some forms of cancer), Fe accumulation, etc. Finally, because there are so many variables involved in the Mg metabolism, evaluating the effect of Mg in many diseases has frustrated many researchers who have simply tried supplementation with Mg, without undertaking the task of ensuring its absorption and preventing excessive elimination, rendering the study of Mg deficiency much more difficult than for most other nutrients.
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PMID:The multifaceted and widespread pathology of magnesium deficiency. 1142 81

Although sudden cardiac death, myocardial infarction, or stroke can occur at any time of day, event rates increase during the waking hours, particularly in the morning. In most people-both normotensive and hypertensive-blood pressure (BP) rises rapidly in the early morning hours, the time when most individuals wake and begin their day. This rise in BP corresponds to increased secretion of catecholamines and increased plasma renin activity. Thus, vascular tone and total peripheral resistance increase in the morning hours, and BP rises as a result. At the same time, heart rate increases. In the late morning or early afternoon, BP reaches its peak. After that, BP declines, falling 15 to 20 mm Hg between about 8 PM and 2 AM, the time when BP is usually lowest. These findings have led to an interest in chronotherapy for hypertension. A major objective of chronotherapy for hypertension is to deliver the drug in higher concentrations during the early-morning post-awakening period, when BP is highest, and in lesser concentrations during the middle of a sleep cycle, when BP is low. Traditional sustained-release pharmacologic agents, which deliver a near-constant drug concentration, were not designed to complement the circadian pattern. There are currently two antihypertensive agents, Verelan PM (verapamil HCl) and Covera HS (verapamil HCl), that provide chronotherapy for hypertension. These drugs use novel delivery systems that provide 24-h BP control while maximizing drug concentrations in the morning and minimizing drug concentrations during sleep.
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PMID:Pharmacology of cardiovascular chronotherapeutic agents. 1158 43

BACKGROUND: In general clinical practice, physicians prescribe calcium channel blockers to a wide range of patients with differing demographic characteristics and hypertension history. This study was undertaken to investigate the effectiveness and safety of sustained-release verapamil (Verelan((R)), verapamil HCl) in patients with essential hypertension, studied under "usual use" conditions. METHODS: In this prospective, open-label, postmarketing surveillance study, 25 089 patients with hypertension received once-daily verapamil therapy for 4 weeks, during which they were evaluated by 8106 physicians at baseline and at two follow-up visits (weeks 2 and 4). In this study, hypertension was defined as an average sitting diastolic blood pressure (DBP) of greater-than-or-equal 90 mm Hg at baseline. Previously diagnosed hypertensive patients with a sitting DBP <90 mm Hg but experiencing untoward effects requiring discontinuation of current antihypertensive therapy were also included. RESULTS: Eighty-five percent (n = 21 446) of the total patients enrolled at baseline completed this office-based trial. Nearly 24% of patients were newly diagnosed hypertensives. At baseline, the mean systolic blood pressure (SBP) and diastolic blood pressure were 161 and 96 mm Hg, respectively. In evaluable patients with mild, moderate, and severe hypertension, as stratified by baseline measurements, treatment with verapamil produced DBP reductions of 12, 19, and 29 mm Hg, respectively. Verapamil treatment produced clinically similar SBP, DBP, and HR (heart rate) reductions across gender and racial groups studied (white, black, Hispanic, and Asian). Only 6.1% of patients failed to complete the study because of any reported adverse experiences (4.5% of patients discontinued because of adverse experiences considered drug related). Constipation (5.0%) and headache (1.1%) were the most commonly reported adverse events. CONCLUSION: In general clinical practice, verapamil is well tolerated and effective in a broad range of hypertensive patients.
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PMID:Large-Scale Postmarketing Surveillance of Hypertensive Patients Treated with Verapamil. 1185 Jun 91

Nicardipine hydrochloride (NC-HCl), a calcium channel blocker for the treatment of chronic stable angina and hypertension, seems to be a potential therapeutic transdermal system candidate, mainly due to its low dose, short half-life, and high first-pass metabolism. The objective of the present study was to evaluate its flux and elucidate mechanistic effects of formulation components on transdermal permeation of the drug through the skin. Solubility of NC-HCl in different solvent systems was determined using a validated HPLC method. The solubility of drug in various solvent systems was found to be in decreasing order as propylene glycol (PG)/oleic acid (OA)/dimethyl isosorbide (DMI) (80:10:10 v/v) > PG > PG/OA (90:10 v/v) > polyethylene glycol 300 > ethanol/PG (70:30 w/w) > transcutol > dimethyl isosorbide (DMI) > ethanol > water and buffer 4.7 > 2-propanol. Propylene glycol was then selected as the main vehicle in the development of a transdermal product. As a preliminary step to develop a transdermal delivery system, vehicle effect on the percutaneous absorption of NC-HCl was determined using the excised skin of a hairless guinea pig. Vehicles investigated included pure solvents alone and their selected blends, chosen based on the solubility results. In vitro permeation data were collected at 37 degrees C, using Franz diffusion cells. The skin permeation was then evaluated by measuring the steady state permeation rate (flux) of NC-HCl, lag time, and the permeability constant. The results showed that no individual solvent was capable of promoting NC-HCl penetration. Permeation profiles of the drug through hairless guinea pig skin using saturated solutions of drug were constructed. Among the systems studied, the ternary mixture of PG/OA/DMI and binary mixture of PG/OA showed excellent flux. The flux value of the ternary system was nearly three times higher than the corresponding values obtained for the binary solvent. A similar trend also was observed for the permeation constant, while the values of lag time were reversed. The ternary mixture was then selected as a potential absorption enhancement vehicle for the transdermal delivery of drug. In general, higher fluxes were observed through hairless guinea pig skin as compared with the human stratum corneum. Based on the results obtained from the release study of NC-HCl from saturated solutions of the drug, a novel lecithin organogel (microemulsion-based gel) composed of soybean lecithin, propylene glycol, oleic acid, dimethyl isosorbide, and isopropyl myristate was developed as a possible matrix for transdermal delivery of NC-HCl. In vitro percutaneous penetration studies from this newly developed gel system through giunea pig skin and human stratum corneum revealed that the organogel system has skin-enhancing potential and could be a promising matrix for the transdermal delivery of nicardipine. Furthermore, higher permeation rates were observed when nicardipine free base was incorporated into the gel matrix instead of hydrochloride salt.
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PMID:Transdermal delivery of nicardipine: an approach to in vitro permeation enhancement. 1251 Dec 2

Recent hypertension guidelines recommend initiating antihypertensive therapy with a combination of two or more agents in patients whose blood pressure exceeds their appropriate blood pressure goal by 20/10 mm Hg. This recommendation is based on the knowledge that the majority of patients with blood pressures of this magnitude will not achieve sufficient blood pressure reduction with monotherapy. Further, compared with high-dose monotherapy, combination therapy is often associated with fewer adverse effects and, for this reason, may improve patient adherence. Bringing patients to blood pressure goal quickly is likely to improve clinical outcomes. This article discusses the rationale for using combination antihypertensive therapy as initial therapy for high blood pressure in selected patients and reviews data from a study of 364 high-risk patients with Stage 2 hypertension in which a fixed-dose combination product (amlodipine besylate/benazepril HCl) proved more successful as initial therapy than high-dose monotherapy (amlodipine besylate) in reducing blood pressure.
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PMID:Rationale for combination therapy as initial treatment for hypertension. 1294 92

A novel diltiazem HCl extended-release (ER) tablet formulation was developed for evening administration in the management of angina and hypertension. Pharmacokinetics of the formulation were evaluated to identify variations in morning (7 a.m. or 8 a.m.) versus evening (10 p.m.) drug administration. Single-dose (360 mg) and multiple-dose (360 mg once daily for 7 days), open-label, randomized, two-way crossover studies of the new diltiazem HCl ER tablets were completed in 48 healthy volunteers. Serial plasma samples were collected via direct venipuncture up to 48 hours postdose and analyzed for diltiazem and its two major metabolites by high-performance liquid chromatography (HPLC). The primary parameters used to assess the data were AUC0- infinity, AUC0-tau, AUC6 a.m.-12 p.m., Cmax, and tmax. Statistical comparisons using ANOVA were evaluated after logarithmic transformation of dose-dependent parameters. Diltiazem HCl ER tablets administered in the evening exhibited 17% and 22% greater bioavailability compared to morning administration under single-dose and steady-state conditions, respectively. The two times of drug administration were bioinequivalent in both studies. The evening schedule also provided more than twofold higher plasma diltiazem levels in the critical morning hours, when both blood pressure and the incidence of cardiovascular events are the highest.
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PMID:Pharmacokinetics of a novel diltiazem HCl extended-release tablet formulation for evening administration. 1451 97

Adhering to medication regimens has the potential to significantly improve clinical outcomes for persons with high blood pressure. A patient-related factor likely to affect adherence to treatment is the convenience of the prescribed drug regimen. The authors hypothesized that medication adherence would be superior and cost benefits would accrue in subjects who receive a once-daily, single-capsule, fixed-dose combination product for blood pressure control, compared with subjects who receive a similar regimen of separate components. A managed care organization that provides benefits for members enrolled in various health plans provided the data for this retrospective analysis. The database was used to assess medication adherence patterns for two groups of hypertensive subjects. Group 1 included subjects who had been prescribed the single-capsule, fixed-dose combination of amlodipine besylate/benazepril HCl. Group 2 comprised subjects who had been prescribed a regimen including an angiotensin-converting enzyme inhibitor and a dihydropyridine calcium channel blocker as separate drugs. Adherence was measured by the medication possession ratio, and medical resource utilization by the two groups was assessed during the study period. Group 1 (n=2754) and Group 2 (n=2978) were balanced with regard to age (mean, 53 years; range, 18-64 years) and sex (men, 50%; women, 50%). The overall medication possession ratio for Group 1 was significantly higher than that for Group 2 (80.8% vs. 73.8%; p<0.001). The average annual cost of cardiovascular-related care per subject was significantly lower in Group 1 compared with Group 2 (p<0.001). Subjects receiving the once-daily, single-capsule, fixed-dose combination of amlodipine/benazepril HCl demonstrated significantly better medication adherence and required fewer medical resources than did subjects receiving an angiotensin-converting enzyme inhibitor and a dihydropyridine calcium channel blocker as separate components.
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PMID:Adherence to antihypertensive therapy with fixed-dose amlodipine besylate/benazepril HCl versus comparable component-based therapy. 1468 5


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