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PubMed1998

Comparison of the efficacy of dihydropyridine calcium channel blockers in African American patients with hypertension. ISHIB Investigators Group. International Society on Hypertension in Blacks.

BACKGROUND: Hypertension is a prevalent disease among African Americans, and successful treatment rates are low. Since calcium channel blockers are well-tolerated and efficacious in African Americans, we undertook this study to compare the efficacy, safety, and tolerability of 3 commonly prescribed calcium channel blockers: amlodipine besylate (Norvasc), nifedipine coat core (CC) (Adalat CC), and nifedipine gastrointestinal therapeutic system (GITS) (Procardia XL). METHODS: One hundred ninety-two hypertensive patients across 10 study centers were randomly assigned to double-blind monotherapy with amlodipine besylate (5 mg/d), nifedipine CC (30 mg/d), or nifedipine GITS (30 mg/d) for 8 weeks. Patients not achieving therapeutic response after 4 weeks had their dose doubled for the next 4 weeks. The primary end point was a comparison of the average reduction (week 8 minus baseline) in 24-hour ambulatory diastolic blood pressure (DBP). Secondary end points included a comparison of average 24-hour ambulatory systolic blood pressure (SBP), office SBP or DBP reduction, responder rates, safety, and tolerability. RESULTS: One hundred sixty-three patients were evaluable for efficacy after 8 weeks. There was no significant difference in the average 24-hour ambulatory DBP (-8.5, -9.0, and -6.1 mm Hg, respectively) or SBP (-14.3, -15.7, and -11.8 mm Hg, respectively) reduction. Average office SBP and DBP were reduced to a comparable degree (19-22 mm Hg [P =.50] and 12-14 mm Hg [P =.51], respectively). Responder rates (DBP <90 or reduced by > or = 10 mm Hg) were similar (P = .38). Discontinuation rates and adverse event frequency were distributed similarly across the 3 treatment groups. CONCLUSION: The efficacy, safety, and tolerability of the 3 dihydropyridine calcium channel blockers are equivalent in African Americans with stages 1 and 2 hypertension.

Adult↗
PubMed2001

Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study.

BACKGROUND: Recent reports have drawn attention to the importance of pulse pressure as a predictor of cardiovascular events. Pulse pressure is used neither by clinicians nor by guidelines to define treatable levels of blood pressure. METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination, and all subsequent cardiovascular events were ascertained and classified. RESULTS: At baseline, 1961 men and 2941 women were at risk for an incident myocardial infarction or stroke. During follow-up that averaged 6.7 years, 572 subjects had a coronary event, 385 had a stroke, and 896 died. After adjustment for potential confounders, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure were directly associated with the risk of incident myocardial infarction and stroke. Only SBP was associated with total mortality. Importantly, SBP was a better predictor of cardiovascular events than DBP or pulse pressure. In the adjusted model for myocardial infarction, a 1-SD change in SBP, DBP, and pulse pressure was associated with hazard ratios (95% confidence intervals) of 1.24 (1.15-1.35), 1.13 (1.04-1.22), and 1.21 (1.12-1.31), respectively; and adding pulse pressure or DBP to the model did not improve the fit. For stroke, the hazard ratios (95% confidence intervals) were 1.34 (1.21-1.47) with SBP, 1.29 (1.17-1.42) with DBP, and 1.21 (1.10-1.34) with pulse pressure. The association between blood pressure level and cardiovascular disease risk was generally linear; specifically, there was no evidence of a J-shaped relationship. In those with treated hypertension, the hazard ratios for the association of SBP with the risks for myocardial infarction and stroke were less pronounced than in those without treated hypertension. CONCLUSION: In this population-based study of older adults, although all measures of blood pressure were strongly and directly related to the risk of coronary and cerebrovascular events, SBP was the best single predictor of cardiovascular events.

Aged↗
PubMed2005

Effect of exercise on blood pressure in older persons: a randomized controlled trial.

BACKGROUND: Because of age-related differences in the cause of hypertension, it is uncertain whether current exercise guidelines for reducing blood pressure (BP) are applicable to older persons. Few exercise studies in older persons have evaluated BP changes in relation to changes in body composition or fitness. METHODS: This was a 6-month randomized controlled trial of combined aerobic and resistance training; controls followed usual care physical activity and diet advice. Participants (aged 55-75 years) had untreated systolic BP (SBP) of 130 to 159 mm Hg or diastolic BP (DBP) of 85 to 99 mm Hg. RESULTS: Fifty-one exercisers and 53 controls completed the trial. Exercisers significantly improved aerobic and strength fitness, increased lean mass, and reduced general and abdominal obesity. Mean decreases in SBP and DBP, respectively, were 5.3 and 3.7 mm Hg among exercisers and 4.5 and 1.5 mm Hg among controls (P < .001 for all). There were no significant group differences in mean SBP change from baseline (-0.8 mm Hg; P=.67). The mean DBP reduction was greater among exercisers (-2.2 mm Hg; P=.02). Aortic stiffness, indexed by aortofemoral pulse-wave velocity, was unchanged in both groups. Body composition improvements explained 8% of the SBP reduction (P = .006) and 17% of the DBP reduction (P<.001). CONCLUSIONS: A 6-month program of aerobic and resistance training lowered DBP but not SBP in older adults with mild hypertension more than in controls. The concomitant lack of improvement in aortic stiffness in exercisers suggests that older persons may be resistant to exercise-induced reductions in SBP. Body composition improvements were associated with BP reductions and may be a pathway by which exercise training improves cardiovascular health in older men and women.

Aged↗
PubMed1999

Teaching residents about development and behavior: meeting the new challenge.

OBJECTIVE: To determine the teaching methods, materials currently used, and unmet needs for teaching developmental-behavioral pediatrics (DBP) at pediatric training programs in the United States. DESIGN: Cross-sectional survey of US pediatric residency training programs. The survey questionnaire consisted of 3 instruments: a program director survey, a developmental-behavioral pediatrics survey, and an adolescent medicine survey. PARTICIPANTS: Survey packets were mailed in January 1997 to 211 programs identified by mailing labels from the Association of Pediatric Program Directors. RESULTS: Data from 148 programs (70%) completing both the DBP survey and program director survey were analyzed. Ninety-five percent of programs reported a block rotation, and 95% of those stated that the rotation was mandatory. Eighty-seven percent had a formal curriculum. Most programs reported using articles, lecture outlines, and precepting for teaching DBP. Few programs used standardized case-based or computerized materials. Most programs, however, indicated a desire for these materials. Few programs felt that 4 topics were covered adequately: adoption (12%), violence (24%), substance use (28%), and conduct problems (41%). Programs that perceived that they covered these topics adequately were more likely to use written cases as part of their curriculum (Mann-Whitney test, 1373.5; P=.04). Barriers to teaching included lack of adequate faculty, time, money, and curricular resources. CONCLUSIONS: Pediatric residency programs have made significant gains in mandatory DBP training. However, many programs report a lack of adequate faculty, teaching materials, and methods. Responding programs indicated an interest in case-based materials. This approach may represent an alternative and underutilized resource for teaching DBP.

Adolescent↗
PubMed2006

Potassium supplementation for the management of primary hypertension in adults.

BACKGROUND: Epidemiological evidence on the effects of potassium on blood pressure is inconsistent. OBJECTIVES: To evaluate the effects of potassium supplementation on health outcomes and blood pressure in people with elevated blood pressure. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials, CAB abstracts, and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review. SELECTION CRITERIA: Inclusion criteria were: 1) RCTs of a parallel or crossover design comparing oral potassium supplements with placebo, no treatment, or usual care; 2) treatment and follow-up >=8 weeks; 3) participants over 18 years, with raised systolic blood pressure (SBP) >=140 mmHg or diastolic blood pressure (DBP) >=85 mmHg); 4) SBP and DBP reported at end of follow-up. We excluded trials where: participants were pregnant; received antihypertensive medication which changed during the study; or potassium supplementation was combined with other interventions. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted. MAIN RESULTS: Six RCT's (n=483), with eight to 16 weeks follow-up, met our inclusion criteria. Meta-analysis of five trials (n=425) with adequate data indicated that potassium supplementation compared to control resulted in a large but statistically non-significant reductions in SBP (mean difference: -11.2, 95% CI: -25.2 to 2.7) and DBP (mean difference: -5.0, 95% CI: -12.5 to 2.4). The substantial heterogeneity between trials was not explained by potassium dose, quality of trials or baseline blood pressure. Excluding one trial in an African population with very high baseline blood pressure resulted in smaller overall reductions in blood pressure (SBP mean difference: -3.9, 95% CI: -8.6 to 0.8; DBP mean difference: -1.5, 95% CI: -6.2 to 3.1). Further sensitivity analysis restricted to two high quality trials (n=138) also found non-significant reductions in blood pressure (SBP mean difference: -7.1, 95% CI: -19.9 to 5.7; DBP mean difference: -5.5, 95% CI: -14.5 to 3.5). AUTHORS' CONCLUSIONS: This systematic review found no statistically significant effect of potassium supplementation on blood pressure. Because of the small number of participants in the two high quality trials, the short duration of follow-up, and the unexplained heterogeneity between trials, the evidence about the effect of potassium supplementation on blood pressure is not conclusive. Further high quality RCTs of longer duration are required to clarify whether potassium supplementation can reduce blood pressure and improve health outcomes.

Adult↗
PubMedDate not supplied

Obesity correlates with increased blood pressures in urban Native American youth.

Although obesity is a growing problem with Native American youth living on reservations, little research has been conducted examining the prevalence of obesity and correlations between age, body composition, dietary intake, and blood pressures (BP) for urban Native youth. The purpose of this study was to investigate the relationship of these variables in urban Native American youth. Height and weight were measured for 155 Native American youth, age 5-18 years, and the body mass index (BMI) was calculated and classified into percentile categories. Skinfold thicknesses at the biceps, triceps, suprailiac, and subscapular sites, arm and waist circumferences, and systolic (SBP) and diastolic (DBP) blood pressures were also measured. There was a high proportion of obesity (>95 percentile) for youth in all age groups. The prevalence was 38% for the 5-10-year-olds and 45% for the 11-18-year-olds youth. There were no significant correlations between SBP and DBP and dietary variables. Mean SBP and DBP increased with increasing BMI percentiles. Stepwise regression analyses showed that waist circumference, age, and BMI were strong predictors for SBP, while waist circumference and age were predictors for DBP in the total sample. The findings suggest that overweight/obesity is very prevalent among urban Native American youth and the increased adiposity is associated with increased SBP and DBP.

Adolescent↗
PubMed1990

Genetic epidemiological study of blood pressure in a sedentary rural agricultural population of West Bengal, India.

To study the genetic epidemiology of blood pressure (BP), data on 78 families were collected from a sedentary agricultural population of eastern India. The general levels of both systolic (SBP) and diastolic (DBP) blood pressures are found to be low (mean SBP = 106.41 mm Hg; mean DBP = 63.94 mm Hg). Trends of blood pressures with age are similar to those reported earlier (e.g., in the Framingham study). Environmental variables--e.g., occupation and tobacco use--do not have any direct significant effect on blood pressure variability in this population. Path analysis of family data shows a highly significant familial aggregation and yields a genetic heritability (maximum) estimate of 0.3 for both SBP and DBP. Sib-sib and mother-child correlation estimates are, respectively, 0.3 and 0.25. Father-child correlation estimates are 0.13 for SBP and near zero for DBP. A pseudopolygenic model yields the best fit to the data on SBP, while for DBP a proper resolution of various models considered could not be obtained.

Adolescent↗
PubMed1987

Oral clonidine for rapid control of accelerated hypertension.

Thirty emergency-room patients, 15 men and 15 women, from 27 to 64 years old with diastolic blood pressures (DBP) greater than 115 mm Hg, were admitted to an open-label, oral loading trial of clonidine. At this time, their supine mean arterial pressures (MAP) averaged 150 +/- 2 mm Hg. An initial clonidine dose of 0.1 to 0.2 mg was to be followed every hour by another 0.1 mg until the DBP had been lowered to a level allowing treatment to be continued on an ambulatory basis or until a total of 0.5 mg had been given. A satisfactory response--defined as a reduction of the supine DBP to 105 mm Hg or lower if the baseline was between 115 and 135 mm Hg, or reduction of a baseline DBP greater than 135 mm Hg by at least 30 mm Hg--was achieved in all but one of the patients in an average of 118 minutes; the mean dose required was 0.26 mg. The mean reduction from the baseline MAP was 23.1 +/- 0.9%. Drug-related adverse experiences comprised drowsiness and dry mouth in 13 patients. Thereafter, 28 of the patients were chronically treated with clonidine for an average of 73 days. In 24 patients treated for at least 80 days, the daily clonidine dose averaged 0.375 mg. All the patients required concurrent diuretic therapy. A satisfactory response (as defined above) to this maintenance treatment was shown by 85% of the patients, and full blood-pressure control (supine DBP less than 95 mm Hg) was attained in 78%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Serotonergic blockade compared with beta-adrenergic blockade in systemic hypertension: a double-blind comparison of ketanserin with propranolol.

The safety and efficacy of ketanserin, a competitive serotonin blocking agent, and propranolol were compared in 33 patients with mild to moderate hypertension (sitting diastolic blood pressure [DBP] 95-115 mm Hg) using a placebo run-in, randomized, double-blind parallel study design. All patients received placebo for 4 weeks, then were randomized to receive increasing doses of either ketanserin (20, 40 mg twice daily) or propranolol (40, 80 mg twice daily) to achieve a goal sitting DBP less than 90 mm Hg. Patients not achieving the goal blood pressure with either drug as monotherapy, received the other drug in combination. At the end of the active monotherapy phase (week 10 of the study), propranolol demonstrated a greater decrease in DBP from baseline, as compared to ketanserin (-7.9 +/- 10.9 mm Hg with propranolol, P less than 0.05; -1.0 +/- 7.2 mm Hg with ketanserin, P = NS). Four out of 16 patients achieved goal response on propranolol, compared to 3/17 for ketanserin. With combination treatment, 9/18 patients reached the goal response; the addition of propranolol to ketanserin in non-responders resulted in further reduction of sitting DBP of -10.3 +/- 6.3 compared to monotherapy (P less than 0.001), while the addition of ketanserin to non-responders produced no significant response in sitting DBP. Propranolol showed a consistent effect in slowing heart rate. Ketanserin displayed less frequent side effects than propranolol. Propranolol used twice daily appears to be more effective than twice daily ketanserin use in patients with mild to moderate hypertension.

Adrenergic beta-Antagonists↗
PubMed1988

Dose-response effect of sublingual captopril in hypertensive crises.

Forty-one patients, presenting in the Emergency Service of the Hospital General y Clinico, Tenerife, with symptoms of hypertensive crisis and supine diastolic blood pressure (DBP) greater than 120 mm Hg, were studied. They received 12.5 mg of sublingual captopril and 30 minutes later, if diastolic blood pressure (DBP) was not 100 mm Hg or less, the same dose was repeated by the same route. Supine systolic blood pressure (SBP), DBP and heart rate (HR) were monitored at 0, 5, 10, 15, 30, 45, 60, and 120 minutes after each administration of captopril. In 27 patients (66%) had a satisfactory response (DBP less than or equal to 100 mm Hg), after a single dose, less than 30 minutes after administration, which persisted at 120 minutes. In 14, a second administration was necessary after 30 minutes, and a satisfactory response to the second dose, defined again as DBP reaching values of 100 mm Hg or less, was achieved in 12 of them (29% of the total group). In two patients (5% of total) no full response was obtained. The observed pattern of response suggests that a sublingual dose of 25 mg of captopril is the minimum effective dose, but it is also possible that administration of 12.5 mg of sublingual captopril at 10 to 15 minute intervals, perhaps up to a maximum dose of 37.5 mg, might be considered as an alternative treatment in hypertensive crises.

Administration, Sublingual↗
PubMed1990

A comparison of a controlled release (CR/ZOK) formulation of metoprolol, once daily, with conventional metoprolol tablets, twice daily, in mild to moderate hypertension.

In a randomized double-blind multicenter study in 100 hypertensive patients, the effect of once daily (od) dosing with a new controlled release (CR/ZOK) formulation of metoprolol was compared with that of twice daily (bid) dosing with metoprolol conventional tablets. Eligible patients had a resting seated diastolic blood pressure (DBP) greater than or equal to 95 mm Hg and less than 110 mm Hg at the end of a 6-week open placebo run-in. The active treatment phase lasted 8 weeks. The starting dose was 100 mg od in the CR/ZOK group (N = 53) and 50 mg bid in the tablet group (N = 47). The dose was increased to 200 mg od and 100 mg bid, respectively, in nonresponders (DBP greater than 95 mm Hg) at the end of the first 4-week period. Approximately 40% of both groups received concomitant diuretic therapy throughout the study. The SBP, DBP and HR were reduced compared to baseline in both treatment groups after 4 and 8 weeks. After 4 weeks, 85% of the CR/ZOK group and 74% of the tablet group had DBP less than 95 mm Hg. After another 4 weeks, the corresponding figures were 93% and 93%. There was no statistically significant difference between the treatment groups in the decrease in either SBP, DBP or HR, nor was there any difference in the percentage of responders. Both treatments were equally well tolerated. In conclusion, the antihypertensive effect of once daily dosing (100-200 mg) with the new CR/ZOK formulation of metoprolol is as effective as that of twice daily dosing (50-100 mg) with conventional metoprolol tablets.

Adult↗
PubMedDate not supplied

Cardiovascular parameter changes in patients with erectile dysfunction using pde-5 inhibitors: a study with sildenafil and vardenafil.

Sildenafil is the most prescribed oral agent for patients with erectile dysfunction (ED). Vardenafil is a new phosphodiesterase type 5 (Pde-5) inhibitor that was approved by the US Food and Drug Administration last year to treat patients with ED of various causes. Both of these Pde-5 inhibitors have vasodilating properties and effects on blood pressure (BP), and like nitrates, they work through the nitric oxide cyclic guanosine monophosphate pathway. The aim of this study was to investigate the influence of these Pde-5 inhibitors on BP and heart rate (HR) in normotensive men with ED by a crossover comparison. Thirty-five patients with ED were enrolled to evaluate and compare the effect of sildenafil (50 mg) and vardenafil (10 mg) on BP and HR. At the screening (baseline [B]) visit, sitting systolic blood pressure (B-SBP), diastolic blood pressure (B-DBP), and HR were measured. We performed a multiple administration for both drugs and, therefore, multiple measurements of BP and HR changes, 3 doses a week, on alternate days, late in the afternoon, and on an empty stomach. B-SBP, B-DBP, and HR were recorded before each 50-mg sildenafil dosing and after 30, 60, 120, and 240 minutes. Data were averaged over the 4 time points and compared with the baseline values obtained before each dosing. After a 3-week wash-out period, patients were crossed over to vardenafil (10 mg) with the same study design. After administration of both drugs, we observed a statistically significant decrease of BP and an increase of HR. On average, sildenafil caused a decrease of SBP ranging from 5.1 +/- 3.9 mm Hg during the first dosing to 4.7 +/- 4.2 mm Hg during the third dosing, DBP ranged from 4.4 +/- 4.9 to 4 +/- 4.1 mm Hg, and HR increased 1.8 +/- 2.0 bpm (first dose) and 1.2 +/- 0.9 bpm (third dose). With vardenafil, we recorded a greater variation for SBP and DBP. SBP decreased from 8.02 +/- 8.0 mm Hg during the first dosing to 5.4 +/- 5.5 mm Hg during the third dosing, whereas DBP decreased from 6.6 +/- 7.2 to 5.0 +/- 5.3 mm Hg, respectively. Recorded HR showed an increase of 3.1 +/- 3.2 bpm (first dose) and 2.4 +/- 2.3 bpm (third dose). After the first vardenafil administration, we recorded fainting episodes in 3 patients because of a decrease in BP greater than 20 mm Hg. Two of the patients were in therapy with doxazosin for benign prostatic hyperplasia (BPH). Cardiovascular response was not significantly different after the first dose between the 2 treatments. Vardenafil demonstrated clinically significant differences (fainting) with respect to sildenafil only during the first doses. We suggest that before starting therapies with Pde-5 inhibitors, particularly with the newer ones, that baseline cardiovascular parameters are measured and monitored, especially during the first dose, because of the presence of a "first dose effect." Moreover, it is necessary to pay particular attention to those patients in treatment with other drugs that could have a synergistic hypotensive effect as a result of vasodilation potentiation.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1991

Vitamin D analogs with low affinity for the vitamin D binding protein: enhanced in vitro and decreased in vivo activity.

The affinity of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)2D3] and analogs with side-chain modifications [MC 903 or calcipotriol, MC 1147 or 24,24-dihomo-1 alpha,25-(OH)2D3 and 1,25-(OH)2-16ene-23yne-D3] for the vitamin D receptor and the serum vitamin D binding protein (DBP) were compared. The affinity of MC 903 for the receptor from chick and rat duodenum or from human peripheral blood mononuclear cells or HL-60 cells varied between 60 and 100% relative to the affinity of 1,25-(OH)2D3. The relative affinity of 1,25-(OH)2-16ene-23yne-D3 and MC 1147 varied for the same receptors between 45-70 and 3.5-25%, respectively. The relative affinity of MC 903 for human DBP was 30-fold decreased, whereas the two other analogs did not bind to DBP at all even in more than 1000-fold excess. The in vitro biologic activity of 1 alpha,25-(OH)2D3 on phytohemagglutinin-stimulated normal human lymphocyte proliferation was markedly inhibited by the addition of physiologic amounts of DBP to the cell culture medium. No such inhibition was observed when MC 903 or 1147 was evaluated similarly. DBP therefore reversed the rank order of the in vitro potency of these analogs. Intramuscular injections for 10 consecutive days to vitamin D-deficient chicks demonstrated a greater than or equal to 100-fold lower biologic activity of MC 903, MC 1147, and 1,25-(OH)2-16ene-23yne-D3 compared to that of 1 alpha,25-(OH)2D3 as evaluated by serum calcium and osteocalcin concentrations, as well as by duodenal calbindin D28K and bone calcium content.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Profile of ligand specificity of the vitamin D binding protein for 1 alpha,25-dihydroxyvitamin D3 and its analogs.

The profile of structural preference for the ligand binding domain of the human vitamin D binding protein (DBP) was determined by steroid competition assay of 71 analogs of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3]. The following categories of structural modification were evaluated [values represent fold change; R = reduction, I = increase in binding to the DBP from the reference 1 alpha, 25(OH)2D3]: (1) deletion in the A ring of the 1 alpha-hydroxyl-(20-1600I); (2) conversion of the triene system to the previtamin form (6-40R); (3) addition of substituents to carbon 11 of the C ring (4-14R); (4) inversion of the C/D ring junction (8-20R); (5) unsaturation of the D ring (16-ene; 4-140R); (6) replacement of hydrogen with deuterium atoms (no effect); alteration of the side chain by (7) adding or deleting carbon atoms (5-12R); (8) addition of fluorines (0.2-10R); (9) presence of unsaturation (22-ene, 0-5R; 23-ene, 3R-10I; 23-yne, 5-20R); (10) addition of hydroxyls (2-100R); and (11) addition of an aromatic ring (0-20I). Thus the DBP ligand binding domain could tolerate only modest changes to the structure of 1 alpha,25(OH)2D3 without a reduction in binding of the analog. The increases in binding seen in the aromatic side chain and with a triple bond at carbon-23 may be indicative of a preferred conformation of the flexible 1 alpha, 25(OH)2D3 side chain. In addition, a comparison was made of the DBP ligand binding domain with that of the human HL-60 cell 1 alpha, 25(OH)2D3 nuclear receptor. Both ligand binding domains could equivalently accommodate to the presence of (1) a side-chain cyclopropyl group, (2) 22-ene or 23-yne, (3) lengthening the side chain by two carbons, (4) presence of four to six fluorine atoms, (5) substitution of an oxygen for carbon 22, and (6) presence of a 22-[m-(dimethylhydroxymethyl)phenyl] aromatic group in the side chain. The DPB could tolerate better than the HL-60 cell receptor the presence of a 22-(p-hydroxyphenyl) aromatic group in the side chain and the absence of the 1 alpha-hydroxyl. In contrast, the HL-60 cell receptor could tolerate better than the DBP the following structural modifications: presence of a 16-ene, or 16-ene plus 23-yne unsaturation, and presence of an 11 beta-hydroxyl.

Binding, Competitive↗
PubMedDate not supplied

Evaluation of alternative statistical methods for linear model analysis to compare two treatments for 24-hour blood pressure response.

This paper evaluates alternative statistical methods for the analysis of 24-hour blood pressure data from a clinical trial which compares two treatments for hypertension. The primary objective of the study discussed here was to determine the time course for the blood pressure lowering effects of a test drug given once daily in the treatment of mild to moderate hypertension when compared with placebo. Thirty-five patients (24 on drug and 11 on placebo) were monitored for 24 hours at baseline and at two weeks post treatment, with diastolic blood pressure (DBP) measurements recorded at 22 time points within each 24-hour visit. The changes in DBP from baseline across the 22 time points are the response variables of interest. Various statistical methods for the assessment of treatment effects over the entire 24-hour dosing interval in a setting with small sample size are discussed and illustrated. The results from a special application of weighted least squares analysis of covariance, which employs a smoothed covariance matrix, support the hypothesis that a once daily dose of the drug significantly reduces DBP over the entire 24-hour dosing interval when compared with placebo. This method has the distinct advantage of enabling evaluation of treatment differences for the change in DBP from baseline at the 22 time points with the corresponding 22 baseline DBP as covariates simultaneously in a situation where the treatment group sample sizes are small.

Antihypertensive Agents↗
PubMed1998

Male reproductive tract malformations in rats following gestational and lactational exposure to Di(n-butyl) phthalate: an antiandrogenic mechanism?

Di(n-butyl) phthalate (DBP), a widely used plasticizer suspected of having estrogenic properties, was investigated for its effects on the prenatal and early neonatal development of the reproductive tract. Pregnant CD rats (n = 10) were given DBP at 0, 250, 500, or 750 mg/kg/day (p.o.) throughout pregnancy and lactation until their offspring were at postnatal day 20. Maternal body weights throughout the dosing period were comparable in all groups. At 750 mg/kg/day, the number of live pups per litter at birth was decreased and maternal effects on pregnancy and postimplantation loss are likely to have occurred. Anogenital distance was decreased at birth in the male offspring at 500 and 750 mg/kg/day. The epididymis was absent or underdeveloped in 9, 50, and 71% of adult offspring (100 days old) at 250, 500, and 750 mg/kg/day, respectively, and was associated with testicular atrophy and widespread germ cell loss. Hypospadias occurred in 3, 21, and 43% of males and ectopic or absent testes in 3, 6, and 29% of males at 250, 500, and 750 mg/kg/day, respectively. Absence of prostate gland and seminal vesicles as well as small testes and seminal vesicles were noted at 500 and 750 mg/kg/day. Vaginal opening and estrous cyclicity, both estrogen-dependent events, were not affected in the female offspring, although low incidences of reproductive tract malformations were observed at 500 and 750 mg/kg/day. In the male offspring, DBP produced the same spectrum of effects elicited by the antiandrogen flutamide. Thus, DBP specifically impaired the androgen-dependent development of the male reproductive tract, suggesting that DBP is not estrogenic but antiandrogenic in the rat at these high dose levels. For human risk assessment, determining if this toxicity is metabolite-mediated will be critical, since marked species differences in metabolism exist.

Androgen Antagonists↗
PubMed1998

Assessment of the developmental toxicity, metabolism, and placental transfer of Di-n-butyl phthalate administered to pregnant rats.

The developmental toxicity and placental transfer of di-n-butyl phthalate (DBP) were evaluated in Sprague-Dawley rats given a single oral dose of DBP on Gestational Day 14. In the developmental toxicity study, dams were dosed with 0, 0.5, 1, 1.5, or 2 g DBP/kg and were necropsied on GD21. Increased incidence of resorptions and reduced fetal body weight were observed at 1.5 and 2 g/kg. Higher incidences of skeletal variations were found at doses > or = at 1 g/kg. No embryotoxic or teratogenic effects were observed at a dose of 0.5 g/kg. In the placental transfer study, dams were dosed with 0.5 or 1.5 g [14C]DBP/kg. Maternal and embryonic tissues were collected at intervals from 0.5 to 48 h. Embryonic tissues accounted for less than 0.12-0.15% of the administered dose. Levels of radiocarbon in placenta and embryo were one-third or less of those in maternal plasma. No accumulation of radioactivity was observed in the maternal or embryonic tissues. From HPLC analyses, it was shown that unchanged DBP and its metabolites mono-n-butyl phthalate (MBP) and MBP glucuronide were rapidly transferred to the embryonic tissues, where their levels were constantly lower than those in maternal plasma. MBP accounted for most of the radioactivity recovered in maternal plasma, placenta, and embryo. Unchanged DBP was found only in small amounts. These findings support the hypothesis that MBP, a potent teratogen, largely contributes to the embryotoxic effects of DBP.

Abnormalities, Drug-Induced↗
PubMed1982

Phthalate esters I: Effects on cytochrome P-450 mediated metabolism in rat liver and lung, serum enzymatic activities and serum protein levels.

Dimethylphthalate (DMP), dibutylphthalate (DBP) and di(2-ethylhexyl)phthalate (DEHP) were given i.p. (3.8 mM/kg) to Sprague Dawley rats for 5 days. DBP increased significantly the liver concentration of cytochrome P-450, but decreased the lung concentration by about 40%. DBP decreased the lung concentration of cytochrome b5 and NADPH-cytochrome-c-reductase activity by about 30%. Only minor effects were seen after treatment with DMP and DEHP. The direction of B(a)P metabolism was changed and the formation of 2- and 3-hexanol metabolites were increased in liver microsomes after DBP treatment. All phthalate esters decreased the lung metabolism of B(a)P. The cytochrome P-450 enzyme system in the lung was ten times more effective than that in the liver as far as metabolism of n-hexane was concerned. Only minor effects were observed in serum enzyme activities, but a significant decrease in the serum level of albumin was observed after treatment with DBP. No relationship was found between the carbon chain length of the investigated chemicals and effects on microsomal enzymatic activities.

Animals↗