Dietary patterns are related to cognitive functioning in elderly enriched with individuals at increased risk for Alzheimer's disease.

PURPOSE: To investigate cross-sectional associations between dietary patterns and cognitive functioning in elderly free of dementia. METHODS: Data of 389 participants from the German DELCODE study (52% female, 69 ± 6 years, mean Mini Mental State Score 29 ± 1) were included. The sample was enriched with elderly at increased risk for Alzheimer's disease (AD) by including participants with subjective cognitive decline, mild cognitive impairment (MCI) and siblings of AD patients. Mediterranean and MIND diets were derived from 148 Food Frequency Questionnaire items, and data-driven patterns by principal component analysis (PCA) of 39 food groups. Associations between dietary patterns and five cognitive domain scores were analyzed with linear regression analyses adjusted for demographics (model 1), and additionally for energy intake, BMI, other lifestyle variables and APOe4-status (model 2). For PCA-derived dietary components, final model 3 included all other dietary components. RESULTS: In fully adjusted models, adherence to Mediterranean and MIND diet was associated with better memory. The 'alcoholic beverages' PCA component was positively associated with most cognitive domains. Exclusion of MCI subjects (n = 60) revealed that Mediterranean and MIND diet were also related to language functions; associations with the alcoholic beverages component were attenuated, but most remained significant. CONCLUSION: In line with data from elderly population samples, Mediterranean and MIND diet and some data-derived dietary patterns were related to memory and language function. Longitudinal data are needed to draw conclusions on the putative effect of nutrition on the rate of cognitive decline, and on the potential of dietary interventions in groups at increased risk for AD.

Effects of nadolol beta-blockade on blood pressure in hypertension.

Nadolol, a nonselective beta adrenoceptor antagonist, was evaluated in 9 normal sybjects with essential hypertension for ability to inhibit exercise-induced changes in double-product (systolic pressure x heart rate). Propranolol and placebo were included as positive and negative controls. The beta antagonists were administered orally in single doses at 10, 20, 40, and 80 mg on a crossover basis. Both nadolol and propranolol induced comparable dose-related inhibition of double-product. Duration of beta receptor blockade was greater with nadolol than with propranolol; significant inhibition of double-product occurred 24 hr after a single 80-mg dose of nadolol. The antihypertensive effect of nadolol was evaluated in another series of 46 subjects with essential hypertension. The dose of nadolol ranged from 80 to 320 mg once daily. Consistent decreases in supine heart rate (20%) and diastolic blood pressure (9%) from baseline were observed. During steady state, the oral daily dose of nadolol was proportional to the minimum steady-state serum concentration (Cmin) of nadolol (r = 0.75, p less than 0.001) obtained just before the next dose of nadolol. Statistically significant correlation was observed between the antihypertensive effect and the Cmin for nadolol (r = 0.45, p less than 0.05).

Sex differences in the intramuscular absorption and bioavailability of cephradine.

Six male and six female volunteers each received a single intramuscular injection of cephradine, a new cephalosporin antibiotic, once weekly for 3 consecutive weeks. The drug was injected into the gluteus maximus, vastus lateralis, or deltoid muscle groups. Injection sites were rotated each week so that each subject received an injection into each muscle. Pharmacokinetic evaluation of serum concentrations and urinary excretion data indicated a sex difference with respect to the rate and extent of cephradine absorption from the three injection sites. Smaller areas under the curve and absorption rate constants were observed for females after injection into each muscle group. The most striking difference was observed when cephradine was injected into the gluteus maximus muscle, where the exponential function describing the alpha phase was observed to be 1.16 +/- 0.17 hr(-1) for females and 2.70 +/- 0.34 hr(-1) for males. Total area under the mean serum concentration-time curves, mean time to peak, and peak height parameters consistent with the slower rate of absorption and lesser bioavailability in females were observed. These results show that the vastus lateralis or deltoid muscle groups are preferable to the gluteus maximus as injection sites because of the more rapid rates of drug absorption from those muscles.

Disposition of captopril in normal subjects.

The disposition of captopril, an angiotensin-converting enzyme inhibitor with antihypertensive properties, was studied in 10 normal male subjects after a single 100-mg tablet of 35S-labeled drug. Average absorption parameters for unchanged captopril in blood were Tmax 0.93 +/- 0.08 hr and Cmax 800 +/- 76 ng/ml. For total radioactivity in blood the values were Tmax 1.05 +/- 0.08 hr and Cmax 1,580 +/- 90 ng/ml (as captopril equivalents). Because of the curvilinearity of the semilogarithmic plots of blood concentrations of captopril:time, elimination half-life (t1/2) of unchanged drug could not be determined. At 1 hr unchanged captopril accounted for about 52% of total radioactivity in blood, and the dimeric disulfide metabolite of captopril accounted for about 10%. In the first 5 days after dosing, an average of about 68% of the radioactive dose was recovered in urine and 18% in feces. The distribution of radioactivity in the first 24-hr urine sample (66% of the dose) was 58% captopril (38% of dose), 2% captopril disulfide (1.5% of dose), and 40% unidentified polar metabolites (26% of dose).

Effect of celiprolol, a new beta 1-alpha 2 blocker, on the cardiovascular response to exercise.

The pharmacodynamics of beta blockade with single oral doses of celiprolol 200 and 400 mg, compared with placebo, atenolol 50 and 100 mg, propranolol 80 and 160 mg, metoprolol 100 and 200 mg, and pindolol 5 and 10 mg, were evaluated in an open, incomplete-block study design employing 11 healthy male volunteers. Each subject received five of the 11 possible treatments at weekly intervals. The maximal rate-pressure product (RPP) induced by standardized treadmill exercise was measured 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours after each treatment. During the course of the exercise test, heart rate and systolic blood pressure were recorded at one-minute intervals for five minutes. The maximal RPP, heart rate, and the maximum change from baseline were calculated for each exercise period. The data were analyzed using absolute reduction and percentage reduction of these parameters. All of the beta blockers tested produced significant decreases (P less than .05) in the exercise RPP, ranging from 16% reduction for celiprolol 200 mg to 47% reduction for propranolol 160 mg at peak response. Celiprolol 400 mg reduced the RPP by 31% at peak effect and did not differ significantly from the other treatments. Celiprolol 400 mg and atenolol 100 mg were the only agents that significantly reduced the RPP 24 hours posttreatment (20.7% and 21.7%, respectively) compared with placebo. Celiprolol 400 mg was the only agent to significantly reduce exercise heart rate 24 hours posttreatment (26.6 beats, P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic studies in patients with nadolol: oral and intravenous administration.

Nadolol-14C, 2,3-cis-5-(3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy)-1,2,3,4-tetrahydro-2,3-naphthalenediol, a nonselective beta-adrenergic blocking agent, was administered orally and intravenously at 2-mg doses to patients with mild cases of essential hypertension. Terminal plasma half-times after oral and intravenous doses were an average of 12.2 and 9.8 hours, respectively. After oral doses, an average of 24.6 and 76.9 per cent of the dose was excreted in urine and feces, respectively, whereas, after intravenous doses, an average of 72.9 and 23.3 per cent of the dose was excreted by the same routes. Calculations of absorption, based on urinary excretion and on areas under the plasma concentration-versus-time curves, indicated that oral doses of nadolol-14C were absorbed to the extent of 33.6+/-2.4 per cent (+/- S.E.). The average overall volume of distribution after intravenous administration was 2.09+/-0.51 1./kg (+/- S.E.), and the average volume of the central compartment was 0.30+/-0.04 1./kg. Only unchanged nadolol-14C was excreted in the urine and feces of patients after either oral or intravenous administration of the drug.

Indapamide, a new antihypertensive/diuretic agent, in the treatment of patients with edema.

A multicenter, double-blind, parallel-group study of 219 patients with pitting edema of various causes was undertaken to determine the efficacy and safety of indapamide, administered orally (PO) in a 2.5-, 5-, or 10-mg once-daily dose, as compared with hydrochlorothiazide, administered PO in a 100-mg once-daily dose. Efficacy was evaluated by determining each patient's weight and degree of pitting edema periodically during 12 weeks of active treatment. Lessening of edema was measured by changes in the depth of pitting in the pretibial area, ten to 14 inches below the patella. The depth of pitting was assigned an arbitrary number between 0 and 4, with 0 equivalent to no edema and 4 equivalent to more than 6 mm of pitting edema. After one week of treatment, the mean reduction of pitting edema from baseline, using the 0 to 4 scale, was 1.6 (30%) in both the indapamide (mean of the three groups) and hydrochlorothiazide groups. There were no significant differences among the three dosage levels of indapamide. After 12 weeks of treatment the mean decrease from baseline was 1.8 (34%), indicating a stable reduction of edema. The mean weight loss at one week was 2.5 kg for the three indapamide groups and 2.6 kg for the hydrochlorothiazide group; this loss was maintained for the 12 weeks of the study. The mean decreases in weight and pitting edema were clinically and statistically significant (P less than 0.05) for both medications.

Multicenter dose-response study of the effect of indapamide in the treatment of patients with mild to moderate hypertension.

This study, carried out in three centers in the United States, investigated the antihypertensive effect of three dosages of indapamide in 87 patients with mild to moderate hypertension. The dosages studied were 1 mg, 2.5 mg, and 5 mg daily. A double-blind, parallel study design was used with a six-week placebo run-in period followed by an eight-week treatment period and a two-week follow-up period. Compared with placebo, all dosages caused a significant decrease (P less than 0.05) in blood pressure, with an average decrease of approximately 6 mmHg diastolic and 13 mmHg systolic. The antihypertensive effect seemed to be fully manifest after six weeks of treatment. At all dosage levels, indapamide produced markedly greater therapeutic success rates than did the placebo. Success was defined as either a standing phase-5 diastolic blood pressure of less than 90 mmHg or a decrease by at least 10 mmHg from baseline. Although the decrease in mean serum potassium concentration was dose-related, the decrease was not clinically significant with any dose. A reduction in serum chloride and increases in serum uric acid and glucose were also observed. These changes were slight and did not cause the discontinuation of treatment for any patient. The most frequently observed side effects were mild to moderately severe dizziness, weakness, and headaches.

Indapamide in the stepped-care treatment of obese hypertensive patients.

A double-blind study was carried out in obese patients with moderately severe hypertension to assess the efficacy and tolerability of 2.5 mg indapamide as a once-a-day Step 1 drug compared to 50 mg hydrochlorothiazide also as a once-a-day Step 1 drug; to assess the efficacy and tolerability of a fixed daily dose of 2.5 mg indapamide administered concomitantly with methyldopa starting at 500 mg daily; and to compare the findings of efficacy and tolerability of 2.5 mg indapamide daily with those of 50 mg hydrochlorothiazide daily as Step 1 agents when methyldopa is the Step 2 drug. Twenty-nine patients completed the study and were evaluated. Nine patients achieved the study criterion of reduction of average standing diastolic pressure to 90 mmHg or less when treated with Step 1 medication only. Twenty patients required the addition of methyldopa to their Step 1 medication: 10 patients took 2.5 mg indapamide with an average constant daily dose of 1100 mg methyldopa and 10 patients took 50 mg hydrochlorothiazide with an average constant daily dose of 1575 mg methyldopa to achieve blood pressure control. All groups had mean diastolic pressure controlled at or below the 90 mmHg criterion during the period of constant methyldopa dosage for those patients who required Step 2 therapy. There were no significant differences between groups with respect to diastolic pressure during the constant dosage period. The indapamide patients required significantly (p less than 0.05) less methyldopa than did the hydrochlorothiazide patients in order to maintain satisfactory control of diastolic blood pressure. The number of responders was greater in the 2.5 mg indapamide + methyldopa group than it was in the 50 mg hydrochlorothiazide + methyldopa group, and responses were achieved more rapidly in the former group than in the latter. Indapamide (2.5 mg per day) was effective and well tolerated when used alone or as Step 1 medication in combination with methyldopa as Step 2 medication, and it compared favourably in this regard with hydrochlorothiazide.

Multi-centre clinical investigation of indapamide in the United States: a review.

Indapamide, a new indoline antihypertensive agent, has been the subject of a worldwide programme to develop this drug for general clinical use. The results are described of the multi-centre U.S. clinical programme demonstrating the effectiveness and tolerance of indapamide for the treatment of hypertension. All work was conducted under U.S. Federal Food and Drug Administration guidelines, and resulted recently in a New Drug Application. A total of 1891 subjects or patients participated in 27 separate studies conducted by 91 investigators. In controlled clinical trials comparing 2.5 mg indapamide once daily with 50 mg hydrochlorothiazide once daily for 40 weeks in patients with mild to moderate essential hypertension, indapamide produced a reduction of supine blood pressure of -9.5/-14.3 mmHg as compared with -7.6/-11.4 mmHg for hydrochlorothiazide. In combination with methyldopa, propranolol, clonidine, guanethidine and hydralazine, indapamide consistently produced a greater decrease in arterial pressure than did those agents given alone. Indapamide added to these step-care agents did not result in a meaningful increase in adverse reactions. Indapamide has been the subject of a long-term safety study in which over 100 hypertensive patients have been followed up for 2 years or longer. During this period of time, indapamide was well tolerated and remained effective. No biochemical, electrocardiographic or ophthalmological changes were associated with its use. Other studies with indapamide are discussed describing the systemic and renal haemodynamic effects, pharmacokinetic properties and special safety studies conducted with this agent. The use of indapamide in patients with hepatic or renal impairment is reviewed in detail.

Cephradine and epicillin in body fluids of lactating and pregnant women.

The passage of two antibiotics, cephradine and epicillin, into the milk of 12 lactating women and the amniotic fluid of 48 pregnant women was investigated. All women were given a 500-mg capsule every six hours for at least two days prior to our taking multiple biologic samples from them. Constant levels of both antibiotics were reached in the milk of lactating women as well as in the amniotic fluid of mid-term and full-term pregnant women during the sample period. The ratio of drug concentrations in serum to that in milk was about 5.0 for each antibiotic. In the midtrimester women, the ratio of concentrations in serum to amniotic fluid of both antibiotics was approximately 1.0, suggesting the development of an equilibrium between these two compartments. This ratio was 0.2 for both drugs in the full-term women, demonstrating that the antibiotics concentrated in the amniotic fluid compartment.

Endocrine and cardiovascular consequences of angiotensin converting enzyme inhibition.

One of several novel peptidic inhibitors of angiotensin converting enzyme (CEI) has been studied intravenously both in normal male volunteers and severely hypertensive patients without any clinically significant adversity or intolerance. Hypertensive patients experienced a significant yet gradual reduction in resting arterial pressure without hypotension. The addition of a diuretic agent was observed to potentiate this antihypertensive effect. Normal, sodium replete volunteers received this nonapeptide intravenously in doses up to 2-0 mg/kg without any significant cardiovascular effect. Both patients and normal subjects exhibited reversible dose related increases in angiotensin I and renin levels after receiving the peptide. The plasma renin response to tilting was also potentiated by CEI. These findings suggest that intravenous CEI may be of value in the treatment of severely elevated hypertension and as a tool to evaluate vasoconstrictor and volume factors in hypertension.

Chlorthalidone-triamterene: a potassium-sparing diuretic combination for the treatment of oedema.

The efficacy of a once-daily combination of chlorthalidone 50 mg plus triamterene 50 mg or chlorthalidone 100 mg plus triamterene 100 mg was compared to that of chlorthalidone 50 mg or 100 mg. This double-blind study was carried out in eighty-eight patients over a treatment period of 12 weeks. All patients entered the active medication period of 12 weeks after a placebo run-in period of 3 to 7 days, during which pretibial or malleolar pitting oedema averaging 2 to 4 mm developed. All patients started at the lower doses, i.e. forty-one started on chlorthalidone 50 mg plus triamterene 50 mg and forty-seven started on chlorthalidone 50 mg. The protocol provided for doubling the dose (but not for reducing it thereafter) at any time during the 12-week period when control of oedema was deemed inadequate. Eight of the combination therapy patients and sixteen of those on chlorthalidone required the higher doses. By Week 12, 96% of the chlorthalidone plus triamterene patients and 100% of the chlorthalidone patients had shown a reduction of at least 2 mm in depth of pits, and 92% and 72%, respectively, had complete disappearance of oedema. The decreases in pitting oedema were paralleled by mean weight losses of 2.4 kg and 3.1 kg, respectively, for the combination treatment group and the chlorthalidone group. Average serum potassium levels throughout the 12-week treatment period were 3.70 mEq/L for the patients taking the combination compared to 3.41 mEq/L of those taking chlorthalidone.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy of a potassium-sparing combination of chlorthalidone and triamterene in the control of mild and moderate hypertension. I.

Chlorthalidone 25 mg/triamterene 50 mg in once-daily oral doses was as effective in reducing blood pressure as chlorthalidone 25 mg alone. The decrease in serum potassium was statistically significantly less with the combination than for chlorthalidone. There were no notable differences between the treatments in any other measure of laboratory safety or adverse reactions.

The efficacy of a potassium-sparing combination of chlorthalidone and triamterene in the control of mild and moderate hypertension. II.

Chlorthalidone 50 mg/triamterene 50 mg in once-daily oral doses was as effective in reducing blood pressure as chlorthalidone 50 mg alone. The decrease in serum potassium was statistically significantly less with the combination than for chlorthalidone. There were no notable differences between the treatments in any other measure of laboratory safety or adverse reaction.

Pharmacokinetics and clinical pharmacology of indapamide.

Indapamide is a new antihypertensive diuretic agent indicated for the treatment of hypertension and edema. Indapamide shows an alteration in vascular reactivity to calcium and other agonists, suggesting the possibility of a direct vascular effect. The drug is recommended in doses of 2.5 to 5 mg once a day. It is rapidly and completely absorbed from the gastrointestinal tract, resulting in maximal blood levels in approximately 2.3 hours. Coadministration of indapamide with food or antacids does not reduce bioavailability. Linear proportionality of blood concentration with increasing doses is evident following both single and multiple doses. Other pharmacokinetic parameters are not dose related. Indapamide is widely distributed in the body with extensive binding to erythrocytes. Binding to plasma proteins is approximately 76%. Disappearance of indapamide from the blood is biphasic, with a terminal half-life of approximately 16 hours. Renal clearance represents less than 10% of the total systemic clearance of the parent drug, showing the dominant role of hepatic clearance. Studies of 14C-labeled indapamide in humans demonstrate that 70% of the radioactivity is excreted in urine and 23% in feces. Indapamide is extensively metabolized; less than 7% of the dose is excreted in urine as unchanged compound. Studies of patients with renal impairment showed little or no accumulation of indapamide in the blood in comparison to patients with normal renal function. Clinical studies demonstrate that indapamide has diuretic properties. Free water clearance studies indicate a site of action in the cortical diluting segment of the distal tubules. No adverse effect of indapamide on renal function is evident in normal volunteers, hypertensive patients, or geriatric hypertensive patients, as determined by glomerular filtration rate or effective renal plasma flow. Hemodynamic studies of indapamide in patients with mild to moderate hypertension show a significant (p less than 0.05) decrease in mean blood pressure (16%) and total peripheral resistance (15%). No other significant hemodynamic effects are evident. The data suggest that indapamide may produce antihypertensive activity through a dual mechanism of action--diuretic and direct vascular. Additionally, it appears to be safe even for patients with impaired renal function.

Elimination of nadolol by patients with renal impairment.

1 Nadolol excretion was studied in 24 patients with chronic renal failure. 2 The amount of nadolol excreted during the 120-h period after receiving the drug ranged from less than 1% in functionally anephric, patients up to 11.5% in patients with average creatinine clearance of 57.9 +/- 3.6 ml/min/1.73 m2. 3 Renal clearance of nadolol was found to correlate with creatinine clearance; nadolol elimination is retarded in patients with renal failure. 4 Nadolol serum half-life is prolonged in proportion to the remaining renal function. Therefore, dosage intervals in renal patients receiving nadolol should be adjusted to creatinine clearance. 5 Haemodialysis effectively reduced serum concentration of the drug; it may therefore be a useful therapy for drug intoxication.