Cascade genetic testing for mismatch repair gene mutations.

Mismatch repair gene mutation carriers have a high risk of developing colorectal cancer, and can benefit from appropriate surveillance. A combined population based ascertainment cascade genetic testing approach provides a systematic and potentially effective strategy for identifying such carriers. We have developed a Markov Chain computer model system which simulates various factors influencing cascade genetic testing; including demographics, uptake, genetic epidemiology and family size. This was used to evaluate cascade genetic testing for mismatch repair gene mutations in theory and practice. Simulations focussed on the population of Scotland by way of illustration, and were based on a 20-year programme in which index cases were ascertained from colorectal cancer cases aged<55 years at onset. Results indicated that without practical barriers to cascade genetic testing, 545 (95% CI=522, 568) carriers could be identified; 42% of the population total. This comprised approximately 140 index cases, 302 asymptomatic relatives and 104 previously affected relatives. However, when realistic ascertainment and acceptance rates were used to inform simulations, only 257 (95% CI=246, 268) carriers, about 20% of the carrier population, were identifiable. Of these approximately 112 were index cases, 108 were asymptomatic relatives, and 37 were previously affected relatives. This contrast emphasises the importance of ascertainment and acceptance rates. Likewise the low number of index cases shows that case identification is a limiting factor. In the absence of robust data from epidemiological studies, these findings can inform decisions about the use of cascade genetic testing for mismatch repair gene mutations.

Double-blind comparison of captopril and enalapril in mild to moderate hypertension.

To compare the antihypertensive and humoral effects of the angiotensin-converting enzyme inhibitors captopril and enalapril, 20 patients with essential hypertension, not receiving treatment for 2 weeks and consuming a prescribed sodium ion intake, were randomly assigned to two parallel, double-blind treatment groups with stratification based on race and untreated seated diastolic blood pressure. These groups received a placebo (day -1) followed by either captopril, 200 mg every 12 hours (n = 9), or enalapril maleate, 20 mg every 12 hours (n = 11), alone (days 1 to 14) and then with hydrochlorothiazide, 25 mg every 12 hours (days 16 to 28). Captopril and enalapril were coadministered alone (day 15) and with hydrochlorothiazide (day 29) to assess whether further decreases in blood pressure would occur. Captopril and enalapril alone caused comparable decreases (p less than 0.05) in the mean 12 hour time-averaged seated diastolic blood pressure from values on day -1 (placebo), on day 1 (11 and 9 mm Hg, respectively) and day 14 (8 and 7 mm Hg, respectively). The addition of hydrochlorothiazide further decreased (p less than 0.05) blood pressure in each group (7 and 8 mm Hg, respectively) from values on day 14. Combined use of captopril and enalapril did not result in further reduction. Coupled with the comparable changes observed in each treatment group in serum angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration, these data support the view that captopril and enalapril have similar antihypertensive effects and mechanisms.

Calcium antagonists in elderly and black hypertensive patients. Therapeutic controversies.

Calcium antagonists are now recommended as monotherapy for the treatment of mild to moderate essential hypertension by the Joint National Committee (JNC) on the Detection, Evaluation, and Treatment of High Blood Pressure. Based on a statement in the 1988 JNC report that black and elderly patients tend to respond better to calcium antagonists, we reviewed the literature to examine the predictive value of age and race to the antihypertensive response of calcium antagonists. The majority of studies we reviewed failed to substantiate the JNC statement and well-promulgated reports in the literature suggesting preferential action of calcium antagonists in the elderly, or their superiority when compared with diuretics, beta-adrenergic blockers, and angiotensin-converting enzyme inhibitors. Although not noted by the JNC, pretreatment blood pressure appeared to be an important predictor of the antihypertensive response to calcium antagonists. The literature reviewed indicates that calcium antagonists have comparable efficacy in black and white hypertensive patients. However, the limited comparative studies reviewed support the JNC statement that, as with diuretics, blacks have a greater antihypertensive response with calcium antagonists than with beta-adrenergic blockers or angiotensin-converting enzyme inhibitors.

Calcium blockers in smooth-muscle disorders. Current status.

Calcium-entry blockers have proven efficacy in a variety of cardiovascular disorders. The effects of these agents on ionic calcium fluxes and, thus, on smooth-muscle contraction suggest that several noncardiac conditions involving smooth-muscle dysfunction may be managed with calcium antagonists. Beneficial therapeutic results have been reported in various forms of hypertension and Raynaud's phenomenon. The results of preliminary studies in treating pulmonary hypertension, cerebral arterial spasm, migraine headache, esophageal motility disorders, and myometrial hypercontractile states are encouraging. Carefully designed, large-scale and long-term clinical trials are needed to establish the therapeutic value of calcium-entry blockers in these disorders.

Low-dose captopril: its use in mild to moderate hypertension unresponsive to diuretic treatment.

The effect of low doses (25 mg three times a day) of captopril was evaluated in 16 patients with mild to moderate essential hypertension, previously uncontrolled by hydrochlorothiazide. After a no-treatment period, mean eight-hour seated diastolic blood pressure (SDBP, mm Hg) was 103 +/- 5 on placebo, 95 +/- 8 after a single dose of captopril, 96 +/- 4 after two weeks of captopril alone, and 90 +/- 6 after its combination with hydrochlorothiazide. Though nine patients had at least a 10% fall in SDBP after the initial dose of captopril, only three had a comparable fall after two weeks; after captopril and hydrochlorothiazide, however, 12 patients had such a response. Captopril decreased mean angiotensin-converting enzyme activity and plasma aldosterone, though to a lesser extent with continued therapy. Because its side effects appear dose related, low doses of captopril combined with a diuretic are effective and may be better tolerated.

Trimethoprim inhibition of the renal clearance of procainamide and N-acetylprocainamide.

To test the effect of trimethoprim (an antibiotic commonly administered with sulfamethoxazole) on the disposition of the antiarrhythmic procainamide hydrochloride and its active metabolite N-acetylprocainamide, 10 healthy men received 1 g of procainamide hydrochloride orally on two occasions, coadministered with placebo or trimethoprim (100 mg twice a day for 2 days before and then 200 mg with the procainamide dose). Trimethoprim decreased the mean (+/- SD) renal clearance by 45% after the dose of procainamide was administered (487 +/- 129 vs 267 +/- 123 mL/min) and that of N-acetylprocainamide by 26% (275 +/- 78 vs 192 +/- 82 mL/min) compared with placebo. The mean area under plasma concentration--time curve 0 to 12 hours after dosing increased 39% for procainamide (19.8 +/- 4.8 vs 27.6 +/- 7.2 mg.h/L) and 27% for N-acetylprocainamide (9.1 +/- 2.1 vs 11.4 +/- 2.8 mg.h/L). The corrected QT electrocardiographic interval at 2 hours after the procainamide dose was 0.40 +/- 0.02 second with placebo and 0.43 +/- 0.03 second with trimethoprim. Trimethoprim may increase procainamide and N-acetylprocainamide plasma concentrations, resulting in increased pharmacodynamic response apparently caused by the competition for renal tubular cationic secretion.

Spironolactone and hydrochlorothiazide in normal-renin and low-renin essential hypertension.

The relative blood pressure response and side effects of spironolactone (S), 400 mg/day, and hydrochlorothiazide (H), 100 mg/day, were evaluated in a double-masked crossed comparison. Subjects were 24 essential hypertensives, 13 normal and 11 with low renin activity. Upright renin levels were determined in the AM after 3 days of moderately low sodium diet (less than 100 mEq/day) and at the end of each drug treatment period. The values were not revealed to one investigator until completion of the study. After 4-week placebo control periods, either S or H was given in divided doses for 6 weeks. Blood pressure measurements and side effects were evaluated at biweekly intervals. The fall in blood pressure from control was the same for each drug and was independent of renin activity. Side effects occurred more often in patients treated with S, and H was judged superior by risk/benefit analysis. We conclude that S is no more beneficial than H in hypertensive patients with either low or normal renin activity but induces a higher incidence of adverse effects in the dose used in this study. We found no evidence for a greater effectiveness of S in low-renin essential hypertension.

Food-induced gastric retention and absorption of sustained-release procainamide.

The relationship between variations in the gastric residence time and the absorption of procainamide from a waxed matrix, sustained-release tablet was evaluated in a repeated-measures study conducted in eight healthy men. Subjects received sustained-release procainamide together with a Heidelberg capsule, alone and with food. Blood and urine samples were collected for up to 24 hours before and after gastric emptying of the Heidelberg capsule for procainamide and N-acetylprocainamide concentration determinations. The gastric residence time of the Heidelberg capsule was prolonged by food (median 3.5 [range 1.5 to 10.0] vs. 1.0 [range 0.5 to 2.5] hours; P less than 0.02). No significant differences (median [range]; fasting vs. fed) in procainamide lag time (0.5 [0.5 to 1.0] vs. 0.5 [0.5 to 1.5] hours) or time at which peak procainamide plasma concentrations occurred (2.9 [1.0 to 4.3] vs. 2.8 [2.0 to 6.0] hours) were evident with feeding. Slight increases in procainamide AUC and peak concentrations occurred with feeding. No alteration in the extent of urinary excretion of procainamide or N-acetylprocainamide occurred with feeding. Thus food did not influence the absorption of sustained-release procainamide despite apparent prolonged gastric retention.

Adrenocortical function after chronic inhalation of fluocortinbutyl and beclomethasone dipropionate.

Fluocortinbutyl (FCB) is a C-21 ester, topically active corticosteroid; no adrenal suppression has been noted after large doses. We compared safety and effects on adrenocortical function of orally inhaled FCB (40 mg/day), beclomethasone dipropionate (BDP) (2 mg/day), and placebo administered in four monitored divided doses for 4 wk by three groups of five healthy men. Circadian plasma cortisol concentration and daily urinary free cortisol excretion were determined before and after 3- and 4-wk exposure. Although pretreatment mean area under the curve (micrograms . hr . dl-1) for plasma cortisol did not differ among groups, mean values after weeks 3 and 4 of treatment were lower (p less than 0.05) in the BDP group (95.1 and 83) than in the FCB (155.8 and 153.7) and placebo (141 and 135.8) groups. Mean urinary cortisol excretion after week 4 for the BDP group (29 micrograms) was less (p less than 0.05) than in the FCB (59 micrograms) and the placebo (69 micrograms) groups. Slopes of individual regression lines noting time trends in plasma and urinary cortisol in the BDP group were negative and less (p less than 0.05) than those of the other groups. A cosyntropin test given intravenously after 4 wk of exposure resulted in similar plasma cortisol responses among groups. No serious adverse effects were noted. Thus after long-term high-dose treatment BDP but not FCB suppressed basal adrenocortical function, but neither suppressed the adrenocortical response to cosyntropin.

Effects of cimetidine and ranitidine on the conversion of prednisone to prednisolone.

Prednisone is a glucocorticoid that must be converted in vivo to prednisolone for pharmacologic activity. We examined the effects of the H2-receptor antagonists cimetidine and ranitidine on the time course of plasma prednisolone concentrations after an oral dose of prednisone. Nine healthy men received each of three oral treatments in a double-blind, balanced, crossover manner: cimetidine (300 mg every 6 hours), ranitidine (150 mg twice a day), or placebo for 4 days, with prednisone (40 mg) taken also on day 4. Serial blood and urine samples were collected for 30 hours after prednisone dosing. Prednisone and prednisolone plasma and urine concentrations were analyzed by HPLC. No differences were found between treatments in the maximum prednisolone plasma concentration, t1/2, apparent volume of distribution, and AUC. Cimetidine reduced the mean (+/- SD) ratio of prednisone dose to the plasma prednisolone AUC (16.6 +/- 2.9 L/hr) below that ratio after ranitidine (19.2 +/- 4.2 L/hr) and placebo (19.3 +/- 2.8 L/hr), and resulted in the lowest fractional excretion of prednisolone in the urine (5.2% +/- 2.2%, 9.8% +/- 4.5%, and 12.4% +/- 4.9%, respectively). The minor alterations in prednisolone kinetics during concomitant cimetidine dosing are not likely to induce clinically significant alterations in steroid effect.

Comparison of oral indacrinone with furosemide.

The oral dose response and time course of action of indacrinone was compared with that of furosemide in six healthy men on a sodium and potassium-controlled diet. The single doses were 5, 10, 20, 40, and 80 mg indacrinone and 20, 40, and 80 mg furosemide. Diuretic, natriuretic, and kaliuretic effects revealed that indacrinone was more potent, had a longer duration of action, and induced a greater sodium for equivalent potassium loss during its period of peak activity than furosemide. During the 8 hr after drug, all doses of indacrinone decreased serum uric acid levels and increased uric acid clearance while furosemide generally increased serum uric acid and decreased uric acid clearance. After 24 hr, serum uric acid and uric acid clearance were the same for the two drugs. A rise in plasma renin activity was observed 2 hr after an 80-mg dose of furosemide but not after indacrinone.

Sulindac disposition when given once and twice daily.

To investigate whether sulindac once daily in the evening might be equivalent to the currently recommended twice-daily dose schedule in sustaining plasma concentrations of bioactive sulfide metabolite, 12 healthy subjects received, in a randomized crossover study, sulindac, 200 mg b.i.d. (at 9:00 A.M. and 9:00 P.M.) and 400 mg once daily (at 9:00 P.M.), each for 7 days. At steady state the area under the plasma concentration-time curve (AUC) over 24 hr for sulfide metabolite was greater after once-daily dosing (112 and 84 micrograms . hr . ml-1, P less than 0.05), while mean trough concentrations did not differ. The greater AUC seemed to be related to diurnal variation in metabolite cumulation. A circadian rhythm was apparent at steady state during twice-daily dosing; the mean AUC and peak plasma concentration (C(max)) were greater between 9 A.M. and 9 P.M. than between 9 P.M. and 9 A.M. (50 and 34 micrograms . hr . ml-1; 6.85 and 4.23 micrograms/ml). Although C(max) values of sulfide were higher after morning doses of sulindac, it was apparent that much of the plasma sulfide after morning doses was actually derived from the previous evening dose. This may be a consequence of circadian rhythm in gallbladder emptying. While renal clearance of sulindac was related to urinary pH, diurnal changes in urinary acidity did not cause the fluctuations in the plasma sulfide. Since once-daily sulindac in the evening is as, if not more, effective than twice-daily drug in sustaining plasma sulfide levels, further studies on the therapeutic efficacy of once-daily dosing are warranted.

Effects of enalapril, a new converting enzyme inhibitor, in hypertension.

The new angiotensin converting enzyme inhibitor enalapril maleate was given in single oral doses of 2.5, 5, and 10 mg to 11 hospitalized patients with uncomplicated essential hypertension who were on a 150-mEq sodium diet. All doses of enalapril induced reduction of mean seated diastolic blood pressure (SDBP). The magnitude of the initial SDBP reduction was not dose related, but the duration of effect was longer (greater than 12 hr) after the 5 and 10 mg. After dosing, mean plasma angiotensin converting enzyme activity (ACE) and aldosterone concentration (PAC) fell, while plasma renin activity (PRA) rose. Serum concentrations of the active diacid from of enalapril increased linearly with dosage; ACE was inhibited maximally at concentrations above 10 ng/ml. During repeated dosing in the outpatient trial there was attenuation of the antihypertensive effect (12 to 24 hr after dosing) in eight of 10 patients. Despite dose increases only two patients achieved SDBP control (less than or equal to 90 mm Hg). In the five patients in whom 50 mg/day hydrochlorothiazide was added near the end of the trail mean SDBP was further reduced. Enalapril was well tolerated. Further studies of the drug, especially in combination with diuretic, are needed.

Pharmacology of enantiomers and (-) p-OH metabolite of indacrinone.

Indacrinone, a racemic mixture, is a loop-blocking diuretic with effects on uric acid elimination that differ from those of furosemide. A series of studies in healthy men was undertaken to characterize the pharmacologic activity of the positive (+) and negative (-) enantiomers (E) of indacrinone and its (-) p-OH metabolite, (-) MET. All subjects were on sodium- and potassium-controlled diet; each experiment was similar in design and included placebo and positive controls. Oral (-)E and (-)MET exerted dose-related natriuretic and diuretic effects; intravenous doses of (-)E were more effective than (-)MET. The effects of (-)E and (-)MET on serum uric acid were the same as those reported with indacrinone. After (-)E, both (-)E and generated (-)MET appeared to contribute to the natriuresis. (+)E induced dose-related decreases in serum uric acid up to 24 hr after dosage; at the higher doses of (+)E, the hypouricemic effects were of the order of those after 500 mg of probenecid. Thus, indacrinone is a novel loop diuretic with enantiomers and a (-)MET, each of which has a different pharmacologic profile.

Clinical applications of angiotensin-converting enzyme inhibitors.

Although only recently introduced, angiotensin-converting enzyme inhibitors have been utilized to treat a wide variety of clinical disorders. Their uses to date, approved by the Food and Drug Administration, have been in the treatment of refractory hypertension and congestive heart failure. However, they have been evaluated with mixed results in numerous other conditions in which the renin-angiotensin-aldosterone system may play a role. Their current status in the treatment of hypertension, congestive heart failure, and these other conditions is reviewed.

Bucindolol, a beta-adrenoceptor blocker with vasodilatory action: its effect in systemic hypertension.

Bucindolol is a newly developed, nonselective beta-adrenergic blocking agent with intrinsic sympathomimetic activity and direct vasodilator properties. In 14 patients with mild to moderate essential hypertension, the effects of bucindolol, hydrochlorothiazide and their combination on blood pressure (BP), heart rate (HR) and parameters of the renin-aldosterone system were compared with those after placebo. Bucindolol's antihypertensive effect was evident within the first hour after drug administration, maximal at 2 to 3 hours, and lasted for as long as 12 hours. Compared with placebo values (108 +/- 5 mm Hg), both bucindolol (97 +/- 9 mm Hg) and hydrochlorothiazide (99 +/- 10 mm Hg) alone significantly and comparably reduced the 12-hour averaged standing diastolic BP, with the combination resulting in approximately additive effects (91 +/- 9 mm Hg). Although bucindolol alone did not affect HR, it attenuated the hydrochlorothiazide-induced increase in HR. There was a tendency for bucindolol to decrease plasma renin activity. Except for transient postural hypotension in 2 patients, bucindolol was well tolerated.

Antihypertensive efficacy of once daily MK-521, a new nonsulfhydryl angiotensin-converting enzyme inhibitor.

The effects of the new nonsulfhydryl-containing oral converting-enzyme inhibitor MK-521 on blood pressure, heart rate, angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration were assessed in 10 hypertensive patients. After a 2-week no-treatment period, patients received placebo and then 14 days each: MK-521 20 mg once daily, hydrochlorothiazide 50 mg once daily and the latter 2 in combination. During the last day of each treatment, the mean (+/- standard deviation) time-averaged (1- to 12-hour) standing diastolic blood pressure decreased from 106 +/- 8 (placebo) to 95 +/- 10 mm Hg with MK-521, 95 +/- 13 mm Hg with hydrochlorothiazide (p less than 0.05 vs placebo) and 88 +/- 11 mm Hg with the combination (p less than 0.05 vs all other treatments). The antihypertensive effect of MK-521 was maintained 24 hours after dosing. Heart rate did not change significantly after MK-521 treatment. MK-521 caused a marked suppression of converting enzyme activity for over 24 hours; plasma renin activity increased significantly after each active treatment and MK-521 significantly decreased the hydrochlorothiazide-induced elevation of plasma aldosterone concentration. In this short-term trial, MK-521 was well tolerated.

In vivo and in vitro inhibition of human histidine decarboxylase by (S)-alpha-fluoromethylhistidine.

Histidine decarboxylase (HDC) activity in Ficoll-Hypaque purified human peripheral blood leukocytes (PBL) was determined by measuring the formation of [3H]histamine from L-[3H]histidine. HDC activity was inhibited in vitro to more than 90% by (S)-alpha-fluoromethylhistidine (alpha-FMH) at concentrations of 10(-5) M and above. Both polymorphonuclear and mononuclear cells possessed HDC activity, but on a per cell basis the former had several-fold higher enzyme activity than the latter. In safety and tolerability studies, alpha-FMH was administered orally to healthy human subjects twice daily for 7 days at doses of 2.5, 10, 50 and 100 mg per person. A dose-dependent inhibition of HDC activity was observed in PBL that were isolated both at 12 hr after administration of the first dose of alpha-FMH and after treatment for 1 week. At the 50 and 100 mg doses of alpha-FMH, there was complete inhibition of HDC activity and partial inhibition at the 10 mg dose. Twenty-four hours after the last dose, HDC activity had recovered to 64-100%, 44-46%, and 30-52% of control values in subjects that received 10, 50 and 100 mg alpha-FMH respectively.

Comparisons of beta-adrenergic blocking properties of S- and R-timolol in humans.

In animals, the R-enantiomer of timolol causes a significant reduction in intraocular pressure but had only 1/80 the activity of the S-enantiomer at extraocular receptors. The beta 1- and beta 2-adrenoceptor blocking properties of orally administered R- and S-timolol were compared in a double-blind placebo controlled trial in two groups of healthy men. Each subject in group A (n = 6) received placebo, 1 and 3 mg S-timolol and 25 and 75 mg R-timolol in random order, group B (n = 5) received placebo, 0.5, and 1 mg S-timolol and 3 and 10 mg R-timolol. In both groups, R- and S-timolol comparably inhibited isoproterenol-induced increases in heart rate (P < .05), forearm blood flow (P < .05, except at 3 micrograms/minute of isoproterenol after the R-doses in group B), and finger tremor (P < .05) in comparison with placebo. The findings for the R-enantiomer in this study were unexpected based on the animal studies and previous studies that demonstrated marked differences in beta blocking effects of other beta-blockers in which the R-enantiomers were less inhibitory.

Antihypertensive response to ketanserin: influence of race and weight.

The antihypertensive effects of the 5-HT2 receptor antagonist ketanserin were evaluated in 16 patients with uncomplicated essential hypertension. Following a three week single-blind placebo treatment period, patients were randomized to receive in a double-blind manner oral ketanserin 20 mg or 40 mg twice a day for 10 weeks. In the racially mixed patient population, mean (+/- SD) seated blood pressure 12 hours after the last dose of placebo was 161 +/- 11/99 +/- 9 mm Hg and 155 +/- 19/98 +/- 10 mm Hg after ketanserin (P greater than .05). Ketanserin 20 mg twice a day did not lower blood pressure significantly. In contrast, 40 mg twice a day significantly decreased systolic blood pressure (P less than .02), and lowered diastolic blood pressure (P = .06). White patients (N = 7) showed a significant decrease in blood pressure (BP) with ketanserin treatment (158 +/- 5/98 +/- 8 vs. 147 +/- 13/92 +/- 6 mm Hg, P less than .05) while black patients (N = 9) did not (165 +/- 13/100 +/- 9 vs. 161 +/- 21/102 +/- 10 mm Hg, P greater than .05). For black patients only, significant correlations were observed between body weight and the change in diastolic BP (r = -.86, P less than .005). The racial difference in response to ketanserin could not be attributed to differences between the two groups in age, sex, body weight, pretreatment blood pressure or ketanserin dose. The nature of the racial difference in the chronic antihypertensive response to ketanserin warrants further evaluation.