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.

Wernicke-Korsakoff syndrome in head injury: a missed insult.

A survey of the use of thiamine in patients at risk from Wernicke-Korsakoff syndrome (WKS) in Scottish specialist neurosurgical units, and a 2-year retrospective study of 218 at-risk patients admitted to a regional neurosurgical unit with a head injury were undertaken. Although responses to the survey indicated otherwise, the study revealed that there was no consistent practice regarding thiamine administration. Overall, 20.6% of patients received thiamine, with an alcohol history being the only factor correlating with thiamine administration. Of known alcoholics and heavy drinkers, 56.1% and 26.2% respectively received thiamine as in-patients; 44.5% of patients received additional carbohydrate loads in the form of i.v. dextrose or parenteral nutrition, but only 28.9% of these received thiamine as well. Although the actual thiamine status of these patients was not known, given the difficulties of diagnosing WKS in the presence of a head injury, the conclusion is that written protocols are needed in units to ensure that head injury patients at risk of WKS receive appropriate thiamine treatment or prophylaxis.

Thiamine deficiency in head injury: a missed insult?

Practice regarding the use of thiamine in head-injured patients at risk of Wernicke-Korsakoff syndrome in Scottish neurosurgical units was surveyed by questionnaire and revealed no clear policy. A 2 year retrospective study of 218 admissions to one of these units of patients who had taken alcohol shortly before sustaining head injury is also described. The minority (20.6%) of the total had been given thiamine, with just over half (56.1%) of those categorized as alcoholic receiving this treatment. Additional carbohydrate loads, in the form of i.v. dextrose or parenteral nutrition, had been given to 44.5% of patients and only 28.9% of this group had also been given thiamine. The dose and duration of thiamine given was inadequate in most cases. It is suggested that failure to ensure that head injury patients at risk of Wernicke-Korsakoff syndrome receive appropriate thiamine prophylaxis represents a missed and treatable additional insult to the damaged brain.

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.

Bioavailability of fluvoxamine given with and without food.

The influence of concomitant food intake on plasma concentrations of the antidepressant drug fluvoxamine maleate was investigated in a two-way, crossover study design. Eight male and four female healthy, young volunteers received a single oral dose of fluvoxamine maleate (50 mg, tablet) on two occasions: after an overnight fast and immediately after a breakfast. Food did not affect maximum fluvoxamine plasma levels (Cmax), or the time to reach Cmax (tmax). The plasma AUC of fluvoxamine was on average 7 per cent lower in the fed than in the fasted state. It is concluded that the effect of food on the pharmacokinetics of fluvoxamine is negligible.

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.

Characterization of dexamethasone binding in normal and uremic human serum.

The purpose of this study was to examine the extent and linearity of dexamethasone binding over a wide concentration range in normal and uremic serum. Tritiated dexamethasone was added to both untreated and charcoal-treated pooled normal serum and to pooled uremic serum to produce concentrations similar to those attained therapeutically (10-1000 ng/mL). Protein binding was determined by equilibrium dialysis at 37 degrees C. Dexamethasone serum binding was linear over the entire range of concentrations for each set of pooled serum. The mean (+/- SD) percent bound (mean +/- SD) for dexamethasone was similar for untreated (75.1 +/- 3.6 percent) and charcoal-treated (77.3 +/- 3.5 percent) normal serum. Dexamethasone binding (69.2 +/- 1.8 percent, p less than 0.05) and serum albumin concentrations (39.9 vs. 55.1 mmol/L) were significantly less in uremic vs. normal serum, respectively. These results suggest that (1) the binding of dexamethasone is linear and occurs primarily to albumin, with little or no binding to corticosteroid-binding globulin; (2) endogenous cortisol does not compete with dexamethasone for protein binding sites; and (3) steroid pharmacokinetics may be altered in uremic patients due to the 24 percent higher free fraction of dexamethasone in this population.

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.

Ranitidine-induced changes in the renal and hepatic clearances of procainamide are correlated.

Ranitidine, procainamide and its active N-acetyl metabolite (NAPA) are renally secreted bases which can compete for carrier-mediated transport processes. The effect of ranitidine on the disposition of procainamide and NAPA was evaluated in 13 healthy men. Subjects were randomized to receive p.o. procainamide (1000 mg) alone (base line) and after p.o. ranitidine, 150 mg twice a day for 4 days. Blood and urine samples were collected at frequent intervals for 24 hr after the procainamide dose. There were no significant differences in the mean pharmacokinetic parameters of procainamide and NAPA after ranitidine coadministration compared to base line. However, individual changes did occur and regression analysis revealed a correlation between base-line procainamide renal clearance (CLR) and the change (delta) in CLR after ranitidine (r = 0.69, P less than .01). Subsequently, individuals were separated into Group I (n = 7) if they had a decrease or Group II (n = 6) if they had an increase in procainamide CLR after ranitidine. Mean +/- S.D. base-line procainamide CLR was 539 +/- 114 ml/min for Group I vs. 410 +/- 61 ml/min for Group II (P less than .01). During ranitidine coadministration, Group I had a 23% decrease in mean procainamide CLR (P less than .05), whereas Group II had a 21% increase (P less than .05). There were no significant differences in the metabolic clearance (CLM) of procainamide between the two groups at base line. However, Group I had a 45% increase (P less than .01) whereas Group II had a 41% decrease (P less than .05) in mean procainamide CLM with concomitant ranitidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of once-daily captopril or enalapril in mild essential hypertension.

The purpose of this study was to assess the effect of a daily low dose of the angiotensin-converting enzyme (ACE) inhibitors, captopril or enalapril, in mild essential hypertension. Nine men with seated diastolic blood pressure between 95 and 104 mm Hg on placebo participated in the study. After one month of placebo, captopril 25 mg was administered; blood pressure, heart rate, ACE activity and plasma renin activity were measured hourly for 4 hours. Each patient then received captopril 50 mg once daily for 8 weeks and similar measurements were made 24 hours post-dose every 2 weeks. After another month of placebo, the identical protocol was repeated after enalapril 5 mg. Although blood pressure and ACE activity decreased significantly (P less than 0.05) within 2-4 hours of the acute doses of each inhibitor, neither captopril or enalapril produced significant reductions 24 hours after the small daily dose. Thus, neither ACE inhibitor alone was adequate to control blood pressure in mild hypertension when given once daily during 8 weeks of treatment.

Effect of repeated doses of L-5-hydroxytryptophan and carbidopa on prolactin and aldosterone secretion in man.

To evaluate changes in serum prolactin and plasma and urine aldosterone after a serotonergic challenge, 8 healthy men (19 to 42 yr), taking dexamethasone (0.75 mg qid), received the serotonin precursor L-5-hydroxytryptophan (L5HTP; 100 mg qid) with the peripheral decarboxylase inhibitor carbidopa (C; 50 mq qid) or matching placebos in a randomized, crossover manner. Serum prolactin concentration increased in all subjects after L5HTP/C in comparison to placebo, mean (SD) prolactin (ng/ml) at 8 h after dosing was 19.8 +/- 6.3 after L5HTP/C and 12.0 +/- 3.1 after placebo (p less than 0.05). In contrast, in comparison to values on placebo, L5HTP/C had no apparent effect on mean plasma concentration at all observation times; mean (SD) aldosterone (ng/dl) at 8 h after dosing was 12.0 +/- 5.1 and 12.0 +/- 3.8 after placebo (NS). Mean (SD) urinary aldosterone (micrograms/24 h), Na+(mEq/24 h) and K+(mEq/24 h) excretion were 7.0 +/- 4.4, 49.3 +/- 30.6, 30.1 +/- 11.2, after L5HTP/C and 7.4 +/- 5.8, 59.7 +/- 23.9, 33.3 +/- 7.4 after placebo (NS). Under these study conditions, subacute serotonergic stimulation with oral L5HTP/C resulted in prolactin but not aldosterone release.

Angiotensin-converting enzyme inhibitors: mechanistic controversies.

Many studies have investigated the mechanisms responsible for the therapeutic effects of the angiotensin converting enzyme inhibitors. Initially, the hemodynamic changes that occur with these agents were attributed solely to the inhibition of the renin-angiotensin-aldosterone system in plasma. Further research suggested other mechanisms were operable as a relationship was not always evident between hemodynamic changes and inhibition of the plasma renin-angiotensin-aldosterone system. A relationship between the pharmacodynamics of these agents and the inhibition of vascular and tissue renin-angiotensin systems, however, has been observed. Mechanisms less likely to contribute to the actions of the angiotensin converting enzyme inhibitors are increases in bradykinin and prostaglandin concentrations, or inhibition in the renin-angiotensin system within the central nervous system. Ancillary cardiovascular effects of angiotensin converting enzyme inhibitors offer possible new therapeutic gains. An understanding of these mechanistic controversies and newly-defined cardiovascular actions of angiotensin converting enzyme inhibitors are important to clinicians using these agents.

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.

Angiotensin-converting enzyme inhibitors.

There is convincing evidence that ACE inhibitors, alone or in combination with a diuretic, effectively lower blood pressure in patients with all grades of essential or renovascular hypertension and that they are of particular benefit as adjunctive therapy in patients with congestive heart failure. The hemodynamic, hormonal and clinical effects of the presently available ACE inhibitors, captopril and enalapril, are comparable and their side effect profiles are extremely favorable. One important difference between the two oral ACE inhibitors, however, is their pharmacokinetics; enalapril's action is slower to begin and is of longer duration. Compared with other agents, ACE inhibitors offer important advantages, among them an improved feeling of well being. It is, therefore, expected that ACE inhibitors will gain greater acceptance by patients and physicians in the future.

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.

Hemodynamic effects during rest and exercise of bucindolol in hypertensive men.

Bucindolol is an investigational beta-adrenergic blocking agent with intrinsic sympathomimetic and vasodilatory activity in animals. In a double-blind, six-way, crossover study of six mild-to-moderate hypertensive men, the effects of bucindolol 100, 200, and 300 mg/d on resting blood pressure, heart rate, forearm blood flow, and vascular resistance measured by pneumoplethysmography, and blood pressure and heart rate after cycle and handgrip exercise were compared with those of propranolol 160 and 320 mg/d and placebo after q12h administration for five doses. Both bucindolol and propranolol significantly suppressed heart rate after cycle exercise in comparison with placebo (-33 to -48 beats/min), demonstrating beta blockade. Suppression of resting heart rate by propranolol (-20 beats/min) was significantly (P less than .05) greater than bucindolol (-7 to -8 beats/min); a similar treatment difference in heart rate was noted after handgrip exercise (-18 to -19 vs -1 to -8 beats/min, respectively). Bucindolol and propranolol decreased resting blood pressure to the same extent (in comparison with placebo; P less than .05 at peak activity, 2 hr postdose). Bucindolol tended to increase forearm blood flow and decrease forearm vascular resistance (P less than .05 at 4 hr postdose) in comparison with placebo. The effect of propranolol on forearm blood flow and forearm vascular resistance was not significant compared with placebo. These data are consistent with intrinsic sympathomimetic and vasodilatory activity of bucindolol in hypertensive men.