Effects of an 11ß-hydroxysteroid dehydrogenase type 1 inhibitor, MK-0916, in patients with type 2 diabetes mellitus and metabolic syndrome.

AIM: We examined the effects of the 11ß-hydroxysteroid dehydrogenase type 1 (HSD1) inhibitor, MK-0916, on the multiple components of the metabolic syndrome (MetS) in patients with type 2 diabetes (T2DM) and MetS. METHODS: This was a 12-week, multicentre, randomized, double-blind, placebo-controlled study. Patients with T2DM (mean baseline A1C: 7.3%) and National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)-defined MetS were randomized 1 : 1 : 1 : 1 to 0.5, 2 or 6 mg/day MK-0916 or placebo. The primary efficacy endpoint was a change from baseline at week 12 in fasting plasma glucose (FPG). Secondary endpoints included glycosylated haemoglobin A(1c) (A1C), 2-h postprandial glucose (2-h PPG), body weight, waist circumference, blood pressure and lipid profile. RESULTS: Treatment with MK-0916 had no significant effect relative to placebo on FPG at week 12. Compared to placebo, 6 mg MK-0916 produced a modest, significant (p = 0.049) reduction in A1C of 0.3% at week 12, but no significant difference was observed in 2-h PPG. Six milligram MK-0916 increased LDL-C relative to placebo by 10.4% (p = 0.041). Treatment with MK-0916 led to modest dose-dependent decreases in blood pressure and body weight. Overall, MK-0916 was generally well tolerated. MK-0916 produced mechanism-based activation of the hypothalamic-pituitary-adrenal axis, resulting in mean increases in adrenal androgen levels that remained within the normal range at all doses tested. CONCLUSIONS: Inhibition of HSD1 with MK-0916 was generally well tolerated in patients with T2DM and MetS. Although no significant improvement in FPG was observed with MK-0916 compared to placebo, modest improvements in A1C, body weight and blood pressure were observed.

The efficacy and safety of miglitol therapy compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone.

OBJECTIVE: To compare the therapeutic effects of the alpha-glucosidase inhibitor miglitol (BAY m 1099), the sulfonylurea glibenclamide, and placebo on parameters of metabolic control and safety in patients with NIDDM that is inadequately controlled by diet alone. RESEARCH DESIGN AND METHODS: After a 4-week placebo run-in period, 201 patients in 18 centers in 4 countries were randomized in a double-blind manner to miglitol (50 mg t.i.d., followed by 100 mg t.i.d.), glibenclamide (3.5 mg q.d/b.i.d.), or placebo for 24 weeks. Efficacy criteria were changes from baseline of HbA1c, fasting and postprandial blood glucose and insulin levels, body weight, and serum triglycerides. RESULTS: Efficacy was assessed in 119 patients who completed the full protocol, and the results were similar to those obtained in 186 patients who fulfilled the validity criteria for analysis. Compared with placebo, mean baseline-adjusted HbA1c decreased by 0.75% (P = 0.0021) and 1.01% (P = 0.0001) in the miglitol and glibenclamide treatment groups, respectively. Blood glucose decreased slightly in the fasting state and considerably in the postprandial state in both treatment groups but not in the placebo group. Fasting insulin levels increased slightly (NS) in all treatment groups; however, postprandial insulin levels decreased with miglitol, while increasing markedly with glibenclamide (P = 0.0001 between all treatment groups). Gastrointestinal side effects (flatulence and diarrhea) occurred mostly in the miglitol-treated patients, while some glibenclamide-treated patients had symptoms suggestive of hypoglycemia. CONCLUSIONS: Miglitol monotherapy is effective and safe in NIDDM patients. Compared with glibenclamide, it reduced HbA1c less effectively and caused more gastrointestinal side effects. On the other hand, glibenclamide, unlike miglitol, tended to cause hypoglycemia, hyperinsulinemia, and weight gain, which are not desirable in patients with NIDDM.

Long-term titrated-dose alpha-glucosidase inhibition in non-insulin-requiring Hispanic NIDDM patients.

OBJECTIVE: To assess the long-term safety and effectiveness of a titrated dose of the alpha-glucosidase inhibitor miglitol (BAY m 1099) in Hispanic NIDDM patients. RESEARCH DESIGN AND METHODS: A 1-year double-blind randomized placebo-controlled study in which diet-treated or diet plus sulfonylurea-treated Hispanic NIDDM patients received either placebo (n = 131) or miglitol in doses of 50, 100, 150, 200 mg t.i.d. (n = 254), up-titrated and down-titrated based on tolerability. Efficacy parameters included changes from baseline in HbA1c, fasting and 2-h postprandial plasma glucose and serum insulin, fasting serum lipids, and urinary albumin-to-creatinine ratio (ACR). Safety assessments consisted primarily of tabulation of adverse events and intercurrent illnesses, and of periodic laboratory determinations. RESULTS: Reductions from baseline in HbA1c levels at the 6-month (primary efficacy) endpoint were significantly greater by 0.83% in the miglitol group than in the placebo group. HbA1c reductions in the miglitol treatment group significantly exceeded those in the placebo group by 0.63, 0.73, and 0.92% at 3, 9, and 12 months of treatment, respectively. Reductions in 120-min postprandial glucose and insulin levels were significantly greater in the miglitol group than in the placebo group at all postbaseline visits. There was little difference between treatments for changes in fasting insulin or lipid levels. Miglitol-associated reductions versus placebo in fasting plasma glucose (P = 0.0587 at 6 months) and in ACR (P = 0.0541 at 1-year) were nearly statistically significant. These efficacy results were not notably different between the 6-month endpoint, at which time the mean miglitol dose was 100 mg t.i.d., and the 1-year visit, when the mean miglitol dose was 149 mg t.i.d. Notable adverse events seen significantly more often in the miglitol group than in the placebo group were flatulence and diarrhea (or soft stools). The incidence of these gastrointestinal adverse events appeared to be dose dependent. CONCLUSIONS: Miglitol treatment of non-insulin-requiring Hispanic NIDDM patients at doses from 50 to 200 mg t.i.d. produced statistically and clinically significant reductions of HbA1c, primarily associated with reduction of glucose and insulin levels in the postprandial period, which were sustained over a year of treatment. Adverse events related to the drug's mechanism of action were common, but generally well tolerated. Doses above 100 mg t.i.d. were not associated with notably enhanced efficacy in most patients.

Chronic treatment of African-American type 2 diabetic patients with alpha-glucosidase inhibition.

OBJECTIVE: To evaluate the long-term efficacy, safety, and tolerability of the alpha-glucosidase inhibitor miglitol in the treatment of African-American patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 345 African-American type 2 diabetic patients (mean age 55.6 years, BMI 31.9 kg/m2, duration of diabetes 4.9 years, baseline HbA1C 8.7%) treated with either diet alone or sulfonylurea were randomized to 1 year of double-blind treatment with either placebo (n = 117) or miglitol (n = 228) at doses of 50 or 100 mg t.i.d., titrated based on tolerability. The primary efficacy criterion was change from baseline in HbA1C at the 6-month visit. Secondarily efficacy parameters included changes from baseline in plasma glucose and serum insulin (both fasting and 120 min after a standardized test meal), fasting lipids, and urinary albumin-to-creatinine ratio. Safety and tolerability evaluations were primarily based on reporting of adverse events and symptoms and on periodic laboratory analyses. RESULTS: Miglitol treatment was associated with a mean placebo-subtracted reduction in HbA1C from baseline of 1.19% at 6 months. Fasting and 120-min postprandial plasma glucose levels were reduced in parallel to HbA1C, in association with miglitol treatment. Significant reductions versus placebo in 120-min postprandial insulin levels, in LDL cholesterol, and in fasting triglycerides, were also seen in the miglitol group at individual study time points. Softer, more frequent stools and flatulence were significantly more common in the miglitol group. Urinary tract infections, hematuria, and herpes simplex infections were significantly more common in the placebo group. CONCLUSIONS: Miglitol treatment appears to be at least as efficacious in the African-American type 2 population as in the U.S. type 2 population at large, with comparable tolerability. alpha-Glucosidase treatment may be an important therapeutic option in these patients in view of their greater risk for microvascular complications and the accumulating body of evidence that better glucose control reduces the risk of these complications.

Erythrocyte membrane transport in hypertensive humans and rats. Effect of sodium depletion and excess.

Sodium transport by erythrocyte membranes was studied in hypertensive and normotensive humans and in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The rate constants of sodium efflux were increased in both hypertensive humans and rats, and this increase was due mostly to an increase in the ouabain-resistant component of efflux. Both the furosemide-sensitive and furosemide-resistant components of efflux were increased. The ouabain-sensitive efflux was also increased, as confirmed by the ouabain-sensitive rubidium influx in rats. In rats, the intracellular sodium content was also increased in the SHR with respect to the WKY. The transport abnormalities of red cell membrane associated with hypertension were similar in humans and rats. In rats, sodium depletion failed to affect the transport abnormality, while sodium load made the difference in transport between SHR and WKY undetectable. Cross-incubation experiments, using plasma and erythrocytes of WKY and SHR, are more suggestive of a flux abnormality that is intrinsic to the cell membrane than of one that is humoral in nature.

Lymphocyte membrane sodium-proton exchange in spontaneously hypertensive rats.

The sodium-proton exchange activity was determined in lymphocytes of spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), and domestic Wistar rats. Uptake of sodium was determined by measuring the osmotic swelling of lymphocytes after activation of the exchanger by suspension of the cells in sodium propionate and consequent intracellular acidification by the permeant weak acid. Fractional swelling (mean +/- SEM) in 16 SHR and 16 WKY was 0.44 +/- 0.03 and 0.35 +/- 0.02, respectively (p less than 0.01). The swelling was partially inhibitable by amiloride and, at 10(-4) M concentration, the amiloride-sensitive swelling was 0.21 +/- 0.02 in SHR and 0.11 +/- 0.01 in WKY (p = 0.001). Progressive extracellular ion substitutions of chloride for propionate or of potassium for sodium showed that the exchange activity was related linearly to cellular acidification; however, the dependence on extracellular sodium displayed saturation characteristics, with the same apparent Km for cells from SHR and WKY and a Vmax of 0.54 +/- 0.03 for SHR and 0.39 +/- 0.02 for WKY (p less than 0.002). External lithium could replace sodium on the exchanger but abolished the differences between strains. Results in the domestic Wistar rats were similar to those of WKY. These results suggest that lymphocytes of the SHR have a greater capacity for sodium uptake through the sodium-proton exchanger, as compared with normotensive strains. If shared by other cells, such an increased capacity could have a pathophysiological role in genetic hypertension. In particular, its presence in proximal renal tubular cells would support the hypothesis of a primary role for the kidney in the pathogenesis of genetic hypertension.

Toxic interaction between acetazolamide and salicylate: case reports and a pharmacokinetic explanation.

Two elderly patients, who were chronically receiving aspirin, developed lethargy, incontinence, and confusion after dosing with acetazolamide. Unbound plasma acetazolamide concentrations were elevated and plasma protein binding was reduced, suggesting an interaction with aspirin. In vitro studies demonstrated a concentration-dependent effect of salicylate on acetazolamide binding to serum proteins. At a therapeutic serum acetazolamide level of 8.0 micrograms/ml, the unbound percentage of acetazolamide in serum was 3.3% and increased to 11.0% and 30.0%, with serum salicylate levels of 200 and 386 micrograms/ml, respectively. Furthermore, the apparent association constant of acetazolamide for binding to serum proteins was decreased by 58% and 86% of its control value at these respective salicylate concentrations. The maximal binding capacity of serum for acetazolamide was not affected by salicylate. Pharmacokinetic studies in four volunteers showed that the plasma protein binding and renal clearance of acetazolamide were significantly reduced during chronic salicylate dosing. Salicylate appears to competitively inhibit the plasma protein binding of acetazolamide and simultaneously to inhibit acetazolamide renal tubular secretion. Caution is advised when acetazolamide and salicylate are used concurrently.

Internal potassium balance and the control of the plasma potassium concentration.

The plasma potassium concentration is determined both by external potassium balance and by the distribution of potassium between extracellular and intracellular fluid compartments, i.e., "internal potassium balance." Whenever external potassium balance is altered, the resultant change in the plasma potassium concentration is strongly influenced by concomitant alterations in internal potassium balance. Several factors alter internal potassium balance independently of changes in external balance. Acid-base disturbances produce shifts of potassium into or out of cells, but attempts to quantify these effects are not likely to be clinically useful. Hypertonicity produces a shift of potassium out of cells. Several hormones (insulin, aldosterone, catecholamines, glucagon, and growth hormone) may have roles in internal potassium balance. Digitalis and succinylcholine, by producing efflux of potassium from cells, may cause hyperkalemia. Potassium is released from skeletal muscle during exercise, causing an increase in the plasma potassium concentration. The periodic paralyses are associated with well-defined transient alterations in internal potassium balance.

Cellular mechanism of action of loop diuretics: implications for drug effectiveness and adverse effects.

The loop diuretics inhibit a transport system that moves sodium, potassium and chloride across cell membranes of many tissues, including the thick ascending loop of Henle. This inhibitory effect is responsible for their natriuretic effect. Of the agents available for clinical use, bumetanide is the most powerful; it has an in vitro transport inhibitory potency and an in vivo natriuretic effectiveness that is approximately 50-fold that of furosemide. This increased potency and the consequent decreased dose requirement give bumetanide the potential for increased effectiveness and decreased incidence of adverse effects.

Increased platelet membrane sodium-proton exchange rate in spontaneously hypertensive rats.

It has been proposed that increased Na-H exchange activity is involved in the pathophysiology of genetic hypertension. We studied platelets of spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto (WKY), and domestic Wistar rats (DWR), since platelets have similarities to smooth muscle cells and have been shown to have potentially related ion metabolism abnormalities, such as increased intracellular calcium activity. We determined the exchange rate by the intracellular acidification-dependent, extracellular sodium-dependent volume increase. The rate of increase during the first 3 min is linear and is shown to be higher in SHR (0.475 X min-1) than in WKY (0.410 X min-1) or DWR (0.389 X min-1). We conclude that the Na-H activity is increased in platelets of SHR. Similar findings in lymphocytes and neutrophils of SHR, and analogous findings in platelets of humans with essential hypertension, suggest that this abnormality is expressed by several cell types, some of which may be involved in the pathophysiology of genetic hypertension in both rats and humans.

A comparison of once-daily atenolol and metoprolol using office and ambulatory blood pressure monitoring.

The authors compared the relative safety and efficacy of changing treatment from once-daily atenolol to metoprolol in patients with essential hypertension. A parallel-group randomized clinical trial was conducted in two phases: a 4-week baseline single-blind phase using atenolol 50 mg, followed by a 4-week randomized double-blind treatment phase using either atenolol 50 mg or metoprolol 100 mg administered once daily at noontime. Patients with well-controlled hypertension already prescribed 50 mg of atenolol (with or without the addition of a diuretic) for control of hypertension were selected for participation from the outpatient hypertension clinic of the Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania. Seated blood pressure (BP) and pulse were obtained during the baseline phase and during the randomized treatment phase. Twenty-four-hour ambulatory BP monitoring was performed once during the baseline phase and once during the randomized treatment phase, near the end of each 4-week period. There were no within- and between-treatment differences in office systolic and diastolic BP. There was a slight increase in pulse (average = 5.2 beats/minute; P = .02) for those participants treated with metoprolol. For within-treatment groups, the ambulatory BP data showed no significant differences in systolic and diastolic BPs, except for an increase in morning diastolic BP for those randomized to metoprolol (average = 6.2 mm Hg; P = .01). For between-treatment groups, the metoprolol arm had a higher morning systolic BP (P = .01), a higher morning diastolic BP (P = .03), and a higher nighttime heart rate (P = .01).(ABSTRACT TRUNCATED AT 250 WORDS)

The safety and efficacy of once-daily nifedipine coat-core in combination with atenolol in hypertensive patients. Adalat CC Cooperative Study Group.

The efficacy and safety of once-daily nifedipine coat-core when added to a regimen of atenolol (ATN; 50 mg/day) were compared with ATN and placebo in 251 patients with essential hypertension in this 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Mean net reductions (ATN effect subtracted) in supine diastolic blood pressure at endpoint were 7.9 mmHg, 9.4 mmHg, and 9.9 mmHg at 30, 60, and 90 mg/day of nifedipine coat-core, respectively, and 4.1 mmHg on ATN+placebo. Beyond the first week of double-blind therapy, all reductions produced by nifedipine coat-core combined with ATN were statistically significant (P < 0.05) compared with ATN+placebo. On ambulatory blood pressure monitoring, trough-to-peak ratios of the change in diastolic blood pressure for the 30, 60, and 90 mg/day doses were 41%, 68%, and 78%, respectively. Adverse events were generally mild or moderate and most reflected the vasodilatory properties of nifedipine (eg, edema, headache). Nifedipine coat-core, when combined with ATN in patients not controlled by ATN alone, had significant antihypertensive activity for the entire 24-hour dosing interval and was well tolerated by the majority of patients in the study.

The efficacy and safety of once-daily nifedipine coat-core in the treatment of mild-to-moderate hypertension. Adalat CC Cooperative Study Group.

The efficacy and safety of once-daily nifedipine coat-core, a new, extended-release formulation, were examined in 245 patients with essential hypertension in this 10-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Mean net reductions in trough supine diastolic blood pressure at endpoint were 6.5 mmHg, 7.7 mmHg, and 11.7 mmHg at 30, 60, and 90 mg/day of nifedipine, respectively. All reductions were statistically significant, compared with placebo. Trough-to-peak ratios for supine diastolic blood pressure change following the 30, 60, and 90 mg/day doses were 49%, 67%, and 61%, respectively. Adverse events were generally mild or moderate, and most reflected the vasodilatory properties of the drug (eg, headache, edema). Reports of adverse events decreased as treatment progressed. The nifedipine coat-core tablet provided good control of blood pressure for the entire 24-hour dosing interval and was well tolerated by the majority of patients in the study.

Effect of potassium removal during hemodialysis on the plasma potassium concentration.

The effect of potassium removal by hemodialysis on the plasma potassium concentration (PK) was observed during 20 studies on 7 anuric patients. The following was observed: (1) The pattern of change in PK is consistent with at least a two-compartment distribution; hence, in contrast to urea, PK shows a marked postdialytic rebound and the simple equation for solute removal from a single pool cannot predict postdialysis PK. (2) The magnitude of the fall in PK correlated with the predialysis PK; this was not only due to increased potassium removal, but also due to a dependence of the apparent volume of distribution of potassium on the state of potassium balance. The fractional decrement in plasma potassium concentration, contrary to that of urea, is a function of predialysis concentration, and prediction of the effect of dialysis on plasma potassium concentration can assume neither a single pool nor a constant distribution volume for this ion.

Presence of sodium transport inhibiting factor in dog plasma during volume expansion.

Plasma dialysates from volume-expanded dogs (E) were compared directly to dialysates from the same dogs when hydropenic. In a double-blind study, E caused relative inhibition of short-circuit current in toad urinary bladder. We therefore confirm the presence of a sodium transport inhibiting factor in plasma of volume-expanded dogs.

Dependence of the driving force of the sodium pump on rate of transport.

The driving force for active transport of Na+ in the isolated toad bladder, ENa, was measured as the reciprocal slope of the change in conductance with change in short-circuit current after stimulation with antidiuretic hormone. The base-line short-circuit current was altered by change in ambient Na+ concentration or addition of amiloride, maneuvers which alter availability of Na+ at the site of active transport. In the absence of a chemical gradient for Na+ across the bladder, ENa was found to be inversely related to the rate of Na+ transport, a finding incompatible with the simple electrical analogue that has been proposed for the system. The results provide additional support for the view that ENa measured in this way has both energetic and kinetic components.

The disposition of intravenous potassium in normal man: the role of insulin.

1. Potassium infusion causes an increase in immunoreactive insulin levels in dogs, but either a small (30%) or no increase in humans. Since insulin stimulates the uptake of K+ by cells, a regulatory role for K+-induced insulin release has been postulated. To study the role of insulin in regulating cellular K+ uptake, six fasting normal volunteer subjects underwent two K+ infusions on separate days. Both infusions delivered 0.6 mmol h-1 kg-1 for 3 h. In one subject glucose was simultaneously infused at 0.67 mmol h-1 kg-1 (a rate known to increase peripheral insulin levels by 40-100%); the other infusion contained no glucose. 2. Plasma insulin levels did not increase during the glucose-free infusions. During glucose-containing infusions, insulin levels were 40% higher than those during glucose-free infusions. Despite this, neither urinary potassium excretion nor the increment in plasma K+ concentration or the calculated cellular K+ uptake differed significantly during the 3 h of glucose-free and glucose-containing infusions respectively. 3. These data do not support the view that potassium-induced insulin secretion regulates cellular potassium uptake within the physiological range of plasma K+ concentration.

Inverse changes in erythroid cell volume and number regulate the hematocrit in newborn genetically hypertensive rats.

Erythrocytosis and microcytosis have been described in strains of genetically hypertensive rats and in essentially hypertensive humans. Published discussion of these phenomena has centered around their relationship to observed alterations in ionic transport and the pathogenesis of hypertension. In presenting data for another strain of spontaneously hypertensive rats in which these findings are exhibited, we note that erythroid cell size decreases concurrently with the increase in cell numbers so that the hematocrit and the mean corpuscular hemoglobin concentration remain constant. Data from the literature support the hypothesis that erythroid cell size is inversely proportional to cell count in a large number of species. Erythrocytosis, as it develops in the neonatal rat, is a consequence of the marked immaturity of this species at birth. Erythrocytosis in the spontaneously hypertensive rat is not due to a difference in the affinity of its hemoglobin for oxygen or to significant tissue anorexia. Microcytosis in the spontaneously hypertensive rat is the consequence of a continuation of the linear volume decrease with age of its erythroid cells seen in the normotensive animals and may be accounted for by the production of smaller cells with concomitant regulation of individual cell volume.