The efficacy and safety of ezetimibe/simvastatin combination compared with intensified lipid-lowering treatment strategies in diabetic subjects with and without metabolic syndrome.

AIMS: The objective was to assess the consistency of effect of switching to ezetimibe/simvastatin 10/20 mg versus doubling the baseline statin dose (to simvastatin 40 mg or atorvastatin 20 mg) or switching to rosuvastatin 10 mg across subgroups of subjects with (n = 617) and without (n = 191) metabolic syndrome (MetS). METHODS: This was a post hoc analysis of a randomized, double-blind, 6-week study of adults 18-79 years with cardiovascular disease and diabetes mellitus with low-density lipoprotein cholesterol (LDL-C) ≥70 and ≤160 mg/dl. The percent change in LDL-C and other lipids was estimated within each subgroup separately. Safety and tolerability were assessed. RESULTS: In subjects with MetS, percent changes in LDL-C and other lipids were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin, except high-density lipoprotein cholesterol and apolipoprotein (Apo) AI (mean percent changes in LDL-C were: -22.49% ezetimibe/simvastatin, -9.64% doubled baseline statin and -19.20% rosuvastatin). In subjects without MetS, percent changes in LDL-C, total cholesterol and Apo B were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin (mean percent changes in LDL-C were: -25.14% ezetimibe/simvastatin, -4.75% doubled baseline statin and -19.75% rosuvastatin). Safety profiles were generally similar. CONCLUSION: These results showed that switching to ezetimibe/simvastatin 10/20 mg was more effective at reducing LDL-C, total cholesterol and Apo B versus doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg regardless of MetS status. These results were generally similar to those of the full cohort.

Matrix study of irbesartan with hydrochlorothiazide in mild-to-moderate hypertension.

The purpose of this study was to assess the safety and antihypertensive dose-response effects of irbesartan and hydrochlorothiazide (HCTZ) in patients with mild-to-moderate hypertension. After a 4- to 5-week single-blind placebo lead-in period, 683 patients with seated diastolic blood pressure (SeDBP) between 95 and 110 mm Hg were randomized to receive once-daily dosing with one of 16 different double-blind, fixed combinations of irbesartan (0, 37.5, 100, and 300 mg irbesartan) and HCTZ (0, 6.25, 12.5, and 25 mg HCTZ) for 8 weeks. The primary efficacy variable was the change from baseline in trough SeDBP after 8 weeks of therapy. Data were analyzed by response surface modeling. At Week 8, mean changes from baseline in trough SeDBP (mm Hg) ranged from -3.5 for placebo, -7.1 to -10.2 for the irbesartan monotherapy groups, -5.1 to -8.3 for the HCTZ monotherapy groups, and -8.1 to -15.0 for the combination groups. Irbesartan plus HCTZ produced additive reductions in both SeDBP and seated systolic BP, with at least one combination producing greater BP reduction than either drug alone (P < .001). All treatments were well tolerated; there were no treatment-related serious adverse events. Irbesartan tended to ameliorate the dose-related biochemical abnormalities associated with HCTZ alone. In conclusion, the combination of HCTZ in doses up to 25 mg with irbesartan, in doses up to 300 mg, is safe and produces dose-dependent reductions in BP.

An elective-titration study of the comparative effectiveness of two angiotensin II-receptor blockers, irbesartan and losartan. Irbesartan/Losartan Study Investigators.

This multicenter, randomized, double-masked, elective-titration study was designed to compare the effectiveness, safety, and tolerability of irbesartan and losartan, two angiotensin II subtype AT1-receptor blockers, in the treatment of patients with mild-to-moderate hypertension. After a 3-week, single-masked, placebo lead-in period, 432 patients with a mean seated diastolic blood pressure (SeDBP) of 95 to 115 mm Hg were randomly allocated to receive either irbesartan 150 mg once daily (n = 213) or losartan 50 mg once daily (n = 219). At week 4, if SeDBP at trough (i.e., 24 +/- 3 hours after the previous dose) was > or = 90 mm Hg, the daily dose was doubled (to irbesartan 300 mg or losartan 100 mg). At week 8, if trough SeDBP was > or = 90 mm Hg, hydrochlorothiazide 12.5 mg once daily was added to the regimen; consistent with the prescribing information for losartan, the dose of losartan was reduced to 50 mg once daily on the addition of hydrochlorothiazide. A total of 370 patients (178 irbesartan and 192 losartan) were evaluable for efficacy. The mean change in trough SeDBP at week 8, the primary efficacy end point, was significantly greater in patients receiving irbesartan monotherapy than in those receiving losartan monotherapy (-10.2 mm Hg vs -7.9 mm Hg, respectively). At week 12, reductions in trough SeDBP and seated systolic blood pressure were greater with irbesartan treatment than with losartan treatment (-13.8 mm Hg vs -10.8 mm Hg and -18.0 mm Hg vs -13.9 mm Hg, respectively), and a greater proportion of irbesartan patients responded to therapy (i.e., trough SeDBP < 90 mm Hg or reduction in trough SeDBP > or = 10 mm Hg) compared with losartan patients (78% vs 64%, respectively). Both regimens were well tolerated.

Gastrointestinal absorption of pravastatin in healthy subjects.

The bioavailability of pravastatin, a hypocholesterolmic agent, may be enhanced by decreasing its exposure to stomach contents, where it may be converted nonenzymatically to a relatively inactive metabolite. The pharmacokinetics of pravastatin and its metabolite were determined after infusion of pravastatin directly into the stomach (locus for greatest bioavailability for the metabolite), duodenum (greatest bioavailability for pravastatin), jejunum, or ileum. An enterically coated formulation of pravastatin may increase its bioavailability.

Steady state serum concentrations of pravastatin and digoxin when given in combination.

Pravastatin is an HMG CoA reductase inhibitor used in the treatment of hypercholesterolaemia. The steady state pharmacokinetics of pravastatin (20 mg) and digoxin (0.2 mg) were evaluated in 18 healthy male subjects following the administration of each drug alone or in combination for 9 days. Serum and urine were collected for up to 48 h after the ninth dose in this open, randomized 3-way crossover study. Digoxin concentrations were measured by radioimmunoassay, and pravastatin and its metabolites. SQ 31,906 and SQ 31,945 were measured by GC-MS. Digoxin and pravastatin pharmacokinetics were unchanged following combined administration. Combination therapy with pravastatin and digoxin is unlikely to expose patients to additional risk compared with pravastatin alone.

Analogs of Ac-CCK-7 incorporating dipeptide mimics in place of Met28-Gly29.

A series of analogs of Ac-CCK-7 [Ac-Tyr(SO3H)-Met28-Gly29-Trp-Met-Asp- Phe-NH2, (1)] were prepared in which the Met28-Gly29 dipeptide was replaced by omega-aminoalkanoic acids. Compounds were assessed in binding assays using homogenated rat pancreatic membranes and bovine striatum as the source of CCK-A and CCK-B receptors, respectively, and for anorectic activity after intraperitoneal administration to rats. The analog incorporating 4-aminobutanoic acid (5) was only 8 times less potent than 1 in the pancreatic binding assay, was more potent in the striatal binding assay, and was more potent than 1 in reducing food intake in rats. Using a bioactive cyclic analog of Ac-CCK-7 as a template, several rigid spacers were designed and tested as substitutes for the Met28-Gly29 dipeptide. The analogs incorporating 3-aminobenzoic acid (20) and (1S)-trans-2-aminocyclopentanecarboxylic acid (26) proved highly effective in the binding assays and as anorectic agents. We hypothesize that for stimulation of CCK-A receptors, the main function of the N-terminal tripeptide of Ac-CCK-7 is to orient the tyrosine sulfate with respect to Trp30 and that the bioactive arrangement of these elements lies among those which are readily available to both 20 and 26. NOESY and distance-constrained molecular dynamics experiments carried out on 20 and 26 identified conformations in which the relative orientation of the tyrosine hydroxide and the alpha-carbon atom of tryptophan were similar, providing the basis for further drug design efforts.

Structure activity studies of tryptophan30 modified analogs of Ac-CCK-7.

Cholecystokinin represents a family of gut hormones which among other activities, have been proposed to participate in satiety signaling. Ac-CCK-7[Ac-Tyr(SO3H)-Met-Gly-Trp30-Met-Asp-Phe-NH2 (2)] possesses the full spectrum of activity and potency of the intact hormone; thus analogs of 2 may be useful as anorectic agents. A series of derivatives has been prepared in which the tryptophan indole moiety of 2 has been modified. The new compounds were assayed in CCK binding assays using homogenated rat pancreatic membranes and bovine striatum as a source of CCK-A and CCK-B receptors respectively and in vivo in rats for anorectic activity. Although previous studies have concluded that the indole ring of Trp30 is a critical pharmacophore for the interaction of CCK with both its A and B type receptors, we find 2-Nal30-Ac-CCK-7 (20) to be nearly equipotent to 2 in both CCK binding and as an anorectic agent sensitive to blockade by the Merck CCK-A receptor antagonist MK-329. The extreme structural sensitivity of this anorectic activity is illustrated by the 1-naphthylalanine30 (19) and (benzo[b]thien-2-yl)alanine30 (21) analogs which are 30 and 100 times less potent than 2 respectively. Other mono- and bicyclic Trp30 replacements, including substituted phenylalanines, 3-quinolinylalanine, and 2-(5,6,7,8-tetrahydro)naphthylalanine, gave inactive compounds.

Single-dose pharmacokinetics of pravastatin and metabolites in patients with renal impairment.

The disposition of a single 20-mg oral dose of pravastatin was assessed in subjects with various degrees of renal function. Sixteen subjects (13 males, 3 females) with creatinine clearance values ranging from 15 to 112 mL/min/1.73 m2 completed the study. Area under the serum concentration-time curve, maximum serum concentration, time to maximum serum concentration, terminal serum elimination half-life, apparent clearance, and apparent volume of distribution for pravastatin were not affected by renal impairment, whereas the renal clearance of pravastatin decreased as creatinine clearance decreased (r2 = 0.697, P less than .001). The area under the serum concentration-time curve and time to maximum serum concentration of SQ 31,945 (a hepatic metabolite) increased in patients with renal impairment, whereas the terminal elimination rate constant and renal clearance of SQ 31,945 significantly decreased as a function of creatinine clearance. The renal clearance of another metabolite (SQ 31,906) also significantly declined with decreasing renal function. This single-dose study demonstrates that pravastatin pharmacokinetics were not affected in patients with renal impairment, probably because of its dual route of elimination.

Pharmacokinetic interaction between propranolol and the HMG-CoA reductase inhibitors pravastatin and lovastatin.

1. Single oral 20 mg doses of the HMG-CoA reductase inhibitors pravastatin and lovastatin, with and without concomitant propranolol (40 mg twice daily), were administered to 16 healthy male subjects participating in a randomized, four-way crossover study. 2. Serum concentrations of total and active inhibitors were measured by bioassay and concentrations of pravastatin, two pravastatin metabolites and lovastatin acid were measured by gas chromatography/mass spectrometry. 3. Coadministration of propranolol with pravastatin reduced the mean area under the serum concentration-time curve (AUC) of total inhibitors by 23%, of active inhibitors by 20% and of pravastatin by 16%. 4. Coadministration of propranolol with lovastatin also resulted in decreases in the mean serum AUC of total inhibitors by 18%, of active inhibitors by 12% and of lovastatin acid by 13%. 5. These decreases in systemic drug concentrations may reflect enhanced drug first-pass hepatic clearance in the presence of propranolol. 6. The clinical significance of these changes is likely to be small.

Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects.

The capability of pravastatin and lovastatin, HMG-CoA reductase inhibitors likely to be taken chronically for hypercholesterolemia, to cross the blood-brain barrier was investigated in normal male volunteers. Lovastatin, which is lipophilic, was detected in cerebrospinal fluid (CSF) at concentrations that may have a pharmacologic effect. Pravastatin, which is hydrophilic, was not detected in CSF. It is concluded that pravastatin may have less potential for causing CNS-related side effects than lovastatin.

Carboxylic acids and tetrazoles as isosteric replacements for sulfate in cholecystokinin analogues.

A series of analogues of the satiety-inducing peptide cholecystokinin (CCK-8) was prepared in which the sulfated tyrosine required for activation of peripheral receptors was replaced with a carboxy(alkyl)- or tetrazolyl(alkyl)-phenylalanine to investigate whether an organic acid could serve the role of the sulfate group at the receptor. The necessary intermediates were prepared by previously reported procedures or by alkylation of carboxy(alkyl)- or tetrazolyl(alkyl)phenylmethyl bromides with a glycine-derived anion followed by protecting-group manipulations, and these were incorporated into derivatives of acetyl-CCK-7 using solid-phase synthesis. Peptide analogues were evaluated in a CCK-binding assay for affinity for either peripheral (CCK-A) receptors using homogenated rat pancreatic membranes as the receptor source or for central (CCK-B) receptors using bovine striatum as the receptor source. They were further evaluated for effects on food intake in rats after intraperitoneal (ip) injection. A number of the compounds reported are active in the CCK-A receptor binding assay although less potent than acetyl-CCK-7 and decrease food intake with comparable potency to acetyl-CCK-7. In a meal feeding model designed to assess appetite suppressant activity, acetyl-CCK-7 has an ED50 of 7 nmol/kg ip, while the ED50s of Ac-Phe(4-CH2CO2H)-Met-Gly-Trp-Met-Asp-Phe-NH2 (28) and Ac-Phe[4-(tetrazol-5-yl)]-Met-Gly-Trp-Met-Asp-Phe-NH2 (34) were 9 and 11 nmol/kg ip, respectively. An analogue of 28 lacking the N-terminal acetamido group, 3-[4-(carboxymethyl)-phenyl]propanoyl-Met-Gly-Trp-Met-Asp-Phe-NH2 (50), was also active in the meal feeding assay with an ED50 of 3 nmol/kg ip. Its anorexic effect was blocked by simultaneous administration of the CCK-A receptor antagonist MK 329, indicating that the observed anorexic activity is mediated by CCK-A receptors. We conclude from this work that the requirement for a negative charge at the CCK-A receptor provided in the natural substrate by a sulfate group can be satisfied by organic acids.

Effect of centrally and peripherally administered beta-endorphin on food intake in rats.

A role for beta-EP in the regulation of food intake has been suggested as a contributory factor in the obesity of some genetically obese animal models. Studies undertaken to determine whether continuous administration of beta-EP could alter food intake in normal rats are described. The present studies demonstrated that continuous subcutaneous infusion with beta-EP was ineffective in modulating food intake, but that acute intraperitoneal or intracerebroventricular administration stimulated food intake in previously food deprived or satiated animals, respectively. These results suggest that beta-EP is not involved in the long-term regulation of food intake, but under certain conditions it may play some role in the regulation of individual meals. It is speculated that the latter activity may result from the action of other appetitive regulatory hormones.

Synthesis and biological evaluation of pNPY fragments.

Peptide fragments of pNPY corresponding to the C-terminal segments (13-36) and (25-36), the N-terminal segments (1-12) and (1-24), the segments (6-14) and (7-20), which contain a putative beta-turn, and the internal segments (13-24) and (20-30) were synthesized using solid phase methodology. These fragments were assayed for NPY receptor binding activity in the rat hypothalamus membrane preparation, enhancement of food intake in the rat following ivt administration and inhibition of electrically stimulated muscle contraction in the rat vas deferens. Only the C-terminal fragment (13-36) retained some of the activities of pNPY, appearing to act as a weak agonist, having an additive effect with pNPY on the inhibition of muscle contraction and prolonging the duration of action of pNPY in the feeding assay. It also had considerable alpha-helical character, as did pNPY. None of the other peptide fragments had any agonist or antagonist activity. These results suggest that the expression of full biological NPY activity requires both the C- and the N-terminal segments as well as a putative amphiphilic alpha-helical segment (14-31).

Metabolism of the anti-obesity agent, 4-amino-5-ethyl-3-thiophenecarboxylic acid methyl ester hydrochloride, in rats and dogs.

1. In 24 h, male rats excreted in urine 1% of an intra-gastric 100 mg/kg dose of 4-amino-5-ethyl-3-[4-14C]thiophenecarboxylic acid methyl ester hydrochloride (I) as unchanged I and 59% as 4-amino-5-ethyl-3-thiophenecarboxylic acid (II), mostly conjugated. 2. In rats dosed intra-duodenally with I (50 mg/kg), little I was found in the systemic circulation (less than 2 micrograms/ml) but high concentrations (26 micrograms/ml) were present at five minutes in portal plasma. At five minutes, II was found at 89 and 93 micrograms/ml in systemic and portal plasma, respectively. First-pass ester hydrolysis by the duodenum and liver may explain the near absence of I and the high concentrations of II in systemic plasma. 3. Dogs which received 30 mg/kg 14C-I intra-gastrically, excreted 0.3% I, 30.8% II and 6.8% as 5-ethyl-4-(methylamino)-3-thiophenecarboxylic acid (III), the N-methyl derivative of II. 4. Dogs which received approximately equivalent intra-venous or intra-gastric doses of non-radioactive I and II had high plasma concentrations of II but only small concentrations of I. Plasma concentrations of II after intra-gastric doses of non-radioactive I or II were similar, indicating that both compounds are pharmacokinetically equivalent. I may be a prodrug of II.

Resistance to diet-induced obesity: food intake, pancreatic sympathetic tone, and insulin.

After 15 wk on a moderately high-calorie high-fat (CM) diet, 43% of 40 3-mo-old male Sprague-Dawley rats developed diet-induced obesity (DIO) (29% more weight gain), whereas 57% of diet-resistant (DR) rats gained no more weight than 20 chow-fed controls. When switched to chow for another 7 wk, DR rats ate 13% less, gained 55% less weight, and had 49% lower food efficiency, whereas DIO rats ate 4% less but had comparable weight gain and efficiency to controls. DIO rats had 29% more carcass lipid (percent of carcass weight). DIO rat retroperitoneal white adipose pads had 65% more cells that were the same size as those in chow-fed pads; DR rat cells were similar to controls. Both DR and DIO rats increased norepinephrine turnover in their interscapular brown adipose pads by greater than 90%. DIO rats also had 40% lower pancreatic turnover; their plasma insulin levels were 327% of controls after 15 wk on the CM diet and 188% after 7 wk on chow. DR levels were the same as controls at both times. Therefore, regulation of caloric intake, pancreatic sympathetic tone, and plasma insulin levels were three important differences between rats that resisted and those that developed DIO on high-energy diets.

Infusion of cholecystokinin between meals into free-feeding rats fails to prolong the intermeal interval.

The sulfated octapeptide of cholecystokinin (CCK-8) was infused intraperitoneally into 7 free-feeding male Sprague Dawley rats over a 6-day period. Infusions were given near the end of each free-feeding meal (1.87 microgram/meal/rat), and also during the intermeal interval in gradually increasing doses (0.10-0.63 microgram/5 min/rat). Food intake was continuously monitored and the infusions were controlled by microcomputer. Meal patterns, total food intake, and body weights during drug infusion were compared with data collected during a baseline period when only saline was infused. Meal-contingent CCK-8 infusion produced a significant 29.9% decrease in meal size which persisted throughout the drug-infusion period. Intermeal infusion of CCK-8 failed to prolong the intermeal interval (IMI) but it did initially prevent the compensatory decrease in IMI and increased feeding frequency expected after meal size was reduced. By the last day of drug infusion, total daily food intake recovered to baseline levels due to increased feeding frequency. Body weight was only transiently reduced by CCK-8 infusion. These findings show that tolerance does not develop to the action of CCK-8 to suppress meal size, and the administration of exogenous CCK-8 to free-feeding rats does not persistently prolong the intermeal interval.