Pravastatin Sodium Research Articles

後発医薬品の生物学的同等性試験における試験間差

The equivalencies of generic drugs are assessed by biological equivalency tests. These tests are conducted on healthy subjects by the crossover method in comparison with the original product, which makes them a useful method for comparing bioequivalencies among generics. However, since a large variation in the results is sometimes observed, we decided to determine what causes this.We requested 28 companies to provide biological equivalency test results for pravastatin sodium tablet (23 products) and compared pharmacokinetic parameters among them. There was a large variation in pharmacokinetic parameters, especially in maximum serum drug concentration, area under the serum concentration to time curve and elimination half-life, though there were no differences between the original product and generic product in each test.On comparing individual parameters from two tests that were carried out according to nearly the same protocol, there was a marked difference in the distribution of data among subjects, indicating that this was a factor causing parameter differences between tests. Thus, when pharmacists are thinking of using a generic drug, it is important for them to notonly consider average parameter values but also the process by which these values have been obtained.

Additive benefits of pravastatin and aspirin to decrease risks of cardiovascular disease: randomized and observational comparisons of secondary prevention trials and their meta-analyses.

In randomized trials of secondary prevention, pravastatin sodium and aspirin reduce risks of cardiovascular disease. Pravastatin has a predominantly delayed antiatherogenic effect, and aspirin has an immediate antiplatelet effect, raising the possibility of additive clinical benefits. In 5 randomized trials of secondary prevention with pravastatin (40 mg/d), comprising 73 900 patient-years of observation, aspirin use was also prescribed in varying frequencies, and data were available on a large number of confounding variables. We tested whether pravastatin and aspirin have additive benefits in the 2 large trials (Long-term Intervention With Pravastatin in Ischaemic Disease trial and the Cholesterol and Recurrent Events trial) that were designed to test clinical benefits. We also performed meta-analyses of these 2 trials and 3 smaller angiographic trials that collected clinical end points. In all analyses, multivariate models were used to adjust for a large number of cardiovascular disease risk factors. Individual trials and all meta-analyses demonstrated similar additive benefits of pravastatin and aspirin on cardiovascular disease. In meta-analysis, the relative risk reductions for fatal or nonfatal myocardial infarction were 31% for pravastatin plus aspirin vs aspirin alone and 26% for pravastatin plus aspirin vs pravastatin alone. For ischemic stroke, the corresponding relative risk reductions were 29% and 31%. For the composite end point of coronary heart disease death, nonfatal myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or ischemic stroke, the relative risk reductions were 24% and 13%. All relative risk reductions were statistically significant. More widespread and appropriate combined use of statins and aspirin in secondary prevention of cardiovascular disease will avoid large numbers of premature deaths.

Pravastatin potentiates the anticoagulant effects of low molecular weight heparin

Introduction: Statins have been shown in randomized trials to reduce coronary events independent of baseline LDL-C level. In the case of pravastatin sodium (PS), there is conflicting evidence as to what is the actual mechanism of its non-lipid lowering beneficial effects. Because pravastatin has been found to prolong the clotting time in vitro, we conducted a study to determine if pravastatin plus low molecular weight heparin (LMWH) would result in a synergistic effect on the in vitro clotting time, thus supporting the hypothesis that pravastatin exerts antithrombotic effects through reduction of fibrin formation. Materials and methods: Aliquots of PS were combined with dalteparin, a LMWH, in 500 μl of human whole blood. The clotting time in seconds was analyzed on a Sonoclot® Coagulation Analyzer, a miniviscometer that is sensitive to early fibrin generation. Results: PS and LMWH, each resulted in a significant prolongation of the clotting time compared with control. The combination of PS and LMWH resulted in a significantly prolonged clotting time compared with either given alone. All values were significantly different from each other ( p<0.05). Our results showed that the combination of PS and a LMWH prolongs the clotting time to a significantly greater degree when compared to either administered alone. Conclusions: The synergistic effect of PS and LMWH on prolongation of the clotting time suggests that PS exerts its effect by inhibition of the coagulation cascade and fibrin formation.

ＨＭＧ‐ＣｏＡ還元酵素阻害薬ｐｒａｖａｓｔａｔｉｎ ｓｏｄｉｕｍ後発医薬品の医薬品添付文書における薬物動態情報のあり方に関する研究

The pharmacokinetic information provided in the package insert of the original pravastatin sodium product and the package inserts of 22 pravastatin sodium generics was examined. Pharmacokinetic parameters had been determined following the oral administration of 10 mg of pravastatin sodium. Package inserts were examined to see if all parameters were given or not and the ratios between the individual pharmacokinetic parameters of the original product (Op) and those of the generic products (Gp) were calculated using the formula PPr=Gp/Op (PPr= pharmacokinetic parameter ratio).While the package insert of the original product gave values for all of the pharmacokinetic parameters, i.e., Cmax, Tmax, T1/2, and AUC, the package inserts of only 10 of the 22 generic products had values for all four parameters. The PPrs of the generic products were 2.63 ± 0.61, 1.03 3.61 (mean ± S.D., min-max) for Cmax, 0.55 ± 0.09, 0.45-0.80 for Tmax, 1.98±0.78, 0.89-3.92 for T1/2, and 2.95±1.10, 1.25-5.23 for AUC.Though these results show that the generic products are definitely bioequivalent to the original product, many of them fall outside the acceptability limits (0.8-1.25) for bioequivalence when only the information in their package inserts is compared. Therefore, the package inserts of generic products should specify the name and manufacturer of the reference product used in the bioequivalence studies and also give the pharmacokinetic parameters determined for it. This information will make the package inserts of generic products more useful.

ＨＭＧ−ＣｏＡ還元酵素阻害剤におけるジェネリック医薬品の情報量の評価

The establishment in 2002 of additional remuneration for the use of branded generic drugs in medical treatment has led to an increase in their use. However, debate continues on various issues, a major one the availability of drug information (DI) on such products, since DI is such a vital component in all assessments of the safety and effectiveness of pharmaceuticals. We therefore conducted an objective evaluation of the adequacy of DI on branded generic forms of pravastatin sodium and simvastatin, using the media of drug package inserts and interview forms.On a scale setting the amount of DI provided for the original drugs at 100, the quantities of DI available for generic pravastatin sodium and simvastatin were 34.1±11.0% (Mean±SD) and 37.3±12.2% (Mean±SD), respectively. Comparison of the amounts of DI available at present with those at the time the original drugs first appeared on the market showed increases of 39.4 % for pravastatin sodium and 47.1% for simvastatin.The branded generic forms of the drugs considered in this study have only recently become commercially available. So, information gained through experience of using such drugs in the clinical setting hereafter will be incorporated into future package inserts and interview forms, providing healthcare professionals with fuller descriptions of their uses, interactions, and adverse reactions.

沖縄県における高脂血症用剤の処方せん発行実態調査

We investigated the characteristics of hypolipidemic drug use at hospitals in Okinawa. We constructed a drug information database for prescriptions issued by 5 hospitals with over 300 beds in Okinawa (Okinawa Hokubu Hospital, Okinawa Chubu Hospital, Urasoe General Hospital, University of the Ryukyus Hospital and Okinawa Kyodo Hospital). A total of 16, 250 prescriptions was issued by the 5 hospitals from June 1 to 7, 1999 and among them 999 (6.1%) were for hypolipidemic drugs.Hypolipidemic drugs comprised the highest proportion of prescriptions in the 65-74 years age group and in the 45-84 years age group they accounted for 92.9% of the total. By chemical structure, HMG-CoA reductase inhibitors were prescribed the most among hypolipidemic drugs and nicotinic acid derivatives came second, followed by fibrates and probucol. In terms of individual drugs, pravastatin sodium was most prescribed and then came simvastatin, tocopherol, nicotinate, bezafibrate and probucol in that order. These five drugs accounted for more than 95% of all prescriptions. As for prescriptions for combinations of hypolipidemic drugs, the combination of HMG-CoA reductase inhibitors and fibrates accounted for about 25%. Since such combinations are contraindicated in principle, particular attention should be paid to adverse effects. Looking at combinations of hypolipidemic drugs and other drugs, the most frequently prescribed other drug type was vasodilators, followed by antipyretic analgesics, antihypertensive agents, peptic ulcer drugs, and antidiabetic drugs.

Cholestasis associated with the use of pravastatin sodium

celecoxib (a cytochrome P450 2D6 inhibitor) at a constant dose between Days 1 and 95, and meropenem (not a documented cytochrome P450 2D6 inhibitor) between Days 51 and 95. These patterns of administration suggest that neither of these drugs had a significant effect on perhexiline concentration. On the other hand, the laboratory evidence of a marked inhibition of perhexiline metabolism during treatment with citalopram suggests that caution is required when prescribing citalopram (or any other SSRI) for a patient taking perhexiline.

Pravastatin sodium, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, decreases serum total cholesterol in Japanese White rabbits by two different mechanisms

Pravastatin sodium (pravastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), when orally administered to male Japanese White (JW) rabbits at 1–30 mg/kg for 21 days, decreased the concentrations of total cholesterol, low density lipoprotein (LDL)-cholesterol and high density lipoprotein (HDL)-cholesterol in a dose-dependent manner. On the other hand, pravastatin did not change the concentration of serum triglycerides and very low density lipoprotein (VLDL)-cholesterol. On day 21, LDL-cholesterol was significantly decreased at doses higher than 3 mg/kg, whereas HDL-cholesterol was significantly reduced at doses higher than 10 mg/kg. The concentrations of hepatic LDL receptor proteins determined by immunoblot analysis increased at the same dose at which the concentrations of LDL-cholesterol decreased. The serum concentrations of HDL-cholesterol were decreased at the same dose at which VLDL-cholesterol secretion rates from the liver were reduced. The present study suggests that in JW rabbits , pravastatin decreases the serum concentration of LDL-cholesterol through an LDL receptor pathway, whereas the agent lowers the concentration of HDL-cholesterol by the mechanisms associated with a reduction of VLDL-cholesterol secretion from the liver.

Influence of high cholesterol diet and pravastatin sodium on the initiation of liver regeneration in rats after partial hepatectomy

OBJECTIVES: Liver regeneration is influenced by cholesterol and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA-reductase). HMG-CoA-reductase is a key enzyme for cholesterol synthesis. Recent studies have shown that inhibitors of HMG-CoA-reductase improve liver functions after 67% partial hepatectomy (PH). METHODS: Male Wistar rats (W) and Prague hereditary hypercholesterolemic rats (PHHC) were used. Aqua pro injectione (AI) or pravastatin (prava; 1 mg/kg) was administered orally once daily. Group 1: W, standard diet (SD) + AI; group 2: W, SD + prava; group 3: W, cholesterol-enriched diet (chol) + AI; group 4: PHHC, chol + AI; group 5: PHHC, chol + prava. After 27 d, PH was performed in all groups. RESULTS: Groups fed chol before PH had significantly higher liver triacylglycerol content (group 3: 25.8 ± 2.6 mg/g of liver weight; group 4: 16.0 ± 1.0 of liver weight; group 5: 22.0 ± 1.0 of liver weight) than did the groups fed SD (group 1: 6.1 ± 0.5; group 2: 5.9 ± 0.7). Liver DNA synthesis after PH was significantly lower in chol-fed groups (group 3: 561 ± 78; group 4: 472 ± 92) than in SD-fed groups (group 1: 1645 ± 574; group 2: 2935 ± 1298), except the chol-fed PHHC given prava (group 5: 3230 ± 527). CONCLUSIONS: In prava-treated rats, the induction of HMG-CoA activity overcame the inhibitory capability of pravastatin. The induction of HMG-CoA-reductase activity had a stimulatory effect on the initiation of liver regeneration.

Potency of select statin drugs in a new mouse model of hyperlipidemia and atherosclerosis

Poloxamer-407 (P-407) is a nonionic surfactant that induces atheroma formation in the aortas of C57BL/6 mice with long-term (14 weeks) administration. The objectives of the present study were to determine the mechanism(s) responsible for the induction of hypercholesterolemia as well as to determine whether this animal model may be of potential use in rank ordering the efficacy (lipid lowering) of various statin drugs. The effect of long-term (16 weeks) administration of P-407 on the catalytic activities of rate-limiting enzymes of cholesterol biosynthesis [HMG-CoA reductase (HMGR)] and catabolism [microsomal cholesterol 7α-hydroxylase (C7αH) and mitochondrial sterol 27 hydroxylase (S27H)] was assessed in C57BL/6 mice. Effects of P-407 on these enzymes were compared in mice fed an atheroma-inducing diet (high-cholesterol, supplemented with cholic acid) and animals maintained on a basal diet and injected with saline (controls) after 16 weeks. The mean value for the activities of C7αH in P-407-injected mice was 24.3±3.8 pmol min −1 mg −1 and was significantly ( P<0.05) less than the mean value determined for sham-injected control animals (37.0±14.3 pmol min −1 mg −1). In contrast, the mean values for the catalytic activities of S27H and HMGR did not change with P-407 administration. Neither C7αH nor S27H activity in mice fed the high-cholesterol diet differed from values for control animals, whereas the mean HMGR activity was drastically reduced (−94%, P<0.05). The hypercholesterolemic effect of P-407 is not due to altered cholesterol biosynthesis, but is mediated by reduced cholesterol catabolism due to decreased activity of the rate limiting enzyme (C7αH) in the classic bile acid synthetic pathway. Plasma triglyceride lowering resulting from the oral administration of equal doses of various statin drugs appeared, in general, to be positively correlated with their relative aqueous solubility and paralleled the efficacy of these agents to lower low-density-lipoprotein-associated cholesterol (LDL-C) in humans. The plasma triglyceride lowering effect of the five statin drugs tested produced the following rank order; pravastatin sodium (−44%)>atorvastatin calcium (−36%)>simvastatin (−33%)>lovastatin (−25%)>fluvastatin sodium (−19%). While reductions in plasma total cholesterol following administration of the statin drugs was not as profound as that observed with triglycerides, the relative rank order or trend was preserved. The percent reduction in plasma triglycerides in the present model appears to be a useful parameter with which to predict the relative reduction in plasma LDL-C expected for these agents in humans.

Use of the statins in patients after acute myocardial infarction: does evidence change practice?

To compare the use of lipid-lowering agents in 42 628 elderly patients (aged > or =65 years) after acute myocardial infarction, before and after the publication of the Scandinavian Simvastatin Survival Study (4S), using the Ontario Myocardial Infarction Database. Multivariate regression models were created to estimate changes in the rate of statin use over time in monthly cohorts of elderly patients after acute myocardial infarction in Ontario from April 1, 1992, to March 31, 1997. Changes in the rate of statin use over time were estimated using patient and prescriber characteristics. We found a 3.6-fold significant increase in the monthly rate of statin use after the publication of 4S compared with before the publication of 4S (P<.001); specifically, the rate of increase in simvastatin and pravastatin sodium use was higher after the publication of 4S (P<.001 for each). Before the publication of 4S, the rate of increase in statin use in younger patients (aged 65-74 years) was 2.7 times higher than in older patients (aged > or =75 years) (P =.02), while after the publication of 4S, the rate of increase in statin use was only 1.8-fold higher in the younger group (P<.001). After the publication of 4S, there was a 1.6-fold higher rate of increase in statin use in male compared with female patients (P =.006). Also after the publication of 4S, specialists (cardiologists and internists) had a 2-fold higher rate of increased use of the statins than did generalists (P<.001). It is possible to shift practice if the evidence of benefit is strong, the intervention is easy to implement, and the intervention is marketed aggressively.

Lipid-Lowering Therapy and Coagulation/Fibrinolysis Parameters in Patients on Peritoneal Dialysis

Patients on continuous ambulatory peritoneal dialysis (CAPD) often have abnormalities of lipid metabolism or coagulation and fibrinolysis, these patients may thus be more susceptible to atherosclerosis than those on hemodialysis. It has been reported that hypercoagulability and hyperfibrinolysis are correlated with abnormalities of lipid metabolism. Therefore, we investigated the effect of a decrease in lipids on the coagulation and fibrinolysis system in CAPD patients with hyperlipidemia who received lipid-lowering therapy. The patients included 5 men and 13 women, with a mean age of 52.5 years. Pravastatin sodium (10 mg/day) and ethyl icosapentate (1800 mg/day) were administered concomitantly for 8 weeks. Lipid levels and coagulation/fibrinolysis parameters were measured before and after therapy. The patients were divided into two groups depending on their response to therapy: responders showed a decrease in total cholesterol or triglycerides by at least 20% and non-responders showed less improvement. In the responders, the levels of protein C, tissue plasminogen activator/plasminogen activator inhibitor-I complex, factor XIII, alpha2-plasmin inhibitor, and D-dimer were significantly lower after therapy than before therapy. Protein C, factor XIII, and alpha2-plasmin inhibitor were also significantly decreased after therapy in non-responders, but the extent of the decrease was smaller. The plasminogen level was significantly increased after therapy in non-responders. These findings suggest that a decrease in lipid levels and/or some other action by lipid-lowering agents may correct abnormalities of coagulation and fibrinolysis in CAPD patients.

処方せんデータベースを活用した高尿酸血症治療薬の処方実態調査 薬剤の適正使用に関する考察

In order to study the proper use of urate-lowering drugs, we searched and analyzed a recently established database of 151, 804 community pharmacy records for the one-year period ending in August 1997. A total of 5, 312 prescriptions for typical urate-lowering drugs, allopurinol and benzbromarone, were searched. The number of male patients was found to be approximately 6.5 times that of females (578 and 89, respectively). The average age was 59.8 years (range 15 to 90 years). Of the 5, 312 prescriptions examined 81.4% were for allopurinol, 17.1% for benzbromarone and 1.5% for both. The number of prescriptions for allopurinol was approximately 4.5 times greater than that for benzbromarone. Hyperuricemia is classified into three types. The first type, includes patients who under-excrete uric acid, occurs in approximately 55% of patients. Uricosuric drugs such as benzbromarone are considered to be the drugs of choice. The second type, consists of over-producers of uric acid, occurs in approximately 10% of patients. The third type, comprising a mixed category, accounts for the remaining 30%. Allopurinol is recommended for the latter group of both under-excreters and over-producers. Given this classification, benzbromarone should thus be prescribed on a relatively frequent basis.The average number of drugs per prescription was 5.9 (range 1 to 25 drugs) thus indicating that patients with hyperuricemia tend to be prescribed multiple-drug regimens. From the analysis of concomitant drugs, it was found that the most frequently prescribed drug was furosemide (22.4%), followed by nifedipine sustained-release preparations (15.7%), pravastatin sodium (11.7%) and aspirin diaulminate for children (10.7%). The most frequently prescribed drug group was vasodilators (60.2%) including calcium antagonists and nitrates, followed by peptic ulcer agents (44.4%), anti-arteriosclerotic agents (27.1%), anticoagulants (25.1%), diuretics (24.2%) and ACE inhibitors (20.7%). These finding suggest that patients with hyperuricamia tend to have multiple complications such as hypertension, hypercholesterolemia, and ischemic cardiopathies.Inappropriate drug use and combinations are as follows: Alkalinizing agents, which prevent urate stone formation and are recommended for hyperuricemia, appear to be under-utilized (only 11.8%). Diuretics, trichlormethiazide (2.5%) and furosemide (22.4%) commonly cause hyperuricemia and thus should be avoided. When allopurinol and captopril are administered concomitantly (2.9%), a dangerous hypersensitivity reaction can also sometimes occur.These results indicate that doctors and pharmacists need to obtain a greater awareness of inappropriate drug use and dangerous drug combinations.

Crystallization and preliminary X-ray diffraction analysis of cytochrome P450sca-2 from Streptomyces carbophilus involved in production of pravastatin sodium, a tissue-selective inhibitor of HMG-CoA reductase.

Cytochrome P450sca-2 from Streptomyces carbophilus catalyzes the hydroxylation of ML-236B sodium salt to pravastatin sodium, a tissue-selective inhibitor of 3-hydroxy-3-methylglutaryl-coenzymeA (HMG-CoA) reductase. HMG-CoA reductase is a key enzyme in cholesterol biosynthesis. Crystals of the protein were obtained by the vapour-diffusion method, using ammonium sulfate as a precipitant. The crystals belong to the trigonal space group P3121 (or its enantiomorph, P3221) with unit-cell dimensions a = 103.5, c = 79.8 A. Assuming the presence of one molecule in the asymmetric unit, the calculated value of Vm is 2.68 A3 Da-1. A native data set was collected to a resolution of 2.2 A.

Protective effect of fluvastatin sodium (XU-62-320), a 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitor, on oxidative modification of human low-density lipoprotein in vitro

We investigated the protective effect of fluvastatin sodium on the oxidation of low-density lipoprotein (LDL) induced in vitro by copper ions. The extent of lipid peroxidation was assessed by monitoring the increase of UV absorbance at 234 nm, which is the peak absorbance of a conjugated diene. Fluvastatin sodium (1–30 μM) not only prolonged the lag time of oxidation in the initiation step, but also decreased the rate of oxidation in the propagation step, both concentration dependently. Fluvastatin sodium and α-tocopherol showed an additive effect when both compounds were added before oxidation. However, when the lag time was prolonged initially by α-tocopherol, and fluvastatin sodium and α-tocopherol, were further added into the reaction mixture at the end point of the lag phase, fluvastatin sodium still showed an antioxidative effect, whereas α-tocopherol showed a pro-oxidative effect. Therefore, the antioxidative property of fluvastatin sodium differs from that of α-tocopherol. In this experiment, as neither the double bond-reduced derivative of fluvastatin sodium nor pravastatin sodium showed any protective effect, we concluded that the antioxidative effect of fluvastatin sodium is not a common property of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, but may be derived from its unique chemical structure. Since the oxidative modification of LDL plays an important role in the genesis of atherosclerosis, fluvastatin sodium may help reduce the risk of atherosclerosis, not only by reducing plasma LDL levels but also by protecting LDL from oxidative modification.

Combination treatment with troglitazone, an insulin action enhancer, and pravastatin, an inhibitor of HMG-CoA reductase, shows a synergistic effect on atherosclerosis of WHHL rabbits

We examined whether improving insulin resistance augments the antiatherosclerotic effect of LDL reduction. Since WHHL rabbits show hyperinsulinemia and insulin resistance, we administered troglitazone (100 mg/kg), an insulin action enhancer, pravastatin sodium (50 mg/kg), an HMG–CoA reductase inhibitor, and a combination of both drugs to 2-month-old WHHL rabbits for 32 weeks. As compared to the control, total cholesterol levels in the plasma and LDL were decreased significantly by ≈20% in the pravastatin and combination groups. Basal immunoreactive insulin levels and insulin index were decreased significantly by ≈50% in the troglitazone and combination groups. Surface lesion area of atherosclerosis on the thoracic aorta was decreased significantly by 36% in the combination group and was less in the troglitazone group. Coronary atherosclerosis was decreased significantly by 39% in the combination group and was less in the pravastatin and troglitazone groups. The collagen content in the plaques was decreased in the troglitezone and combination groups and the extracellular lipid deposits were decreased in the pravastatin and combination groups. The incidence and severity of xanthomata in the digital joints were also decreased significantly in the three treated groups. In conclusion, the antiatherogenic effect of the combination treatment is stronger than that of the monotherapy.

Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions.

We tested the hypothesis that pravastatin (PRA) activates endothelial nitric oxide synthase (eNOS). Pravastatin has been found to have clinical benefits beyond those predicted by its actions in reducing plasma low density lipoprotein cholesterol (LDL). Both PRA and simvastatin (SIM) are equally effective in reducing LDL, but only PRA reduces platelet aggregation and is an effective vasodilator. Nitric oxide (NO) also inhibits platelet aggregation and vasodilates. We determined PRA and SIM effects on vasorelaxation in aortic rings and NO production by cultured bovine aortic endothelial cells. Nitric oxide was measured by using a NO electrode and by an assay for conversion of hemoglobin to methemoglobin. Specificity of NOS activation was tested by using the NOS inhibitor nitro-L-arginine methyl ester (L-NAME, 1 mmol/liter) in the presence or absence of excess L-arginine (L-ARG, 1 mmol/liter). Endothelium-dependent vasorelaxation was maximal with acetylocholine (ACH, 100%), followed by PRA (62.8%) and then SIM (37.1%). Direct measurement of NO confirmed that vasorelaxation is due to NO release and showed that PRA and ACH had similar dose-dependent effects on NO production, while SIM was only 25% to 30% as effective. Methemoglobin assay confirmed these results and demonstrated their specificity for NOS activity. The L-NAME blunted the responses to 45% of initial values. Excess L-ARG reversed this effect and potentiated NO production to 133% of initial levels. Both PRA and SIM activate eNOS, but SIM is much less effective. Clinical benefits with PRA not explained by LDL reductions may be the result of an independent action of PRA on eNOS activation.

Escape phenomenon with pravastatin during long-term treatment of patients with hyperlipidemia associated with diabetes mellitus

The escape phenomenon is considered to be a type of drug resistance caused by an increase in drug metabolism or an induction of enzymes or functional proteins toward which the drug is targeted. In practice, however, little evidence supports the actual occurrence of the escape phenomenon; rather, deterioration of compliance may be a more plausible cause. To address this issue, we compared changes in serum lipids in two groups of patients with diabetes mellitus during long-term treatment of hyperlipidemia with pravastatin sodium, a soluble 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Sixteen male and female patients with non-insulin-dependent diabetes mellitus and hyperlipidemia were enrolled in this study. All 16 patients had maintained decreased serum total cholesterol (TC) levels of 15% or more (from 261.5 ± 5.6 mg/dL to 195.6 ± 2.1 mg/dL, mean ± SE) for 3 months or longer after beginning pravastatin therapy. Their serum TC levels had then increased by 10% or more from the reduced levels (from 195.6 ± 2.1 mg/dL to 231.6 ± 3.3 mg/dL, mean ± SE). At this point, patients were randomly separated into two groups—group A receiving reinforcement of drug compliance and diet therapy and group B receiving no reinforcement. Changes in serum lipids, plasma glucose, glycated hemoglobin A 1c (Hb A 1c), and body weight were studied. Serum TC levels decreased significantly (234.4 ± 4.3 mg/dL to 205.6 ± 4.3 mg/dL) in serum group A, but remained unchanged (228.4 ± 4.6 mg/dL to 230.1 ± 2.9 mg/dL) in group B. No significant changes were observed in the levels of plasma glucose, Hb A 1c, or body weight. Results of this study suggest that insufficient diet therapy and poor drug compliance, rather than the escape phenomenon, account for a re-increase in serum TC levels after an initial decrease in levels with pravastatin therapy

2.P.53 Effects of long-term (for 5 years) treatment using pravastatin sodium on hyperlipidemia in diabetics

2.P.53 Effects of long-term (for 5 years) treatment using pravastatin sodium on hyperlipidemia in diabetics

Induction of fatty acid synthesis by pravastatin sodium in rat liver and primary hepatocytes

We examined the effect of pravastatin sodium (pravastatin), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on fatty acid synthesis in rat liver. The repeated administration of pravastatin to rats at 250 mg/kg for 7 days led to a 2.8-fold increase in fatty acid synthesis in the liver. The diurnal change of fatty acid synthesis was not affected by the treatment. Hepatic fatty acid synthase activity was increased 3.2-fold, while acetyl-CoA carboxylase activity was not changed by the repeated administration of pravastatin. In rat hepatocytes, the incubation with 2 μg/ml pravastatin for 24 h increased fatty acid synthase activity 1.5-fold, as well as HMG-CoA reductase activity 2.8-fold. These results suggest that HMG-CoA reductase inhibitors might increase fatty acid synthesis in vivo through the induction of hepatic fatty acid synthase.