Comparative study on the in vivo and in vitro antilipolytic effects of etofibrate, nicotinic acid and clofibrate in the rat

The release of both glycerol and free fatty acids (FFA) into a medium by epididymal fat pad pieces from fed rats incubated in Krebs Ringer bicarbonate-albumin buffer supplemented or not with epinephrine decreased more in the presence of etofibrate than in the presence of equimolecular doses of nicotinic acid or clofibrate. The first drug was the only one to stimulate the rate of fatty acid re-esterification when incubations were done under basal conditions. By 3 h after their acute oral administration all three drugs decreased plasma FFA levels, although the effect from etofibrate was largest, the drugs enhanced or decreased plasma glycerol levels depending on both the dose and the time after treatment. Plasma triglycerides also decreased at 3 h after oral drug administration, and this effect was similar with etofibrate and nicotinic acid but less with clofibrate. With the exception of a decrease at 7 h after the highest dose (1.2 mmol/kg) of either etofibrate or nicotinic acid (but not clofibrate), plasma cholesterol levels remained stable at 7 h after the respective treatments. Thus, the hypocholesterolemic effect of these drugs seems secondary to their hypotriglyceridemic effect, which would be a consequence of their respective antilipolytic actions, and follows an efficiency sequence of etofibrate, nicotinic acid and clofibrate.     

Disposition of etofibrate, clofibric and nicotinic acid esters, and their products in dogs

Etofibrate, the ethylene glycol diester of clofibric and nicotinic acids, on intravenous infusion into dogs, has a terminal half-life of 2 min. The intermediate half-esters, the nicotinate and the clofibrate, have respective terminal half-lives of 4.6 and 1.7 min and appear fleetingly when etofibrate is administered. In contrast to the 42-h terminal half-life of clofibric acid, the other final transformation product, nicotinic acid, shows saturable or dose-dependent pharmacokinetics in dogs that conform to the Michaelis-Menten equation with a terminal half-life of 4.4 min at low concentrations (less than 6.9 microM/kg). Three distinct metabolites of nicotinic acid can be identified and assayed chromatographically in the urine. The partition properties were similar to nicotinic acid. Nicotinic acid is excreted 30% unchanged into urine with a renal clearance of 70 mL/min in 27-kg dogs.     

阿斯匹林与烟酸联合应用时血药浓度测定

阿斯匹林与烟酸给家兔同时ⅳ后,采用新建立的溶剂萃取,分光光度法和Carlson法分别测定两药血浆浓度。结果用微机分析拟合曲线,符合二室开放模型。两药联合应用后,烟酸T_1/2β(2.3374 h)和AUC(361.63μg·h/ml)较单用炳酸时T_1/2β(0.9846h)和AUC(157.71μg·h/ml),差异非常显著(P<0.01)。其它参数在两种情况下均无显著差别。     

Pharmacokinetics and hypolipidemic activity of clofibrate-nicotinic acid combinations in rats.

Male albino rats were given various oral doses of clofibrate and nicotinic acid. both alone and in combination, daily for 1 week. In normal animals, the combination of drugs produced greater decreases in serum lipids, notably triglycerides, than equimolar doses of either drug alone. Synergistic decreases in serum triglycerides were observed in rats rendered hypertriglyceridemic with fructose and treated simultaneously with both drugs. The peak level of serum nicotinic acid was higher and the area under the serum nicotinic acid concentration-time curve (AUC) was 59 per cent greater when nicotinic acid was given with clofibric acid (CPIB) than when given alone. Pretreatment for 1 week with nicotinic acid slightly increased the apparent volume of distribution and the elimination half-life of intravenously injected CPIB. The presence of nicotinic acid in rat serum did not affect the protein binding of CPIB. The results show that the combined hypolipidemic effect of clofibrate and nicotinic acid in rats is accompanied by changes in the pharmacokinetics of the drugs, the most pronounced being a decrease in the rate of elimination of nicotinic acid.     

Immunomodulatory activity of anti-atherogenic drugs: effects on blastogenesis, humoral response, delayed hypersensitivity and passive anaphylaxis by immune complexes

The effect of several anti-atherogenic drugs (ticlopidine, nicotinic acid and etofibrate) on immune responses and immune complex anaphylaxis has been studied in mice. All the drugs enhanced the activation by concanavalin A, phytohemagglutinin, and lipopolysaccharide of lymphocytes taken from treated animals. Contact hypersensitivity to trinitrochlorobenzene was inhibited by similar treatments with the same drugs, possibly through inhibition of the efferent phase of the reaction. Nicotinic acid produced a slight enhancement of antibody responses to sheep erythrocytes, whereas etofibrate inhibited the response at the highest dose studied. In addition, treatment with these drugs variably protected the mice from anaphylactic shocks induced by immune complexes. Marked protection was also observed using the antiserotoninic, cyproheptadine. These results indicate that drugs used to prevent atherogenic processes modulate different proliferative and effector immunological reactions.     

Toxicokinetic study of norfloxacin-induced arthropathy in juvenile animals

A toxicokinetic study of norfloxacin-induced arthropathy in juvenile animals was undertaken using nalidixic acid as a standard drug. Norfloxacin and nalidixic acid were subcutaneously administered to rats and rabbits, orally administered to dogs, and norfloxacin was orally dosed to monkeys once a day for 7 consecutive days. Of the dose levels tested, the minimum arthropathic doses of norfloxacin were 100, 25, and 50 mg/kg/day in rats, rabbits, and dogs, respectively. At these doses, the peak serum concentrations (Cmax) on Day 6 were 16.1, 9.73, and 5.11 micrograms/ml, and the areas under the serum concentration/time curve (AUC0----infinity) were 31.9, 22.9, and 26.2 micrograms.hr/ml, in respective animals. Monkeys showed no arthropathy with norfloxacin at doses of less than 500 mg/kg/day, at which the Cmax and AUC0----infinity were 15.6 micrograms/ml and 103 micrograms.hr/ml, respectively. The minimum arthropathic doses of nalidixic acid were 50, 100, and 25 mg/kg/day in rats, rabbits, and dogs, respectively. The Cmax and AUC0----infinity of nalidixic acid were higher than those of norfloxacin in all animals. Joint tissues took up more norfloxacin than nalidixic acid, but when arthropathy was present the articular cartilage concentrations of the two drugs were in the same range. The penetration of norfloxacin into the articular cartilage was the same regardless of the joint's anatomical locations, but differed among species, being highest in rats and lowest in monkeys. The Cmax and AUC0----infinity of norfloxacin in animals at their arthropathic doses were far higher than those measured clinically in children, whereas those of nalidixic acid in animals did not differ much from its clinical parameters.     

Serum concentrations and bioavailability of rifampicin and isoniazid in combination.

The bioavailability of rifampicin and isoniazid from formulations containing these drugs in combination has been compared to that from formulations containing either drug alone. No formulation-related differences in either rates or extent of bioavailability were found after administration of each formulation. Mean peak serum concentrations of rifampicin (8.2-11.7 mug/ml) occurring 2 to 4 h after doses of 600 mg, and isoniazid (3.6-4.8 mug/ml) occurring 0.5 to 1 h after doses of 300 mg, were similar to those reported in the literature.     

Synthesis and antimalarial activity of artemisinin derivatives containing an amino group

In search of water-soluble artemisinin derivatives that are more stable than sodium artesunate, over 30 derivatives containing an amino group (compounds 3-5) were synthesized and tested in mice. All products tested (except 5a and 5b) are the beta isomers. These basic compounds combined with organic acids (oxalic acid, maleic acid, etc. ) to yield the corresponding salts. Generally, the maleates have better solubility in water than the corresponding oxalates. The aqueous solutions of these salts can be kept at room temperature for several weeks without any discernible decomposition. Compounds 3f, 3h, and 3r are much more active against P. berghei than artesunic acid by oral administration and therefore were further tested in monkeys. However, their oral efficacies are poorer than that of artesunic acid against P. knowlesi in rhesus monkeys. It is interesting to note that 3f, 3h, and 3r showed much lower efficacies against P. berghei when they were administered subcutaneously than orally.     

Hepatic induction potency of hypolipidaemic drugs in the rat following long-term administration: influence of different dosing regimens

1. The effects of different dosing regimens of three hypolipidaemic, peroxisome-proliferator drugs on hepatic enzymes in the Fischer rat following 26 weeks treatment have been studied. 2. In study 1, with once-daily dosing (dose levels based on comparative antisecretory activity), the liver/body weight ratio and peroxisomal beta-oxidation were significantly increased in the order: ciprofibrate greater than bezafibrate greater than clofibric acid. Glutathione peroxidase activity was decreased to 65% and 77% control after treatment with ciprofibrate and bezafibrate, respectively, but not after treatment with clofibric acid. 3. In study 2, dosing regimens were adjusted to compensate for the different drug pharmacokinetic profiles in rat, with clofibric acid and bezafibrate administered twice daily and ciprofibrate once every 48 h. Liver enlargement and increases in peroxisomal beta-oxidation were similar with all three drugs when compensation for differences in drug clearance was made. Glutathione peroxidase activity was decreased to similar extents by all three compounds. 4. The induction profiles of these hypolipidaemic drugs, largely different with once-daily dosing, were shown to be similar after adjusting the frequency of dosing with respect to drug half-life.     

In vivo covalent binding of clofibric acid to human plasma proteins and rat liver proteins

Recent studies have shown that acyl-glucuronide conjugates are chemically reactive electrophilic metabolites that can undergo transacylation reactions resulting in intra-molecular rearrangement, hydrolysis and covalent binding of aglycone to albumin both in vitro and in vivo. The hypolipidaemic agent clofibrate is eliminated almost entirely as clofibric acid glucuronide in humans and rats. The formation of clofibric acid-protein adducts was investigated in 14 patients receiving 0.5-2.0 g/day of clofibrate for hypercholesterolaemia, and in liver homogenates from 20 rats administered 280 mg/kg/day of clofibric acid for up to 21 days. Total clofibric acid concentrations in the patients ranged from 0 to 114 mg/L. Covalently bound clofibric acid-protein adducts were detected in all patients, even in one subject in whom there was no measurable plasma clofibric acid. Concentrations ranged from 2.2 to 53.4 ng/mg protein and, in eight patients receiving 1.0 g/day of clofibrate, were correlated (P less than 0.05) with renal function as assessed by creatinine clearance. Clofibric acid-protein adducts were also present in rat liver homogenates, and increased with increasing duration of treatment (P less than 0.0001), from a mean (SE) of 10.1 (0.7) to 32.3 (1.6) ng/mg protein. The covalent binding of drugs to tissue macromolecules has traditionally been associated with toxicity. Further research is required to elucidate the role of acyl-glucuronide conjugates in the formation of drug-protein adducts and their biological consequences.     

L-656,575 (OCP-9-176): a novel oxacephem. Pharmacokinetics and experimental chemotherapy

L-656,575 is a new oxacephem that, based on studies in rhesus monkeys, is expected to have a moderately long half-life in humans. After administration of a 10-mg/kg dose by the intramuscular route to rhesus monkeys, peak serum concentrations of 32-54 micrograms/ml were seen at about 30 minutes, and the half-life was estimated to be 63 minutes. Urinary recovery of administered dose was greater than 94% in 6 hours. In mice given a 20-mg/kg dose by the subcutaneous route, a peak serum concentration of 22.9 microgram/ml was observed at 15 minutes after dosing, and the half-life in serum was about 18 minutes. Urinary recovery of the dose was 59% in 6 hours. In another study in mice, administration of probenecid did not extend the half-life of L-656,575, suggesting that the antibiotic is excreted primarily by glomerular filtration in this species. Binding to human plasma proteins was 30% at drug concentrations from 25-100 micrograms/ml. L-656,575 also was shown to be efficacious in experimental bacteremias due to Gram-positive and Gram-negative pathogens in mice, thus confirming the broad spectrum of activity demonstrated for L-656,575 in vitro.     

Pharmacokinetics of triflusal and its main metabolite in rats and dogs.

The methods for determining plasma concentrations of triflusal (2-acetoxy-4-trifluoromethyl benzoic acid) that have been described, do not distinguish between the drug and its main metabolite HTB (2-hydroxy-4-trifluoromethyl benzoic acid). In the present study, we have developed a new analytical technique based on HPLC that enabled us to carry out a pharmacokinetic study of the drug and its metabolite in animals. An intravenous or oral dose of 50 mg/kg was administered to male Sprague-Dawley rats, and 15 mg/kg was administered to beagle dogs. Plasma levels of triflusal and HTB were determined. In rats, triflusal was quickly eliminated from plasma with a biological half-life (t1/2) of 2.7 min and a clearance (Cl) of 73.4 (ml/kg)/min. The elimination of HTB was much slower with a t1/2 of 21.5 h and a Cl of 5.1 (mg/kg)/h. The maximum concentration (Cmax) of triflusal in rats after an oral administration was 8.1 +/- 2.0 micrograms/ml reached between 2.5 and 10 min. The Cmax of HTB was 237.7 micrograms/ml and was achieved at 0.7 h. The bioavailability of triflusal in rats was only 10.6% while the bioavailability of HTB was more than 100% indicating an important first pass effect. In dogs the t1/2 of triflusal was 14.4 +/- 5.9 min and the Cl was 25.1 +/- 4.7 (ml/kg)/min. HTB was also eliminated very slowly with a t1/2 of 71.1 +/- 12.5 h and a Cl of 2.4 +/- 0.3 (ml/kg)/h. The Cmax of triflusal in dogs was 13.3 +/- 2.9 micrograms/ml and was reached after 19.2 +/- 6.1 min (tmax).(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasmolysis, red blood cell partitioning, and plasma protein binding of etofibrate, clofibrate, and their degradation products

Etofibrate (I), the ethylene glycol diester of clofibric and nicotinic acids, degrades almost equally through both half-esters with half-lives of approximately 10 and 1 min in fresh dog and human plasma, respectively. The nicotinate V degrades with half-lives of approximately 12 hr and 50 min in fresh dog and human plasma, respectively. Ester III and clofibrate VI degrade by saturable Michaelis-Menten kinetics in fresh human plasma, with similar maximum initial rates and respective terminal first-order half-lives of 12 and 26 min. Tetraethyl pyrophosphate at 100 micrograms/ml inhibited human plasma and red blood cell esterases permitting plasma protein binding and red blood cell partitioning studies. The red blood cell-plasma water partition coefficient was 5.4 for 0.2-80 micrograms/ml of I. Clofibrate (VI) showed a saturable erythrocyte partitioning that decreased from 7.8 (10 micrograms/ml) to 1 (50 micrograms/ml). The strong binding of I and VI to ultrafiltration membranes necessitated the determination of their plasma protein binding by the method of variable plasma concentrations of erythrocyte suspensions to give 96.6% (0.2-80 micrograms/ml) and 98.2% (13.6-108.4 micrograms/ml) binding, respectively. Methods for the determination of the parameters of saturable and nonsaturable plasma protein binding for unstable and membrane-binding drugs by the method of variable plasma concentrations in partitioning erythrocyte suspensions are presented.     

Pharmacokinetics of cefatrizine after oral administration in human volunteers

The oral bioavailability of cefatrizine was studied in four groups, each of ten healthy young male volunteers. Capsules and suspension formulations were each administered at doses of 250 and 500 mg. Both the capsules and suspensions had mean peak plasma levels at 1.6 h at both dose levels. Mean peak plasma levels were 4.1 and 4.3 micrograms/ml for the 250 mg capsule and suspension doses respectively and 7.1 and 7.5 micrograms/ml for the 500 mg capsules and suspension doses respectively. The overall mean half-life was 1.7 h. For both types of formulations and at both dose levels 63-65% of the doses were excreted in the urine as intact cefatrizine, 85% of this amount within 8 h. The overall mean renal clearance was 157 ml/min. The cefatrizine capsule and suspension formulations were completely bioequivalent in regard to both rate and extent of bioavailability. Plasma concentrations and urinary recoveries of cefatrizine were higher than those previously reported, due to precautions taken in sample collection and storage.     

Relative bioavailability of three cefixime formulations

Three galenic formulations of cefixime (tablet, syrup and dry suspension) containing 200 mg each were compared with respect to their relative bioavailability in twelve healthy volunteers. All three formulations showed reliable absorption. Mean peak plasma concentrations were reached after 3.3-3.5 h, mean terminal half lives were 2.9-3.1 h. 18-24% of the dose administered were recovered unchanged in the urine. Best bioavailability was obtained with the dry suspension (AUC0-infinity = 25.8 +/- 7.0 micrograms/ml h; Cmax = 3.4 +/- 0.9 microgram/ml), followed by the tablet (AUC0-infinity = 20.9 +/- 8.1 micrograms/ml h; Cmax = 3.0 +/- 1.0 micrograms/ml) and the syrup which is based on triglycerides (AUC0-infinity = 17.8 +/- 5.9 micrograms/ml h; Cmax = 2.4 +/- 0.7 micrograms/ml). The statistical analysis resulted in bioinequivalence between dry suspension and syrup. It is concluded that best bioavailability of cefixime after oral administration is guaranteed when taken in an "aqueous medium" either as dry suspension or as tablet with "plenty of liquid".     

Effect of etofibrate on bile production in the normolipidemic rat

• 1.1. The effect of etofibrate, the ethandiol-1,2 diester of nicotinic and clofibric acids on bile production was studied in male rats that received a daily dose of 300 mg of etofibrate/kg body weight by stomach tube for 10 days and were compared with control rats receiving the medium.
• 2.2. The bile duct was cannulated, animals were intravenously given 1 μCi (4-¹⁴C)-cholesterol/100 b.w. and bile was collected at different intervals for a total of 4 hr.
• 3.3. Etofibrate treatment decreased plasma cholesterol and triglyceride concentrations and increased the bile flow. The cummulative amount of both bile volume and total bile radioactivity secreted increased linearly in all the animals; the respective slopes being higher in etofibrate treated rats than in controls.
• 4.4. The main labelled component found in the bile was always bile acids rather than cholesterol and the proportion of each of these compounds was similar in both groups. Neither was any difference between the groups found in the concentration of bile acids, cholesterol and phospholipids nor in the cholesterol/(bile + phospholipid) ratio.
• 5.5. Besides other factors, the present results indicate that an increase in bile flow and biliary cholesterol excretion in its free form and after its conversion into bile acids should contribute to the hypocholesterolemic effect of etofibrate.

     

Myometrial responses in situ to nicergoline, acebutolol, phentolamine and noradrenaline of the rat in proestrus

The effects of two adrenoceptor antagonists, nicergoline (alpha 1) and acebutolol (beta 1), on the contraction of myometrium in the proestrous rat were compared to those of noradrenaline and phentolamine. The spontaneous myometrial contractions of Wistar rats on the day of proestrus were recorded isometrically and the data were analysed using Wilcoxon non-parametric statistics. All drugs were administered i.v. and the doses are expressed as microgram/kg body weight. Noradrenaline (1200 micrograms/kg per h) induced a 32.5% reduction (P less than 0.001) of the uterine contraction amplitude. Nicergoline did not alter uterine motility significantly when administered alone at doses ranging from 400 to 1600 micrograms/kg. However, successive injections of nicergoline in the same range given during noradrenaline infusion at 600 micrograms/kg per h potentiated the relaxing action of the latter (38%, P less than 0.01). Phentolamine (120 micrograms/kg) reduced myometrial activity by 25% (P less than 0.05). This inhibitory response rose to 65% (P less than 0.001) when the dose of phentolamine was increased to 960 micrograms/kg. When a single injection of nicergoline (400 micrograms/kg) was followed by the administration of increasing doses of acebutolol (120, 1200, 2400 micrograms/kg) the slight inhibitory effect on uterine motility observed after administration of each of the two agents separately became more pronounced (P less than 0.05). It appears from these results that combining noradrenaline with nicergoline and nicergoline with acebutolol leads to potentiation of their relaxing effects. Furthermore the results confirm that nicergoline is a partial alpha-blocker.     

Treatment of hyperlipoproteinemia type II with etofibrate

Seven patients with hyperlipoproteinemia (HLP) type II (four patients with type II A and three patients with type II B), who were experienced to be resistant to hypolipidemic drugs, were treated for 6 months with etofibrate, a double-ester of nicotinic acid and clofibrinic acid, at a dose of 0.3 g t.i.d. Mean serum cholesterol level decreased by up to 18% from a pre-treatment value of 7.7 +/- 1.4 mmol/l. The reduction of serum cholesterol was due both to a decrease in very low density (VLDL) and low density (LDL) lipoprotein cholesteral by 61 and 25%, respectively (after 6 months). Furthermore alpha-LP (HDL) cholesterol increased by 8%, (after 6 months). All seven patients had previously received clofibrate and had obtained a mean decrease in plasma cholesterol by 6%. There was a slight transient increase in S-ASAT and S-ALAT simultaneous with in increase in serum urate. However, these values returned after 3 months to pre-treatment level. No influence on glucose tolerance was recorded. There were no bothersome side effects except a transient discomfort in the form of flushing or acid indigestion which occurred after 1--2 months of treatment with etofibrate.     

Fosfomycin susceptibility of clinical isolates from otorhinolaryngological infections

To investigate the clinical and bacteriological usefulness of orally administered fosfomycin calcium (FOM), the susceptibility of 558 strains to FOM was determined. These strains were isolated at our Center, between Feb. 1982 and Feb. 1983 from otorhinolaryngological infections. Several other drugs were also tested on the same strains for comparison. The results were as follows. The MIC80 of FOM was 6.25 micrograms/ml against each of aerobic Gram-positive cocci such as S. aureus, S. pyogenes, S. pneumoniae, anaerobic Gram-positive cocci such as Peptococcus spp., and H. influenzae. P. mirabilis, indole-positive Proteus spp., P. aeruginosa and K. pneumoniae were inhibited, respectively, at 3.13, 12.5, 12.5 and 50 micrograms/ml. Most of the MICs were between 3.13 and 12.5 micrograms/ml, and the difference between the MIC50 and the MIC90 was only 1 to 2 tubes since there were few resistant strains. With the comparative drugs, there was a reduction seen in the sensitivities of pipemidic acid (PPA), ampicillin (ABPC), and cephalexin (CEX) against, respectively, P. aeruginosa, beta-lactamase-producing H. influenzae and S. aureus. FOM showed good and constant sensitivity for the weakly PPA-sensitive P. aeruginosa, weakly ABPC-sensitive beta-lactamase-producing H. influenzae and weakly CEX-sensitive S. aureus. The MICs of FOM against the main problematic isolates from otorhinolaryngological infections were mostly between 3.13 and 12.5 micrograms/ml, including the above weakly PPA-, ABPC- and CEX-sensitive strains. Based on these values, FOM may be said to have moderate antibacterial efficacy when administered orally in the usual dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of coumarin and 7-hydroxycoumarin in the rhesus monkey after intravenous and peroral administration

Coumarin (C, Venalot) and 7-hydroxycoumarin (7-OHC) were administered in a dose of 1 mg/kg to rhesus monkeys intravenously and perorally. The concentrations of C, 7-OHC and their metabolite, 7-hydroxycoumarin glucuronide (7-OHCG) were measured in whole blood. The terminal half-life, t1/2, the apparent distribution volume, Vd, and the total clearance, CL, of C and 7-OHC after i.v. administration are 1.64 +/- 0.41 h and 0.8 +/- 0.29 h, 2.55 +/- 0.95 l/kg and 6.96 +/- 3.44 l/kg, and 19.05 +/- 5.41 ml/min/kg and 103.7 +/- 34.4 ml/min/kg (mean +/- SEM), respectively. The rates of absorption of C and 7-OHC are 12.8 +/- 2.38 and 4.62 +/- 1.08 h-1, respectively. The rate of metabolism of C via 7-OHC to 7-OHCG is 7.96 +/- 2.16 h-1 and that of 7-OHC to 7-OHCG is 27.99 +/- 11.73. The p.o. absolute bioavailability is 45 +/- 14% for C and 17.0 +/- 5% for 7-OHC. The pharmacokinetics of C in the rhesus monkey are similar to that in the dog. In man the p.o. absolute bioavailability is only 3.4%.