Drug utilization by the 30–64 year-old people in two cities in the Federal Republic of Germany in 1984

Summary A study has been done to describe and compare the drug utilization profiles of the 30–64 yr-old populations in two cities in the Federal Republic of Germany. Subjects from two community surveys, based on random samples in 1984, from the communities of Augsburg in the south, and Luebeck in the north, were asked to bring to interview any medications taken in the preceding seven days. Total drug use in the two communities was very similar. Women took more drugs than men. The drug categories used by at least 5% of men were analgesics/antirheumatics and antihypertensives. The prevalence of use of different drug categories by men was remarkably similar in the two cities, and the only significant difference was a greater consumption of antihypertensive drugs by Luebeck men (9.8%) compared to Augsburg men (6.3%). The drugs taken by at least 5% of women were sex hormones, analgesics/antirheumatics, antihypertensives, thyroid preparations, psychotropics, cardiac drugs and antihypotensives. Consumption by Augsburg women was significantly greater for sex hormones, cardiac drugs, thyroid drugs, and migraine drugs, whereas Luebeck women consumed significantly more antihypertensives. The high use of thyroid drugs by Augsburg women (11%) is indicative of the high frequency of endemic goitre in the southeastern quarter of the FRG. Although it has been shown from sales data that the FRG has a high consumption of cardiac glycosides, the 6% prevalence of use of preparations of them by 30–64 yrold Augsburg women represents more precise exposure information and reflects a relatively young group of users.     

强直性脊柱炎患者血清基质金属蛋白酶-3水平及意义

目的探讨强直性脊柱炎(AS)患者血清基质金属蛋白酶-3(MMP-3)的水平及意义,为临床治疗、判断预后提供新的理论依据。方法采用酶联免疫吸附实验(ELISA)测定175例AS患者(就诊前6个月内未用过慢作用药及糖皮质激素)和95名健康对照者血清MMP-3的水平,同时测定其治疗前的其他实验室指标:红细胞沉降率(ESR)、C反应蛋白(CRP)、白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α)、骶髂关节X线。分析它们与MMP-3的相关性。结果 AS患者血清MMP-3水平[(226±169)ng/ml]明显高于健康对照组[(53±21)ng/ml],P<0.05;不同临床特点AS患者血清MMP-3水平差异无统计学意义(P>0.05);MMP-3水平与AS患者的ESR、C反应蛋白(CRP)、患者血清CRP、BASDAI评分、白细胞介素6(IL-6)、TNF-α呈正相关(P<0.05);而与发病年龄、病程、晨僵时间、X线分级无明显关系(P>0.05)。结论 MMP-3在AS患者血清中高水平存在。它既能够反映AS关节骨质破坏,又能更好地反映疾病活动程度,可作为除ESR、CRP外提示AS疾病进展与改善的血清学指标。     

Effect of Ilex extracts and isolated compounds on peroxidase secretion of rat submandibulary glands.

Free radicals are involved in diverse disorders such as tumoral, central nervous system alterations, immunological and inflammatory pathologies. Peroxidase is an oral enzyme involved in the defense of the oral cavity. Ilex species such as Ilex paraguariensis St. Hil. and the commercial product made with it "Yerba Mate" are used traditionally as antirheumatics and for the treatment of gastrointestinal diseases among others and also as a beverage with nutritional and stimulant properties. The presence of polyphenolic derivatives and flavonoids in the aqueous extract has been determined by HPLC analysis. In this study, the activity of aqueous extracts of I. paraguariensis and "Yerba Mate" on peroxidase secretion in female rat submandibular glands was investigated. The contribution to this pharmacological activity by some major hydrocynnamic acid derivatives present in the crude extracts, such as chlorogenic acid and caffeic acid and the most abundant methylxanthine, caffeine, was also evaluated. Spectrophotometrical determination of peroxidase activity showed that both extracts produced a significant increase in both secreted peroxidase and total peroxidase activity, though "Yerba Mate" showed a higher activity (EC(50) "Yerba Mate": 148+/-10 microg/ml; EC(50)I. paraguariensis: 841+/-20 microg/ml). The HPLC/DAD analysis of the crude extracts was performed and chlorogenic acid, caffeic acid and caffeine were identified and quantified. The results (expressed as W/W percentage of dried material) were as follows: I. paraguariensis: chlorogenic acid: 2.80+/-0.30, caffeic acid: 0.023+/-0.004, caffeine: 1.06+/-0.06; "Yerba Mate": chlorogenic acid: 1.98+/-0.37; caffeic acid: 0.020+/-0.003, caffeine: 0.70+/-0.06. Caffeine and chlorogenic acid were proved to play an important role in the induction of peroxidase secretion induced by the extracts.     

Drug-induced peripheral neuropathies.

Review of the various drugs in current clinical use showed that over 50 of them may cause a purely sensory or mixed sensorimotor neuropathy. These include antimicrobials, such as isoniazid, ethambutol, ethionamide, nitrofurantoin, and metronidazole; antineoplastic agents, particularly vinca alkaloids; cardiovascular drugs, such as perhexiline and hydrallazine; hypnotics and psychotropics, notable methaqualone; antirheumatics, such as gold, indomethacin, and chloroquine; anticonvulsants, particularly phenytoin; and other drugs, including disulfiram, calcium carbimide, and dapsone. Patients receiving drug treatment who complain of paraesthesie, pain, muscle cramps, or other abnormal sensations and those without symptoms who are receiving drugs that are known or suspected to be neurotoxic should undergo neurological examination and studies of motor and sensory nerve conduction. This will allow the incidence of drug-induced peripheral neuropathy to be determined more precisely.     

The testing of long-term antirheumatics in animals

There is no group proof of long acting antirheumatics (LAA) in laboratory animal models, and it is not to be expected without an identical rheumatoid arthritis model in animals and with regard to the heterogeneity of LAA. However, LAA are to be detected according to D-penicillamine-like, levamisol-like etc. actions, which can be disclosed in the adjuvant arthritis as well as in the B. pertussis-vaccine pleuritis in rats the latter model best by including parameters of inflammatory exudate cells. Modification of the models or of model parameters (BCG-sensibilization, PPD reaction, vasoreactivity, RNA content of exudate cells, SH groups, copper zinc) are hardly advantageous, contrarily to dosage. Other models, among them paw edemas, do not permit sufficient testing of LAA, even not the methyl-albumin mice paw edema. There is no problem of pharmacologically separating LAA actions from nonsteroidal or steroidal antiphlogistics actions.     

Consumption of analgesics and anti-inflammatory drugs in the nordic countries between 1978–1988

Summary Comparative wholesale statistics from the five Nordic countries show an increase of 15–42% in the total consumption of analgesics and anti-inflammatory drugs (including antirheumatics) in the period 1978–1988. Denmark had the highest total consumption (112 DDD/1000 inhab/day in 1988) and Norway had the lowest (61 DDD/1000 inhab/day). Iceland and Finland, with the highest increases in total consumption (45% and 35%), overtook Norway in the early to mid 1980's. Division of total consumption into subgroups showed that Denmark had the highest consumption of analgesics (90 DDDs) and that Finland and Iceland had the lowest figure. The latter countries, however, had the highest consumption of non-steroidal anti-inflammatory drugs (NSAID), 35 and 30 DDDs, respectively, in 1988. The increase in NSAID consumption was 57% in Finland and 54% in Iceland, while Denmark had only an 18% increase. The new NSAIDs introduced in the 1970's appear to have increased the overall consumption of pain relievers in the Nordic countries, especially in Finland and Iceland.     

Repeat adverse drug reactions causing hospitalization in older Australians: a population-based longitudinal study 1980-2003

AIM: To examine trends in the rate of repeat adverse drug reactions (ADRs) causing hospitalization in older Australians and to identify the most common ADRs and drugs most often implicated in repeat and first-time ADRs. METHODS: Analysis of routinely collected hospital record administrative data, with International Classification of Diseases external cause codes for ADRs extracted from the Western Australia (WA) Hospital Morbidity Data System and WA Death Register, for people aged > or =60 years in 1980-2003. RESULTS: A total of 37 296 people aged > or =60 years with an ADR-related hospitalization were identified. Among them, 6853 (18.4%) patients had 10 212 repeat ADRs. Repeat ADRs consistently increased from 1980 and reached 30.3% of all ADRs by 2003. The mean time interval declined with each successive repeat ADR (810, 606 and 299 days for the first, second and higher ranked repeat episodes, respectively). The most common repeat ADRs were nausea/vomiting (8.0%), haemorrhage due to anticoagulants (5.5%), drug-induced osteoporosis (4.8%) and poisoning by cardiovascular agents (3.9%). The drugs most often involved in repeat ADRs were cardiovascular agents (15.6%), antineoplastic drugs (11.0%), corticoids (10.1%), anticoagulants (8.6%), antirheumatics/nonsteroidal anti-inflammatory drugs (5.1%) and opioids (4.9%). The trends of anticoagulants and antineoplastic drugs implicated in repeat ADRs were still rising at the end of the study. The specific drug classes involved in repeat ADRs differed in relative importance from first-time ADRs. CONCLUSIONS: Repeat ADR-related hospitalizations have consistently increased in elderly Australians from 1980 to 2003. Strategies to ensure the safer use of medicines, in particular anticoagulants, in this population are warranted.     

Pharmacology of iotroxic acid, a new intravenous cholangiographic agent. II. Experimental animal study of side effects

The general, neural and cardiovascular tolerance of iotroxic acid (Biliscopin) and its deleterious effect on membranes were investigated in comparison with iodipamic- (Biligrafin), ioglycamic- (Biligram, Bilivistan) und iodoxamic acids in different experimental models. Tolerance (DL50) of iotroxic acid after i.v. injection in the rat proved to be significantly better than that of all the reference substances. The difference was most apparent in animals which had previously been given histamine. Neural tolerance was found to be best after iotroxic acid and iodipamic acid and poorest after iodoxamic acid. In in vitro investigations the erythrocyte membranes were far less damaged by iodoxamic acid and iotroxic acid than by iodipamic acid. Iotroxic acid was also particularly well tolerated after intracisternal injection and after injection into the carotid artery of the rat. The effect of iotroxic acid on the cardiovascular system of the cat was distinctly weaker than that of ioglycamic acid and, when given in high doses, evidently also weaker than that after administration of iodoxamic acid. The excellent general tolerance of iotroxic acid can be explained by the fact that its deleterious effect on membranes is less than that of iodipamic acid and that its neurotoxicity is distinctly lower than that of iodoxamic acid.     

In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid

Dietary polyphenols are thought to be beneficial for human health as antioxidants. Coffee beans contain a common polyphenol, chlorogenic acid. Chlorogenic acid is the ester of caffeic acid and quinic acid. Although these polyphenols have received much attention, there is little evidence indicating a relationship between the effect and the rate of absorption. In this study, we focused on the beneficial effects of chlorogenic acid and caffeic acid, a major metabolite of chlorogenic acid. We carried out in vitro and in vivo experiments. In the in vitro study, caffeic acid had stronger antioxidant activity than that of chlorogenic acid. The uptake of chlorogenic acid by Caco-2 cells was much less than that of caffeic acid. The physiological importance of an orally administered compound depends on its availability for intestinal absorption and subsequent interaction with target tissues. We then used an intestinal ischemia-reperfusion model to evaluate antioxidant activities in vivo. We found that both chlorogenic acid and caffeic acid had effects on intestinal ischemia-reperfusion injury. Since caffeic acid has a stronger antioxidant activity than that of chlorogenic acid and chlorogenic acid is hydrolyzed into caffeic acid in the intestine, it is possible that caffeic acid plays a major role in the protective effect of chlorogenic acid against ischemia-reperfusion injury.     

Montmorillonite adsorbs uric acid and increases the excretion of uric acid from the intestinal tract in mice

Objectives The aim was to evaluate the adsorbing effect of montmorillonite on uric acid, promoting diffusion of uric acid from blood to intestine, preventing absorption of uric acid in intestine and reducing uric acid level in serum. Methods The adsorbing effect of montmorillonite on uric acid was observed in vitro. The intestine and blood vessel of rats were circularly perfused with intestinal perfusate and vascular perfusate, respectively. A model of hyperuricaemia in mice was prepared by intraperitoneal injection of hypoxanthine and potassium oteracil. The concentration of uric acid was determined by the method of urate oxidase and peroxide enzyme. Key findings The results showed that different concentrations of montmorillonite could adsorb uric acid in a concentration‐dependent manner. The adsorbing effect was fast. The adsorptive rate was high in acid solution and was low in alkaline solution. When blood vessels were circularly perfused by vascular perfusate containing uric acid, the concentration of uric acid in vascular perfusate was decreased and the concentration of uric acid in intestinal perfusate was increased, suggesting that uric acid in blood vessels diffused into the intestine. When the intestine was perfused with intestinal perfusate containing uric acid, the uric acid concentration in vascular perfusate was increased, but the uric acid concentration of intestinal perfusate was decreased, suggesting that uric acid was absorbed in the intestine. The uric acid concentrations of intestinal perfusate and vascular perfusate in montmorillonite 0.5 and 1.0 g/kg groups were lower than the control group. Concentrations of uric acid in serum and urine in the montmorillonite 1 and 2 g/kg groups were lower compared with mice in the hyperuricaemic group. Conclusions The results suggested that montmorillonite adsorbed uric acid and promoted diffusion of uric acid from blood vessels to intestine, prevented absorption of uric acid in intestine and decreased uric acid level in serum.     

13-cis retinoic acid and isomerisation in paediatric oncology--is changing shape the key to success?

Retinoic acid isomers have been used with some success as chemotherapeutic agents, most recently with 13-cis retinoic acid showing impressive clinical efficacy in the paediatric malignancy neuroblastoma. The aim of this commentary is to review the evidence that 13-cis retinoic acid is a pro-drug, and consider the implications of retinoid metabolism and isomerisation for the further development of retinoic acid for cancer therapy. The low binding affinity of 13-cis retinoic acid for retinoic acid receptors, low activity in gene expression assays and the accumulation of the all-trans isomer in cells treated with 13-cis retinoic acid, coupled with the more-favourable pharmacokinetic profile of 13-cis retinoic acid compared to other isomers, suggest that intracellular isomerisation to all-trans retinoic acid is the key process underlying the biological activity of 13-cis retinoic acid. Intracellular metabolism of all-trans retinoic acid by a positive auto-regulatory loop may result in clinical resistance to retinoic acid. Agents that block or reduce the metabolism of all-trans retinoic acid are therefore attractive targets for drug development. Devising strategies to deliver 13-cis retinoic acid to tumour cells and facilitate the intracellular isomerisation of 13-cis retinoic acid, while limiting metabolism of all-trans retinoic acid, may have a major impact on the efficacy of 13-cis retinoic acid in paediatric oncology.     

Role of quisqualic acid receptors in the hypermotility response produced by the injection of AMPA into the nucleus accumbens

alpha-Amino-3-hydroxy-5- methylisoxazole-4-propionate (AMPA) is an excitatory amino acid which on the basis of electrophysiological and binding studies appears to act as a quisqualic acid receptor agonist. AMPA and other excitatory amino acids, such as quisqualic acid, kainic acid, and N-methyl-D-aspartic acid, as well as picrotoxin, an inhibitor of endogenous GABA, produce a marked stimulation of locomotor activity after bilateral injection into the nucleus accumbens. The intraacumbens injection of gamma-D-glutamylaminomethylsulphonate (GAMS) was found to inhibit the hypermotility responses produced by AMPA and quisqualic acid at doses that were unable to inhibit the hypermotility responses produced by kainic acid, N-methyl-D-aspartic acid, and picrotoxin. These results suggest that GAMS is able to selectively inhibit quisqualic acid receptors in the nucleus accumbens. The intraacumbens injection of D-alpha-aminoadipic acid at a dose that significantly inhibited N-methyl-D-aspartic acid-stimulated locomotor activity did not produce a significant inhibition of AMPA-stimulated locomotor activity, suggesting that AMPA is not acting at N-methyl-D-aspartic acid receptors. Thus, these results suggest that the activation of quisqualic acid receptors in the nucleus accumbens produces a hypermotility response.     

Comparative effects of oxygen and sulfur-substituted fatty acids on serum lipids and mitochondrial and peroxisomal fatty acid oxidation in rat.

Feeding tetradecyloxyacetic acid (a 3-oxa fatty acid) to rats led to decreased serum cholesterol and decreased serum triacylglycerol, resembling the effects of the corresponding 3-thia fatty acid (tetradecylthioacetic acid). The 3-oxa fatty acid inhibited strongly the mitochondrial fatty acid oxidation and led to the development of fatty liver, while the 3-thia fatty acid stimulated the mitochondrial fatty acid oxidation. Feeding tetradecyloxypropionic acid (a 4-oxa fatty acid) had less effect on the serum lipids. It stimulated fatty acid oxidation in the mitochondria and lowered the hepatic level of triacylglycerol. The corresponding 4-thia fatty acid (tetradecylthiopropionic acid) inhibited mitochondrial fatty acid oxidation and induced development of fatty liver. All these compounds, both the oxa and the thia fatty acids, induced some increase in the activity of the peroxisomal acyl-CoA oxidase. Repeated administration of 3-oxadicarboxylic acid to rats resulted in no lipid lowering effects, and marginal changes of fatty acyl-CoA oxidase activity. Oxidation of the S-atom of the 3-thia fatty acid to the corresponding sulfoxide or sulfone eliminated the metabolic effects of the thia fatty acid. The study has shown that the effects of 3- and 4-oxa fatty acids are in some ways opposite to those of the 3- and 4-thia fatty acids. The possibility that the lipophilicity of the fatty acid analogues may be an important factor behind the differences observed are discussed. It is suggested that these oxa- and thia-analogues of fatty acids may be useful in studies on the regulation of fatty acid metabolism.     

Metabolic fate of gallic acid orally administered to rats

The metabolic behavior of orally administered gallic acid was investigated by HPLC and 4-O-methyl gallic acid was found to be the main metabolite in rat peripheral blood and urine. After oral administration of gallic acid, maximum concentration in portal vein and inferior vena cava occurred at 15 and 30 min, respectively. In portal vein, gallic acid was preferentially detected relative to 4-O-methyl gallic acid, whereas gallic acid and 4-0-methyl gallic acid were equally detected in inferior vena cava. On the other hand, 4-O-methyl gallic acid but not gallic acid was found in liver. The contents of gallic acid and 4-O-methyl gallic acid in urine were nearly 100 times higher than those in blood. The ratio of 4-O-methyl gallic acid to total gallic acid metabolites in urine was from 0.55 to 0.76, indicating that a considerable amount of gallic acid was excreted without being metabolized. In this study we found that gallic acid administered orally existed in the blood for 6 h at most, and more than half was metabolized to 4-O-methyl gallic acid, followed by excretion into urine.     

Effects of dehydroepiandrosterone on oleic acid accumulation in rat liver

The purpose of the present study was to determine whether dehydroepiandrosterone (DHEA) affects de novo fatty acid synthesis, oleic acid formation, fatty acid oxidation, and very low density lipoprotein (VLDL) secretion, in relation to the accumulation of lipid containing oleic acid, in rat liver. The rates of hepatic de novo synthesis of both fatty acid and monounsaturated fatty acid, determined by incorporation of 3H from 3H(2)O into fatty acid, were increased markedly when rats were fed a diet containing 0.5% (w/w) DHEA for 14 days. The treatment of rats with DHEA also enhanced the conversion of [14C]stearic acid into oleic acid in the liver in vivo. DHEA did not suppress fatty acid degradation in the liver. Namely, mitochondrial palmitic acid oxidation in liver homogenates and isolated hepatocytes was increased approximately 1.9- and 5-fold, respectively, in DHEA-treated rats. Peroxisomal palmitic acid oxidation in isolated hepatocytes from rats treated with DHEA, however, was not significantly different from that of the control, despite the fact that peroxisomal degradation of palmitic acid in the liver homogenates was increased markedly. The rate of hepatic VLDL secretion in DHEA-treated rats was decreased markedly. These results indicate that the elevation of the hepatic fatty acid content, especially oleic acid, by DHEA feeding is due to an increase in both de novo fatty acid synthesis and the formation of oleic acid and to a decrease in the rate of hepatic VLDL secretion. Mitochondrial and peroxisomal fatty acid degradation does not appear to play a significant role in the accumulation of hepatic lipids.     

Monocarboxylate transporter mediates uptake of lovastatin acid in rat cultured mesangial cells

To clarify the uptake mechanism(s) for statins, we examined whether monocarboxylate transporter (MCT) contributed to the uptake of lovastatin acid by rat cultured mesangial cells. Expression of mRNAs for MCT1, 2, and 4 was confirmed in mesangial cells. The uptake of lovastatin acid by mesangial cells increased with decreasing extracellular pH. There was clear overshooting in lovastatin acid uptake by the ATP-depleted cells in the presence, but not in the absence, of an inwardly directed H(+)-gradient. The representative MCT substrates/inhibitors inhibited the lovastatin acid uptake. In particular, the inhibition of lovastatin acid uptake by L-lactic acid at the concentration of 80 mM reached 70%, and L-lactic acid and valproic acid inhibited the uptake competitively. On preloading of mesangial cells with L-lactic acid or valproic acid, the lovastatin acid uptake was significantly stimulated. The inhibition constant of L-lactic acid for the lovastatin acid uptake was 32 mM, and this value is comparable to the Michaelis constant (>20 mM) of L-lactic acid for MCT4 described elsewhere. These results demonstrate that lovastatin acid was largely taken up by mesangial cells via MCT, and suggest that MCT4 might contribute to lovastatin acid uptake in the cells.     

Synthesis and biologic distribution of mercapto derivatives of palmitic acid.

Mercapto derivatives of palmitic acid are capable of binding 99mTc. Based on the hypothesis that 99mTc-labeled palmitic acid derivatives would behave biologically like palmitic acid and thus could be used as myocardial imaging agents, three mercaptopalmitic acid derivatives have been prepared. The synthesis of 2-mercaptopalmitic acid, 2-mercapto-1,16-hexadecanedioic acid, and 16-mercaptopalmitic acid was accomplished by reaction of the corresponding bromo compound with thiourea. The 35S-labeled compounds and [16-14C]palmitic acid were evaluated in rats with a heat-inflicted myocardial infarction to study the effect of the introduction of the mercapto group. The organ distribution of 2-[35S]mercaptopalmitic acid was most similar to that of [16-14C]palmitic acid.     

Pharmacokinetics of talniflumate,a prodrug of niflumic acid,following oral administration to man

Plasma profile of niflumic acid following oral administration of talniflumate tablets (Somalgen) was compared to that of niflumic acid tablets in man. Plasma niflumic acid was assayed by HPLC method. Plasma niflumic acid profile from the talniflumate tablets was similar to that from the niflumic acid tablets resulting in no differences in AUC,C _max,t _max and MRT. It demonstrates that talniflumate is a prodrug of niflumic acid, and undergoes extensive first-pass biotransformation to niflumic acid. However, plasma niflumic acid concentration at 30 min after talniflumate dosing was significantly (p<0.05) higher than that of niflumic acid dosing. The more potent analgesic activity of talniflumate than niflumic acid might be related to this higher plasma drug concentration at the earlier phase. Considering that talniflumate is less irritant to gastrointestinal mucosa than niflumic acid, talniflumate seems to be advantageous over niflumic acid in therms of activity and side effects.