Urinary excretion ofD-glucaric acid,an indicator of drug metabolizing enzyme activity,in patients with impaired renal function

Summary The urinary excretion rate ofD-glucaric acid, an in vivo parameter of the activity of drug metabolizing enzymes, has been determined in patients with chronic renal insufficiency (glomerular filtration rate 4.5–80 ml/min/1.73 m²). The mean value of 22.3 µmoles/d (SD 7.2; n 28) was almost identical to that of healthy controls (22.1 µmoles/d, SD 7.3; n 22). Thus, no inhibitory or enhancing effect of renal insufficiency could be detected. The ability of this parameter to indicate alterations in the activity of hepatic drug metabolism, even in patients with renal insufficiency, was demonstrated by the increased excretion rate of glucaric acid (107 µmoles/d, SD 43.5; n 8; p<0.001) after treatment for 7 days with the enzyme inducer phenobarbital. No significant correlation was found between glucaric acid excretion and sex, age, body weight or body surface in 50 patients. Glucaric acid excretion, therefore, should not be related to the creatinine content of urine samples, since creatinine excretion decreases with severity of renal insufficiency and varies with sex, age, body weight and many other conditions. A single dose of dipyrone (Novalgin^®), a further in vivo indicator of drug metabolism, increased glucaric acid excretion on the same day, but no interference was found after a single dose of cortisol.     

The Effect of Nitric Oxide Synthase Inhibitors on the Development of Analgesic Tolerance to Dipyrone in Mice

Recent investigations have shown that, similarly to opioids, tolerance develops to the analgesic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Nitric oxide has been shown to play an important role in opioid-induced analgesic tolerance; we, therefore, planned to determine if nitric oxide also plays role in the analgesic tolerance to dipyrone, a NSAID. Using the hot-plate test in mice, an analgesic tolerance developed to dipyrone with its 150 and 300 mg/kg intraperitoneal doses after 7 days; no tolerance was observed with its dose of 600 mg/kg. Neither 7-nitroindazole (50 mg/kg, i.p.), a neuronal NOS inhibitor, nor aminoguanidine (30 mg/kg, i.p.), an inducible NOS inhibitor, had any effect on dipyrone-induced analgesic tolerance with doses, which also had no analgesic effect when used alone. Our results show that nitric oxide does not play role in the analgesic tolerance to dipyrone; however, further experiments are required to delineate the mechanisms and to take preventive measures against this problem, which will possibly limit the use of NSAIDs.     

The effects of chronic administration of sumatriptan and dipyrone on serotonergic system in the rat brain: an immunohistochemical study

Objective – To investigate the effects of chronic high dose sumatriptan and dipyrone treatment on central serotonergic system in rats. Materials and methods – Male Sprague–Dawley rats (seven per group) were daily injected with sumatriptan (3 mg/kg), dipyrone (400 mg/kg) or saline for 30 days. The brains of animals were surgically removed and immunohistochemically stained for serotonin. Serotonin‐positive stained cells were counted automatically by using a computerized image analysis program. Statistical analysis carried out using one‐way ANOVA followed by post hoc Tukey test. Results – A significant decrease in serotonin‐positive cells in the brainstem was observed after chronic sumatriptan administration while chronic use of dipyrone induced a significant increase in serotonin‐positive cells both in the cortex and midbrain. Conclusion – Our data suggest that central serotonergic system might be modified by chronic use of sumatriptan and dipyrone.     

Effect of topical application of dipyrone on dental sensitivity reduction after in-office dental bleaching: A randomized,triple-blind multicenter clinical trial

Background

Tooth sensitivity commonly occurs during and immediately after dental bleaching. The authors conducted a trial to compare tooth sensitivity after in-office bleaching after the use of either a topical dipyrone or placebo gel.

The early history of non-opioid analgesics

The late 19th century gave rise to the discovery of the three prototypes of modern non-opioid antipyretic analgesics: acetaminophen (acetanilide), aspirin and salicylic acid, and phenazone. At three different sites at almost the same time in Germany the zest for finding substitutes for quinine, ie antipyretic drugs, led to synthetic efforts culminating at Erlangen in the synthesis of phenazone (antipyrine), at Strasbourg of acetanilide (antifebrin), and at Wuppertal of aspirin (acetylsalicylic acid). The rationales for synthesising these drugs were not stringent, but proved, nonetheless, successful. Thereafter chemists concentrated their attempts merely on modifying the drugs discovered with the help of the rapidly expanding and improving organic chemistry. Although no new principles were discovered, the ‘relatives’ of the originals, namely aspirin and its modifications, acetaminophen and propyphenazone, as well as dipyrone, still make up for about 50% of the market of the antipyretic analgesics worldwide.Some of these compounds have attracted new interest recently. This is particularly the case with dipyrone (metamizole, Novalgin). After more than 50 years of clinical use (without major research efforts) state of the art investigation was commenced, and at its 75th birthday this compound is now thoroughly investigated. The side effect profile and risks, as well as the pharmacokinetic parameters, are defined and the mode of action has been elucidated. Although several clinical studies show effectiveness, probably due to the 75 year-long worldwide experience, modern therapy orientated studies proving usefulness in specific indications, claimed by many physicians and patients (eg after bone marrow transplantation, against migraine, and in osteoarthrosis), are still unavailable. In this respect, further research efforts and extension of knowledge is required, since this drug lacks gastrointestinal and renal toxicity, blood coagulation is only marginally influenced, and the widely discussed agranulocytosis is extremely rare and nearly never fatal.     

Influence of food on the pharmacokinetics of dipyrone

Summary Twelve healthy volunteers were given a single oral dose of dipyrone 1 g, once while fasting and once after a standard breakfast. Plasma levels of the active dipyrone metabolite — Methylaminoantipyrine (MAA) were measured and the calculated pharmacokinetic parameters were compared.Taking dipyrone with food resulted in a small delay in the mean time to peak from 1.5 h to 1.9 h (p<0.01). However, there was no significant difference in AUC, C_max or K_elim between fasting and nonfasting conditions. The rate of absorption, expressed as the mean K_abs, was somewhat slower in the nonfasting state, but not significantly so.It is suggested that dipyrone may be taken regardless of the times of eating.     

安乃近滴液在正常人体内的生物利用度

比较了6例健康志愿者,单剂量po lg安乃近滴液和单剂量po lg安乃近片剂的生物利用度。采用高效液相色谱法,测定受试者体内安乃近的活性代谢产物,4-甲氨基安替比林(MAA)血浆浓度。其MAA在血浆中的达峰时间(Tp):滴液组平均为1.08±0.25h,片剂组平均为1.36±0.13h,(P<0.05)。其相对生物利用度(F=RUC滴液/AUC片剂)为1.26±0.44,P>0.05。     

Study of unilateral postherniorraphy analgesia with local anaesthetic and monitored anaesthesia care

Local anaesthetic with monitored anaesthetic care (MAC) is a very good technique for unilateral-inguinal herniorraphy. We looked at the analgesia produced by the infiltration with local anaesthetic, the intensity of pain in the immediate postsurgery period; the efficiency of oral analgesics and the satisfaction of the patients. Between January and July 1997, 63 patients underwent unilateral-inguinal herniorraphy (Shouldice type) using local anaesthetic (300 mg of mepivacain 1% and 50 mg of bupivacain 0.25%) and MAC (fentanyl, mydazolan and propofol). The intensity of pain was measured using two evaluation scales: visual analogue scale (EV) and verbal scale (Eve). When the patients asked for an analgesic they were given magnesic metamizol (Nolotil), every 6 h. Five patients (8%) felt no pain and 58 felt pain 4 h 36 min after local anaesthetic infiltration (EV=2.5; Eve=1.45) of these 58 patients, 49 took a first dose of ‘Nolotil’ 6 h 40 min after local anaesthetic induction (EV=4; Eve=1.97), 43 received a second dose of ‘Nolotil’ at 13 h 40 min (EV=3; Eve=1.49) and 22 a third dose at 17 h 40 min (EV=3.2; Eve=1.7). Every patient that was very satisfied with the anaesthetic technique, said that the postsurgery pain was bearable and they would be happy to be operated on again with the same anaesthetic-surgery technique. The efficacy of the anaesthetic technique (local anaesthetic with conscious sedation) was very good, 8% of the patients never felt pain and 21% never received any analgesic. The time passed until the first analgesic dose was 6 h 40 min, and the tolerance of the pain was excellent.