Antipyretic efficacy and safety of a single intravenous administration of 15 mg/kg paracetamol versus 30 mg/kg propacetamol in children with acute fever due to infection

OBJECTIVES: An intravenous formulation of paracetamol and an intravenous formulation of propacetamol (prodrug of paracetamol) were compared in children with acute fever due to infection in order to determine the antipyretic efficacy and safety during the 6-hour period after administration. METHODS: A total of 67 patients aged 1 month to 12 years and with a rectal body temperature between 38.5 degrees C and 41 degrees C, were randomized to receive either intravenous paracetamol 15 mg/kg (n = 35) or propacetamol 30 mg/kg (n = 32) under double-blind conditions. RESULTS: The non-inferiority of intravenous paracetamol compared to propacetamol was demonstrated (non-inferiority margin = 0.5 degrees C) by the median body temperature reduction of 1.9 degrees C in the intravenous paracetamol group and the reduction of 2.05 degrees C in the propacetamol group. The difference in the incidence of local adverse events was statistically significant (p = 0.0134) with more local adverse events in the propacetamol group (9, 28.1%) than in the intravenous paracetamol group (2, 5.7%). CONCLUSION: This double-blind, randomized, clinical trial demonstrates the non-inferiority of a single administration of 15 mg/kg intravenous paracetamol in comparison to 30 mg/kg propacetamol in terms of body temperature reduction in children aged 1 month to 12 years with acute fever due to infection. It confirms the better local safety of intravenous paracetamol in comparison to propacetamol.     

Antipyretic effect of tenoxicam and paracetamol in febrile children

The antipyretic activity of tenoxicam was compared with that of paracetamol. Thirty-eight inpatients aged between 6 months and 16 years, with a rectal temperature of above 38.5 degrees C, were divided into four groups. Patients received tenoxicam (0.3, 0.6 or 1.2 mg/kg) or paracetamol (10 mg/kg) in a single oral dose. Rectal temperatures were recorded before admission, 30 min and 1, 2, 3, 4, 5 and 6 h after administration of the drug. The fall in temperature was significant in the paracetamol group and in one tenoxicam group with a dose of 1.2 mg/kg. Doses of 0.3 and 0.6 mg/kg of tenoxicam had only a slight effect. It was concluded that tenoxicam has a slight antipyretic effect, but is not an alternative to paracetamol as an antipyretic drug in the treatment of fever in children.     

The curative effects of cysteamine,cysteine, and dithiocarb in experimental paracetamol poisoning

In a curative test (i.p. injection 1 hr after administration of paracetamol) cysteamine (100 mg/kg), cysteine (200 mg/kg), and dithiocarb (100 mg/kg) reduced the death rate from paracetamol poisoning (1.5g/kg p.o.) in male mice from 67 to 10, 15 or 10%, respectively. A reduction of mortality rate to 30 or 35% was induced by glutathione (100 mg/kg) and thiazolidine carboxylic acid (50 mg per kg), respectively, whereas penicillamine, thioctic acid, silymarin, and dimercaprol were ineffective. When given 2 or 4 hrs after paracetamol, cysteine, unlike cysteamine, had a curative effect on paracetamol toxicity.Hepatotoxic activity of paracetamol (0.5 g/kg p.o.) was evident by high increases in the levels of serum enzymes (GOT, GPT, GLDH, SDH). Paracetamol-induced enzyme elevations were prevented completely by treatment with cysteamine (50 mg/kg) or cysteine (100 mg/kg) and partially by treatment with dithiocarb (100 mg/kg) 1 hr after paracetamol. LD₅₀ values (i.p. injection) were 450 mg per kg for cysteamine, 660 mg/kg for cysteine, and 1800 mg/kg for dithiocarb. With regard to the therapeutic index cysteamine, cysteine, and dithiocarb can be recommended as antidotes for paracetamol poisoning.A nearly total depletion of hepatic glutathione occurred after paracetamol (0.5 g/kg p.o.). Administration of cysteine (100 mg/kg), one hr after paracetamol, induced a complete repletion of liver glutathione whereas cysteamine (100 or 200 mg/kg) and dithiocarb (100 mg/kg) induced a partial repletion. Glutathione repletion probably accounts for the antidote efficiency of cysteine, cysteamine, and dithiocarb. Its mechanism, however, remains obscure.     

In vivo studies on toxic effects of concurrent administration of paracetamol and its N-acetyl-DL-methionine ester (SUR 2647 combination)

1. Single p.o. doses of paracetamol 400 and 800 mg/kg or SUR 2647 combination (free paracetamol + paracetamol-N-acetyl-DL-methionate, paracetamol/methionine ratio 2:1) equivalent to paracetamol 400 and 800 mg/kg were given to Bom:NMRI mice. Vehicle treated (1% w/v aqueous methylcellulose) mice were established as a control group. 2. All treatment groups irrespective of medication caused an initial GSH depletion. However, SUR 2647 combination 400 mg/kg caused a much earlier hepatic GSH recovery than paracetamol 400 mg/kg. SUR 2647 combination 800 mg/kg caused a higher hepatic GSH level than paracetamol 800 mg/kg. 3. There was no significant difference in the plasma ALAT level after SUR 2647 combination 400 or 800 mg/kg and the control group. Paracetamol 400 and 800 mg/kg caused significant plasma ALAT elevations compared to the control group. 4. The addition of N-acetyl-DL-methionine esterified to paracetamol, as in the SUR 2647 combination, enhances the hepatic GSH synthesizing capacity in Bom:NMRI mice after experimental overdosage and offers protection of hepatic cell integrity as assessed by plasma ALAT level compared to paracetamol alone.     

Pharmacokinetic Interactions of Antihepatotoxic Wedelolactone with Paracetamol in Wistar Albino Rats

Abstract

Eclipta alba. (Linn.) Hassk. (Asteraceae), popularly known as “bhringraj,” is effective against liver damage caused by various hepatotoxins and is used traditionally in Indian phytoformulations. For enhanced in vitro. production of wedelolactone (W), leaves of aseptically germinated seedlings were cultured on Murashige and Skoog's (MS) medium supplemented with plant growth regulators under controlled and standardized chemical and environmental conditions. The wedelolactone was extracted, isolated, purified, chemically characterized, and quantitatively estimated. Rats were divided into four groups of six animals each and given paracetamol (250 mg/kg, p.o.), paracetamol (250 mg/kg, p.o.) with wedelolactone (100 mg/kg, p.o.), paracetamol (250 mg/kg, p.o.) with plant leaves extract (250 mg/kg, p.o.), paracetamol (250 mg/kg, p.o.) with leaf callus extract (250 mg/kg, p.o.), respectively. Blood samples were collected at 1, 2, 3, 4, and 6 h after drug administration, and plasma paracetamol concentration was determined. Pharmacokinetic studies revealed that concomitant administration of wedelolactone with paracetamol does not affect the bioavailability of paracetamol. There was no change in C_max between paracetamol and paracetamol with wedelolactone, but the T_max of paracetamol was 2 h in control animals while administration of wedelolactone and extracts with paracetamol resulted in shifting of T_max from 2 to 3 h without affecting the area under the curve (AUC). Because wedelolactone does not alter the bioavailability of paracetamol significantly and also shows a hepatoprotective effect, its use may be recommended in prolonged paracetamol therapy or paracetamol toxicity.     

Developmental effects of propyphenazone in analgesic and antipyretic combination with caffeine or paracetamol

The aim of the study was to determine the influence of an over-the-counter (OTC) mixture of propyphenazone with caffeine or paracetamol on prenatal development. Propyphenazone:caffeine and propyphenazone:paracetamol mixtures were prepared with constant 3:1 and 3:5 ratios, respectively. Three dose levels of each of the mixtures were administered separately in Tween-80 water suspension once a day to pregnant Wistar rats on gestation days 8-14. The low dose was similar to the OTC preparations, 2.1 mg/kg of propyphenazone, 0.7 mg/kg of caffeine or 3.5 mg/kg of paracetamol. The middle dose was 21.0, 7.0 or 35.0 mg/kg, and the highest 210.0, 70.0 or 350.0 mg/kg for propyphenazone, caffeine or paracetamol, respectively. On day 21 of gestation the fetuses were delivered by hysterectomy. Dead or live fetuses, resorptions and the number of implantation sites were counted. Live fetuses were examined for external, visceral and skeletal malformation. Postimplantation mortality was calculated. Dose-dependent effects in the middle and high dose groups on fetal body weight/length and placental weight were found. No increase in external or internal congenital anomalies was found in any of the mixture-exposed groups. Prenatal coadministration of propyphenazone with caffeine or paracetamol caused intrauterine growth retardation but did not increase external or internal congenital anomalies. The risk of midline defects (umbilical hernia and gastroschisis) is discussed.     

HPLC法同时测定复方银翘氨敏胶囊中对乙酰氨基酚与维生素C的含量

目的建立HPLC法同时测定复方银翘氨敏胶囊中对乙酰氨基酚与维生素C的含量。方法采用Zorbax SB C18色谱柱,乙腈-0.02mol·L^-1磷酸二氢钾溶液-三乙胺（10∶90∶0.02）为流动相;流速：0.8mL.min-1;检测波长：249nm;柱温：30℃。结果对乙酰氨基酚的浓度在10～160mg·L^-1范围内线性关系良好,r=0.9990;维生素C的浓度在5～80mg·L^-1范围内线性关系良好,r=0.9991。平均回收率：对乙酰氨基酚为100.3%（RSD=0.6%）,维生素C为98.7%（RSD=1.3%）。结论本方法测定复方银翘氨敏胶囊中对乙酰氨基酚与维生素C的含量简便？快速？准确,且分离效果好。     

A SIMPLE HPLC ASSAY FOR URINARY PARACETAMOL METABOLITES AND ITS USE TO CHARACTERIZE THE C3H MOUSE AS A MODEL FOR PARACETAMOL METABOLISM STUDIES

1. A high performance liquid chromatographic (HPLC) assay for unchanged paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates in the urine of man, mouse and rat is described. The method is simple, rapid and reproducible. 2. The metabolite assay has been used to characterize the male C3H mouse, which shows sensitivity to paracetamol toxicity similar to man, as a model for paracetamol metabolism studies. 3. In male C3H mice there was no evidence to suggest saturability of the glucuronidation pathway on increasing the paracetamol dose from 50 to 300 mg/kg. By contrast, the metabolic ratio and fractional excretion of both the sulphate and glutathione-derived conjugates decreased with increasing paracetamol dose. 4. For animals administered a 200 mg/kg dose of paracetamol, pretreatment with phenobarbitone or 3-methylcholanthrene increased the fractional excretion and metabolic ratio of the glutathione-derived and glucuronic acid conjugates. Piperonyl butoxide pretreatment of animals administered the same dose of paracetamol inhibited glutathione and glucuronic acid conjugation.     

复方对乙酰氨基酚维生素C分散片在健康人体药物动力学和相对生物利用度

目的：研究复方对乙酰氨基酚维生素C分散片在健康人体的药物动力学和相对生物利用度。方法：用随机分组自身对照方法,20名健康志愿者分别单次剂量服用复方对乙酰氨基酚维生素C分散片与参比制剂泡腾片,HPLC法检测对乙酰氨基酚和维生素C的血浓度,采用DAS1．0程序计算药物动力学参数并进行生物等效性评价。结果：分散片与泡腾片中,对乙酰氨基酚的AUC0→t分别为（39．74±9．76）和（39．83±6．76）mg·h·L^-1,AUC0→∞分别为（41．43±10．25）和（40．88±7．13）mg·h·L^-1;Cmax分别为（10．57±2．45）和（10．27±1．75）mg·L^-1;tmax分别为（0．52±0．34）和（0．75±0．51）h;维生素C的AUC0→t分别为（91．35±28．29）和（89．47±23．10）mg·h·L^-1,Cmax,分别为（7．71±1．80）和（7．53±2．15）mg·L^-1;tmax分别为（2．36±0．91）和（2．36±0．85）h;分散片平均相对生物利用度分别为（102．94±15．96）％（以对乙酰氨基酚计算）和（100．09±12．75）％（以维生素C计算）。结论：分散片和参比制剂具有生物等效性。     

Dose-dependent biliary and renal excretion of paracetamol in the rat.

In rats, the biliary and renal excretion of paracetamol changed in a dose-dependent manner. After an oral nonhepatotoxic dose of 200 mg/kg paractamol, the drug excreted in the bile amonted to only 5.5% within 24 h, whereas 72% of the dose were excreted into the urine. Following an oral hepatoxic dose (1,000 mg/kg), the biliary excretion of thotal paracetamol was enhanced to 13.5% whereas the renal elimination was reduced to 51% of the dose. After a nontoxic intravenous treatment with paracetamol (25-100-400 mg/kg), both the excretion of paracetamol conjugates into the bile and the elimination of free paracetamol into the urine were augmented in a dose-dependent manner. Hepatic damage due to carbon tetrachloride pretreatment (0.5 ml/kg i.p. 24 h before 100 mg/kg paracetamol i.v.) diminished both the bile flow and the biliary excretion of paracetamol conjugates, whereas the renal elimination was not affected.     

Systematic evaluation of the nefopam–paracetamol combination in rodent models of antinociception

1. The aim of the present study was to explore the concept of multimodal anaesthesia using a combination of two non‐opioid analgesics, namely nefopam, a centrally acting non‐opioid that inhibits monoamine reuptake, and paracetamol, an inhibitor of central cyclo‐oxygenases. The antinociceptive characteristics of the combination were evaluated using four different animal models of pain. 2. In the mouse writhing test, antinociceptive properties were observed with ED₅₀ values of 1.5 ± 0.2 and 120.9 ± 14.8 mg/kg for nefopam and paracetamol, respectively. In the mouse formalin test, both compounds significantly inhibited the licking time of the injected hind paw, with ED₅₀ values in the early phase of 4.5 ± 1.1 and 330.7 ± 80.3 mg/kg for nefopam and paracetamol, respectively, compared with 4.3 ± 0.2 and 206.1 ± 45.1 mg/kg for nefopam and paracetamol, respectively, in the inflammatory phase. Isobolographic analysis revealed that this drug combination was synergistic in the writhing test and additive in the formalin test. 3. In a rat incision model of postoperative thermal hyperalgesia, coadministration of nefopam at a non‐analgesic dose (3 mg/kg) with paracetamol at a low analgesic dose (300 mg/kg) showed the appearance of a strong antihyperalgesic effect, maintained for at least 3 h. In rat carrageenan‐induced tactile allodynia, the combination of low analgesic doses of nefopam (10 or 30 mg/kg) with a non‐analgesic dose of paracetamol (30 mg/kg), significantly blocked allodynia with a longer duration of efficacy. 4. In conclusion, coadministration of nefopam with paracetamol is worthy of clinical evaluation.     

A comparison of vitamin K antagonism by warfarin,difenacoum and brodifacoum in the rabbit

The pharmacological response to vitamin K₁ (Konakion^’) in anticoagulated (prothrombin complex activity <30%) New Zealand white rabbits was determined by measuring prothrombin complex activity (P.C.A.) in peripheral plasma. In animals pretreated with either brodifacoum (1 mg/kg or 10 mg/kg) or difenacoum (0.85 mg/kg or 8.5 mg/kg) P.C.A. reached a maximum 4 hr after administration of vitamin K₁ (0.5 mg/kg) and declined at a rate indicating complete inhibition of clotting factor synthesis. A different response to vitamin K₁ (0.5 mg/kg) was observed in rabbits pretreated with warfarin (63 mg/kg); after an initial rise P.C.A. appeared to plateau for 11 hr and then fall at a rate which indicated incomplete inhibition of clotting factor synthesis. The response to several doses of vitamin K₁ (0.5, 1, 2.5 and 5.0 mg/kg) was investigated in the same group of brodifacoum (1 mg/kg) anticoagulated animals. There was a linear relationship between the duration of clotting factor synthesis and the logarithm of the dose of the vitamin K; the pharmacological half-life of vitamin K₁ was only 1.7 ± 0.1 hr. The duration of action of brodifacoum and difenacoum was much longer than that of warfarin. Six weeks after administration of brodifacoum (1 mg/kg) animals were still anticoagulated (P.C.A. < 30%). In conclusion, we have found that brodifacoum and difenacoum are both more potent and persistent antagonists of vitamin K₁ than warfarin in vivo. In cases of poisoning with these compounds it will be necessary to give repeated and frequent doses of vitamin K to maintain clotting factor synthesis.     

Combined treatment of ascorbic acid or alpha-tocopherol with dopamine receptor antagonist or nitric oxide synthase inhibitor potentiates cataleptic effect in mice

Rationale Drugs like haloperidol (Hal) that decrease dopamine (DA) neurotransmission in the striatum induce catalepsy in rodents and Parkinson disease-like symptoms in humans. Nitric oxide synthase (NOS) inhibitors interfere with motor activity, disrupting rodent exploratory behavior and inducing catalepsy. Catalepsy induced by NOS inhibitors probably involves striatal DA-mediated neurotransmission. Antioxidants such as ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) have also been shown to interfere with movement modulation and the DA system. Objective The objective of the study is to investigate if the antioxidants vitamins C and E would influence the catalepsy produced by Hal and NOS inhibitors. Methods The effects of the following treatments on catalepsy were examined using the hanging-bar test on male Swiss mice (25–30 g): (1) vitamin C (30–1,000 mg/kg)×Hal (1 mg/kg); (2) vitamin C (90–1,000 mg/kg)×N ^G-nitro-l-arginine (LNOARG, 10 and 40 mg/kg); (3) vitamin C (300 mg/kg)×N ^G-nitro-l-arginine methylester (LNAME, 20–80 mg/kg); (4) vitamin C (300 mg/kg) × 7-nitroindazole (7NI, 3–50 mg/kg); (5) vitamin C (90 mg/kg i.p.) × LNOARG [40 mg/kg twice a day during 4 days (subchronic treatment)]; (7) vitamin E (3–100 mg/kg) × Hal (1 mg/kg); and (6) vitamin E (3–100 mg/kg) × LNOARG (40 mg/kg). Results Vitamin C enhanced the catalepsy produced by NOS inhibitors and Hal. Treatment with vitamin C did not affect tolerance to LNOARG cataleptic effect induced by subchronic treatment. Vitamin E potentiated the catalepsy induced by LNOARG at all doses tested; in contrast, catalepsy induced by Hal was enhanced only by the dose of 100 mg/kg. Conclusions Results support an involvement of dopaminergic and nitrergic systems in motor behavior control and provide compelling evidence that combined administration of the antioxidants vitamins C and E with either Hal or NOS inhibitors exacerbates extrapyramidal effects. Further studies are needed to assess possible clinical implications of these findings.     

Metabolism of [14C]Paracetamol and its Interactions with Aspirin in Hamsters

1. The metabolism of [¹⁴C]paracetamol (150 mg/kg) and its interactions with aspirin (200 mg/kg) were studied in male hamsters.

2. Aspirin was found to slow the rate of paracetamol absorption from the gastro-intestinal tract, but did not affect the rate of elimination.

3. Metabolism studies showed that >80% of the radioactivity was excreted in the urine in 24 h. Paper chromatography of the urine separated the radioactivity into five peaks, four of which were identified as paracetamol and its glucuronide, sulphate and mercapturate conjugates.

4. The other peak, comprising of < 10% of the total radioactivity, was a mixture of two or more other metabolites. A major component was isolated and characterized as methyl 2-hydroxy-5-acetamidophenyl sulphone.

5. Aspirin inhibited the metabolism of paracetamol by the sulphate conjugation pathway.     

HPLC法同时测定复方银翘氨敏胶囊中维生素C及对乙酰氨基酚的含量

目的建立复方银翘氨敏胶囊中对乙酰氨基酚和维生素C的含量测定方法。方法色谱柱：Kromasil C18柱（4.6 mm×250 mm,5μm）;甲醇-乙腈-0.02%磷酸（5∶10∶85）为流动相;流速：1.0 ml·min^-1;柱温：35℃;测定波长：219 nm。结果对乙酰氨基酚、维生素C分别在8.948-178.96 mg·L^-1和4.328-86.560 mg·L^-1范围内呈良好线性关系,平均回收率分别为99.66%（RSD=0.52%）和99.44%（RSD=0.46%）。结论该方法简便快速,结果准确,可以有效控制该药品质量。     

Effect of antioxidants on pyrogallol-induced delay in gastric emptying in rats

The effect of a free radical generator pyrogallol on gastric emptying was studied in rats. Pyrogallol at doses of 25, 50, 100 and 150 mg/kg (i.p.) produced dose-dependent inhibition of gastric emptying. Pretreatment with vitamin C (100 and 500 mg/kg, p.o.), and vitamin E (100 and 500 mg/kg, p.o.) significantly reversed the inhibition in gastric emptying caused by pyrogallol 100 mg/kg. However, the combination of vitamin C and vitamin E (100 mg/kg) produced synergistic effect. Glutathione (100 mg/kg i.v.) 5-min pretreatment also reversed the inhibition of gastric emptying caused by pyrogallol 100 mg/kg. Ondansetron (3 mg/kg, p.o.) significantly reversed the pyrogallol effect. The effect of pyrogallol on malondialdehyde (MDA) levels and 5-HT levels in the stomach tissue was also studied. Pyrogallol at a dose of 100 mg/kg, i.p., significantly increased MDA levels and 5-HT levels in the stomach. Pretreatment with a combination of vitamin C and vitamin E (100 mg/kg, p.o.) and glutathione (100 mg/kg, i.v.) significantly ameliorated the rise in stomach tissue MDA caused by pyrogallol but had no significant effect on the rise in 5-HT levels caused by pyrogallol. The effect of different doses of 5-HT on gastric emptying was also studied. 5-HT had a differential effect on gastric emptying. The low and high doses (0.1, 0.3 and 30 mg/kg, i.p.) significantly inhibited the gastric emptying while doses ranging from 1 to 10 mg/kg, i.p., had no significant effect on the gastric emptying. The pretreatment with antioxidants, combination of vitamin C and vitamin E (100 mg/kg each, p.o.) and glutathione (100 mg/kg, i. v.) had no effect on the 5-HT (0.3 mg/kg, i.p.)-induced delay in gastric emptying. The result indicate the role of free radicals gastric emptying, and antioxidants may be of potential therapeutic value in disease conditions where free radicals are known to be released and the gastrointestinal effects are observed as symptoms or side effects of drug therapy.     

Effects of vitamin C and E on liver enzymes and biochemical parameters of rabbits exposed to aflatoxin B1

Hepatotoxic substances such as aflatoxin B1 (AFB1) produce free radical reactions during biotransformation damage to liver cells. Vitamins C and E are important natural antioxidants suppressing free radicals. This study investigated the effects of vitamins C and E on liver enzymes and other biochemical parameters in rabbits experimentally exposed to AFB1. The first group was control and fed the diet with dimethyl sulfoxide; the second group received 0.1 mg AFB1/kg diet; the third group received vitamin C (100 mg L-ascorbic acid/kg diet); the fourth group received vitamin E (100 mg alpha-tocopherol/kg diet); and the fifth group received vitamin C+vitamin E (100 mg L-ascorbic acid/kg diet+100 mg alpha-tocopherol/kg diet). Diets of the second, third, fourth and fifth groups were mixed with 0.1 mg AFB/kg diet) and feedings were continued for 10 w. Levels of aspartate transaminase, alanine transaminase, alkaline phosphatase, creatine phosphokinase and lactate dehydrogenase after receiving AFB1 were significantly increased, while activities of aspartate transaminase, alanine transaminase, amylase, creatine phosphokinase and lactate dehydrogenase in groups receiving AFB1 + vitamins C, E or C+E were significantly lower than that of the AFB1-alone group. Although of the activity of alkaline phosphatase increased with AFB1 exposure, it decreased with vitamin C administration. Levels of urea, triglyceride, cholesterol and albumin were affected by AFB1 and AFB1+vitaminC. AFB1 affected some liver enzymes and other biochemical parameters, but vitamins C, E and C+E partially prevented an increase in these liver enzymes and some the biochemical parameters induced by AFB1.     

The influence of divalent cations on the analgesic effect of opioid and non-opioid drugs

It is generally accepted that divalent cations are involved in the nociceptive pathway. The effect of systemic co-administration of magnesium sulfate and calcium channel blockers (nifedipine, verapamil) on the analgesic effect of opioid (mixed mu/kappa: butorphanol) and non-opioid drugs (paracetamol) was investigated. Albino mice and rats were used as experimental animals. Magnesium sulfate and calcium channel blockers were given i.p., 30 min before the administration of butorphanol tartrate and paracetamol. Analgesia was measured using "hot-plate" ( 52.5( composite function)C), "tail-flick" (radiant heat source), "writhing" (acetic acid, 1%, i.p.) and "tail-clip" tests. The pain threshold was evaluated before and after the administration (i.p.) of the different agents. The effect of the combined administration of different agents on behavior, blood pressure and heart rate, was also determined. Nifedipine (5 mg kg(-1), i.p.) and verapamil (10 mg kg(-1), i.p.) potentiated the analgesic effect of butorphanol tartrate (0.25-2 mg kg(-1), i.p.) in all tests (synergism) and enhanced analgesic effect of paracetamol (50-125 mg kg(-1), i.p.), only in acetic acid writhing and tail-clip tests. Magensium sulfate (2.5 mg kg(-1), i.p.) potentiated the analgesic effect of butorphanol, but not that of paracetamol. Co-administration of nifedipine and verapamil with either of butorphanol (0.25-2 mg kg(-1)) or paracetamol (50-125 mg kg(-1), i.p.) produced no significant effects on motor coordination, motor performance, locomotor activity, long-term memory or on the blood pressure and heart rate of experimental animals. Co-administration of magnesium sulfate, however, significantly induced sedation, inhibition of locomotor activity, motor performance and coordination, as well as impairing of long-term memory, as compared with butorphanol and paracetamol, administered alone. We conclude that the systemic co-administration of calcium channel blockers potentiated the analgesic effect of butorphanol against thermal, mechanical and chemical pain but enhanced that of paracetamol only against mechanical and chemical pain. Magensium sulfate enhanced the analgesic effect of butorphanol, but not that of paracetamol. These findings, merit further studies in animals and humans to evaluate the potential therapeutic benefits of such interactions.     

Effect of sulphydryl drugs on paracetamol-induced hepatotoxicity in mice

It has been shown that the major in vivo biotransformation of thiol-containing drugs such as captopril (CP) and penicillamine (PA) involve mixed disulphide formation with endogenous thiols derived from cysteine. At high doses, both drugs produced a dose-dependent depletion of glutathione (GSH) and may perturb GSH and related GSH-enzymes. In this study the possible interactions of these drugs with paracetamol, which produce hepatotoxicity after GSH depletion, were investigated. Following co-administration of CP (50-250 mg/kg) or PA (43-257 mg/kg) with paracetamol (300 mg/kg), the hepatotoxic effect produced by paracetamol was diminished. The protective effect was comparable to that produced by N-acetylcysteine (500 mg/kg) and L-cysteine (500 mg/kg). However, pre-treatment with buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, abolished the protective effects of CP, N-acetylcysteine and L-cysteine while the protective effect of PA was unaffected. This suggests that, although both CP and PA may act as alternative sulphydryl nucleophiles to GSH to prevent arylation of essential cellular macromolecules by the reactive metabolite of paracetamol, the underlying mechanisms of these drug interactions may be distinctly different.     

Effect of different doses of S-adenosyl-L-methionine on paracetamol hepatotoxicity in a mouse model

This study investigated the hepatoprotective effects of N-acetylcysteine and different doses of S-adenosyl-L-methionine after a single intraperitoneal overdose of paracetamol in mice. Plasma concentrations of paracetamol metabolites were also determined. Female mice (Souris OFl strain) 16 weeks old and weighing 30 g were fasted for 18 h prior to intraperitoneal (i.p.) administration of 375 mg/kg (2.5 mmol/kg) of paracetamol. Experimental subgroups included mice administered paracetamol only (control group), those given of N-acetylcysteine 1 g/kg (6.13 mmol/kg) i.p. immediately after paracetamol overdose (T0) and 6 h after dosing (T6) and those administered S-adenosyl-L-methionine at doses of 20 mg/kg (0.05 mmol/kg) and 1 g/kg (2.5 mmol/kg) i.p. at T0 and T6. Twenty-four hours after paracetamol overdose, mortality and liver necrosis were significantly lower (p < 0.01) in mice treated with 2.5 mmol/kg of S-adenosyl-L-methionine and N-acetylcysteine at T0 as compared with the remaining subgroups. Plasma ALT concentrations were significantly lower (p < 0.01) in mice treated with 2.5 mmol/kg of S-adenosyl-L-methionine than in those given N-acetylcysteine. Plasma concentrations of paracetamol metabolites showed an increase in the glucuronide conjugate and a decrease in the mercapturic acid conjugate in N-acetylcysteine-treated mice and an overall decrease in the conjugation pathway without changes in the oxidative pathway in S-adenosyl-L-methionine-treated animals. We conclude that S-adenosyl-L-methionine at doses of 1 g/kg (2.5 mmol/kg) i.p. was equally effective as 1 g/kg (6.13 mmol/kg) N-acetylcysteine for preventing hepatotoxicity after paracetamol overdose in mice. S-adenosyl-L-methionine may be a therapeutic alternative to N-acetylcysteine as an antidote for poisoning with paracetamol.