Effect of pazufloxacin mesilate, a new quinolone antibacterial agent, for intravenous use on QT interval

The potential for QT interval prolongation of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, was investigated by in vitro and in vivo electrophysiology studies. Following results were obtained. In vitro electrophysiology study using guinea pig papillary muscles: PZFX mesilate (30-300 microM) had no effects on resting membrane potential (RMP), action potential amplitude (APA) and action potential duration (APD). Reference quinolones, sparfloxacin (3-30 microM) and moxifloxacin (10-100 microM), had no effects on RMP and APA, but significantly prolonged APD at more than 3 and 10 microM, respectively, while ciprofloxacin (10-100 microM) had no effect on each parameter. In vivo electrophysiology study using anesthetized dogs: PZFX mesilate had no effects on electrocardiograph parameter (PR interval, QRS interval, QT interval and QTc) after intravenous administration of 3-30 mg/kg. These results suggest that PZFX mesilate has low potential for QT interval prolongation.     

In vitro and in vivo antibacterial activities of pazufloxacin mesilate,a new injectable quinolone

We investigated the in vitro and in vivo antibacterial activities of pazufloxacin mesilate (PZFX mesilate), a new injectable quinolone, and obtained the following results. 1) The MIC50 and MIC90 values of PZFX against clinically isolated Gram-positive and -negative bacteria, ranged from 0.0125 to 12.5 micrograms/ml and 0.025 to 100 micrograms/ml, respectively. PZFX showed broad spectrum activity. The antibacterial activities of PZFX against quinolone-susceptible, methicillin-resistant Staphylococcus aureus, beta-lactamase-negative, ampicillin-resistant Haemophilus influenzae, extended spectrum beta-lactamase possessing Klebsiella pneumoniae and imipenem/cilastatine (IPM/CS)-resistant Pseudomonas aeruginosa were superior to those of ceftazidime (CAZ), ceftriaxone, IPM/CS, meropenem and panipenem/betamipron. 2) PZFX showed superior bactericidal activity against S. aureus, Escherichia coli, Proteus mirabilis, Serratia marcescens and P. aeruginosa to those of CAZ and IPM/CS after treatment for 15 minutes at the drug concentration equivalent to that in human serum at clinical dose to be continued for 15 minutes. 3) CAZ and IPM/CS had no bactericidal activity at the 16 times of MIC against P. aeruginosa in human polymorphonuclear leucocytes, while PZFX exhibited potent bactericidal activity in a dose-dependent manner against such bacteria. 4) PZFX inhibited both DNA gyrase and topoisomerase IV from S. aureus at nearly the same level. PZFX showed poor inhibitory activity against topoisomerase II from human placenta and showed high selectivity to bacterial topoisomerase. 5) PZFX mesilate showed superior therapeutic activity to that of CAZ with following infection model caused by S. aureus and P. aeruginosa or each; systemic infection with cyclophosphamide-treated mice, systemic infection in mice with high challenge doses, CMC pouch infection in rat, and calculus infection in rat bladder. 6) Intravenous administration of PZFX with high plasma concentration just after administration, showed more excellent therapeutic effect against the rat intraperitoneal infection, than p.o. and s.c. administration.     

新喹诺酮类抗菌药甲磺酸帕珠沙星

甲磺酸帕珠沙星是与左氧氟沙星(LVFX)同一母环系的10-(1-氨基环丙基)喹诺酮类药物.本品对葡萄球菌属的MIC90为3.13～25mg·L-1,其活性相当于或优于LVFX和环丙沙星(CPFX);对链球菌属和肠球菌属的MIC90为3.13～ 6.25mg·L-1,其活性除了对屎肠球菌优于LVFX外,其余均逊于LVFX和CPFX;对绝大多数G-菌的MIC90为0.013～ 6.25mg·L-1,其活性大体上与LVFX和CPFX相当.日本的临床研究表明,静注本品对呼吸道感染的总有效率为75.1%(181/241);对复杂性尿路感染的总有效率为78.7%(118/150);对外科感染的总有效率为81.8%(63/77).不良反应发生率为2.4%(13/532),主要是轻或中度的头疼、头晕、药疹、腹泻、胃部不适感等.     

新型非甾体抗炎药darbufelone mesilate的合成工艺研究

目的合成新型非甾体抗炎药环氧化酶-2和5-脂氧合酶双重抑制剂darbufelone mesilate.方法 以2,6-二叔丁基-4-甲基苯酚为起始原料,经3步反应制得目标化合物,其结构经1H-NMR谱和MS谱确证.结果 对各步反应条件进行了优化,总收率达到52.6%,较文献收率提高20%.结论合成路线简便可行,适合工业化生产.     

Effects of drugs on the convulsions induced by the combination of a new quinolone antimicrobial, enoxacin, and a nonsteroidal anti-inflammatory drug, fenbufen, in mice]

The effects of drugs on the convulsions induced by the combination of a new quinolone antimicrobial, enoxacin, and a nonsteroidal anti-inflammatory drug, fenbufen, were studied in mice. The combination of enoxacin at 30 or 100 mg/kg, p.o. and fenbufen at 100 mg/kg, p.o. induced convulsions; and the mice died as a result of the convulsions. Pretreatment with either phenobarbital, phenytoin, valproic acid intraperitoneally, or morphine intravenously did not influence the convulsions. A high dose of diazepam or clonazepam prolonged the survival time, but could not prevent the mice from dying. After the occurrence of convulsions induced by enoxacin with fenbufen, administration of the excitatory amino acid antagonist MK-801 at 1 mg/kg, i.v. extended the survival time, even though all the mice died as a result of the convulsions. Simultaneous intravenous injections of MK-801 and diazepam suppressed the convulsions. This suppression was stronger than that produced by MK-801 or diazepam, injected separately. However, no mouse survived at the end. From these results, participation of both GABA-ergic and excitatory amino acidergic systems in the convulsions induced by enoxacin and fenbufen was discussed.     

Adverse drug interactions between pyridonecarboxylic acids and nonsteroidal antiinflammatory drugs: convulsion after oral or intracerebral administration in mice

Comparing with other pyridonecarboxylic acids (PCAs), the neurotoxicity of (+/-)-7-(3-amino-1-pyrrolidinyl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate hydrate (T-3262), which is a new PCA, was investigated in mice in a combination with fenbufen (FBF). T-3262, ofloxacin (OFLX) and nalidixic acid (NA) did not produce convulsion, but enoxacin (ENX) and norfloxacin (NFLX) produced it after an oral administration with FBF. The intracerebral injection of drugs alone to mice revealed that both FBF and 4-biphenylacetic acid (BPAA), which is principally responsible for FBF's antiinflammatory action, scarcely had convulsant activity. While all the PCAs had convulsant activity and the order of potency was as follows; NFLX greater than ENX greater than OFLX greater than penicillin G potassium greater than the free base of T-3262 (T-3262 base) greater than or equal to NA. When orally pretreated with BPAA, the convulsive threshold was scarcely lowered for T-3262 base and OFLX, but for ENX and NFLX it was lowered to about 1/300 and 1/100 of the respective activity. As the result, convulsant activities of ENX and NFLX were greatly potentiated, and their potencies became almost equal. The adverse drug interactions between T-3262 and FBF were scarcely observed in mice.     

Association between nonsteroidal anti-inflammatory drug use and brain tumour risk: a meta-analysis

Aims

Several epidemiological studies have evaluated the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and brain tumour risk. However, results from these studies have been inconsistent. The aim of this detailed meta-analysis is to review and summarize the evidence on this association.

Methods

A comprehensive search for articles published up to September 2013 was performed. Studies evaluating the association between exposure to NSAIDs and risk of brain tumours were included. Random-effects meta-analytical models were used to calculate the relative risk (RR) and corresponding 95% confidence intervals (CIs). Sensitivity analyses, Galbraith plots and subgroup analyses were also performed.

Results

Ten studies (six case–control studies, three cohort studies and one randomized controlled trial), published between 2003 and 2013, were included in this analysis. Compared with non-use, overall use of NSAIDs was not statistically significantly associated with brain tumour risk based on the random-effects models (RR = 1.01; 95% CI = 0.89, 1.15). No differences were observed when analyses were stratified by gender and brain tumour subtype. Specific analysis for aspirin and non-aspirin NSAIDs yielded similar results. However, a slightly increased risk of brain tumour in NSAID users was observed in cohort studies (RR = 1.32; 95% CI = 1.06, 1.64; P = 0.014). Furthermore, our analysis did not show a significant association between frequency and dose of aspirin use and brain tumour risk.

Conclusions

Use of NSAIDs (aspirin and non-aspirin NSAIDs) does not appear to be associated with brain tumour risk, but larger studies are needed to substantiate this relationship.     

Phototoxic retinal degeneration and toxicokinetics of sitafloxacin, a quinolone antibacterial agent, in mice

We examined drug concentrations and the incidence of retinal degeneration in the eyes of albino BALB/c mice after a single intravenous administration of sitafloxacin plus a 4 h period of UVA irradiation. Retinal degeneration was induced at 40 mg/kg or more plus UVA irradiation, and there was little decrease in ocular sitafloxacin concentration under UVA irradiation. We then examined the incidence of retinal degeneration with various periods of UVA irradiation in BALB/c mice given a single intravenous administration of 40 mg/kg sitafloxacin. Retinal degeneration occurred in all the groups receiving UVA irradiation immediately after sitafloxacin administration, whereas no retinal degeneration occurred in the groups receiving UVA irradiation starting 30 min or later after administration. In addition, we examined both the retinal degeneration and auricular inflammation in BALB/c mice given a 7-day repeated administration of sitafloxacin at 1, 3.3 and 10 mg/kg per day, which never induce retinal or auricular change by a single administration. Retinal degeneration was not induced at any dose level, although auricular skin inflammation was augmented by repeated administration. These results suggest that the occurrence of retinal degeneration depends on maximum ocular sitafloxacin concentration during UVA irradiation, whereas the severity of auricular inflammation is directly proportional to the total decrease in area under the drug concentration curve for auricular sitafloxacin under UVA irradiation. This difference between retinal degeneration and auricular inflammation may derive from their respective mechanisms of pathogenesis.     

Effect of etodolac, a new nonsteroidal anti-inflammatory drug, in MRL/lpr mice with articular lesions.

Etodolac, a new nonsteroidal anti-inflammatory drug, was administered orally at doses of 1 and 5 mg/kg to MRL/MpJ-lpr/lpr (MRL/lpr) mice, and its effect on articular lesions was compared with that of indomethacin. Both etodolac and indomethacin significantly reduced swelling of the hind paw. Histopathological examination showed that etodolac significantly reduced cartilage and bone damage, whereas indomethacin treatment did not achieve a statistically significant effect. Rheumatoid factors were not affected by either etodolac or indomethacin. These results indicate that etodolac delays the development of arthritis in MRL/lpr mice, and reduces cartilage and bone damage.     

Pharmacokinetics of piroxicam, a new nonsteroidal anti-inflammatory agent, under fasting and postprandial states in man

The kinetic disposition of piroxicam, under evaluation in man as a new anti-inflammatory drug, was studied in human volunteers given a single oral dose after both overnight fasting and food. Total absorption was uninfluenced by food intake, although the data indicate that food causes some delay in attainment of peak serum levels. The half-life of drug in plasma in the fasting subjects (37.5 +/- 2.4 hr) was similar in both the fasting state and after food, suggesting that once-daily dosing may be appropriate for maintaining therapeutic plasma levels. Mean pharmacokinetic parameters for both studies in the fasting state and after meals are volume of distribution divided by availability, 0.140 or 0.136 liter/kg; total plasma clearance divided by availability, 2.68 or 3.12 ml/hr/kg. Approximately 10% of a single dose of piroxicam was eliminated in the urine within 8 days after oral drug administration. Renal clearance of the drug (0.28 +/- 0.10 ml/hr/kg) was 10.4% or less of plasma clearance, suggesting that piroxicam is extensively metabolized. In this study one subject showed a reduction in white blood count on the sixteenth day after a 60-mg dose; however, hematology values evaluated in both intra- and intersubject comparisons did not show any other differences in the present study.     

Possible relationship between phototoxicity and photodegradation of sitafloxacin, a quinolone antibacterial agent, in the auricular skin of albino mice.

We compared the phototoxic potential of the quinolone antibacterial agent sitafloxacin with those of lomefloxacin and sparfloxacin. Female BALB/c mice were given a single intravenous administration of sitafloxacin, lomefloxacin, or sparfloxacin at 10 or 40 mg/kg, followed by ultraviolet-A (UVA) irradiation for 4 h (21.6 J/cm(2)). At 10 mg/kg, all quinolones induced either none or minimum inflammation in the auricle. At 40 mg/kg, sitafloxacin induced mild phototoxic inflammation in the dermal skin, while lomefloxacin and sparfloxacin induced very severe inflammation. In particular, 2/5 animals of the lomefloxacin group showed partial necrosis in the dermis and epidermis. We then determined the time course change of sitafloxacin concentrations in serum and auricular tissue by high performance liquid chromatography. Sitafloxacin concentrations in the auricle were markedly decreased under UVA irradiation, whereas those in sera were not affected. Furthermore, we examined the severity of sitafloxacin-induced phototoxicity under varied duration of UVA irradiation. The severity of phototoxicity increased with increasing duration of UVA irradiation, and statistical analysis showed a close correlation between the severity and the decreased area under the drug concentration curve under UVA irradiation (DeltaAUC(auricle)). The severity was decreased with delay in commencement of UVA irradiation, indicating the importance of commencement time of irradiation in the experimental condition of the phototoxicity study. It might be attributed to the decrease in DeltaAUC(auricle) after administration. These results suggest that sitafloxacin possesses milder phototoxic potential than lomefloxacin or sparfloxacin and is degraded in the auricular skin under UVA irradiation, and that the severity of phototoxicity is directly proportional to the DeltaAUC(auricle).     

Pharmacokinetics of piroxicam,a new nonsteroidal anti-inflammatory agent,under fasting and postprandial states in man

The kinetic disposition of piroxicam, under evaluation in man as a new anti-inflammatory drug, was studied in human volunteers given a single oral dose after both overnight fasting and food. Total absorption was uninfluenced by food intake, although the data indicate that food causes some delay in attainment of peak serum levels. The halflife of drug in plasma in the fasting subjects (37.5±2.4hr) was similar in both the fasting state and after food, suggesting that once-daily dosing may be appropriate for maintaining therapeutic plasma levels. Mean pharmacokinetic parameters for both studies in the fasting state and after meals are volume of distribution divided by availability, 0.140 or 0.136 liter/kg; total plasma clearance divided by availability, 2.68 or 3.12 ml/hr/kg. Approximately 10% of a single dose of piroxicam was eliminated in the urine within 8 days after oral drug administration. Renal clearance of the drug (0.28±0.10 ml/hr/kg) was 10.4% or less of plasma clearance, suggesting that piroxicam is extensively metabolized. In this study one subject showed a reduction in white blood count on the sixteenth day after a 60-mg dose; however, hematology values evaluated in both intraand intersubject comparisons did not show any other differences in the present study.This work was supported in part by a grant from Japan Rheumatoid Foundation (JRP).     

Synthesis and structure-activity relationships of 7-diazabicycloalkylquinolones, including danofloxacin, a new quinolone antibacterial agent for veterinary medicine.

A series of novel 6-fluoro-7-diazabicycloalkylquinolonecarboxylic acids substituted with various C8 (H, F, Cl, N) and N1 (ethyl, cyclopropyl, vinyl, 2-fluoroethyl, 4-fluorophenyl, 2,4-difluorophenyl) substituents, as well as, 9-fluoro-10-diazabicycloalkylpyridobenzoxazinecarboxylic acids, were prepared and evaluated for antibacterial activity against a range of important veterinary pathogenic bacteria. The diazabicycloalkyl side chains investigated at the 7-position (benzoxazine 10-position) include (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (2), (1S,4S)-2,5-diazabicyclo[2.2.1]heptane (3), (1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (4), 8-methyl-3,8-diazabicyclo[3.2.1]octane (5), 9-methyl-3,9-diazabicyclo[4.2.1]nonane (6), 1,4-diazabicyclo[3.2.2]nonane (7), 1,4-diazabicyclo[3.3.1]nonane (8), and 9-methyl-3,9-diazabicyclo[3.3.1]nonane (9). Among these side chains, in vitro potency was not highly variable; other properties therefore proved more critical to the selection of possible development candidates. However, the relative potencies observed for several of these compounds in mouse, swine, and cattle infection models correlated well with those seen in vitro. A combination of the N1 cyclopropyl group and the C7 (1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl appendage conferred the best overall antibacterial, physiochemical, and pharmacodynamic properties. Hence, danofloxacin (Advocin, 2c) (originally CP-76,136, 1-cyclopropyl-6-fluoro-7-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1] hept-2-yl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid) was selected as a candidate for development as a therapeutic antibacterial agent for veterinary medicine.     

Inhibition of human thiopurine S-methyltransferase by various nonsteroidal anti-inflammatory drugs in vitro: a mechanism for possible drug interactions.

Thiopurine S-methyltransferase (TPMT) is a biotransformation phase II enzyme responsible for the metabolic inactivation of thiopurine drugs. The present study was carried out to investigate the inhibitory potential of 15 nonsteroidal anti-inflammatory drugs (NSAIDs) on human TPMT activity in vitro. TPMT activity was measured in pooled human erythrocytes in the absence and presence of various NSAIDs using the previously published high-performance liquid chromatography-UV method. To determine the inhibition type and K(i) value for each compound, we performed kinetic analysis at five different inhibitor concentrations close to the IC(50) value obtained in preliminary experiments. Naproxen (K(i) = 52 microM), mefenamic acid (K(i) = 39 microM), and tolfenamic acid (K(i) = 50 microM) inhibited TPMT activity in a noncompetitive manner. The estimated K(i) values for the inhibition of TPMT by ketoprofen (K(i) = 172 microM) and ibuprofen (K(i) = 1043 microM) indicated that the propionic acid derivatives were relatively weak inhibitors of TPMT. Our results suggest that coadministration of thiopurines and various NSAIDs may lead to drug interactions.     

Disposition of a new diacid angiotensin-converting enzyme inhibitor after intravenous administration of drug or prodrug to monkeys and dogs.

The disposition of [4S-[4 alpha,7 alpha,(R*),12b beta]]-7- [S-(1-carboxy-3-phenylpropyl)amino]-1,2,3,4,6,7,8,12b-octahydro-6- oxo- pyrido[2,1-a][2]benzazepine-4-carboxylic acid (MDL 27,088), a new a new angiotensin-covering enzyme inhibitor, was studied in cynomolgus monkeys and beagle dogs given intravenous (iv) doses of MDL 27,088 or its prodrug, MDL 27,210. Although in both species iv-administered MDL 27,210 was extensively (> 99.9%) metabolized and excreted in the urine and feces as MDL 27,088, the disposition of MDL 27,088 appeared to be significantly influenced by its mode of administration. For example, the mean terminal half-life of MDL 27,088 in plasma was longer when MDL 27,088 was given as its prodrug (3.65 and 2.23 h in monkeys and dogs, respectively) than when it was administered directly (0.84 and 1.05 h in monkeys and dogs, respectively). The renal excretion of MDL 27,088 also increased (from 33 to 73% of the dose in monkeys and from 9 to 17% of the dose in dogs) when MDL 27,088 was administered directly versus when it was given as its prodrug. These and other results of this study suggest that the disposition of MDL 27,088 can be significantly altered by iv administration of its prodrug form. Such changes in disposition also suggest that iv administration of prodrug may influence the pharmacological activity of MDL 27,088.     

A pharmacokinetic interaction in man between phenobarbitone and fenoprofen, a new anti-inflammatory agent

1 The effect of repeated administration of phenobarbitone on the plasma disposition of fenoprofen (±-2-(3-phenoxyphenyl) propionic acid) was investigated in rats and man.

2 The plasma elimination rate constants increased significantly and the rats excreted proportionately more metabolized fenoprofen in the urine. These findings are consistent with an increase in the rate of metabolism of fenoprofen.

3 This interaction between phenobarbitone (and presumably other inducers of drug metabolizing enzymes) and fenoprofen should be considered when evaluating the clinical usefulness of fenoprofen.

     

Pharmacokinetics and metabolism of a novel antifibrotic drug pirfenidone,in mice following intravenous administration

The present study describes the pharmacokinetics and metabolism of pirfenidone (PD), a compound which has been shown to have significant antifibrotic effects in rodent models of pulmonary and cardiac fibrosis. Despite the fact that this compound is currently in phase II clinical trials, little data are available on the metabolism and disposition of this agent in rodents or humans. Radioactive PD [benzene ring (14)C(U)] was administered i.v. to mice at 40 mg PD/kg body weight, and animals were killed at varying times for determination of parent compound and metabolites in various tissues. The disappearance of parent compound from the plasma followed apparent 2-compartment elimination kinetics with a terminal elimination half-life of 8.6 min. Cl (0.10 ml/min/g) and V(d(ss)) (0.67 ml/g) indicated that PD was rapidly distributed in body water. This is consistent with the finding that peak tissue radioactivity occurred within 5 min following the i.v. administration of [(14)C]-PD and that well-perfused tissues, kidney>liver>lung have much higher levels of parent compound and metabolites than did fat. Two peaks isolated from plasma samples by HPLC yielded mass spectra that were consistent with initial oxidation to the alcohol followed by further metabolism to the carboxylic acid. The radioactivity recovered in the 24 h urine samples averaged 97% of the administered dose and none of that was associated with the parent compound. The short plasma half-life of parent compound in mice supports the need for additional studies in humans where the compound has been shown to have clinical benefits.     

Pharmacokinetics and antitumour activity of a new anthracycline,DA-125, after intravenous administration to subcutaneously implanted Lewis-lung-carcinoma-bearing mice

The pharmacokinetics and tissue distribution of M1–M4 were compared after intravenous (IV) administration of DA-125, 25 mg kg^?1, to BDF₁ mice (n = 5 at each sampling time) and subcutaneously implanted Lewis-lung-carcinoma-bearing BDF₁ mice (n = 10 at each sampling time). The mean plasma concentrations of M1–M4 were not significantly different between the two groups of mice, and hence similar pharmacokinetic parameters for M1–M4 were obtained. The amount of M1 in the lung was significantly greater in the tumour-bearing mice than in the control mice, resulting in a greater AUA, in the tumour-bearing mice (18 600 against 8940 μg min g^?1), and vice versa in the liver (962 against 3840 μg min g^?1). However, the corresponding values for other tissues were comparable between the control and tumour-bearing mice. The amount of M1 was greatest in the lung for up to 2 h in the tumour-bearing mice. M2 was the predominant metabolite among M1–M4 excreted in 24 h urine by both groups of mice; 8.36 and 10.7% of the IV dose were excreted in 24 h urine as M2–expressed in terms of DA-125—by the control and tumour-bearing mice, respectively. The amount of M1 in the tumour mass reached a mean C_max of 3.75 μg g^?1 immediately after IV administration of DA-125 to the tumour-bearing mice, then declined very slowly to an amount that remained almost constant for up to 24 h. This suggested that M1 has high affinity for the subcutaneously implanted Lewis lung carcinoma. The antitumour activity, such as the increase in life span (ILS) and tumour growth inhibition (TGI) of DA-125, 6–48 mg kg^?1, and adriamycin (ADM), 3–18 mg kg^?1, were also compared in subcutaneously implanted Lewis-lung-carcinoma-bearing BDF₁ mice after four weekly IV administrations of the drugs on days 1, 8, 15, and 22 following tumour implantation. More than three out of six mice survived as tumour-free for longer than 70 d at a DA-125 dose range of 6–24 mg kg^?1, but there were no tumour-free mice at any dose of ADM. Assuming ILS values higher than 30% to be effective, DA-125 doses ranging from 6 to 24 mg kg^?1 were effective in increasing the life span, which ADM dose only within the dose range of 6–12 mg kg^?1.     

Apomorphine-induced and pilocarpine-induced hypothermia in mice: Drug interactions and changes in drug sensitivity after caudate nucleus lesions

1 Apomorphine and pilocarpine each produced dose-dependent hypothermic effects in mice. However, the dose-response curve for pilocarpine was steeper than that for apomorphine.2 Bilateral lesions of the caudate nucleus produced a permanent decrease in sensitivity to apomorphine but had no effect on sensitivity to pilocarpine.3 Apomorphine and pilocarpine had synergistic effects; i.e. the hypothermic effect was greater following a combination of the drugs than following either drug alone.4 The effect of apomorphine was antagonized by either haloperidol or scopolamine; only scopolamine antagonized the effect of pilocarpine.5 These results suggest that a mechanism involving dopaminergic neurones in the caudate nucleus has a modulatory role in temperature regulation.