噻芬太尼的主要药效和致依赖性潜力的实验研究

本文研究噻芬太尼的镇痛药效和制动作用,评价其致身体依赖性潜力。小鼠热板法测得噻芬太尼的镇痛作用强度分别为吗啡、芬太尼和埃托啡的3260,22和1.5倍。以瘫痪作为制动指标测得噻芬太尼对大鼠、家兔、狗和猴制动作用强度为埃托啡的2～3倍。小鼠跳跃实验和大鼠饮药液自然戒断实验表明该药具有一定致身体依赖性潜力。大鼠ⅳ快速成瘾实验及长达20周的猴身体依赖性实验则未出现依赖性戒断症状。     

Intravenous midazolam significantly enhances the lethal effect of thiopental but not that of ketamine in mice

Intravenous (i.v.) drug combinations are used in clinical anaesthesia in order to combine the desired effects and minimize toxicity from large doses of single agents. This fundamental assumption has not been systematically evaluated. We examined its validity by testing the influence of midazolam on the lethal effect of i.v. thiopental and ketamine in mice. Dose-response curves were constructed for the lethal effect of i.v. thiopental and ketamine, and for the loss of righting reflex effect by midazolam, in sexually mature male ICR mice weighing 20-40 g. For each curve, six or seven groups of eight to 10 mice each were used. A quarter of the median effective dose (ED50) for loss of righting reflex by midazolam was combined with the two other drugs to deduce dose-response curves for the lethal effect of the combinations. The ED50 for loss of righting reflex by i.v. midazolam was 43.5 mg x kg(-1) (95% confidence interval [CI], 40.4-46.5). The median lethal dose (LD 50) of i.v. thiopental was 50.6 mg x kg(-1) (95% CI, 50.0-54.9) and that of ketamine 42.9 mg x kg(-1) (95% CI, 32.3-52). In the presence of 10 mg x kg(-1) midazolam, the LD50 of thiopental was reduced to 20 mg x kg(-1) (17.7-22.2), but that of ketamine remained 44.4 mg x kg(-1) (37.7-54.9). Midazolam increased the lethal effect of thiopental 2.5-fold, but did not affect that of ketamine. Interactions at the toxic level between commonly used anaesthetic agents may differ from those at the hypnotic or analgesic levels, which should prompt evaluation of such combinations before their introduction to routine clinical use.     

Effect of morphine and morphine-like analgesics on susceptibility to seizures in mice

In mice, the influence of small (analgesic range) doses of morphine, fentanyl, meperidine and pentazocine on the thresholds for seizures induced by electroshock and pentetrazole was studied. The antinociceptive ED50 was determined against writhing induced by acetic acid or morphine (0.43 mg/kg, s.c.), fentanyl (0.018 mg/kg, s.c.), meperidine (2.6 mg/kg, s.c.), and pentazocine (2.0 mg/kg, s.c.). The electroconvulsive threshold was significantly elevated at doses slightly greater than (fentanyl and meperidine) or about twice the antinociceptive ED50 (morphine and pentazocine). Naloxone antagonized this effect in the case of morphine and fentanyl, but not in the case of meperidine and pentazocine. The threshold for clonic convulsions induced by intravenous infusion of pentetrazole was not influenced by morphine, fentanyl and meperidine, in the dose range studied, but was slightly increased by the smaller doses (2 and 4 mg/kg) of pentazocine. The tonic phase of pentetrazole-induced convulsions was suppressed by the larger doses of fentanyl, meperidine and pentazocine, though smaller doses of pentazocine significantly reduced the threshold for the extensor phase.     

Antinociceptive activity of Vitex-negundo Linn leaf extract

Tail flick test in rats and acetic acid induced writhing in mice were employed to study the antinociceptive activity of ethanolic leaf extract of Vitex-negundo (VN) (100, 250 and 500 mg/kg, p.o). The effect was compared with meperidine (40 mg/kg, sc) in tail flick method and aspirin (50 mg/kg, p.o) in writhing test as a standard control respectively. An interaction with naloxone hydrochloride was also studied in tail flick method for its mechanism of central analgesic action. The test drug showed significant analgesic activity in dose dependant manner in both the experimental models. In comparison to standard drug (meperidine), more than ten times dose of VN extract was required to produce comparable significant antinociceptive activity. The sub-effective dose (5 mg/kg, po) of VN potentiated the analgesic activity of meperidine (4 mg/kg, sc) and aspirin (25 mg/kg, po). Naloxone (1 mg/kg, sc) did not reverse the analgesic effect of VN extract. Our observations suggest that VN possesses both central and peripheral analgesic activity. The central analgesic action does not seem to be mediated through opioid receptors. It, may prove to be a useful adjuvant therapy along with standard analgesic drug.     

Doses of acetyl salicylic acid and morphine in combination which provided either maximal levels of analgesia or the highest potentiation effect in the rat

The analgesic efficacy of the combination of acetyl salicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID), and morphine, a μ-opiate receptor agonist, was evaluated in the pain-induced functional impairment in the rat (PIFIR) model. Groups of 6 rats received either vehicle, ASA (175.4, 311.9, 555.1, 986.9, 1,755.2, or 3,121.3 μmol/kg p.o.), morphine (3.1, 5.5, 9.8, 17.5, 31.1, or 55.2 μmol/kg s.c.), or a combination of ASA and morphine (24 different combinations). This allowed us to detect the profile of analgesic interaction of the combinations. Furthermore, we set out to determine the optimal degree of potentiation obtained with a specific combination of the above drugs by means of the “surface of synergistic interaction” of the combinations. The ED₅₀ values for ASA and morphine were 1,167.9 ± 6.7 and 18.4 ± 3.7 μmol/kg, respectively. Eleven combinations of ASA and morphine produced a level of analgesia significantly greater than can be accounted for by simple addition of the analgesic effects of each analgesic drug alone (P < 0.01). The combination of ASA (3,121.3 μmol/kg) and morphine (31.1 μmol/kg) produced the maximum analgesic effect. However, three combinations of ASA + morphine (555.1 + 31.1, 986.9 + 9.8, and 1,755.2 + 9.8 μmol/kg, respectively) produced the highest potentiation effects (P < 0.01). The surface of synergistic interaction clearly showed which combination of these analgesic drugs produced the highest degree of potentiation in the rat. This study showed that it is possible to rationally predict the specific combinations of analgesic drugs and their dosages which will provide either maximal levels of analgesia or the highest potentiation effect in the rat. © 1995 Wiley-Liss, Inc.     

The Effect of Thiabendazole on Pain Threshold

Abstract: Thiabendazole significantly increased the reaction time to thermal stimulus. However, in mice treated with morphine, the reaction time was not in any way different from those treated with combined doses of thiabendazole and morphine. Thiabendazole was found to have an antinociceptive action. The protective dose for 50% of animal (ED50) against p–benzoquinone–induced writhing reflex was found to be 310 mg/kg. The ED50 for aspirin alone was 140 mg/kg. When the ED50 of aspirin was determined in combination with different dose levels of thiabendazole, it showed a marked reduction in the values reaching 50 mg/kg, when 300 mg of thiabendazole was used in combination. Toxicological studies revealed that the oral LD50 for thiabendazole in mice was 2200 mg/kg, and when combined with 140 mg/kg of aspirin, the LD50 was reduced to 900 mg/kg. These findings indicate that thiabendazole possesses an analgesic activity which is potentiated by aspirin, though aspirin was found to significantly enhance its toxicity     

Changes in effective and lethal doses of intravenous anesthetics and lidocaine when used in combination in mice

We studied the interactions between a local anesthetic agent, lidocaine, and two general anesthetic drugs, propofol and ketamine, in mice. We used two end points: hypnosis, reflected by loss of the righting reflex, and death. The ED50 for hypnosis and the LD50 were determined for each drug separately, and a dose-response curve was prepared for each drug, using combinations of propofol-lidocane and ketamine-lidocaine at three different dose ratios. Probit and isobolographic analyses revealed supra-additive (synergistic) interactions between lidocaine and each of the other anesthetic agents regarding both the effective dose and the lethal dose. No significant difference was found between propofol and ketamine regarding the supraadditive effect.     

Analgesic activity and safety of ash of silver used in Indian system of medicine in mice: a reverse pharmacological study

Objective:

To study the analgesic activity of ash of silver used in Indian system of medicine and to explore its safety.

Materials and Methods:

Albino mice of either sex (20-30 gm) were used to investigate the role of ash of silver against noxious stimuli: thermal (Eddy''s hot plate and analgesiometer), mechanical (tail clip), and chemical (0.6% acetic acid induced writhing). An effort was made to find nature and site of action of ash of silver following naloxone pre-treatment. Maximum tolerated dose (MTD) and lethal dosage 50 (LD50) were also studied along with toxicological aspects of ash of silver.

Results:

Test drug (ash of silver) at a dose of 50 mg/kg p.o exhibited analgesic activity against thermal, mechanical, and chemical stimuli. Analgesic effects were compared with the standard drug, morphine, in thermal and mechanical noxious stimuli and to aspirin in chemical stimulus. Analgesic activity of the test drug was reduced following naloxone pre-treatment. MTD was found out to be greater than 1.5 g/kg p.o. LD50 was 2 g/kg p.o. Fraction of mice showed symptoms of argyria as explained by autopsy reports.

Conclusion:

Test drug exhibited moderate analgesic activity at 50 mg/kg p.o against all type of noxious stimuli, also suggesting a role of opioidergic system. The ash of silver was been found to be safe upto a dose of 1.5 g/kg p.o. in mice without any untoward toxicity. Further studies are required to explore the effect of ash of silver on pain mediators and excitatory neurotransmitters like glutamate, aspartate, or N-methyl-D-aspartic acid (NMDA).KEY WORDS: Ash of silver, analgesic, argyria, nanosilver     

Verapamil increases the toxicity of local anesthetics

The calcium channel blocker verapamil has, in addition to its other properties, been shown to be a local anesthetic. Its concurrent use in a patient undergoing regional anesthesia may, therefore, increase the potential risk for local anesthetic toxicity. To evaluate this possibility, the effect of verapamil on the median lethal dose (LD50) of lidocaine and bupivacaine in mice was determined. Immediate pretreatment with verapamil increased the mortality of mice given the LD50 dose of lidocaine to 74%, and in mice given the LD50 doses of bupivacaine, to 82%. In animals pretreated with verapamil and calcium chloride, the mortality associated with the administration of LD50 doses of lidocaine and bupivacaine decreased to 43% and 48%, respectively, thus returning the mortality rate back to the LD50 of the local anesthetics when administered alone. It seems that the combined administration of local anesthetic and verapamil results in a significant drug interaction: the resulting blockade of sodium and calcium channels apparently impairs membrane function to a greater degree than with either drug alone. Additional investigation is warranted, and caution should be exercised in giving verapamil to patients during regional anesthesia. Should an adverse drug interaction ensue, the administration of calcium may be beneficial.     

Interaction of diazepam with meperidine or normeperidine on analgesia and lethality

The effects of meperidine and normeperidine were determined alone and after pretreatment with 10 mg/kg of diazepam on the tail-withdrawal measure of analgesia in rats. Lethal doses of normeperidine were determined alone and in combination with three doses of diazepam, and lethal doses of meperidine were determined alone and in combination with 10 mg/kg of diazepam. Diazepam potentiated the analgesic effects of meperidine and increased the dose of normeperidine necessary to produce lethality.     

风湿骨痹口服液急性毒性研究

目的观察小鼠灌胃风湿骨痹口服液的急性毒性反应,测定半数致死量（LD50）及最大给药量,为临床安全用药提供依据。方法小鼠给予风湿骨痹口服液灌胃,通过预试验测定LD50及最大给药量。结果 LD50未测出;小鼠最大给药量为1236 g生药/kg,相当于临床人用量的1799倍,在此剂量下灌胃对小鼠无急性毒性反应。结论风湿骨痹口服液毒性较低,在临床规定用法用量下安全可靠。     

Influence of atropine on the acute toxicity of isometamidium.

The effectiveness of atropine in blocking the acute toxic effects of the antitrypanosomal drug isometamidium (ISMM) was evaluated in mice and goats using lethality as the primary index. The median lethal dose (LD50) of ISMM in nonatropinized mice was 45.3 mg/kg bodyweight (SE +/- 5.3 mg/kg bodyweight), whereas the LD50 of ISMM in mice pre-treated with atropine was 71.7 mg/kg bodyweight (SE +/- 13.2 mg/kg bodyweight). The increase in LD50 was about 60%. The ratio of the slope of the dose-response curve for ISMM in non-atropinized mice to that in atropinized mice was about 4:1. The results showed that atropine was effective in considerably reducing the lethal effect of ISMM in mice. In contrast, experiments in goats showed markedly different results; atropine was not effective in reducing the lethality of ISMM. It was concluded that in mice atropine has some beneficial action in cases of overdosage or poisoning by ISMM. Treatment with atropine should be attempted as an antidotal measure in humans accidentally poisoned with ISMM.     

Influence of felbamate on the antinociceptive action of morphine, metamizol and indomethacin in mice

The influence of felbamate (200 mg/kg or 50 mg/kg) on antinociceptive effect of morphine (10 mg/kg), metamizol (500 mg/kg) and indomethacin (10 mg/kg or 1.4 mg/kg) was investigated in a mouse model using the hot-plate test. All drugs were injected intraperitoneally. Felbamate was administered to mice 30 min before applying the analgesic drugs. Measurement of nociception was performed within 2 h after felbamate administration. The research studies were further conducted with a multiple (10 days) drug dosage. Felbamate in the dose of 200 mg/kg significantly increases the analgesic effect of morphine and weakens the effect of metamizol and indomethacin. Multiple administration of felbamate does not affect the activity of morphine and metamizol, but decreases analgesic effect of indomethacin.     

Interaction of clonidine and morphine with lidocaine in mice and rats

Morphine and clonidine both elevated plasma levels of lidocaine to the same extent in mice while slowing lidocaine metabolism to deethylated products. The effects of clonidine on lidocaine disposition were reversed by yohimbine. Mice given morphine, 20 mg/kg sc, or clonidine, 0.2 mg/kg sc, had similar, 30-50%, elevation of plasma lidocaine levels at 15 min after lidocaine, 15 mg/kg iv, when compared to saline-treated animals. Despite similarity of effect on plasma lidocaine, mice treated with morphine were much more susceptible to lethal effects of lidocaine than were mice given clonidine. At iv doses of 22 mg/kg or higher, lidocaine caused death in nearly all morphine-treated mice, while even 32 mg/kg lidocaine caused only 11% mortality after saline or clonidine. Clonidine, 0.5 mg/kg sc, and morphine, 20 mg/kg sc, both raised plasma lidocaine levels in rats, but only morphine depressed respiration, causing hypoxia, hypercapnia, and acidosis and increasing lidocaine lethality. These data suggest that potentiation of lidocaine toxicity by morphine is due primarily to changes in blood gases rather than to elevation in lidocaine levels.     

Synergistic antihypersensitive effects of pregabalin and tapentadol in a rat model of neuropathic pain

Neuropathic pain is a clinical condition which remains poorly treated and combinations of pregabalin, an antagonist of the α2δ-subunit of Ca(2+) channels, with tapentadol, a μ-opioid receptor agonist/noradrenaline reuptake inhibitor, or with classical opioids such as oxycodone and morphine might offer increased therapeutic potential. In the rat spinal nerve ligation model, a dose dependent increase in ipsilateral paw withdrawal thresholds was obtained using an electronic von Frey filament after IV administration of pregabalin (1-10mg/kg), tapentadol (0.316-10mg/kg), morphine (1-4.64 mg/kg) and oxycodone (0.316-3.16 mg/kg), with ED(50) values (maximal efficacy) of 4.21 (67%), 1.65 (94%), 1.70 (96%) and 0.63 mg/kg (100%), respectively. Equianalgesic dose combinations of pregabalin and tapentadol (dose ratio 2.5:1), morphine (2.5:1) or oxycodone (6.5:1) resulted in ED(50) values (maximal efficacy) of 0.83 (89%), 2.33 (97%) and 1.14 mg/kg (100%), respectively. The concept of dose-equivalence suggested an additive interaction of pregabalin and either oxycodone or morphine, while a synergistic interaction was obtained with pregabalin and tapentadol (demonstrated by isobolographic analysis). There was no increase in contralateral paw withdrawal thresholds and no locomotor impairment, as measured in the open field, for the combination of pregabalin and tapentadol; while a significant increase and impairment was demonstrated for the combinations of pregabalin and either morphine or oxycodone. Because combination of pregabalin and tapentadol resulted in a synergistic antihypersensitive activity, it is suggested that, beside the use of either drug alone, this drug combination may offer a beneficial treatment option for neuropathic pain.     

Quercetin,a bioflavonoid,reverses development of tolerance and dependence to morphine

Quercetin, a bioflavonoid (25 and 50 mg/kg), when chronically administered for 9 days, failed to produce any significant change in tail flick latency as compared to control mice. However, repeated administration of quercetin (25 and 50 mg/kg) for 9 days attenuated the development of tolerance to the analgesic effect of morphine (10 mg/kg). Quercetin (25 and 50 mg/kg) also suppressed naloxone (2 mg/kg)‐precipitated withdrawal jumps on day 10 in morphine‐tolerant mice. Pretreatment of mice with quercetin (10–50, ip) significantly reversed the morphine (5 mg/kg)‐induced delay in gastric transit, whereas a higher dose of quercetin (100 mg/kg) did not have any significant effect on morphine‐induced delay in gastric transit. Quercetin per se had no effect on gastric transit. In conclusion, the results of the present study suggest potential use of quercetin in alleviating the adverse effects of opioid treatment. Drug Dev. Res. 57:167–172, 2002. © 2003 Wiley‐Liss, Inc.     

Comparison of the analgesic actions of THIP and morphine

The antinociceptive actions of intraperitoneally-administered 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and morphine were compared using three strains of mice. With the hot-plate assay, ED50 values for the action of THIP were about 4 mg/kg in OF1, CD1 and NMRI strains, whereas ED50 values for morphine varied among strains, being 6.8 mg/kg for OF1, 16.9 mg/kg for CD1, and about 29 mg/kg for NMRI mice; thus, the genetic control of the analgesic action of THIP appears to differ from that of morphine. The analgesic action of THIP in the hot-plate test was not blocked by naloxone, bicuculline, phentolamine or methysergide, but was partially reversed by a high dose of atropine, indicating that classic opiate-receptors, bicuculline-sensitive GABA-receptors, alpha-adrenoceptors and serotonin-receptors do not appear to mediate the action of THIP but that cholinergic receptors might be indirectly involved. THIP was about equipotent or more potent than morphine in the phenylbenzoquinone writhing test, evasion test, and traction test. Since the ED50 values for THIP in OF1 mice were similar for hot-plate, evasion and traction tests, the analgesic action of THIP might not be readily dissociated from its sedative or myorelaxant action.     

Lack of effect of single high doses of buprenorphine on arterial blood gases in the rat.

High dose buprenorphine, a potent semisynthetic agonist-antagonist for opiate receptors, is now used in substitution treatment of human heroin addiction. Deaths have been reported in addicts misusing buprenorphine. We determined the median lethal dose (LD(50)) and studied the effects of high doses of intravenous buprenorphine on arterial blood gases in rats. Male Sprague-Dawley rats were administered buprenorphine intravenously to determine the LD(50) using the up-and-down method. Subsequently, catheterized groups of 10 restrained rats received no drug, saline, acid-alcohol aqueous solvent (required to dissolve buprenorphine at a high concentration), or 3, 30, or 90 mg/kg of buprenorphine intravenously. Serial arterial blood gases were obtained over 3 h. The LD(50) determined in triplicate was 146.5 mg/kg (median of 3 series, range: 142.6-176.5). The mean dose received by surviving animals was 96.9 +/- 46.7 mg/kg. There was a significant effect of the acid-alcohol aqueous solvent on arterial blood gases. Excluding the solvent effect, 3, 30, and 90-mg/kg buprenorphine doses had no significant effects on arterial blood gases. The toxicity of intravenous buprenorphine in adult rats, assessed by the LD(50), is low. These data are consistent with a wide margin of safety of buprenorphine. The mechanism of death after the intravenous administration of a lethal dose of buprenorphine remains to be determined.     

Analgesic synergy between topical opioids and topical non-steroidal anti-inflammatory drugs in the mouse model of thermal pain

The main aim of the study was to examine analgesic effects of the topical opioids and non-steroidal anti-inflammatory drugs (NSAIDs) in a radiant heat tail-flick nociception model. Also, we have tested whether the addition of lauric acid to propylene glycol improves skin permeation for the opioids and NSAIDs. We found that the addition of lauric acid to propylene glycol dramatically improves the penetration of the drugs, measured by the drug's ED(50). We observed a significant dose response shift to the left for all tested drugs. So, morphine's ED(50) was decreased by 19-fold. The duration of the analgesic activity of morphine dissolved in a combination of propylene glycol and lauric acid was much longer compared with the same dose of the drug dissolved in propylene glycol only. Methadone and hydrocodone also produced analgesic activity in this experimental paradigm. We then assessed potential interactions between opioids, ibuprofen and diclofenac using a fixed, low dose of each. The inclusion of either S-ibuprofen or diclofenac to a fixed, low dose of morphine raised the analgesic response from around 20% to 50% and 80%, respectively. Topical methadone and diclofenac alone produced analgesia in 30% of mice. The combination produced analgesia in 100% of mice (100% versus 60%, P<0.001) and the analgesic effect was observed for 90 min. Alone, topical methadone and S-ibuprofen produced analgesia in 25% and 30% of mice, respectively. The combination elicited analgesia in 100% of mice (100% versus 55%, P<0.001) and this analgesic effect lasted for 120 min. Our current findings support the supra-additive interaction of topical mu opioids, S-ibuprofen and diclofenac in a model of moderate to severe pain, radiant heat tail-flick assay.