Methotrimeprazine and UV light.
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Carcinoma↗
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Effects of methotrimeprazine, other phenothiazines and related compounds on the levels of norepinephrine in the mouse heart.
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Amitriptyline↗
A comparison of the actions of some drugs on decerebrate rigidity, muscle spindle activity and alpha-adrenoceptors.
1 The relative potencies of methotrimeprazine, (+)-methotrimeprazine, (+/-)-10-(3-dimethylamino-2-methylpropyl)-2-valeroyl phenothiazine hydrochloride (M & B 18,706) and (+)-M & B 18,706 in reducing the pressor action of noradrenaline in the spinal cat, reducing intercollicular decerebrate rigidity, and muscle spindle afferent activity have been studied.2 Methotrimeprazine was eight times as potent as (+)-methotrimeprazine in reducing the pressor action of noradrenaline and six times as potent in reducing decerebrate rigidity. M & B 18,706 was also eight times as potent as (+)-M & B 18,706 in reducing the pressor action of noradrenaline and six times as potent in reducing decerebrate rigidity.3 For the above compounds and chlorpromazine there was a significant correlation between the effective doses for the inhibition of the pressor action of noradrenaline and for the reduction of decerebrate rigidity.4 The doses which reduced decerebrate rigidity were similar to those that reduced muscle spindle afferent discharge. It is likely that these drugs reduce decerebrate rigidity by inhibiting fusimotor activity.5 Desipramine increased decerebrate rigidity and increased spindle afferent discharge.6 It is thought that the phenothiazine derivatives studied reduce decerebrate rigidity and spindle afferent discharge by inhibiting receptors for noradrenaline in the central nervous system.
Animals↗
Characterization of the potential antioxidant and pro-oxidant actions of some neuroleptic drugs.
It has been suggested in the literature that neuroleptic drugs may be able to exert antioxidant and/or pro-oxidant actions in vivo. The feasibility of this was tested by measuring the ability of chlorpromazine, prochlorperazine, metoclopramide, methotrimeprazine and haloperidol to scavenge biologically relevant oxygen-derived species in vitro. None of the drugs reacted with superoxide radical at a significant rate. Chlorpromazine, prochlorperazine, metoclopramide and methotrimeprazine were very powerful scavengers of hydroxyl radicals, reacting at almost a diffusion-controlled rate. Chlorpromazine showed some ability to inhibit iron ion-dependent hydroxyl radical formation. Chlorpromazine, methotrimeprazine, promethazine and prochlorperazine were powerful inhibitors of iron ion-dependent liposomal lipid peroxidation, scavengers of organic peroxyl radicals and inhibitors of haem protein/hydrogen peroxide-dependent peroxidation of arachidonic acid. Chlorpromazine, prochlorperazine, metoclopramide, methotrimeprazine and haloperidol were powerful scavengers of hypochlorous acid. Haloperidol showed no ability to inhibit lipid peroxidation or to scavenge peroxyl radicals, and reproducibly increased lipid peroxidation catalysed by haem proteins, in both the presence and absence of hydrogen peroxide. The relevance of these in vitro observations to events in vivo is discussed.
Antioxidants↗
The role of stereoselectivity of chemosensitizers in the reversal of multidrug resistance of mouse lymphoma cells.
The effect of three different stereoisomer pairs of CNS (central nervous system) active compounds was studied on the activity of human mdr1 p-glycoprotein. The methotrimeprazine, clopenthixol and butaclamol isomers had an antiproliferative effect (ID50) on the mdr1 expressing cells at 0.250 microgram/ml, while the parental cells were less sensitive having ID50 at 0.37-0.69 microgram/ml. Enantiomers of methotrimeprazine and clopenthixol had similar effectivity on the drug efflux of mdr cells. However, (-)butaclamol was found to inhibit mdr efflux-pump activity much more than the CNS active (+) isomer. Based on these results, tricyclic compounds does not seem to have stereoselectivity in methotrimeprazine and clopenthixol on the mdr reversal effect. In general, both active and inactive members of stereoisomers had a similar effect on the drug accumulation of the mdr cells. Therefore, hypothetically the CNS inactive member of stereoisomer pairs can be used as a resistance modifier without any risk in patients suffering from drug resistant cancer.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Determination of several psychiatric drugs in whole blood using capillary gas-liquid chromatography with nitrogen phosphorus detection: comparison of two solid phase extraction procedures.
A simple and reliable gas chromatographic method with nitrogen-phosphorus detection without derivatization was developed for the detection of several psychiatric drugs in whole blood as part of systematic toxicological analyses (STA). Drugs included mirtazapine, chlorpromazine, methotrimeprazine (levomepromazine), clothiapine, olanzapine, clozapine, haloperidol, and thioridazine. All drugs were studied at concentrations of 100-2,000 microg/L, except haloperidol that was studied at concentrations of 400-8,000 microg/L. In order to select the best blood purification procedure and therefore increase the signal to noise ratio we have compared two solid-phase extraction (SPE) columns, Chem Elut and Bond Elut Certify, for their recovery, precision, sensitivity and matrix purification efficiency. Recoveries for these drugs using Chem Elut columns at 500 and 2,000 microg/L (2,000 and 8,000 microg/L for haloperidol) were in the range 21-65%, with intra-assay and inter-assay precisions of less than 17% and 19%, respectively. Limits of detection (LODs) and limits of quantitation (LOQs) for mirtazapine, chlorpromazine, methotrimeprazine, clothiapine, olanzapine, clozapine, and thioridazine ranged from 62 to 161 microg/L and from 205 to 531 microg/L, respectively. LOD and LOQ for haloperidol were 442 and 1,458 microg/L, respectively. Recoveries of these compounds using Bond Elut Certify columns at 500 and 2,000 microg/L (2,000 and 8,000 microg/L for haloperidol) were in the range 44-97%, with intra-assay and inter-assay precisions of less than 7% and 14%, respectively. LODs and LOQs for mirtazapine, chlorpromazine, methotrimeprazine, clothiapine, olanzapine, clozapine, and thioridazine ranged from 37 to 66 microg/L and from 122 to 218 microg/L, respectively. LOD and LOQ for haloperidol were 156 and 515 microg/L, respectively. Linearity was observed in the studied range for all compounds with r(2) values of >0.999. The use of the mixed-mode bonded-silica Bond Elut Certify columns showed advantages comparing with Chem Elut columns for the screening of these psychotropic agents such as higher recoveries, cleaner extracts, better sensitivity, better precision and less solvent consumption and subsequent disposal.
Adult↗
A preliminary trial comparison of several anesthetic techniques in cats.
The aim of this study was to investigate the effect of several drug combinations (atropine, xylazine, romifidine, methotrimeprazine, midazolam, or fentanyl) with ketamine for short term anesthesia in cats. Twelve cats were anesthetized 6 times by using a cross-over Latin square protocol: methotrimeprazine was combined with midazolam, ketamine, and fentanyl; midazolam and ketamine; romifidine and ketamine; and xylazine and ketamine. Atropine was combined with romifidine and ketamine, and xylazine and ketamine. Temperature, heart rate, and respiratory rate decreased in all groups. Apnea occurred in 1 cat treated with methotrimeprazine, romifidine, and ketamine, suggesting that ventilatory support may be necessary when this protocol is used. Emesis occurred in some cats treated with alpha 2-adrenoceptor agonists, and this side effect should be considered when these drugs are used.
Anesthesia, General↗
Neuroleptanalgesia in the rabbit.
The efficacy of the neuroleptanalgesic combinations of fentanyl-fluanisone with diazepam; and etorphine-methotrimeprazine, either alone, or with diazepam, was investigated in the rabbit. The effects of these drugs on some cardiovascular variables were studied in chronically catheterized rabbits. Fentanyl-fluanisone and diazepam produced good surgical anaesthesia. Although respiratory depression occurred, this had little effect on blood gas values. In contrast, etorphine-methotrimeprazine and diazepam produced severe respiratory depression with consequent hypercapnia and acidosis.
Acidosis↗
Phenothiazine treatment and respiratory distress syndrome in a child.
An 11-year-old boy who was treated with a relatively high dose of methotrimeprazine meleate (Levemepromazine) a phenothiazine antipsychotic drug, was admitted to the pediatric intensive care unit suffering from respiratory distress syndrome. He required intensive treatment and support for 13 days. The persistent effects of methotrimeprazine meleate on various organs are typical of the prolonged biological action of the phenothiazine metabolites. The association of phenothiazine overdose and respiratory distress syndrome merits consideration.
Child↗
An assessment of a sedative algorithm for sleep in an intensive care unit.
The difficulty for intensive care unit (ICU) patients to obtain frequent and extensive sleep has been well-documented. This project assessed the benefit of an algorithm of pharmacological assistance (lorazepam and methotrimeprazine) on sedation level and sleep duration in the ICU. The setting was a 15-bed closed ICU dealing with medical and surgical patients in a tertiary care, teaching hospital. Desired and actual levels of sedation for individual patients were determined hourly by the bedside nurse. Medications could be administered to facilitate achieving the desired level of sedation. Our results should no difference occurred in the achievement of the target sedation or duration of sleep with the implementation of the sedation algorithm. The amount of additional medication required during the night did change with the implementation of the sedation algorithm. A reduction in the amount of diazepam, morphine, and additional methotrimeprazine was noted. Efforts to change nursing practice will be required to improve the quality and quantity of sleep in ICU patients. This clinical evaluation demonstrates that the implementation of an algorithm for medication use is not effective alone in obtaining the desired level and duration of sleep in ICU patients. Nursing practice should continue to look at non-pharmacological factors, such as environmental noise, patient interruptions, and patient care practice to determine strategies in addition to medications which would aid the critically ill patient in achieving adequate sleep.
Algorithms↗
Enantioseparation of phenothiazines in cyclodextrin-modified capillary zone electrophoresis using sulfated cyclodextrins as chiral selectors.
In this study, enantioseparations of five phenothiazines, including promethazine, ethopropazine, trimeprazine, methotrimeprazine, and thioridazine, in CD-modified CZE using dual CD systems consisting of randomly sulfate-substituted CD (MI-S-beta-CD) and a neutral CD as chiral selectors in a citrate buffer (100 mM) at pH 3.0 were investigated. The results indicate that MI-S-beta-CD is an excellent chiral selector for enantioseparation of ethopropazine. The enantiomers of promethazine can also be baseline-resolved with MI-S-beta-CD at concentrations in the range of 0.5-1.0% w/v. On the other hand, thioridazine and trimeprazine interact strongly with neutral CDs. As a result, the enantioselectivity of these two phenothiazines is remarkably and synergistically enhanced with increasing the concentration of neutral CDs in the presence of MI-S-beta-CD and simultaneous enantioseparations of these phenothiazines, except for methotrimeprazine, could favorably be achieved with the use of dual CD systems. Moreover, by varying the concentration of beta-CD or gamma-CD at a fixed concentration of MI-S-beta-CD (0.75% w/v) reversal of the enantiomer migration order of promethazine occurred. This may be attributable to the opposite effects of charged and neutral CDs on the mobility of the enantiomers of promethazine.
Cyclodextrins↗
Comparative plasma concentrations of quinidine following administration of one intramuscular and three oral formulations to 13 human subjects.
A GLC method, based on flame-ionization detection, was developed for the assay of methotrimeprazine and its sulfoxide in plasma. For a 6-ml aliquot, the sensitivity was 2-3 ng/ml for the unchanged drug and 4-5 ng/ml for the sulfoxide. The coefficient of variation, calculated from duplicate analyses of plasma samples, was 8-15% for concentrations between 10 and 100 ng/ml. Patients treated with orally administered methotrimeprazine had higher plasma levels of the sulfoxide than of unmetabolized drug. The method also was applied to the analysis of promazine and chlorpromazine in patient plasma.
Administration, Oral↗
Enantioseparation of phenothiazines in capillary zone electrophoresis using cyclodextrins as chiral selectors.
In this study, enantioseparations of five phenothiazines, including promethazine, ethopropazine, trimeprazine, methotrimeprazine, and thioridazine, in cyclodextrin (CD)-modified capillary zone electrophoresis were investigated using a phosphate buffer (40 mM) at pH 3.0. We focussed on the separation of phenothiazines with the use of CDs at low concentrations. Three different CDs, including beta-CD, hydroxypropyl-beta-CD (HP-beta-CD) and gamma-CD, were chosen as chiral selectors. The results indicate that effective enantioseparation of phenothiazines, except for methotrimeprazine, is simultaneously achievable with addition of gamma-CD at a concentration of 2.5-6.0 mM. The enantiomers of ethopropazine and trimeprazine are effectively separated with addition of HP-beta-CD at low concentrations, in the range 0.4-6.0 mM, whereas those of promethazine and trimeprazine are baseline resolved with beta-CD at much lower concentrations (0.02-3.0 mM) than with HP-beta-CD. The results also confirm that the separation window is greatly enlarged at low CD concentrations. Moreover, the drastic variations of the electrophoretic mobility of phenothiazines as a function of CD concentration reveal that phenothiazines interact very strongly with CDs in the order gamma-CD<HP-beta-CD<beta-CD.
Cyclodextrins↗
Pharmacological approaches other than opioids in chronic non-cancer pain management.
Many pains are controlled by non-addictive procedures ranging from exercise to a variety of analgesic medications. Some pains are controlled by analgesic drugs, but at the cost of intolerable side effects. This is true both for non-steroidal anti-inflammatory drugs and opioids. The worst pains are most often controlled by opioids, but problems of tolerance and addiction limit these successes. This contribution provides a statement on non-addictive, non-opioid drugs which help to control pain. Just as these vary in their success, so they vary also in the strength of the scientific evidence which supports their use. The groups of drugs to be considered can be evaluated in three respects; evidence of analgesic effect in controlled trials; evidence of side-effects compared with control substances and with standard experience; evidence of usefulness in clinical practice. The latter which is the most important for practice often has the least scientific proof. Six main classes of drugs are recognized which provide analgesic effects, other than opioids. 1) Non-steroidal anti-inflammatory drugs are widely accepted as analgesics on the basis of animal studies, numerous controlled investigations and clinical practice. Acetaminophene may not be anti-inflammatory, but is recognized as an effective analgesic which in many other respects resembles the above. 2) Muscle relaxants, e.g. cyclobenzaprine or baclofen have varied actions, but often provide some relief of pain. 3) Antidepressants may be analgesic if they relieve depression which is giving rise to pain. This applies to all anti-depressants. Some antidepressants have been shown to be analgesic in the absence of depression. The best accredited of these is amitriptyline. Antidepressants too have significant side effects. A serotoninergic hypothesis is insufficient to explain the actions of antidepressants in relieving pain in the absence of depression. 4) Phenothiazine neuroleptics (and possibly some others) may be analgesic. Drugs reported to be analgesic include chlorpromazine, fluphenazine, perphenazine, trifluoperazine, methotrimeprazine (levomepromazine) among others. Haloperidol has also been utilized. Well controlled evidence exists with the use of methotrimeprazine (levomepromazine) used as an injection. The analgesic effect of oral neuroleptics is less well established and mostly depends upon clinical observation, withdrawal and re-challenge. 5) Anticonvulsants. 6) Other drugs. Non-steroidal anti-inflammatory drugs and some muscle relaxants, e.g. cyclobenzaprine are best used in the short term. The gastrointestinal side effects of non-steroidal anti-inflammatory drugs have been quite troublesome and over 2% of patients followed over five years are at risk of developing peptic ulceration from such medication. Cyclobenzaprine is best used in short term treatment, but may be used intermittently for chronic pain. Antidepressants, neuroleptics, anticonvulsants and some other drugs can be used long term. Topical analgesic agents may also be used.
Analgesics↗
Structural changes by sulfoxidation of phenothiazine drugs.
The side-chain conformations of psychoactive phenothiazine drugs in crystals are different from those of biologically inactive ring sulfoxide metabolites. This study examines the potential energies, molecular conformations and electrostatic potentials in chlorpromazine, levomepromazine (methotrimeprazine), their sulfoxide metabolites and methoxypromazine. The purpose of the study was to examine the significance of the different crystal conformations of active and inactive phenothiazine derivatives, and to determine why phenothiazine drugs lose most of their biological activity by sulfoxidation. Quantum mechanics and molecular mechanics calculations demonstrated that conformations with the side chain folded over the ring structure had lowest potential energy in vacuo, both in the drugs and in the sulfoxide metabolites. In the sulfoxides, side chain conformations corresponding to the crystal structure of chlorpromazine sulfoxide were characterized by stronger negative electrostatic potentials around the ring system than in the parent drugs. This may weaken the electrostatic interaction of sulfoxide metabolites with negatively charged domains in dopamine receptors, and cause the sulfoxides to be virtually inactive in dopamine receptor binding and related pharmacological tests.
Antipsychotic Agents↗
Anaesthesia for the carcinoid syndrome: a report of nine cases.
Anaesthesia for nine patients with the carcinoid syndrome is described. With the exception of one case in which severe bronchospasm and hypertension occurred, complications were minor. Steroids, aprotonin and methotrimeprazine appear to be useful agents in the management of such patients. An anaesthetic technique employing thiopentone, pancuronium and nitrous oxide proved satisfactory.
Aged↗
The neuroleptics as adjuvant analgesics.
The role of neuroleptic drugs as adjuvant analgesics has been a subject of longstanding controversy. Despite frequent claims of efficacy, evidence from controlled trials supports neither claims of intrinsic analgesic properties nor the routine use of the neuroleptics as a means to reliably induce clinically useful analgesia. Methotrimeprazine is unique in that there is evidence for reliable dose-related analgesia that is comparable to opioid-mediated analgesia, although routine use is not recommended. Despite probable interaction with opioid receptors, there is insufficient evidence to support a role for the butyrophenone category of neuroleptics as adjuvant analgesics. Limited trials of the neuroleptics may be considered for pain that has been unresponsive to more conventional pharmacologic approaches, especially when associated with headache, nerve injury, or psychological distress. The neuroleptics have an important role in the symptomatic management of agitation, delirium, and nausea, particularly in patients with cancer.
Analgesics↗
Analysis of etorphine in postmortem samples by HPLC with UV diode-array detection.
Etorphine is a synthetic narcotic analgesic usually used in veterinary medicine. It possesses an analgesic potency up to 1000 times greater than morphine and is therefore used in low doses, primarily for tranquilising large animals. For veterinary use, etorphine is usually available in its commercial formulation as Immobilon, when in combination with acepromazine or methotrimeprazine. Due to the potency of etorphine, only very low doses are required to produce adverse or fatal effects. This paper describes a method for detecting and quantifying etorphine using HPLC with UV diode array detection (HPLC-DAD) and demonstrates the advantage of the technique for the detection of Immobilon at low doses. In a forensic case involving Immobilon, the etorphine concentrations measured in postmortem femoral vein and heart blood specimens were 14.5 and 23.5 micrograms/l, respectively. No etorphine was detected in the urine. To our knowledge this is the first time postmortem etorphine concentrations have been reported.
Analgesics, Opioid↗