Meserine, a novel carbamate AChE inhibitor, ameliorates scopolamine-induced dementia and alleviates amyloidogenesis of APP/PS1 transgenic mice.

AIMS: To investigate whether Meserine, a novel phenylcarbamate derivative of (-)-meptazinol, possesses beneficial activities against cholinergic deficiency and amyloidogenesis, the two major pathological characteristics of Alzheimer's disease (AD). METHODS: Ellman's assay and Morris water maze were used to detect acetylcholinesterase (AChE) activity and evaluate spatial learning and memory ability, respectively. Both high content screening and Western blotting were carried out to detect ß-amyloid precursor protein (APP), while RT-PCR and ELISA were conducted to detect APP-mRNA and ß-amyloid peptide (Aß). RESULTS: In scopolamine-induced dementia mice, Meserine (1 mg/kg, i.p.) significantly ameliorated spatial learning and memory deficits, which was consistent with its in vitro inhibitory ability against AChE (recombinant human AChE, IC50 = 274 ± 49 nM). Furthermore, Meserine (7.5 mg/kg) injected intraperitoneally once daily for 3 weeks lowered APP level by 28% and Aß42 level by 42% in APP/PS1 transgenic mouse cerebrum. This APP modulation action might be posttranscriptional, as Meserine reduced APP by about 30% in SH-SY5Y-APP695 cells but did not alter APP-mRNA level. And both APP and Aß42 lowering action of Meserine maintained longer than that of rivastigmine. CONCLUSION: Meserine executes dual actions against cholinergic deficiency and amyloidogenesis and provides a promising lead compound for symptomatic and modifying therapy of AD.

Post-surgical pain relief with zero-order intravenous infusions of meptazinol and morphine: a double-blind placebo-controlled evaluation of their effects on ventilation.

A double-blind, placebo-controlled study has been made of the analgesic and respiratory effects of constant rate infusions of meptazinol and morphine in 30 patients after abdominal surgery. Group I received meptazinol, loading dose 50 mg followed by i.v. infusion 0.5 mg.kg-1.h-1, Group II received morphine, loading dose 5 mg and then an infusion of 0.05 mg.kg-1.h-1, and Group III received saline. After recovery from inhalation anaesthesia (without opiates or a local anaesthetic) pain relief and chemoreceptor carbon dioxide tolerance were assessed before and at various times after starting the analgesic infusion. A similar degree of pain relief was found after 10 min in Groups I and II, which lasted until the end of observation period (20 h). Heart rate and systolic and diastolic blood pressures were lower in Group II than in Groups I and III, and respiratory rate fell in Groups I and II. After 6 h arterial carbon dioxide tensions (PaCO2) became significantly higher in Group II than Group III. The maximum percentage fall in mean tidal volume (VT) and expired minute volume (VE) from the preinjection values was significant in Groups I and II. End-tidal carbon-dioxide (PETCO2) and PaCO2 were significantly higher after 20 h of infusion in Group II compared to Group I. The slope of VE/PETCO2 (mean value of S) was increased in Group I and it was significantly reduced in Group II. Analysis of derived variables, such as the CO2 intercept (CO2I) and minute ventilation at 7 kPa (VE7), indicated a shift to the right of the slopes in Groups I and II, initially more so in Group I.(ABSTRACT TRUNCATED AT 250 WORDS)

Meptazinol and morphine in postoperative pain assessed with a new method for onset and duration.

Meptazinol, m-(3-ethyl-1-methyl-hexahydro-1-H-azepin-3-yl) phenol hydrochloride is a centrally active opioid analgesic with a specificity for the mu-1 receptor. It has been reported to lack many of the side effects commonly observed with morphine and morphinelike drugs in man. The objective of this study was to assess the analgesic efficacy and safety of meptazinol (50 mg and 100 mg) relative to morphine (5 mg and 10 mg) when administered intramuscularly for the treatment of postoperative pain. In addition, a new clinical method for measuring onset and duration and a statistical technique for evaluating the study data are presented. One hundred and seventeen patients were evaluated for 6 hours in a randomized double blind, single dose, parallel-groups trial. Estimates of relative potency for hourly pain and relief parameters, and the summary variables sum of pain intensity differences (SPID) and total pain relief (TOTPAR) were performed. The estimate of relative potency of meptazinol to morphine for pain relief was 0.19 at 1/2 hour (i.e. 100 mg of meptazinol was approximately equivalent to 20 mg of morphine). Thereafter, there was a rapid decline of efficacy for meptazinol, with a relative potency estimate of 0.12 at 1 hour and 0.06 at 2 hours. The distribution functions for several time related events were estimated including time to onset, duration and time to remedication. The two drugs had approximately equal onset, but meptazinol had significantly shorter duration. More patients on meptazinol required remedication with a rescue analgesic and at an earlier time than patients on morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia-induced respiratory depression: comparison of meptazinol and morphine in the postoperative period.

Forty-nine patients undergoing elective total hip replacement received either morphine or meptazinol for postoperative analgesia from a patient-controlled analgesia apparatus. Ventilatory rate and volume and arterial oxyhaemoglobin saturation were recorded continuously for the first 24 h following surgery. Episodic hypoxaemia was seen in both groups, associated with disturbances in ventilatory pattern. There was no significant difference in the incidence or severity of observed hypoxia between the groups, or with respect to the class of ventilatory disturbance. Mean linear analogue scores for pain and nausea were significantly (P less than 0.05) greater in the meptazinol group than in the morphine group 8 h after operation, but did not differ significantly at any other time. The mean number of demands for analgesic drugs was similar in the two groups. The meptazinol group had a greater requirement for anti-emetic drugs than the morphine group (P less than 0.05). It was concluded that meptazinol and morphine in equianalgesic doses had similar effects on ventilation in the postoperative period.

Double-blind comparison of the efficacy and safety of single doses of meptazinol as a suppository and morphine by i.m. injection.

The analgesic efficacy of a 150-mg meptazinol suppository was compared with that of morphine 10 mg i.m. in the treatment of moderate postoperative pain. Two groups of 15 female patients took part in a 4-h, randomized double-blind, double-dummy study on the first day after elective abdominal hysterectomy. Meptazinol did not provide satisfactory analgesia in five patients (P less than 0.05). A decrease in mean pain scores (linear analogue scale and verbal rating scale) was seen after the administration of meptazinol, but this was not as great as that produced by morphine i.m., nor was it as long in duration. Significant changes in arterial pressure, heart rate and ventilatory rates were not seen in association with the administration of meptazinol, but were observed after the administration of morphine.

A double-blind comparison of ibuprofen, placebo and ibuprofen with meptazinol in soft tissue rheumatism.

The administration of ibuprofen potentiates and prolongs the analgesic effect of meptazinol when the two drugs are given simultaneously to mice. A double-blind three-way crossover study of placebo, ibuprofen (1600 mg/day) and ibuprofen (1600 mg/day) plus meptazinol (400 mg/day) was carried out in 45 patients with soft tissue rheumatism to see if the same potentiation could be demonstrated in man. Treatment order was randomized and each regimen was given for 2 weeks preceded by 1 week on paracetamol alone. Assessments were made, on entry and after each treatment period, of pain parameters using visual analogue or verbal rating scales. Patients' overall impression and final preference showed both active treatments to be better than placebo and demonstrated a slight preference for the combination.

[Meptazinol, a new analgesic. Hemodynamic and respiratory effects]. / Meptazinol, ein neuartiges Analgetikum. Hämodynamische und respiratorische Effekte.

In a prospective, randomized double-blind study the hemodynamic and respiratory effects of i.v. meptazinol, a new synthetic narcotic agonist-antagonist analgesic given in 2 dosages (2 mg/kg and 4 mg/kg), were compared over 15 min to a control group that received 0.9% saline solution as placebo. In a total of 80 patients scheduled for elective aortocoronary bypass surgery, the study was performed before and during general anesthesia and during extracorporeal circulation (ECC). A dose-dependent increase in mean arterial pressure (MAP) and total systemic resistance (TSR) were the predominant hemodynamic effects of meptazinol before and during anaesthesia (Tables 1 and 2). Within the study period no change in heart rate (HR) or cardiac index (CI) could be observed. Directly measured left ventricular parameters revealed a significant increase in left ventricular pressure (LVEDP, and dp/dtmax (Fig. 1). During ECC meptazinol injection was followed by a dose-dependent increase in perfusion pressure, indicating a direct vasoconstrictive effect; no influence on the capacitance system ("venous pooling") could be observed (Fig. 2). In the spontaneously breathing, premedicated patients (morphine hydrochloride 0.15 mg/kg and flunitrazepam 0.03 mg/kg) paO2 increased and paCO2 decreased, especially after injection of the higher dosage of meptazinol; there was no influence on intrapulmonary right-to-left shunting (Qs/Qt).(ABSTRACT TRUNCATED AT 250 WORDS)

Meptazinol for postoperative pain relief in man. Comparison of extradural and i.m. administration.

The analgesic and cardiorespiratory effects of meptazinol 90 mg, given by the extradural or the i.m. route, were studied in 32 postoperative patients. Plasma meptazinol concentrations were measured in five patients in each treatment group. Evaluation using a linear analogue scale indicated that there were significant differences between the groups in the onset, quality and duration of pain relief, with the extradural route being superior to the i.m. route in each instance. The difference in quality of pain relief was not related to the resultant plasma meptazinol concentrations, which were similar in the two groups. Ventilatory rate was decreased equally in both groups in parallel with pain relief, but no incidence of overt respiratory depression was noted. Meptazinol produced no meaningful changes in measured cardiovascular variables, and side effects were minimal in both groups.

Human pharmacology and abuse potential of meptazinol.

Meptazinol was assessed in nine opioid abusers according to a double-blind, randomized, crossover design to determine if it produced typical morphine effects. A comparison of physiologic and subjective effects was made between morphine, 7.5, 15, and 30 mg, meptazinol, 70, 140, and 280 mg, and placebo. Both drugs constricted pupils. Meptazinol, 140 and 280 mg, decreased body temperature. Valid relative potency estimates of morphine to meptazinol were obtained for self-reported liking, opiate symptoms, and pupillary constriction. Meptazinol did not increase euphoria or sedation scale scores but did increase dysphoria scale scores. In the therapeutic dose range, meptazinol produced miosis, morphine-like identification and symptoms, limited liking, and some dysphoria. Dysphoria predominated at the 280 mg dose of meptazinol. From these data, it is concluded that meptazinol is not a typical morphine-like drug and has limited abuse potential.

[Reduction of circulatory reactions to intratracheal intubation--the effect of meptazinol]. / Reduktion der Kreislaufreaktion auf Trachealintubation--die Wirkung von Meptazinol.

A controlled, randomized, double blind assessment of the efficacy of meptazinol 3 mg kg-1 in reducing the circulatory responses to tracheal intubation was carried out in 20 ASA class I patients. After thiopentone 4 mg kg-1, meptazinol 3 mg kg-1 (ten patients) or saline (ten patients), and suxamethonium 1.5 mg kg-1 tracheal intubation was carried out, and the changes in pulse rate and arterial blood pressure compared between the groups and with control values. Significance was assessed at the 5% level (Student's t-test and paired t-test). Patients who received saline exhibited a rise in pulse rate, significant 1 and 2 min after intubation, and a significant rise in mean arterial pressure for 5 min after intubation. Patients who received meptazinol exhibited no significant rise in pulse rate, but a significant fall in pulse rate occurred from 5 min onwards. Mean arterial pressure rose significantly for 4 min after intubation but the rise was significantly less than that seen in the saline group. Suppression of spontaneous ventilation or movement in 50% of the group lasted for 7 min and 9 min after induction of anaesthesia in the control group and meptazinol treated group respectively. Meptazinol 3 mg kg-1 modifies the circulatory responses to tracheal intubation, preventing the tachycardia and reducing the hypertension, and causes a short delay in the onset of spontaneous respiration or movement.

Meptazinol versus pethidine for postoperative pain relief in children.

A double-blind, randomised, clinical trial was undertaken comparing intramuscular meptazinol (1 mg/kg) with intramuscular pethidine (1 mg/kg) for the relief of post-tonsillectomy pain, in 100 children under 15 years of age. Pethidine provided better analgesia in those patients who were awake after 30 minutes, but thereafter no statistically significant differences between the degree of pain relief could be detected. Meptazinol caused less sedation than pethidine, in that significantly more patients were awake after 40 minutes in the meptazinol group. The incidence of nausea and vomiting was similar in patients of both groups.

Comparative study of meptazinol and pethidine for the relief of pain in labour.

A double-blind comparison of pethidine and meptazinol in the relief of pain during labour was undertaken in 205 healthy women. The protocol allowed 100 mg of the test drug to be repeated at intervals of 2 h to a maximum of three doses. It was noteworthy that only 29 mothers were given a second dose of narcotic. Every woman receiving one injection of meptazinol complained of moderate to severe pain after 2 h; 97% of those receiving one injection of pethidine were complaining of moderate to severe pain after 2 h. There was no difference between the two drugs with regard to pain relief or in side-effects both in mother and baby.

Effect of meptazinol on chronic anticoagulant therapy.

Six elderly hospitalized patients (four female, two male; mean age 85.3 years) stabilized on warfarin therapy were treated with meptazinol (200 mg four times daily) for 7 days. There was no significant difference from pretreatment levels either in mean warfarin dosage prothrombin index after introduction or withdrawal of meptazinol. These findings provide no evidence for any major interaction between warfarin and meptazinol.

Meptazinol. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy.

Meptazinol is a new opioid-type analgesic with mixed agonist/antagonist properties. It may be given orally, intravenously or intramuscularly. In studies in patients with moderate to severe pain of various aetiologies, usually following surgery or in obstetrics, the characteristics of analgesia with meptazinol were comparable to those seen with equianalgesic doses of pentazocine, pethidine or a combination of dextropropoxyphene and paracetamol. Preoperative use and use as a component of anaesthesia require further investigation before conclusions may be drawn on its effectiveness in these areas. Onset of action, recorded in a few studies, was faster than that with the other analgesics but duration was shorter than that of morphine, buprenorphine and pentazocine. Only a small number of patients with chronic pain have received long term therapy with meptazinol; in such patients there was no need for increased doses as treatment progressed. Respiratory depression has only been observed in patients receiving meptazinol as a premedication or while undergoing anaesthesia. Similarly any haemodynamic changes have been limited to preoperative patients or patients undergoing anaesthesia. Like other agonist/antagonist analgesic drugs, the abuse potential of meptazinol seems relatively low, but only wider clinical use for longer periods can establish this with certainty. The most commonly reported side effects have been gastrointestinal in nature, and although the incidence of central nervous system side effects has been relatively low, drowsiness and dizziness have caused occasional problems. Thus, meptazinol is a relatively potent but safe addition to the analgesics available for treatment of the patient with moderate to severe pain.

Epidural meptazinol for pain relief after lower abdominal surgery.

A preliminary investigation is reported into the use of epidural meptazinol for pain relief in 20 patients after major lower abdominal (gynaecological) surgery. Analgesia was rapid in onset (15 minutes), had a median duration of 124 minutes (interquartile range 85-212 minutes) after a single dose of 30 mg and a median duration of 122.5 minutes (interquartile range 70-127 minutes) after a single dose of 60 mg. Overall pain relief, as judged by the patients themselves, was satisfactory in 19 out of the 20 cases. At 30 minutes and 45 minutes pain relief was significantly better with the 60 mg than the 30 mg dose (p less than 0.02). No drug-related adverse effects were observed during the study.

Intramuscular meptazinol and morphine in postoperative pain.

Meptazinol is an agonist-antagonist opioid analgesic believed to be unique in its selectivity for mu1 (high affinity) receptors and its cholinergic activity. Our objectives were to determine the relative analgesic potency of intramuscular meptazinol and morphine and to compare mood and side effects in 102 patients with cancer who have postoperative pain. Meptazinol (50, 100, and 200 mg) and morphine (4, 8, and 16 mg) were given for moderate to severe pain in a double-blind, randomized but balanced, incomplete block design. Serial multiple assessments of pain, relief, mood, and side effects were made. The most precise estimates of relative analgesic potency indicate that meptazinol is equivalent to 10 mg morphine at 120 mg (95% confidence interval 80 to 170 mg) for peak effect and at 175 mg (95% confidence interval 125 to 270 mg) for total effect. Mean (+/- SE) times to peak effect and to remedication were 0.9 +/- 0.1 and 3.6 +/- 0.2 hours for meptazinol and 1.4 +/- 0.1 and 4.8 +/- 0.4 hours for morphine at equianalgesic peak effects. The percentages of subjects with one or more side effects were 18, 49, and 73 for graded meptazinol doses and 32, 49, and 65 for graded morphine doses. Mean numbers of side effects per subject were 0.3, 1.5, and 3.5 for meptazinol and 0.5, 0.7, and 1.7 for morphine. Profiles of side effects differed. Mood improvement and overall satisfaction were dose related and greater for morphine than for meptazinol. Side effects may limit the use of meptazinol in doses that relieve severe postoperative pain.