Title: An Open Study of Clomethiazole in Patients with Acute Cerebral Infarction
Abstract: Recent animal studies have demonstrated neuroprotective properties of clomethiazole following transient global ischemia in the gerbil [1, 2] as well as temporary [3] and permanent [4, 5] focal ischemia, ischemic brain edema [6] and certain drug-induced neurotoxicities in the rat [7]. Clomethiazole is a drug with sedative properties. The purpose of this study was to identify a dose of intravenous clomethiazole which does not produce excessive sedation in patients with acute cerebral infarction and to explore the safety of this drug before evaluating the efficacy of clomethiazole in a large clinical trial. The pharmacokinetics of clomethiazole in relation to dose were also studied as well as the relation between plasma concentrations of clomethiazole and degree of sedation. This was an open phase II dose escalation trial of clomethiazole in acute ischemic stroke patients performed at two stroke centers (Umeå and Karolinska University Hospitals). The study was performed in accordance with the principles of the Declaration of Helsinki and the study protocol was approved by the local ethical committees. Patients with a clinical diagnosis of acute stroke aged ≥40 years who were alert and had motor weakness were included. After inclusion and baseline assessment the patients received an initial loading dose of clomethiazole edsilate (8% of total dose) over 15 min followed by a constant rate infusion maintenance dose over the following 23.75 h. If a patient became excessively sedated (score ≥4, see below) during the maintenance phase, the infusion was interrupted and the dose reduced. An ECG, laboratory tests and a Scandinavian Neurological Stroke Scale (SNSS) examination were done at inclusion, 24 h (not SNSS) and 72 h after the start of treatment. Patients were assessed regularly during the infusion and at the time of blood sampling (fig. 1) for blood pressure, pulse and respiratory rates, tissue oxygenation, body temperature and adverse events including sedation. The level of sedation was recorded using a six-graded rating scale as follows: 1 = fully awake, 2 = drowsy but answers when spoken to, 3 = answers slowly when spoken to, 4 = reacts when spoken to but does not answer, 5 = reacts only to painful stimuli, 6 = does not react to painful stimuli. Eighteen venous blood samples for the determination of concentrations of clomethiazole and its major metabolite 5-(1-hydrox-2-chloroethyl)-4-methylthiazole (NLA-715) were collected over 72 h (fig. 1).Nineteen patients with a clinical diagnosis of acute stroke were included in the study. Two of these patients showed a hemorrhagic stroke on the CT scan. Data from these did not differ from patients with cerebral infarction. The remaining 17 patients were treated as follows. The first 7 patients received 50 mg/kg of clomethiazole and the following 4 subjects 100 mg/kg. Three of these 4 patients required a dose reduction because of excessive sedation (see below). Recruitment into the 100 mg/kg dose was therefore halted and treatment was switched to an intermediate dose of 75 mg/kg clomethiazole. Six patients received the 75 mg/kg dose. The actual mean doses (± SD) administered were 48.6 ± 5.3 mg/kg (50 mg/kg group), 74.6 ± 4.0 mg/kg (75 mg/kg group) and 78.5 ± 16.4 mg/kg (100 mg/kg group). Key patient characteristics for the 50, 75 and 100 mg/kg groups were mean age 69.7, 69.5 and 79.0 years; number of females 2, 5 and 1; mean weight 73.7, 57.0 and 74.0 kg, and mean SNSS long-term item score 29.2, 16.0 and 26.7, respectively. The mean SNSS long-term item scores at the end of the study for the 50, 75 and 100 mg/kg groups were 37.3, 19.3 and 33.3, respectively.As shown in table 1, rhinitis (n = 10), sedation (n = 9), and injection site reactions (n = 6) were the most frequently occurring side effects during clomethiazole infusion followed by hiccup (n = 5), headache (n = 3), yawning (n = 3), increased sputum (n = 3) and fever (n = 3). Severity was mild except for two cases of injection site reaction (moderate) in the 75 mg/kg dose group and 2 patients with somnolence (moderate, severe) in the 100 mg/kg dose group. One patient (75 mg/kg dose group) discontinued the treatment due to tachycardia occurring after 22 h of infusion. Another patient in the 75 mg/kg dose group experienced a progressive stroke which was treated as a serious adverse event. Its relation to the drug could not be judged.In the 50 mg/kg dose group, 1 patient required a dose reduction when the sedation score reached 4. The other patients scored 1 or 2. Patients in the 75 mg/kg dose group scored 1–3. None required a dose reduction. In the 100 mg/kg group, 3 out of 4 patients scored ≥4 on the sedation scale necessitating a dose reduction. All 3 patients were fully awake again 24 h after the end of the clomethiazole infusion. There was no obvious relationship between severity of stroke at admission measured on SNSS and sedation for any of the dose groups.A transient increase in the pulse rate was seen in all dose groups following the loading infusion. The mean differences from baseline for the 50, 75 and 100 mg/kg groups were 9, 22 and 11 beats/min, respectively. A second increase in the pulse rate of similar magnitude was found in the two higher dose groups at 18–24 h after the start of infusion. No major changes were seen in systolic or diastolic blood pressure after loading infusion. A slight and gradual decrease in systolic and diastolic blood pressure occurred over the course of the 24-hour infusion in all dose groups. A gradual increase in respiration rate was seen during clomethiazole treatment while tissue oxygenation was not altered. There were no consistent changes in body temperature, ECG or routine laboratory tests during the infusion in any of the dose groups studied.The plasma concentrations of clomethiazole and its metabolite NLA-715 versus time for the three dose regimen groups are shown in figure 1. A linear relationship was found between the area under the curve (AUC) and the dose of clomethiazole with the following predictive model: AUC (µmol/l × h) = 5.80 × dose (mg/kg). The pharmacokinetic evaluation of clomethiazole in the 17 patients showed a mean total plasma clearance of 11.8 ml/min/kg with a 1.5- to 3.5-fold interpatient variability and a mean plasma elimination half-life of 11.8 h with about a 2-fold interpatient variability. Multiple regression analyses with plasma clearance and half-life as dependent variables and gender, age and body weight as independent variables revealed a statistically significant decrease in plasma clearance of clomethiazole with age (estimated coefficiency = –0.14, p = 0.03) while no other significant relationship was found (p > 0.20). The mean plasma elimination half-life of NLA-715, was 11.3 h. No correlations were found between the level of sedation and plasma concentrations of clomethiazole or NLA-715. Further, plasma concentrations of clomethiazole and its metabolite NLA-715 did not differ in the 4 patients with a sedation score ≥4 compared with 5 patients who were fully awake (sedation score = 1) during the whole study period (data not shown).In conclusion, the potentially neuroprotective drug clomethiazole was well tolerated in acute ischemic stroke patients. The sedative effect is dose-limiting. We could not however establish any relationship between the level of sedation and plasma concentrations of clomethiazole or NLA-715. The 75 mg/kg dose produced a mean plasma concentration of about 13 µM at the end of infusion which corresponds well to plasma levels shown to be neuroprotective in the gerbil model of ischemia [2]. No signs of nonlinear pharmacokinetics of clomethiazole were seen in the dose range tested. We suggest that a dose of 75 mg/kg clomethiazole over 24 h can be recommended for further studies of efficacy and safety in conscious ischemic stroke patients.The study group included the following investigators: Dr. Kjell Asplund, Dr. Bo Carlberg, Dr. Bo Kristensen, Dr. Jan Malm, Dr. Tommy Olsson, Dr. Tage Strand and Dr. Per Wester from Umeå and Dr. Gunnar Hellström, Dr. Carl-Erik Söderström and Dr. Nils-Gunnar Wahlgren from Stockholm.
Publication Year: 1998
Publication Date: 1998-01-01
Language: en
Type: letter
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 38
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