Spasticity and drug therapy

An overview is presented of pathophysiology, classification and measurement of spasticity and of its treatment, especially with dantrolene and baclofen. In spasticity, the balance between excitatory and inhibitory neurotransmitters in the central nervous system is impaired by mechanisms that are for the greater part unknown. Spasticity includes various disorders of motor control, and classification is needed for a meaningful evaluation of antispastic therapy. Cerebral palsy is a specific disorder, sometimes also called spasticity. Measurement of spasticity is complicated and should include signs characteristic of spasticity and parameters for clinical improvement. Dantrolene and baclofen have established their place in the treatment of spastic disorders, but a preference for either drug is hard to give. For tizanidine it is still too early to determine its place in therapy. Dantrolene is a direct acting muscle relaxant which should be avoided in patients with pre-existing liver damage. Its mechanism of metabolism and excretion is for the greater part unknown. The GABA _b agonist baclofen is a centrally acting muscle relaxant. In patients with impaired renal function the dose should be reduced. Abrupt withdrawal carries the risk of unwanted reactions. TheR(–)-enantiomer has proved to be the active isomer. This means that human trials need reappraisal, especially those relating to the pharmacokinetics of the racemate.     

肌松药物巴氯芬类似物的合成及其构效关系的研究

为研究解痉肌松药巴氯芬类似物的构效关系,合成了巴氯芬类似物15个,其中8个化合物是首次报道。采用小白鼠热板法及对抗吗啡竖尾反应实验评价目标化合物的镇痛和肌松作用。筛选结果表明:部分化合物有肌松和镇痛作用,其中Ⅰb,Ⅱb,Ⅲa和Ⅲc的镇痛作用较好,Ⅰd,Ⅱb,Ⅲa和Ⅲb的肌松作用较好,但均未超过巴氯芬。根据本研究及前人的研究结果,提出巴氯芬与GABA_B受体结合取决于巴氯芬分子中氨基、羧基和苯环三种基团。     

The effects of compounds related to γ-aminobutyrate and benzodiazepine receptors on behavioural responses to anxiogenic stimuli in the rat: Extinction and successive discrimination

In a first set of experiments rats were trained to run in a straight alley for food reward on a continuous reinforcement schedule and the running response was then extinguished. On the last 2 days of training and daily throughout extinction different groups of animals were injected IP with saline, 5 mg/kg chlordiazepoxide, 0.75 mg/kg picrotoxin, chlordiazepoxide + picrotoxin, chlordiazepoxide +1.5 mg/kg bicuculline, 0.00125 or 0.25 mg/kg muscimol, 1 mg/kg baclofen, chlordiazepoxide + baclofen, or 0.00125 mg/kg muscimol + baclofen. Chlordiazepoxide increased resistance to extinction, a well-known anxiolytic effect. This effect was blocked by both picrotoxin and bicuculline. Picrotoxin on its own reduced resistance to extinction (an anxiogenic-like effect). Whether given alone or in combination with other drugs, muscimol and baclofen had no effect.In a second set of experiments rats were trained in a successive operant discrimination (signalled by a flashing or steady light) between components in which sucrose reward was available on a variable-interval schedule for barpressing and components in which no reward was given. Chlordiazepoxide at 10 mg/kg increased responding in both rewarded and nonrewarded components, but more in the latter than could be accounted for by change in the former. This effect is as expected with an anxiolytic drug. It was not altered by administration of bicuculline at 1.5 or 1.75 mg/kg; at 2 mg/kg bicuculline acted synergistically with chlordiazepoxide. Picrotoxin (1 and 1.5 mg/kg) also acted synergistically with chloridazepoxide, enhancing the latter's rate-increasing effects, but only during rewarded components. Neither muscimol (0.00125 and 0.25 mg/kg) nor baclofen (0.01 mg/kg) affected response rates, whether given alone or in combination. However, baclofen in a dose of 1 mg/kg, provided it was given to rats also injected with muscimol (0.00125 or 0.25 mg/kg) at other times, significantly reduced responding during nonrewarded components (an apparently anxiogenic effect).The results of the two sets of experiments are discussed in relation to the hypothesis that anxiolytic drugs affect behaviour by increasing GABAergic inhibition. Offprint requests to: C. Buckland     

Evidence for a spinal origin of the effect of baclofen on the myocardial oxygen demand indexes

In a previous study in anaesthetized rabbits we observed that electrical stimulation of the hypothalamic paraventricular nucleus (PVN) elicited substantial rises in the maximum rate of change of left ventricular pressure (dP/dt _max) and in myocardial oxygen demand indexes (rate-pressure product and triple product), similar to the changes observed during stress or physical effort. Baclofen, a selective GABA_B receptor agonist, injected intravenously prevented these responses. In the present study, we show that low doses of baclofen (0.1, 0.3 and 1 g/kg), injected intrathecally (i.t.) at the T9 level, reduced the myocardial oxygen demand during PVN stimulation. After 0.3 g/kg baclofen i.t., the peak value of the triple product during stimulation was 140 ± 20 compared with 193 ± 20 before treatment. An i.t. injection (500 g/kg), of saclofen, a selective GABA_B receptor antagonist, did not modify the resting haemodynamics significantly but attenuated the inhibitory effects of baclofen (3 mg/kg i.v.). These results suggest that the main site of the effects of baclofen is located within the spinal cord and that GABAB receptors probably mediate these effects by modulating the central control of cardiac function. In conclusion, baclofen might be a useful tool to prevent the centrally evoked increases of myocardial oxygen demand.     

大鼠室旁核微量注射GABA受体激动剂镇痛作用的研究

目的：观察GABAa受体激动剂蝇蕈醇及GABAb受体激动剂氯苯氨丁酸的镇痛作用。方法：实验分生理盐水对照组、蝇蕈醇组及氯苯氨丁酸组,经室旁核微量注射药物,在大鼠甩尾测痛模型上测定大鼠的痛阈。结果：室旁核微量注射蝇蕈醇和氯苯氨丁酸均可不同程度地提高大鼠的痛阈（与生理盐水对照组相比,P＜0．001）,最大提高痛阈分别为111．43±31．07％和124．24±29．44％,蝇蕈醇氯和苯氨丁酸间无显著性差异（P＞0.05）。结论：GABA受体激动剂在室旁核能降低动物的痛感受,但与GABA受体功能状态无关。     

Phone-based safety monitoring of the first year of baclofen treatment for alcohol use disorder: the BACLOPHONE cohort study protocol

Background: In France, baclofen is frequently used off-label for alcohol use disorder (AUD). Baclofen has been associated with diverse adverse events (AEs), but the causality of these AEs has never been properly assessed.

Methods/Design: BACLOPHONE is a prospective multicenter cohort study conducted in the Hauts-de-France and Normandie French regions. BACLOPHONE consists of the phone-based monitoring of 792 patients during their first year of baclofen treatment for AUD. Two initial phone interviews assess the medical history, current medications, and substance use as well as complete the alcohol use identification test (AUDIT) and severity of alcohol dependence questionnaire (SADQ). Daily alcohol use and baclofen doses are noted throughout the follow-up. For every reported AE, additional phone interviews determine the seriousness of the AE, the causality of baclofen using validated causality algorithms, and the final outcome. The main objective of the study is to determine the rate of patients who stop baclofen due to an AE during the first year of treatment.

Discussion: BACLOPHONE will provide important safety data on baclofen as a complement to the forthcoming efficacy data of randomized clinical trials.     

巴氯芬联合腺苷钴胺治疗三叉神经痛的临床研究

目的探讨巴氯芬联合腺苷钴胺治疗三叉神经痛的临床疗效。方法选取2015年6月—2016年6月在天津市宝坻区人民医院进行治疗的三叉神经痛患者82例,根据治疗方案的差别分为对照组(41例)和治疗组(41例)。对照组患者肌肉注射注射用腺苷钴胺,1次/d。治疗组在对照组的基础上口服巴氯芬片,初始剂量为5 mg/次,3次/d,每4天增加5 mg,直至所需剂量,最大剂量不超过100 mg/次。两组均连续治疗4周。观察两组患者临床疗效,同时比较两组患者治疗前后生活质量评分、血清C反应蛋白(CRP)、白细胞介素-1β(IL-1β)、IL-6、肿瘤坏死因子-α(TNF-α)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)水平以及疼痛评分变化。结果治疗后,对照组和治疗组总有效率分别为80.49%和95.12%,两组总有效率比较差异具有统计学意义(P0.05)。治疗后,两组患者行动能力和自我照顾能力等各项生活质量评分均明显降低(P0.05);且治疗组的生活质量评分降低程度优于对照组(P0.05)。治疗后,两组患者血清CRP、IL-1β、IL-6及TNF-α水平明显低于治疗前(P0.05);且治疗组上述指标水平优于对照组(P0.05)。治疗后,两组患者血清SOD、GSH-Px水平明显高于治疗前(P0.05);与对照组相比,治疗组增高的更明显(P0.05)。治疗后,两组患者VAS评分明显降低(P0.05);且治疗组比对照组降低的更明显(P0.05)。结论巴氯芬联合腺苷钴胺治疗三叉神经痛效果显著,可明显提高患者睡眠质量,减轻机体炎性反应和应激反应,具有一定的临床推广应用价值。     

Ca2+-dependent release of endogenous GABA from rat cortical slices from different pools by different stimulation conditions

Summary The previously reported inhibitory effect of (–)-baclofen on the electrically evoked release of endogenous GABA from rat brain slices indicated the possibility of existence of GABA_B autoreceptors. In this study, we have tested an alternative explanation, i. e. the possibility that (–)-baclofen reduced an excitatory glutamatergic input to GABAergic neurons by inhibiting glutamate release, by investigating the interaction of 10 mmol/1 l-glutamate with the inhibitory effect of 10 mol/1(–)-baclofen. l-Glutamate did not affect the electrically evoked release of GABA on its own and did not abolish the effect of (–)-baclofen, suggesting that the latter was not secondary to a reduction of glutamate release. On the other hand, it greatly increased the basal release of GABA and more than doubled the GABA content of the slices at the end of the perfusion, indicating a marked enhancement of GABA synthesis. This additional GABA, apparently formed from exogenous l-glutamate, was not releasable by electrical stimulation at 0.5 or 24 Hz, but at least in part by stimulation with 30 mmol/l K⁺. The previously reported increase of GABA release at 12 Hz as compared to 4 Hz was studied in more detail. GABA released by electrical stimulation at 8–48 Hz was Ca²⁺-dependent and tetrodotoxin-sensitive. No evidence was obtained for a decrease of the amount of GABA released per impulse with increasing frequency in this range. Moreover, neither (–)-baclofen nor muscimol at 10 mol/l altered the release of the amino acid at 24 Hz; the former was also tested at a low Ca²⁺ concentration (0.3 mmol/l) and found to be inactive under these conditions. Thirty mmol/l K⁺ released about 30% higher amounts of GABA than electrical stimulation at 24 Hz under comparable conditions, in a Ca²⁺-dependent manner. K⁺-induced release was not modified by 10 mol/l (–)-baclofen or muscimol. Our results suggest the existence of at least 2 different, presumably neuronally located, releasable pools of GABA. One is sensitive to electrical stimulation at 0.25–4 Hz and responds to (–)-baclofen, suggesting control by GABA_B-type autoreceptors. The existence of a 2nd pool is indicated by the fact that K⁺ releases substantially more GABA than electrical stimulation and by the exclusive sensitivity of K⁺-evoked GABA release to exogenous l-glutamate. GABA released by electrical stimulation at frequencies above 4 Hz may come from a 3rd pool. Both the 2nd and the 3rd pool seem to be insensitive to (–)-baclofen and muscimol. Send offprint requests to P. C. Waldmeier at the above address     

Involvement of both GABAA and GABAB receptors in tonic inhibitory control of blood pressure at the rostral ventrolateral medulla of the rat

Summary The rostral ventrolateral medulla (RVLM) contains vasopressor neurons which increase vasomotor tone. Endogenous GABA is suggested to be involved in mediation of the tonic inhibition of vasopressor neurons in the RVLM. To obtain more precise information about GABAergic mechanisms in the RVLM, we microinjected GABA agonists and antagonists unilaterally into the RVLM and examined their effects on blood pressure and heart rate. In addition, involvement of the other inhibitory amino acids glycine, -alanine and taurine in blood pressure regulation in the rat RVLM was also investigated. Male Wistar rats were anesthetized with urethane, paralyzed and artificially ventilated. The GABA_A agonist muscimol (3–30 pmol) and the GABA_B agonist baclofen (10–100 pmol) microinjected into the RVLM produced a decrease in blood pressure. The GABA_A antagonist bicuculline (300 pmol) abolished the depressor response to muscimol (10 pmol) but not to baclofen (30 pmol) whereas the GABA_B antagonist 2-hydroxysaclofen (1 nmol) abolished the depressor response to baclofen (30 pmol) but not to muscimol (10 pmol). Either bicuculline or 2-hydroxysaclofen alone produced a pressor response. Both antagonists inhibited depressor response to nipecotic acid (7.7 nmol)and GABA (0.3 nmol). Glycine (0.13 – 4.0 nmol), -alanine (0.11 – 3.4 nmol) and taurine (0.08 – 2.4 nmol) microinjected into the RVLM also produced decreases in blood pressure. The glycine antagonist strychnine (0.58 nmol) abolished the depressor response to glycine, -alanine and taurine but not to GABA. The taurine antagonist (6-aminomethyl-3-methyl-4-H-1,2,4-benzothiadiazine-1,1-diox-ide) (1.3 nmol) inhibited the depressor response to -alanine and taurine but not to glycine and GABA. These results show that in the rat RVLM there exist GABA_A and GABA_B receptors, and that endogenous GABA tonically stimulates both GABA_A and GABA_B receptors to decrease arterial pressure. It seems unlikely that glycine and taurine are involved in mediation of the tonic inhibition of vasopressor neurons in the rat RVLM.Correpondence to T Kubo at the above address     

Baclofen prevents the increase of myocardial oxygen demand indexes evoked by the hypothalamic stimulation in rabbits

Summary The electrical stimulation of the paraventricular nucleus (PVN) of the hypothalamus in anaesthetized rabbits elicited important cardiovascular responses which were mainly characterized by increases in arterial pressure, dP/dt_max, and of the indexes of myocardial oxygen consumption, rate-pressure product (from 34±2 to 40±2 mmHg · bpm · 10^–3) and triple product (from 102±12 to 162±19 mmHg² · s^–1 · bpm · 10^–6). The hemodynamic alterations induced by PVN stimulation were similar to those observed during physical effort and stressful situations. Intracerebroventricular (0.1, 0.3 and 1 g · kg^–1) or intravenous administration (1, 3 and 10 mg · kg^–1) of baclofen, a selective GABA_B receptor agonist, induced a dose-related decrease in the peak values of dP/dt_max and of the indexes of myocardial oxygen consumption (rate-pressure and triple products) during the electrical PVN stimulation. After 1 g · kg^–1 baclofen (i.cv.), the peak value of the triple product during PVN stimulation was 101±21 as compared to 149±15 before treatment. At the 10 mg · kg^–1 dose (iv.), the triple product during stimulation only reached 90±20 vs. 150±20 before treatment. These results suggested that a type B GABAergic transmission system is involved in the modulation of central control of the cardiac function. Drugs modulating this system could therefore be designed to blunt the myocardial oxygen demand increases. Correspondence to P. Bousquet