托吡酯引起泌汗障碍的流行病学分析及其发生机制的研究
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摘要
托吡酯(topiramate,TPM)主要用于癫癎及其他神经精神疾病的治疗,通常耐受良好。少汗或无汗是该药物引起的不良反应之一,在儿童患者中发生率较高,一定程度上限制了这一药物的临床应用。托吡酯减少汗液分泌的确切机制尚不明确,对这一问题的探讨可为有效地预防、对抗此种副作用的发生提供依据,从而提高癫癎患者药物治疗的依从性和治疗效果;另一方面,多汗症的治疗手段较少,效果亦欠佳,对托吡酯引起泌汗障碍的机制进行研究可以化害为利,为托吡酯治疗多汗症提供实验证据。
本课题首先应用流行病学研究方法,回顾分析参加2002年全国托吡酯上市后疗效和安全性监测多中心观察的10,612例癫癎患者的资料,探讨托吡酯引起的泌汗障碍的发生率、临床转归及危险因素,以期加深对这种不良反应发生规律的认识,并为其发生机制的研究提供线索。继而,建立托吡酯引起泌汗障碍的小鼠动物模型,以明确托吡酯是否能够抑制小鼠汗腺的分泌及其发生规律和影响因素。在成功建立可靠动物模型的基础上,探讨⑴泌汗效应器(汗腺)是否存在托吡酯已知药理作用的靶点;⑵托吡酯引起的泌汗障碍是否与碳酸酐酶(carbonic anhydrase,CA)抑制作用有关;⑶托吡酯是否影响汗腺形态或汗腺分泌过程中起重要作用的关键蛋白的表达与功能,以期阐明托吡酯引起泌汗障碍的确切机制。
主要研究结果如下:
接受托吡酯治疗的患者中396例(3.73%)发生泌汗障碍,主要为12岁以下儿童,泌汗障碍的发生率在成年以前随年龄增大而逐渐降低;儿童、青少年及成年患者泌汗障碍的发生率分别为5.85%,0.96%和0.30%。泌汗障碍在加量期多见,多可耐受,极少数病例需停药。多数患者的症状在数月内或随天气转凉而消失,少数在服药期间持续存在。性别、发作频率、发作类型、是否加用其他抗癫癎药物及疗效并不影响泌汗障碍的发生,而年龄较低、剂量较高者在夏季较易出现此种不良反应。在控制年龄因素的影响后,托吡酯剂量对泌汗障碍的发生无显著影响;而在控制剂量因素的影响后,年龄仍显著影响泌汗障碍的发生。
2周龄和2月龄小鼠随机分配至托吡酯低剂量组(20 mg/kg/d)、高剂量组(80 mg/kg/d)和对照组,每组12只。经口给予小鼠托吡酯,并动态观察其泌汗功能及体温变化,观察时程为4周。应用硅胶印模技术发现:给予托吡酯后第2周,幼年和成年小鼠高、低剂量组的单个汗腺平均分泌量均较对照组或处理前明显降低;给予托吡酯后第4周,幼年和成年小鼠高、低剂量组的活动汗腺数目均较对照组或处理前明显降低。托吡酯处理后1～4周,各剂量组小鼠各周的平均体温无明显差异,各周不同剂量组的平均体温也没有显著性差异。免疫组织荧光染色未发现在正常小鼠皮肤组织及汗腺的分泌细胞存在γ-氨基丁酸A型(gamma-aminobutyric acid,GABAA)受体α1亚单位、谷氨酸受体亚型α-氨基羟甲基恶唑丙酸(α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid , AMPA )GluR1/2/3/4亚单位和海人酸(kainic acid,KA)受体GluR5/6/7亚单位的表达。少汗小鼠的汗腺形态、碳酸酐酶活性及Na,K-ATP酶活性与对照组无明显差别。应用免疫荧光和western blot技术发现:小鼠在托吡酯处理后泌汗减少,碳酸酐酶同功酶II型(carbonic anhydraseII,CAII)蛋白表达未出现显著变化,但汗腺组织胞膜的水通道蛋白-5(aquaporin-5,AQP5)表达量下调。
本课题组首次对托吡酯引起泌汗障碍的发生率及影响因素进行大规模、大范围的系统流行病学调查分析,并首先建立了实用可靠的动物模型,对这种不良反应的发生机制进行动物实验研究。综合全部实验结果,本研究提示:夏季和低龄是托吡酯引起泌汗障碍的主要危险因素,而托吡酯剂量对泌汗功能的影响较小;托吡酯可以抑制小鼠汗液的分泌,小鼠的年龄并不影响这种抑制作用,但托吡酯对小鼠体温无明显影响;托吡酯并不是通过对GABAA受体及AMPA和KA两种谷氨酸受体亚型的作用而在汗腺分泌细胞抑制泌汗;托吡酯不影响汗腺形态及Na,K-ATP酶活性;汗腺分泌细胞的AQP5功能失调可能与托吡酯引起的泌汗障碍密切相关,而碳酸酐酶抑制作用并不是泌汗功能损害的主要原因。
Topiramate is a monosaccharide D-fructose derivate that functions as a sulfamate and is currently used for the treatment of epilepsy and other neuropsychopathy. Topiramate is generally well tolerated, while decreased sweat secretion is a primary side effect of topiramate in pediatric patients. Topiramate induced hypohidrosis is reversible, but can be clinically significant during heat stress and exercise challenge. This side effect challenges patients’confidence of long term drug therapy. On the other hand, although hypohidrosis is an adverse effect of topiramate when used for other indications, its anti-sweat producing effects may be beneficial in conditions of hyperhidrosis.
How topiramate induces its antiperspirant effects is unclear. A better understanding of these mechanism(s) will provide rational precautionary measures for topiramate–related hypohidrosis and a new therapy for hyperhidrosis. Therefore, in this study, baseline data as well as therapeutic effect and adverse events of 10,106 patients with epilepsy participated in national topiramate post-marketing surveillance (PMS) were reviewed. Incidence rate, clinical characteristic and risk factors for hypohidrosis were analyzed to provide clues for possible mechanisms underlying topiramate-induced hypohidrosis. Then this study aimed to better understand how topiramate decreases sweat secretion by examining if topiramate decreases sweat secretion in mice, as it can in humans, and, if so, to examine its effects on carbonic anhydrase II (CA II) and AQP5 expression in sweat glands. In addition, CA activity, Na, K-ATPase activity and tissue morphology of sweat glands were examined following topiramate administration. Main results are as follow:
396 patients (3.73%) developed hypohidrosis and the incidence rate in children was much higher than that in adults. Most hypohidrosis occurred during drug titration and in warmer seasons. It was well tolerated and seldom resulted in drug discontinuation and inpatient care. Symptoms of most patients disappeared in a few months and coincided with the onset of cool weather, while long-lasting symptoms were scanty. Gender, frequency and type of seizure, therapeutic effect or add-on drug therapy did not have a significant effect on the onset of hypohidrosis. On the other hand, patients with younger age or higher dosage were susceptible to hypohidrosis in summer. There was no significant difference in the average dosage between patients with and without hypohidrosis in each age group. However, there was a significant difference in the average age between patients with and without hypohidrosis in each dosage group.
Both developing and mature mice were treated with a low (20 mg/kg/day) and high dose (80 mg/kg/day) of topiramate for four weeks. Each group contained 12 mice. Sweat secretion was investigated by an established technique of examining mold impressions of hindpaws. In mature mice, two weeks of topiramate treatment decreased sweat output per gland from baseline in both the low and high dose groups. Four weeks of topiramate treatment decreased the number of pilocarpine reactive sweat glands from baseline in both the low and high dose groups. A similar decrease was seen in developing mice. In addition, topiramate did not have a significant effect on body temperature in mice.
Immunofluorescence confirmed that sweat glands in normal mice did not present gamma-aminobutyric acid (GABA) receptor subtype GABAA andα-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainic acid (KA) subtype of glutamate receptor.
Mature mice with reactive sweat glands that declined more than 25% compared to baseline were defined as anhidrotic mice. Sweat gland morphology was examined in toluidine blue-stained plastic-embedded sections. CA II and AQP5 expression levels were determined by immunofluorescence and immunoblotting, while CA activity and Na, K-ATPase activity by a colorimetric assay. Anhidrotic mice treated by topiramate did not differ from controls in average secretory coil diameter, CA II expression, CA activity and Na, K-ATPase activity. In contrast, anhidrotic mice did show a reduction in membrane AQP5 expression in sweat glands after topiramate delivery.
To our best knowledge, the present study is the largest sample-size clinical investigation concerning topiramate induced-hypohidrosis. In summary, our results indicate that hypohidrosis is a frequent adverse effect in children with topiramate therapy. Younger age and hot weather rather than drug dosage are independent risk factors for topiramate-associated hypohidrosis. The resultes also rule out the possibility that topiramate act on its known mechanisms of action, such as potentiating GABA activity at GABAA receptors and antagonizing the AMPA/KA subtype of glutamate receptor in the secretory cells of sweat glands to inhibit sweat secretion. Our data also suggest that topiramate impairs sudomotor function in mice and leads to a significant reduction in AQP5 expression in sweat glands of anhidrotic mice, thus raising the possibility that dysregulation of AQP5 may contribute to topiramate related hypohidrosis. CA inhibition may not be an important contributor since CA II expression and CA activity was intact in anhidrotic mice treated with topiramate.
本课题首先应用流行病学研究方法,回顾分析参加2002年全国托吡酯上市后疗效和安全性监测多中心观察的10,612例癫癎患者的资料,探讨托吡酯引起的泌汗障碍的发生率、临床转归及危险因素,以期加深对这种不良反应发生规律的认识,并为其发生机制的研究提供线索。继而,建立托吡酯引起泌汗障碍的小鼠动物模型,以明确托吡酯是否能够抑制小鼠汗腺的分泌及其发生规律和影响因素。在成功建立可靠动物模型的基础上,探讨⑴泌汗效应器(汗腺)是否存在托吡酯已知药理作用的靶点;⑵托吡酯引起的泌汗障碍是否与碳酸酐酶(carbonic anhydrase,CA)抑制作用有关;⑶托吡酯是否影响汗腺形态或汗腺分泌过程中起重要作用的关键蛋白的表达与功能,以期阐明托吡酯引起泌汗障碍的确切机制。
主要研究结果如下:
接受托吡酯治疗的患者中396例(3.73%)发生泌汗障碍,主要为12岁以下儿童,泌汗障碍的发生率在成年以前随年龄增大而逐渐降低;儿童、青少年及成年患者泌汗障碍的发生率分别为5.85%,0.96%和0.30%。泌汗障碍在加量期多见,多可耐受,极少数病例需停药。多数患者的症状在数月内或随天气转凉而消失,少数在服药期间持续存在。性别、发作频率、发作类型、是否加用其他抗癫癎药物及疗效并不影响泌汗障碍的发生,而年龄较低、剂量较高者在夏季较易出现此种不良反应。在控制年龄因素的影响后,托吡酯剂量对泌汗障碍的发生无显著影响;而在控制剂量因素的影响后,年龄仍显著影响泌汗障碍的发生。
2周龄和2月龄小鼠随机分配至托吡酯低剂量组(20 mg/kg/d)、高剂量组(80 mg/kg/d)和对照组,每组12只。经口给予小鼠托吡酯,并动态观察其泌汗功能及体温变化,观察时程为4周。应用硅胶印模技术发现:给予托吡酯后第2周,幼年和成年小鼠高、低剂量组的单个汗腺平均分泌量均较对照组或处理前明显降低;给予托吡酯后第4周,幼年和成年小鼠高、低剂量组的活动汗腺数目均较对照组或处理前明显降低。托吡酯处理后1～4周,各剂量组小鼠各周的平均体温无明显差异,各周不同剂量组的平均体温也没有显著性差异。免疫组织荧光染色未发现在正常小鼠皮肤组织及汗腺的分泌细胞存在γ-氨基丁酸A型(gamma-aminobutyric acid,GABAA)受体α1亚单位、谷氨酸受体亚型α-氨基羟甲基恶唑丙酸(α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid , AMPA )GluR1/2/3/4亚单位和海人酸(kainic acid,KA)受体GluR5/6/7亚单位的表达。少汗小鼠的汗腺形态、碳酸酐酶活性及Na,K-ATP酶活性与对照组无明显差别。应用免疫荧光和western blot技术发现:小鼠在托吡酯处理后泌汗减少,碳酸酐酶同功酶II型(carbonic anhydraseII,CAII)蛋白表达未出现显著变化,但汗腺组织胞膜的水通道蛋白-5(aquaporin-5,AQP5)表达量下调。
本课题组首次对托吡酯引起泌汗障碍的发生率及影响因素进行大规模、大范围的系统流行病学调查分析,并首先建立了实用可靠的动物模型,对这种不良反应的发生机制进行动物实验研究。综合全部实验结果,本研究提示:夏季和低龄是托吡酯引起泌汗障碍的主要危险因素,而托吡酯剂量对泌汗功能的影响较小;托吡酯可以抑制小鼠汗液的分泌,小鼠的年龄并不影响这种抑制作用,但托吡酯对小鼠体温无明显影响;托吡酯并不是通过对GABAA受体及AMPA和KA两种谷氨酸受体亚型的作用而在汗腺分泌细胞抑制泌汗;托吡酯不影响汗腺形态及Na,K-ATP酶活性;汗腺分泌细胞的AQP5功能失调可能与托吡酯引起的泌汗障碍密切相关,而碳酸酐酶抑制作用并不是泌汗功能损害的主要原因。
Topiramate is a monosaccharide D-fructose derivate that functions as a sulfamate and is currently used for the treatment of epilepsy and other neuropsychopathy. Topiramate is generally well tolerated, while decreased sweat secretion is a primary side effect of topiramate in pediatric patients. Topiramate induced hypohidrosis is reversible, but can be clinically significant during heat stress and exercise challenge. This side effect challenges patients’confidence of long term drug therapy. On the other hand, although hypohidrosis is an adverse effect of topiramate when used for other indications, its anti-sweat producing effects may be beneficial in conditions of hyperhidrosis.
How topiramate induces its antiperspirant effects is unclear. A better understanding of these mechanism(s) will provide rational precautionary measures for topiramate–related hypohidrosis and a new therapy for hyperhidrosis. Therefore, in this study, baseline data as well as therapeutic effect and adverse events of 10,106 patients with epilepsy participated in national topiramate post-marketing surveillance (PMS) were reviewed. Incidence rate, clinical characteristic and risk factors for hypohidrosis were analyzed to provide clues for possible mechanisms underlying topiramate-induced hypohidrosis. Then this study aimed to better understand how topiramate decreases sweat secretion by examining if topiramate decreases sweat secretion in mice, as it can in humans, and, if so, to examine its effects on carbonic anhydrase II (CA II) and AQP5 expression in sweat glands. In addition, CA activity, Na, K-ATPase activity and tissue morphology of sweat glands were examined following topiramate administration. Main results are as follow:
396 patients (3.73%) developed hypohidrosis and the incidence rate in children was much higher than that in adults. Most hypohidrosis occurred during drug titration and in warmer seasons. It was well tolerated and seldom resulted in drug discontinuation and inpatient care. Symptoms of most patients disappeared in a few months and coincided with the onset of cool weather, while long-lasting symptoms were scanty. Gender, frequency and type of seizure, therapeutic effect or add-on drug therapy did not have a significant effect on the onset of hypohidrosis. On the other hand, patients with younger age or higher dosage were susceptible to hypohidrosis in summer. There was no significant difference in the average dosage between patients with and without hypohidrosis in each age group. However, there was a significant difference in the average age between patients with and without hypohidrosis in each dosage group.
Both developing and mature mice were treated with a low (20 mg/kg/day) and high dose (80 mg/kg/day) of topiramate for four weeks. Each group contained 12 mice. Sweat secretion was investigated by an established technique of examining mold impressions of hindpaws. In mature mice, two weeks of topiramate treatment decreased sweat output per gland from baseline in both the low and high dose groups. Four weeks of topiramate treatment decreased the number of pilocarpine reactive sweat glands from baseline in both the low and high dose groups. A similar decrease was seen in developing mice. In addition, topiramate did not have a significant effect on body temperature in mice.
Immunofluorescence confirmed that sweat glands in normal mice did not present gamma-aminobutyric acid (GABA) receptor subtype GABAA andα-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainic acid (KA) subtype of glutamate receptor.
Mature mice with reactive sweat glands that declined more than 25% compared to baseline were defined as anhidrotic mice. Sweat gland morphology was examined in toluidine blue-stained plastic-embedded sections. CA II and AQP5 expression levels were determined by immunofluorescence and immunoblotting, while CA activity and Na, K-ATPase activity by a colorimetric assay. Anhidrotic mice treated by topiramate did not differ from controls in average secretory coil diameter, CA II expression, CA activity and Na, K-ATPase activity. In contrast, anhidrotic mice did show a reduction in membrane AQP5 expression in sweat glands after topiramate delivery.
To our best knowledge, the present study is the largest sample-size clinical investigation concerning topiramate induced-hypohidrosis. In summary, our results indicate that hypohidrosis is a frequent adverse effect in children with topiramate therapy. Younger age and hot weather rather than drug dosage are independent risk factors for topiramate-associated hypohidrosis. The resultes also rule out the possibility that topiramate act on its known mechanisms of action, such as potentiating GABA activity at GABAA receptors and antagonizing the AMPA/KA subtype of glutamate receptor in the secretory cells of sweat glands to inhibit sweat secretion. Our data also suggest that topiramate impairs sudomotor function in mice and leads to a significant reduction in AQP5 expression in sweat glands of anhidrotic mice, thus raising the possibility that dysregulation of AQP5 may contribute to topiramate related hypohidrosis. CA inhibition may not be an important contributor since CA II expression and CA activity was intact in anhidrotic mice treated with topiramate.
引文
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