BACKGROUND & AIMS: PURPOSE:To assess the effect of methazolamide on chronic macular edema in patients with retinitis pigmentosa in a double-masked, placebo-controlled, crossover study. Three subjects who had an initial improvement in their macular edema as demonstrated on fluorescein angiography received a continued course of methazolamide to assess its effect on macular edema. METHODS:Seventeen subjects were enrolled in the initial study. On angiography, nine subjects demonstrated improvement in their macular edema with the use of methazolamide for 3 weeks; three of these continued receiving the drug at a dosage of 50 mg twice daily for either an additional 6 (one subject) or 12 (two subjects) weeks. All subjects were assessed at each visit with fluorescein angiography and on best corrected visual acuity, both undilated and dilated; a subjective impression was also documented. RESULTS:After 6 and 12 weeks of treatment, all three subjects experienced a rebound of angiographic macular edema to some extent. The visual acuity varied only slightly (up to 7 letters) from both the baseline and most recent examinations after 6 and 12 weeks of treatment. CONCLUSION:Results from these few subjects suggest that at least a partial rebound of macular edema seen angiographically may occur with the continued use of methazolamide in patients with retinitis pigmentosa and chronic macular edema. Further study is required to determine if this rebound effect also occurs in treatment of other ocular disorders with chronic macular edema.

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BACKGROUND & AIMS: PURPOSE:To determine the effectiveness of methazolamide for improving visual acuity and macular edema in patients with retinitis pigmentosa. METHODS:Seventeen subjects with retinitis pigmentosa and chronic macular edema participated in a prospective, placebo-controlled, double-masked, crossover design study in which either methazolamide or a placebo was taken for 3 weeks. Visual acuity, fluorescein angiograms, and subjective impressions were obtained at baseline and after 3 weeks of treatment with each substance. A subgroup of subjects were enrolled in a more extended period of methazolamide treatment for an additional 3 months. RESULTS:Methazolamide resulted in the improvement of angiographic macular edema in 9 of 17 subjects. As a group, visual acuity statistically improved with methazolamide. However, improvement in at least one eye, of between two and four lines more than while taking placebo, occurred in only three (undilated pupils) or four (dilated pupils) subjects. Subjective improvement during treatment with methazolamide but not placebo occurred in only one subject. An extended period of methazolamide treatment for an additional 3 months in a subgroup of patients did not result in additional beneficial effects on visual acuity. In fact, a partial rebound in the extent of macular edema was found. CONCLUSIONS:Although angiographic improvement of macular edema can occur in patients with retinitis pigmentosa treated with methazolamide, notable (between 3 and 4 lines) or even moderate (between 2 and 3 lines) visual acuity improvement was seen in relatively few patients. When methazolamide was administered in a placebo-controlled fashion, subjective improvement in visual function also was not readily apparent. A more substantial subjective improvement in visual function had occurred with the use of acetazolamide in five of six subjects who also had participated in a previous treatment trial with the use of acetazolamide.

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BACKGROUND & AIMS: :In hypoxia, endurance exercise performance is diminished; pharmacotherapy may abrogate this performance deficit. Based on positive outcomes in preclinical trials, we hypothesized that oral administration of methazolamide, a carbonic anhydrase inhibitor, aminophylline, a nonselective adenosine receptor antagonist and phosphodiesterase inhibitor, and/or methazolamide combined with aminophylline would attenuate hypoxia-mediated decrements in endurance exercise performance in humans. Fifteen healthy males (26 ± 5 years, body-mass index: 24.9 ± 1.6 kg/m(2); mean ± SD) were randomly assigned to one of four treatments: placebo (n = 9), methazolamide (250 mg; n = 10), aminophylline (400 mg; n = 9), or methazolamide (250 mg) with aminophylline (400 mg; n = 8). On two separate occasions, the first in normoxia (FIO2 = 0.21) and the second in hypoxia (FIO2 = 0.15), participants sat for 4.5 hours before completing a standardized exercise bout (30 minutes, stationary cycling, 100 W), followed by a 12.5-km time trial. The magnitude of time trial performance decrement in hypoxia versus normoxia did not differ between placebo (+3.0 ± 2.7 minutes), methazolamide (+1.4 ± 1.7 minutes), and aminophylline (+1.8 ± 1.2 minutes), all with p > 0.09; however, the performance decrement in hypoxia versus normoxia with methazolamide combined with aminophylline was less than placebo (+0.6 ± 1.5 minutes; p = 0.01). This improvement may have been partially mediated by increased SpO2 in hypoxia with methazolamide combined with aminophylline compared with placebo (73% ± 3% vs. 79% ± 6%; p < 0.02). In conclusion, coadministration of methazolamide and aminophylline may promote endurance exercise performance during a sojourn at high altitude.

背景与目标： : 在缺氧时，耐力运动表现会减弱; 药物疗法可能会消除这种表现缺陷。基于临床前试验的阳性结果，我们假设口服甲唑胺，碳酸酐酶抑制剂，氨茶碱，非选择性腺苷受体拮抗剂和磷酸二酯酶抑制剂，和/或甲唑胺与氨茶碱联合使用可减轻缺氧介导的耐力运动能力下降。15名健康男性 (26   ±   5岁，体重指数: 24.9   ±   1.6  kg/m(2); 平均值 ± SD) 被随机分配到四种治疗方法之一: 安慰剂 (n   =   9)，甲唑胺 (250  mg; N   =   10)，氨茶碱 (400  mg; N   =   9) 或甲唑酰胺 (250  mg) 与氨茶碱 (400  mg; N   =   8)。在两个不同的场合，第一个在常氧 (FIO2   =   0.21) 和第二个在缺氧 (FIO2   =   0.15)，参与者在完成标准化运动回合之前坐了4.5小时 (30分钟，固定自行车，100  W)，然后进行12.5公里的计时赛。安慰剂 (+ 3.0   ±   2.7分钟) 、甲唑胺 (+ 1.4   ±   1.7分钟) 和氨茶碱 (+ 1.8   ±   1.2分钟) 在低氧与常氧之间的时间试验性能下降幅度没有差异，均p>   0.09; 然而，甲唑胺联合氨茶碱在低氧和常氧方面的性能下降小于安慰剂 (+ 0.6   ±   1.5分钟; P   =   0.01)。与安慰剂相比，甲唑酰胺联合氨茶碱在缺氧时SpO2的增加可能部分介导了这种改善 (73%   ±   3% 对79%   ±   6%; P  <  0.02)。总之，在高海拔地区逗留期间，同时服用甲唑胺和氨茶碱可能会促进耐力运动。

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BACKGROUND & AIMS: NEW FINDINGS:What is the central question of this study? Does the combination of methazolamide and theophylline reduce symptoms of acute mountain sickness (AMS) and improve aerobic performance in acute hypobaric hypoxia? What is the main finding and its importance? The oral combination of methazolamide (100 BID) and theophylline (300 BID) improved arterial oxygen saturation but did not reduce symptoms of AMS and impaired aerobic performance. We do not recommend this combination of drugs for prophylaxis against the acute negative effects of hypobaric hypoxia. ABSTRACT:A limited number of small studies have suggested that methazolamide and theophylline can independently reduce symptoms of acute mountain sickness (AMS) and, if taken together, can improve aerobic exercise performance in normobaric hypoxia. We performed a randomized, double-blind, placebo-controlled, cross-over study to determine if the combination of oral methazolamide and theophylline could provide prophylaxis against AMS and improve aerobic performance in hypobaric hypoxia (∼4875 m). Volunteers with histories of AMS were screened at low altitude (1650 m) and started combined methazolamide (100 mg BID) and theophylline (300 mg BID) treatment, or placebo, 72 h prior to decompression. Baseline AMS (Lake Louise Questionnaire), blood (haemoglobin, haematocrit), cognitive function, ventilatory and pulse oximetry ( S p O 2 ) measures were assessed at low altitude and repeated between 4 and 10 h of exposure to hypobaric hypoxia (PB  = 425 mmHg). Aerobic exercise performance was assessed during a 12.5 km cycling time trial (TT) after 4 h of hypobaric hypoxia. Subjects repeated all experimental procedures after a 3-week washout period. Differences between drug and placebo trials were evaluated using repeated measures ANOVA (α = 0.05). The drugs improved resting S p O 2 by ∼4% (P < 0.01), but did not affect the incidence or severity of AMS or cognitive function scores relative to placebo. Subjects' performance on the 12.5 km TT was ∼3% worse when taking the drugs (P < 0.01). The combination of methazolamide and theophylline in the prescribed dosages is not recommended for use at high altitude as it appears to have no measurable effect on AMS and can impair aerobic performance.

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BACKGROUND & AIMS: :Four cases of Stevens-Johnson syndrome considered to be induced by methazolamide were reported. In all of the cases, the first signs of Stevens-Johnson syndrome (i.e., swelling of the skin and mucous membranes or slight fever) appeared about 2 weeks after the patient started taking methazolamide (75 or 100 mg/d). After the appearance of erythema, the skin and mucous membrane lesions progressed rapidly and spread over the entire body, even after the patient ended methazolamide treatment and started treatment with prednisolone. During prednisolone treatment, the skin and mucous lesions became bullous, ruptured spontaneously, and dried with crust or erosion. HLA typing was positive for HLA-B59 in 3 of 4 cases. Methazolamide should be prescribed with caution in patients of Japanese or Korean descent.

背景与目标： : 报道了4例被认为是由甲唑酰胺引起的Stevens-Johnson综合征。在所有情况下，在患者开始服用甲唑胺 (75或100 mg/d) 后约2周出现Stevens-Johnson综合征的第一个迹象 (即皮肤和粘膜肿胀或轻微发热)。出现红斑后，皮肤和粘膜病变迅速进展并扩散到整个身体，即使在患者结束了甲唑胺治疗并开始使用泼尼松龙治疗之后。在泼尼松龙治疗期间，皮肤和粘液病变变为大疱，自发破裂，并伴有结皮或糜烂干燥。4例中有3例HLA分型为HLA-B59阳性。在日本或韩国血统的患者中，应谨慎使用甲唑胺。

BACKGROUND & AIMS: :Serum IgE level was determined in 76 monozygous and 81 dizygous like-sexed twin pairs representing adult twins living in the Helsinki area. Monozygous twin pairs were frequently concordant with respect to elevated IgE levels, although some pairs were strikingly discordant, indicating that there is a wide range of phenotypic expression for each genotype.

背景与目标： : 测定了76对单卵和81对同型同型双生双胞胎的血清IgE水平，代表居住在赫尔辛基地区的成年双胞胎。单卵双胞胎对在IgE水平升高方面经常保持一致，尽管有些对明显不一致，这表明每种基因型的表型表达范围很广。

BACKGROUND & AIMS: :The X-ray crystal structure for the adduct of human carbonic anhydrase (hCA) II with 4-methyl-5-perfluorophenylcarboximido-delta2-1,3,4-thiadiazoline-2-sulfonamide (PFMZ), a topically acting antiglaucoma sulfonamide, has been resolved at a resolution of 1.8 A. This compound is almost 10 times more effective as a hCA II inhibitor (KI of 1.5 nM) compared to the lead molecule, methazolamide, a clinically used drug (KI of 14 nM). Its binding to the enzyme active site is similar to that of other sulfonamide inhibitors, considering the interactions of the sulfonamide zinc anchoring group and thiadiazoline ring contacts, but differs considerably when the perfluorobenzoylimino fragment of the molecule is analyzed. Indeed, several unprecedented strong hydrogen bonds involving the imino nitrogen, carbonyl oxygen, a fluorine atom in the ortho position of the inhibitor, and two water molecules, as well as Gln 92 of the enzyme active site were seen. A stacking interaction of the perfluorophenyl ring of the inhibitor and the aromatic ring of Phe 131 was also observed for the first time in a CA-sulfonamide adduct. All these findings prove that more potent CA inhibitors incorporating perfluoroaryl/alkyl tails may be designed, with potentially improved antiglaucoma properties, in view of the new types of interactions seen here between the enzyme and the perfluorobenzoylated analogue of methazolamide.

背景与目标： : 人碳酸酐酶 (hCA) II与4-methyl-5-perfluorophenylcarboximido-delta2-1，3,4-噻二唑啉-2-磺酰胺 (PFMZ) (一种局部作用的抗青光眼磺酰胺) 的加合物的x射线晶体结构已以1.8 a的分辨率解析。该化合物作为hCA II抑制剂 (KI为1.5 nM) 的效果比铅分子，临床上使用的药物 (KI为14 nM) 高近10倍。考虑到磺酰胺锌锚定基团和噻二唑啉环接触的相互作用，其与酶活性位点的结合与其他磺酰胺抑制剂相似，但是在分析分子的全氟苯并亚氨基片段时差异很大。实际上，看到了几个前所未有的强氢键，涉及亚氨基氮，羰基氧，抑制剂邻位的氟原子和两个水分子以及酶活性位点的Gln 92。还首次在CA-磺酰胺加合物中观察到抑制剂的全氟苯基环和Phe 131的芳环的堆叠相互作用。所有这些发现证明，鉴于酶与甲唑酰胺的全氟苯甲酰化类似物之间的新型相互作用，可以设计出更有效的掺入全氟芳基/烷基尾的CA抑制剂，并具有潜在的改善的抗青光眼特性。

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BACKGROUND & AIMS: BACKGROUND:Increased bone resorption and new bone information are two characteristics of ankylosing spondylitis (AS). Much evidence has shown that carbonic anhydrase inhibitors can restrain bone resorption. We had detected increased expression of carbonic anhydrase I (CA1) in synovium of patients with AS. This study aimed to evaluate the effectiveness and safety of methazolamide, an anti-carbonic anhydrase drug, for treating patients with AS. METHODS:Two patients, called as S and L, were diagnosed with active AS based on BASDAI and BASFI assessments, radiographic data and other clinical indices. They took methazolamide tablets at a dose of 25 mg twice every day. RESULTS:Patient S's BASDAI score fell from 5.4 to 4.4, while patient L's BASDAI fell from 2.4 to 2. Patient S's BASFI score change from 2.7 to 2.9, while patient L's BASFI score fell from 1.2 to 0.2. The ESR values of patient S were considerably reduced, while the ESR value of patient L remained unchanged and in the normal range. The calcium concentration of patient S decreased from 3.05 mmol/L to 2.39 mmol/L. The CT evidence indicates that the articular surfaces of the erosive sacroiliac joints became clearer and the area of the calcium deposits began decreased. No significant systemic side effects were observed in either patient. CONCLUSIONS:The above results indicate that methazolamide was effective for active AS. Methazolamide may improve AS symptoms by inhibiting carbonic anhydrase activity during the processes of bone reporption and new bone formation.

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BACKGROUND & AIMS: :Acetazolamide, a carbonic anhydrase (CA) inhibitor used clinically and to prevent acute mountain sickness, worsens skeletal muscle fatigue in animals and humans. In animals, methazolamide, a methylated analog of acetazolamide and an equally potent CA inhibitor, reportedly exacerbates fatigue less than acetazolamide. Accordingly, we sought to determine, in humans, if methazolamide would attenuate diaphragm and dorsiflexor fatigue compared with acetazolamide. Healthy men (dorsiflexor: n = 12; diaphragm: n = 7) performed fatiguing exercise on three occasions, after ingesting acetazolamide (250 mg three times a day) and then in random order, methazolamide (100 mg twice a day) or placebo for 48 h. For both muscles, subjects exercised at a fixed intensity until exhaustion on acetazolamide, with subsequent iso-time and -workload trials. Diaphragm exercise was performed using a threshold-loading device, while dorsiflexor exercise was isometric. Neuromuscular function was determined pre- and postexercise by potentiated transdiaphragmatic twitch pressure and dorsiflexor torque in response to stimulation of the phrenic and fibular nerve, respectively. Diaphragm contractility 3-10 min postexercise was impaired more for acetazolamide than methazolamide or placebo (82 ± 10, 87 ± 9, and 91 ± 8% of pre-exercise value; P < 0.05). Similarly, dorsiflexor fatigue was greater for acetazolamide than methazolamide (mean twitch torque of 61 ± 11 vs. 57 ± 13% of baseline, P < 0.05). In normoxia, methazolamide leads to less neuromuscular fatigue than acetazolamide, indicating a possible benefit for clinical use or in the prophylaxis of acute mountain sickness. NEW & NOTEWORTHY Acetazolamide, a carbonic anhydrase inhibitor, may worsen diaphragm and locomotor muscle fatigue after exercise; whereas, in animals, methazolamide does not impair diaphragm function. Compared with both methazolamide and the placebo, acetazolamide significantly compromised dorsiflexor function at rest and after exhaustive exercise. Similarly, diaphragm function was most compromised on acetazolamide followed by methazolamide and placebo. Methazolamide may be preferable over acetazolamide for clinical use and altitude illness prophylaxis to avoid skeletal muscle dysfunction.

背景与目标： : 乙酰唑胺，一种碳酸酐酶 (CA) 抑制剂，用于临床和预防急性高山病，恶化动物和人类的骨骼肌乏力。在动物中，据报道，甲唑胺 (乙酰唑胺的甲基化类似物和同样有效的CA抑制剂) 比乙酰唑胺减轻乏力。因此，我们试图确定与乙酰唑胺相比，在人类中，甲唑胺是否会减轻隔膜和背屈肌乏力。健康男性 (背屈肌: n = 12; 膈肌: n = 7) 在摄入乙酰唑胺 (250毫克，每天三次) 后，进行三次疲劳运动，然后随机顺序，甲唑胺 (100毫克，每天两次) 或安慰剂48小时。对于两种肌肉，受试者都以固定的强度运动，直到使用乙酰唑胺耗尽为止，并进行后续的等时间和工作量试验。隔膜运动是使用阈值加载装置进行的，而背屈肌运动是等距的。运动前和运动后，分别通过增强膈肌和腓骨神经的刺激来确定神经肌肉功能。与甲唑胺或安慰剂相比，乙酰唑胺运动后3-10分钟的膈肌收缩力受损更多 (82   ±   10、87   ±   9和91   ±   8% 的运动前值; P <0.05)。同样，乙酰唑胺的背屈肌乏力大于甲唑胺 (平均抽搐扭矩为61  ±   11，而基线的13% 为57  ±  ，P <0.05)。在常氧状态下，甲唑胺比乙酰唑胺引起的神经肌肉乏力更少，表明可能对临床使用或预防急性高山病有益。新的和值得注意的乙酰唑胺，一种碳酸酐酶抑制剂，可能会加剧运动后的diaphragm肌和运动肌肉乏力; 而在动物中，甲唑胺不会损害diaphragm肌功能。与methazolamide和安慰剂相比，乙酰唑胺在休息和力竭运动后显着降低了背屈功能。同样，对乙酰唑胺，其次是甲唑酰胺和安慰剂，隔膜功能受损最大。在临床使用和预防高原疾病以避免骨骼肌功能障碍方面，甲唑胺比乙酰唑胺更可取。

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