BACKGROUND & AIMS: PURPOSE:To formulate aqueous eye drops containing methazolamide 1% in cyclodextrin solution and to evaluate their effect on intraocular pressure (IOP) in a double-blind randomized trial in humans. Methazolamide, a carbonic anhydrase inhibitor (CAI), has been used in oral doses in the treatment of glaucoma but hitherto has not been successfully formulated in eye drops. In this study the effects of methazolamide are compared with those of dorzolamide (Trusopt). METHODS:Methazolamide 1% was formulated in a 2-hydroxypropyl-beta-cyclodextrin with hydroxypropyl methylcellulose in aqueous solution. Eight persons with ocular hypertension were treated with the methazolamide-cyclodextrin eye drops and eight persons with dorzolamide (Trusopt), both groups at dosages of three times a day for 1 week. IOP was measured before treatment was begun and on days 1, 3, and 8 at 9 AM (peak) and 3 PM (trough). RESULTS:After 1 week of treatment, the peak IOP in the methazolamide group had decreased from 24.4 +/- 2.1 mm Hg (mean +/- SD) to 21.0 +/- 2.0 mm Hg, which is a 14% pressure decrease (P: = 0.006). In the dorzolamide group, the peak IOP decreased from 23.3 +/- 2.1 mm Hg to 17.2 +/- 3.1 mm Hg, which is a 26% pressure decrease (P: < 0.001). On average, the IOP declined 3.4 +/- 1.8 mm Hg after methazolamide administration and 6.1 +/- 3.6 mm Hg after dorzolamide. CONCLUSIONS:Through cyclodextrin complexation, it is possible to produce topically active methazolamide eye drops that lower IOP. This is the first double-blind clinical trial that demonstrates the efficacy of the classic CAIs in eye drop formulation.

背景与目标：

BACKGROUND & AIMS: :Sixteen patients with increased intraocular pressure (over 20 mm Hg) received 25 and 50 mg of oral methazolamide, twice daily, during consecutive weeks and then 500 mg (Sequels) of acetazolamide. The two methazolamide regimens produced significant decreases in intraocular pressure. Acetazolamide treatment resulted in a greater decrease in intraocular pressure but more systemic acidosis and side effects.

背景与目标： : 16名眼内压升高 (超过20毫米Hg) 的患者在连续几周内每天两次接受25和50 mg口服美沙唑胺，然后接受500 mg (续集) 乙酰唑胺。两种甲唑胺方案可显着降低眼内压。乙酰唑胺治疗导致眼内压下降幅度更大，但全身酸中毒和副作用更大。

BACKGROUND & AIMS: :Carbonic anhydrase inhibitors used in the treatment of glaucoma are rarely associated with blood dyscrasias. Several case reports of aplastic anemia with use of acetazolamide, and two cases with use of methazolamide, have appeared in the literature. This report documents two cases of aplastic anemia, at least one of which was almost certainly induced by the use of methazolamide, one case of agranulocytosis, and two cases of neutropenia related to the use of methazolamide. In each case several weeks to months elapsed between initiation of therapy and onset of reaction. This suggests that changes in patients' general medical condition should be continually monitored when using these drugs.

背景与目标： : 用于治疗青光眼的碳酸酐酶抑制剂很少与血液异常有关。文献中出现了几例使用乙酰唑胺的再生障碍性贫血病例报告，以及两例使用甲唑胺的病例报告。该报告记录了两例再生障碍性贫血，其中至少一例几乎肯定是由使用甲唑胺引起的，一例是粒细胞缺乏症，以及两例与使用甲唑胺有关的中性粒细胞减少症。在每种情况下，从开始治疗到发生反应之间经过数周至数月。这表明在使用这些药物时，应持续监测患者一般医疗状况的变化。

BACKGROUND & AIMS: :We compared the effects of the carbonic anhydrase inhibitors methazolamide and acetazolamide (3 mg kg(-1), i.v.) on the steady-state hypoxic ventilatory response in 10 anaesthetized cats. In five additional animals, we studied the effect of 3 and 33 mg kg(-1) methazolamide. The steady-state hypoxic ventilatory response was described by the exponential function: *Vi= G exp(-D P(O2)) + A where *Vi is the inspired ventilation, G is hypoxic sensitivity, D is the shape factor and A is hyperoxic ventilation. In the first group of 10 animals, methazolamide did not change parameters G and D, while A increased from 0.86 +/- 0.33 to 1.30 +/- 0.40 l min(-1) (mean +/- s.d., P = 0.003). However, the subsequent administration of acetazolamide reduced G by 44% (control, 1.93 +/- 1.32; acetazolamide, 1.09 +/- 0.92 l min(-1), P = 0.003), while A did not show a further change. Acetazolamide tended to reduce D (control, 0.20 +/- 0.07; acetazolamide, 0.14 +/- 0.06 kPa(-1), P = 0.023). In the second group of five animals, neither low- nor high-dose methazolamide changed parameters G, D and A. The observation that even high-dose methazolamide, causing full inhibition of carbonic anhydrase in all body tissues, did not reduce the hypoxic ventilatory response is reminiscent of previous findings by others showing no change in magnitude of the hypoxic response of the in vitro carotid body by this agent. This suggests that normal carbonic anhydrase activity is not necessary for a normal hypoxic ventilatory response to occur. The mechanism by which acetazolamide reduces the hypoxic ventilatory response needs further study.

背景与目标： : 我们比较了碳酸酐酶抑制剂甲唑酰胺和乙酰唑胺 (3 mg kg(-1)，静脉注射) 对10只麻醉猫的稳态低氧通气反应的影响。在另外五只动物中，我们研究了3和33 mg kg(-1) 甲唑酰胺的作用。稳态低氧通气反应由指数函数描述: * Vi = G exp(-D P(O2)) A其中 * Vi是吸入通气，G是低氧敏感性，D是形状因子，A是高氧通气。在第一组10只动物中，甲唑酰胺不改变参数G和D，而A从0.86 +/- 0.33增加到1.30 +/- 0.40 l min(-1) (平均值 +/- s.d.，P = 0.003)。然而，随后施用乙酰唑胺使G降低了44% (对照，1.93 +/- 1.32; 乙酰唑胺，1.09 +/- 0.92 l min(-1)，P = 0.003)，而A没有显示进一步的变化。乙酰唑胺倾向于降低D (对照，0.20 +/- 0.07; 乙酰唑胺，0.14 +/- 0.06 kPa(-1)，P = 0.023)。在第二组五只动物中，低剂量或高剂量的甲唑酰胺均未改变参数G，D和A。观察到即使大剂量的甲唑胺也会在所有身体组织中引起碳酸酐酶的完全抑制，但并未降低低氧通气反应，这让人想起其他人先前的发现，该发现表明体外颈动脉体的低氧反应幅度没有变化。这种药物。这表明正常的碳酸酐酶活性对于发生正常的低氧通气反应不是必需的。乙酰唑胺降低低氧通气反应的机制需要进一步研究。

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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.

背景与目标：

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.

背景与目标：

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.

背景与目标：

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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