Repurposing FDA-approved sulphonamide carbonic anhydrase inhibitors for treatment of Neisseria gonorrhoeae.

Neisseria gonorrhoeae is a high-priority pathogen of concern due to the growing prevalence of resistance development against approved antibiotics. Herein, we report the anti-gonococcal activity of ethoxzolamide, the FDA-approved human carbonic anhydrase inhibitor. Ethoxzolamide displayed an MIC50, against a panel of N. gonorrhoeae isolates, of 0.125 µg/mL, 16-fold more potent than acetazolamide, although both molecules exhibited almost similar potency against the gonococcal carbonic anhydrase enzyme (NgCA) in vitro. Acetazolamide displayed an inhibition constant (Ki) versus NgCA of 74 nM, while Ethoxzolamide's Ki was estimated to 94 nM. Therefore, the increased anti-gonococcal potency of ethoxzolamide was attributed to its increased permeability in N. gonorrhoeae as compared to that of acetazolamide. Both drugs demonstrated bacteriostatic activity against N. gonorrhoeae, exhibited post-antibiotic effects up to 10 hours, and resistance was not observed against both. Taken together, these results indicate that acetazolamide and ethoxzolamide warrant further investigation for translation into effective anti-N. gonorrhoeae agents.

Compound Danshen Dripping Pill inhibits high altitude-induced hypoxic damage by suppressing oxidative stress and inflammatory responses.

CONTEXT: Previous studies indicate that compound Danshen Dripping Pill (CDDP) improves the adaptation to high-altitude exposure. However, its mechanism of action is not clear. OBJECTIVE: To explore the protective effect of CDDP on hypobaric hypoxia (HH) and its possible mechanism. MATERIALS AND METHODS: A meta-analysis of 1051 human volunteers was performed to evaluate the effectiveness of CDDP at high altitudes. Male Sprague-Dawley rats were randomized into 5 groups (n = 6): control at normal pressure, model, CDDP-170 mg/kg, CDDP-340 mg/kg and acetazolamide groups. HH was simulated at an altitude of 5500 m for 24 h. Animal blood was collected for arterial blood-gas analysis and cytokines detection and their organs were harvested for pathological examination. Expression levels of AQP1, NF-κB and Nrf2 were determined by immunohistochemical staining. RESULTS: The meta-analysis data indicated that the ratio between the combined RR of the total effective rate and the 95% CI was 0.23 (0.06, 0.91), the SMD and 95% CI of SO2 was 0.37 (0.12, 0.62). Pre-treatment of CDDP protected rats from HH-induced pulmonary edoema and heart injury, left-shifted oxygen-dissociation curve and decreased P50 (30.25 ± 3.72 vs. 37.23 ± 4.30). Mechanistically, CDDP alleviated HH-reinforced ROS by improving SOD and GPX1 while inhibiting pro-inflammatory cytokines and NF-κB expression. CDDP also decreased HH-evoked D-dimer, erythrocyte aggregation and blood hemorheology, promoting AQP1 and Nrf2 expression. DISCUSSION AND CONCLUSIONS: Pre-treatment with CDDP could prevent HH-induced tissue damage, oxidative stress and inflammatory response. Suppressed NF-κB and up-regulated Nrf2 might play significant roles in the mechanism of CDDP.

CFTR-mediated anion secretion across intestinal epithelium-like Caco-2 monolayer under PTH stimulation is dependent on intermediate conductance K+ channels.

Parathyroid hormone (PTH), a pleiotropic hormone that maintains mineral homeostasis, is also essential for controlling pH balance and ion transport across renal and intestinal epithelia. Optimization of luminal pH is important for absorption of trace elements, e.g., calcium and phosphorus. We have previously demonstrated that PTH rapidly stimulated electrogenic [Formula: see text] secretion in intestinal epithelial-like Caco-2 monolayers, but the underlying cellular mechanism, contributions of other ions, particularly Cl- and K+, and long-lasting responses are not completely understood. Herein, PTH and forskolin were confirmed to induce anion secretion, which peaked within 1-3 min (early phase), followed by an abrupt decay and plateau that lasted for 60 min (late phase). In both early and late phases, apical membrane capacitance was increased with a decrease in basolateral capacitance after PTH or forskolin exposure. PTH also induced a transient increase in apical conductance with a long-lasting decrease in basolateral conductance. Anion secretion in both phases was reduced under [Formula: see text]-free and/or Cl--free conditions or after exposure to carbonic anhydrase inhibitor (acetazolamide), CFTR inhibitor (CFTRinh-172), Na+/H+ exchanger (NHE)-3 inhibitor (tenapanor), or K+ channel inhibitors (BaCl2, clotrimazole, and TRAM-34; basolateral side), the latter of which suggested that PTH action was dependent on basolateral K+ recycling. Furthermore, early- and late-phase responses to PTH were diminished by inhibitors of PI3K (wortmannin and LY-294002) and PKA (PKI 14-22). In conclusion, PTH requires NHE3 and basolateral K+ channels to induce [Formula: see text] and Cl- secretion, thus explaining how PTH regulated luminal pH balance and pH-dependent absorption of trace minerals.

Secondary paroxysmal dyskinesia in multiple sclerosis: Clinical-radiological features and treatment. Case report of seven patients.

Secondary paroxysmal dyskinesias (SPDs) are short, episodic, and recurrent movement disorders, classically related to multiple sclerosis (MS). Carbamazepine is effective, but with risk of adverse reactions. We identified 7 patients with SPD among 457 MS patients (1.53%). SPD occurred in face ( n = 1), leg ( n = 2), or arm +leg ( n = 4) several times during the day. Magnetic resonance imaging (MRI) showed new or enhancing lesions in thalamus ( n = 1), mesencephalic tegmentum ( n = 1), and cerebellar peduncles ( n = 5). Patients were treated with clonazepam and then acetazolamide ( n = 1), acetazolamide ( n = 5), or levetiracetam ( n = 1) with response within hours (acetazolamide) to days (levetiracetam). No recurrences or adverse events were reported after a median follow-up of 33 months.

Acetazolamide enhances the release of urinary exosomal aquaporin-1.

BACKGROUND: Renal aquaporin-1 (AQP1), a water channel protein, is known to be secreted into urine, conveyed by nano-sized extracellular vesicles called exosomes. A previous study has demonstrated that acetazolamide (AZ), a diuretic that inhibits carbonic anhydrases, alters the expression level of AQP1 in cultured cells. Here we investigated whether AZ alters the release of urinary exosomal AQP1 in vivo. METHODS: The effect of AZ on urinary exosomal AQP1 secretion was examined in rats and compared with furosemide (another diuretic), NaHCO3 (an alkalizing agent) and NH4Cl (an acidifying agent). Urine, blood and kidney samples were obtained 2 h after each treatment. Urinary exosomes were isolated by a differential centrifugation technique and urinary exosomal proteins were analyzed by immunoblotting. RESULTS: The release of exosomal AQP1 into urine was markedly increased after treatment with AZ, accompanied by alkaluria and metabolic acidosis. Immunohistochemistry clearly demonstrated that AZ increased the apical membrane expression of AQP1 in the proximal tubules. AZ did not affect the release of exosomal marker proteins (tumor susceptibility gene 101 protein and apoptosis-linked gene 2 interacting protein X). Treatment with furosemide did not change, whereas NaHCO3 and NH4Cl decreased the exosomal release of AQP1. CONCLUSION: The present findings indicate that AZ increases the release of exosomal AQP1 into urine in association with enhanced apical membrane expression of AQP1.

Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype.

OBJECTIVES: Acetazolamide has been the most commonly used treatment for hypokalemic periodic paralysis since 1968. However, its mechanism of efficacy is not fully understood, and it is not known whether therapy response relates to genotype. We undertook a clinical and genetic study to evaluate the response rate of patients treated with acetazolamide and to investigate possible correlations between response and genotype. METHODS: We identified a total of 74 genotyped patients for this study. These included patients who were referred over a 15-year period to the only U.K. referral center or to a Chinese center and who underwent extensive clinical evaluation. For all genotyped patients, the response to acetazolamide therapy in terms of attack frequency and severity was documented. Direct DNA sequencing of CACNA1S and SCN4A was performed. RESULTS: Only 46% of the total patient cohort (34 of 74) reported benefit from acetazolamide. There was a greater chance of benefit in patients with mutations in CACNA1S (31 responded of 55 total) than in those with mutations in SCN4A (3 responded of 19 total). Patients with mutations that resulted in amino acids being substituted by glycine in either gene were the least likely to report benefit. CONCLUSIONS: This retrospective study indicates that only approximately 50% of genotyped patients with hypokalemic periodic paralysis respond to acetazolamide. We found evidence supporting a relationship between genotype and treatment response. Prospective randomized controlled trials are required to further evaluate this relationship. Development of alternative therapies is required.

Bidirectional influences of acetazolamide on central nervous system oxygen toxicity of rats.

Central nervous system oxygen toxicity, which occurs during diving and hyperbaric oxygen treatment, can lead to very dangerous situations, and it is of great importance to explore its mechanisms. We have speculated that cerebral blood flow plays a pivotal role in its occurrence. Except for acting as an anticonvulsant in clinical applications, acetazolamide is also a vasodilator used in both clinical and laboratory settings. In this study, when acetazolamide from 5 to 500 ug/kg body weight was administered by intracerebroventricular injection, the latency of central nervous system oxygen toxicity detected by electroencephalogram recording in rats subjected to hyperbaric oxygen at 6 atmospheres absolute was prolonged significantly. On the contrary, when the dose of intracerebroventricular injection achieved 5,000 ug/kg body weight, acetazolamide shortened the latency significantly. Intraperitoneal injection of acetazolamide more than 7.5 mg/kg body weight also shortened the latency significantly. Results also showed both intracerebroventricular injection of acetazolamide at a dose of 5,000 ug/kg body weight and intraperitoneal injection at dose of 7.5 mg/kg body weight inhibited the activity of carbonic anhydrase and increased the cerebral blood flow significantly, which helped aggravate oxidation damage and resulted in increased MDA and impaired glutathione peroxidase in brain tissue. But intracerebroventricular injection of acetazolamide at 5 ug/kg body weight had no effect on MDA and glutathione peroxidase, though it inhibited the activity of carbonic anhydrase. These observations indicated acetazolamide covers bidirectional influences on central nervous system oxygen toxicity. Within local brain tissue, especially neurons, it could exert its anticonvulsive effect on the central nervous system at low doses. On the other hand, under high doses, it would display its convulsive-hastening effect through increasing cerebral blood flow to aggravate the oxidation state of brain tissues and exacerbate central nervous system oxygen toxicity when subjected to hyperbaric oxygen. Blood flow of brain plays a pivotal role in central nervous system oxygen toxicity.

Causes and consequences of zinc dyshomeostasis in rats with chronic aldosteronism.

Iterations in Ca2+ and Mg2+ balance accompany aldosteronism (inappropriate for dietary Na+ intake). Increased Zn excretion and Zn translocation to injured tissues, including the heart, also occurs. Several causes and consequences of Zn dyshomeostasis in rats receiving aldosterone/salt treatment (ALDOST) were examined. (1) To study the role of urinary acidification in promoting hyperzincuria, acetazolamide (75 mg/kg), a carbonic anhydrase inhibitor, was used as cotreatment to raise urinary HCO3 excretion. (2) To assess Zn levels in the heart, including cardiomyocyte cytosolic free [Zn2+]i and mitochondrial Zn, the expression of metallothionein (MT-I), a Zn binding protein, and biomarkers of oxidative stress were examined. (3) Oxidative stress and cardiac pathology in response to ZnSO4 supplement (40 mg/d) were also studied. Comparison of controls and rats receiving 4 weeks ALDOST revealed the following: (1) an acidification of urine and metabolic alkalosis associated with increased urinary Zn excretion and hypozincemia, each of which were prevented by acetazolamide; (2) a rise in cardiac Zn, including increased [Zn2+]i and mitochondrial Zn, associated with increased tissue MT-I, 8-isoprostane, malondialdehyde, and gp91(phox), coupled with oxidative stress in plasma and urine; (3) ZnSO4 prevented hypozincemia, but not ionized hypocalcemia, and attenuated oxidative stress and microscopic scarring without preventing the vasculitis and perivascular fibrosis of intramural coronary arteries. Thus, the hyperzincuria seen with ALDOST is due to urinary acidification. The oxidative stress that appears in the heart is accompanied by increased tissue Zn serving as an antioxidant. Cotreatment with ZnSO4 attenuated cardiomyocyte necrosis; however, polynutrient supplement may be required to counteract the dyshomeostasis of all 3 cations that accompanies aldosteronism and contributes to cardiac pathology.

Reduced perfusion reserve in Leukoaraiosis demonstrated using acetazolamide challenge 123I-IMP SPECT.

OBJECTIVE: We examined the relationship between the perfusion reserve as measured by acetazolamide (ACZ)-challenge N-isopropyl-I-123-p-iodoamphetamine (IMP)-single-photon emission computed tomography (SPECT) and the degree of leukoaraiosis (LA) as estimated using magnetic resonance imaging. METHODS: In 51 patients receiving IMP-SPECT with the resting state and ACZ challenge, the unaffected cerebral hemispheres were included in the present study. Mean cerebral blood flow (CBF) in the resting state and ACZ reactivity were acquired. Absolute CBF value and ACZ reactivity were compared among patients with LA grades 0, 1, and 2. The relationship between mean age and LA grade was also assessed. RESULTS: No significant difference in the absolute CBF value in the resting state was observed among the 3 LA groups. Although vasoreactivity in LA grade 0 did not differ from that in grade 1, vasoreactivity in LA grade 2 was significantly lower (P < 0.05) than that in grades 0 or 1. CONCLUSIONS: The perfusion reserve is impaired in advanced LA.

[Effect of acetazolamide on the latency of hyperbaric oxygen-induced convulsion].

The purpose of the present study was to explore the relation between the modulation of cerebral blood flow and the latency of hyperbaric oxygen-induced convulsion. There were two parts in this study. First, the effect of acetazolamide on the latency of hyperbaric oxygen-induced convulsion was observed. 32 Sprague-Dawley (SD) rats were randomly divided into four groups: the acetazolamide 200, 20, 2 mg/kg body weight and normal saline (NS) group. The animals were given intraperitoneally acetazolamide or NS, respectively, before being exposed to the pressure of 6 ATA (absolute atmosphere) of pure oxygen. The time from exposure to the onset of seizure (clonic-tonic convulsion) was recorded for each animal according to behavioral observation. Second, the changes in maleic dialdehyde (MDA) and the activity of glutathione peroxidase (GSH-PX) were measured after acetazolamide treatment. 40 SD rats were randomly divided into five groups: NS group, 6 min with NS group, 6 min with acetazolamide group, 16 min with NS group, and 16 min with acetazolamide group. The dose of acetazolamide was 20 mg/kg body weight. After injection of NS or acetazolamide, the animals were subjected to the pressure of 6 ATA of pure oxygen in respect to its time course group. The rats were decapitated and the cortex, hippocampus, and striatum of brains were dissected and homogenized. The content of MDA and the activity of GSH-PX in these tissues were determined. We found that (1) there was a significant difference in the latency of hyperbaric oxygen-induced convulsion between the acetazolamide 200 mg/kg group and the NS control group, as well as between the acetazolamide 20 mg/kg group and the NS control group (P<0.01), whereas there was no significant difference between the NS group and the acetazolamide 2 mg/kg weight group (P>0.05). The latency of these groups were listed as follows: 9.78+/-1.94 min for 200 mg/kg body weight group, 10.92+/-1.68 min for 20 mg/kg body weight group, 24.32+/-4.33 min for 2 mg/kg body weight group and 22.02+/-4.32 min for NS control group. (2) there was no significant difference between all groups in the activity of GSH-PX, though it varied with the oxidation levels. In the cortex and hippocampus, the activity of GSH-PX boosted up at first, but with the progress of the oxidation it was impaired. In the striatum, the activity of GSH-PX increased stepwise with the aggravation of the oxidation. The MDA content in the cortex increased significantly in the group of 6 min with acetazolamide (P<0.01), as well as the group of 16 min with acetazolamide group both in cortex and hippocampus (P<0.01, P<0.05). The MDA content of all groups is correlated with the dose of acetazolamide and the exposure time. These results suggest that acetazolamide which dilates the brain arteriolar obviously shortens the latency of hyperbaric oxygen-induced convulsion, and that acetazolamide dilates the vessels and increases the supply of the oxygen breaking into the brain tissues and aggravates the oxidation. The hyperbaric oxygen-induced convulsion correlates closely with the oxidation injury.

Prediction of hyperperfusion after carotid endarterectomy by brain SPECT analysis with semiquantitative statistical mapping method.

BACKGROUND AND PURPOSE: Hyperperfusion syndrome is a rare but disastrous complication after carotid endarterectomy (CEA). The aim of this study was to investigate the relationship between preoperative cerebral blood flow (CBF) abnormalities and postoperative hyperperfusion through the use of statistical brain mapping analysis. METHODS: For 41 patients with unilateral carotid stenosis >or=70%, CBF and cerebral vasoreactivity (CVR) were investigated with resting and acetazolamide-challenge single photon emission CT before CEA. CBF 1 day after CEA was also measured. Three-dimensional stereotactic surface projection (3D-SSP) analysis of CBF changes was performed by use of a control database of 20 subjects. RESULTS: Patients with reduced CVR (CVR <10%, n=15) were categorized into 2 groups based on the severity of CBF reduction relative to the control database by 3D-SSP analysis without normalization: type I (ipsilateral CBF decrease <20%, n=8) and type II (ipsilateral CBF decrease >or=20%, n=7). With thalamic normalization, the patients were also categorized into 2 groups: type A (ipsilateral Z score 2, n=5). Severe CBF reduction (>or=20% or Z score >2) was significantly associated with postoperative hyperperfusion (CBF increase >or=100%). However, 3D-SSP with thalamic normalization (Z score) demonstrated a higher predictive value (80%) and specificity (91%) for hyperperfusion than 3D-SSP without normalization (percent reduction) (57% and 73%, respectively). No patients with normal CVR (CVR >or=10%, n=26) demonstrated postoperative hyperperfusion. CONCLUSIONS: Objective evaluation of abnormalities of CBF and CVR with 3D-SSP could identify patients at risk for postoperative hyperperfusion.

Effect of acetazolamide on hypericin photocytotoxicity.

The photodynamic action of hypericin (HYP) in vitro was evaluated using human leukemic HL-60 and lung carcinoma A549 cell lines. After illumination HYP (1 x 10 (-5) M) reduced the proliferation and/or survival of HL-60 and A549 cells vs. controls to almost to 0 % and 29 %, respectively. A lower concentration of HYP (1 x 10 (-6) M) decreased the proliferation and/or survival only in HL-60 cells. Non-cytotoxic concentrations of the carbonic anhydrase inhibitor acetazolamide (ACTZ) (1 x 10 (-3)-1 x 10 (-6) M) significantly potentiated these effects of HYP (1 x 10 (-6)M) in HL-60, but not in the A549 cell line. The highest concentration of ACTZ (1 x 10 (-3) M) also induced an increase of the subdiploid G 0 /G 1 population in HYP (1 x 10 (-6) M) treated HL-60 cells from 14 % to 24 %. The results indicate that the photogenerated pH drop may participate in the potentiation of the photodynamic action of HYP observed in leukemia cells.

Mineral status of embryos of domestic fowl following exposure in vivo to the carbonic anhydrase inhibitor acetazolamide.

Eggs of domestic fowl were given daily injections of vehicle (DMSO) or vehicle plus acetazolamide, a potent inhibitor of the enzyme carbonic anhydrase, beginning on day 12 of incubation. Embryos were removed from eggs on days 16 and 18, and carcasses and yolks were analyzed for calcium, magnesium, and phosphorus. Treatment with acetazolamide did not affect the quantity of calcium or phosphorus in carcasses and the effect, if any, on magnesium in carcasses was small. However, calcium content of yolk was reduced substantially by acetazolamide both on day 16 and day 18. The reduction in calcium content of yolk led, in turn, to a reduction in the total quantity of calcium in eggs on days 16 and 18. Embryos exposed to acetazolamide seemingly mobilized less calcium from the eggshell than did control embryos. When faced with a shortfall in the availability of calcium from the eggshell, embryos defended carcass calcium, and the shortfall was reflected in a reduction in the quantity of calcium deposited in yolk. The results of this study support the concept that the enzyme carbonic anhydrase plays a role in solubilization of the eggshell and provision of calcium to embryos.

Acidocalcisomes are functionally linked to the contractile vacuole of Dictyostelium discoideum.

The mass-dense granules of Dictyostelium discoideum were shown to contain large amounts of phosphorus, magnesium, and calcium, as determined by x-ray microanalysis, either in situ or when purified using iodixanol gradient centrifugation. The high phosphorus content was due to the presence of pyrophosphate and polyphosphate, which were also present in the contractile vacuoles. Both organelles also possessed a vacuolar H(+)-ATPase, an H(+)-pyrophosphatase, and a Ca(2+)-ATPase, as determined by biochemical methods or by immunofluorescence microscopy. The H(+)-pyrophosphatase activity of isolated mass-dense granules was stimulated by potassium ions and inhibited by the pyrophosphate analogs aminomethylenediphosphonate and imidodiphosphate and by KF and N-ethylmaleimide in a dose-dependent manner. The mass-dense granules and the contractile vacuole appeared to contact each other when the cells were submitted to hyposmotic stress. Acetazolamide inhibited the carbonic anhydrase activity of the contractile vacuoles and prolonged their contraction cycle in a dose-dependent manner. Similar effects were observed with the anion exchanger inhibitor 4,4' -diisothiocyanatodihydrostilbene-2, 2' -disulfonic acid and the vacuolar H(+)-ATPase inhibitor bafilomycin A(1). Together, these results suggest that the mass-dense granules of D. discoideum are homologous to the acidocalcisomes described in protozoan parasites and are linked to the function of the contractile vacuole.

Chachacoma ¿un tratamiento alternativo para la prevención del mal agudo de montaña? / Chachacoma, an alternative treatment to prevention od acute mountain sickness?

Chachacoma is an herbal folk remedy used by natives and tourists to avoid high altitude sickness (AMS) when mountain climbing. Chachacoma has been described as a hypotensor. Acetazolamide is presently the best treatment for prevention of AMS and it's function is diuretic. The objectives of the present study was to make a comparative analysis of the efficacy of these two treatments for AMS. A group of 22 healthy subjects (22+- 1 years) with no high altitude experience were divided into two group of 11, one of which received a cup of Chachacoma infusion and a second group of 11 received 250mg of acetazolamide the morning prior to making an ascent (2000 m+). The day prior to the ascent the following parameters were measured on all subjects: heart rate (HR), respiratory rate (RR), systolic and diastolic pressure (SAP,DAP) and oxigen saturation (SatO2). In the following days in Colchane the measurements were repeated and the Lake Louise Test was used to determine AMS symptoms. Values were expressed +- 1 std. deviation and differences were evaluated with a student test ( vs Chachacoma, p>0.05). The incidence of AMS in the Chachacoma group was 55 percent, compared to 36 percent in the acetazolamide group (p<0.05). No significant differences were observed in arterial pressure between groups. However, the point score for AMS for the acetazolamide group was lower than that for the Chachacoma group. It was concluded that acetazolamide was more effient in preventing the symptoms of AMS than Chachacoma.

Chachacoma es un tratamiento etnomedicinal para el MAM en nativos y turistas que ascienden a grandes alturas. Chachacoma es descrita como hipotensor. Acetazolamida actualmente es el mejor tratamiento para prevenir MAM, su función es de diurético. Nuestro objetivo fue comparar su eficiencia en la prevención del MAM. Un estudio fue aplicado a 22 sujetos (22+- 1 años), sanos, sin experiencia a grandes alturas (>2000 m). Un grupo (n=11) con Chachacoma (1 taza con infusión dada en la mañana del ascenso), otro grupo (n=11) con Acetazolamida (250 mg en la mañana del ascenso), El día previo al ascenso se determinaron: frecuencia cardíaca (FC) y respiratoria (FR), presiones sistólicas y diastólicas (PAS,PAD) y saturación de oxigeno (Sat=2). En los siguientes días en Colchane las mediciones fueron repetidas y se usó un test de Lake-Louise para determinar síntomas de MAM. Los valores se expresaron en promedios +- DS, la diferencia fue medida con test de Student (vs Chachacoma, p<0,05). La incidencia de MAM en el grupo de Chachacoma fue 55 por ciento, contra el 36 por ciento del grupo de Acetazolamida )p<0.05). No se observaron cambios en presión arterial en ambos grupos. Sin embargo, el puntaje de MAM para el grupo de Acetazolamida fue menor que el de Chachacoma. En conclusión, Acetazolamida es más eficiente previniendo síntomas de MAM.

Inhibition of bovine carbonic anhydrase by new sulfonamide compounds.

Inhibitory effects of three new derivatives of 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide on bovine carbonic anhydrase have been investigated. The new compounds are 2-(3-chloropropionylamino)-1,3,4-thiadiazole-5-sulfonamide, 2-(2,2-dichloroacetylamino)-1,3,4-thiadiazole-5-sulfonamide, and 2-(3-phenylpropionylamino)-1,3,4-thiadiazole-5-sulfonamide. The new compounds inhibit the esterase activity of carbonic anhydrase noncompetitively and have inhibition constants and I(50) values very similar to those for 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide, the latter being clinically used in the treatment of glaucoma.

[Effects of Rholida on the free radical metabolism and serum creatine kinase after exercise at plateau].

Objective. To study the effect of Rholida on free radical metabolism and serum creatine kinase CK) after exercise at plateau. Method. After staying at high altitude (4100 m) for 20 d, 40 healthy young men were divided into 4 groups randomly (Rholida, Acetazolamide, Xi' s capsule and control, 10 men each group). And their SOD, MDA, GSH-Px CK, and CK-MB were determined respectively. Before, after taking drugs and after finishing the 5 min-stair-exercise. Result. Before taking drugs and after exercise, MAD GSH-Px, CK, CK-MB, increased as compared with quiet state (P<0.05, P<0.01), but SOD showed no significant chang (P>0.05). After taking drugs for 6 d, those who took Rholida, Acetazolamide and Xi's capsule, their MAD, GSH-Px CK, CK-MB increased after exercise as compared with quiet state (P<0.05). In Rholida group SOD increased and had significant change (P<0.05); but there was no significant change in Acetazolamide, Xi' s capsule group, SOD increased, MDA decreased (P<0.05), CK, CK-MB had no significant change (P>0.05), GSH-Px increased in Xi's group (P<0.05), but not in Acetazolamide group (P>0.05). SOD, GSH-Px increased, MDA, CK-MB decreased in Rholida group after taking drugs and the changes were significant (P<0.01). In Acetazolamide and Xi's capsule group, GSH-Px increased significantly, MDA, CK, CK-MB decreased significantly (P<0.05), but SOD didn't (P>0.05). Conclusion. Rholida, Acetazolamide, Xi's capsule could regulate the disorder of free radical metabolism at plateau and Rholida had advantage over the others.

A comparison of topiramate and acetazolamide on seizure duration and paired-pulse inhibition in the dentate gyrus of the rat.

Topiramate is a relatively new antiepileptic drug with several putative anticonvulsant mechanisms. Among them is the ability to inhibit carbonic anhydrase, a property in common with the anticonvulsant acetazolamide. This study examined the effects of topiramate and acetazolamide on the duration of epileptiform activity and on paired-pulse inhibition in the dentate gyrus in urethane anesthetized adult Sprague-Dawley rats. Neither topiramate nor acetazolamide altered excitability in the dentate gyrus, as measured with input-output curves or induction of long-term potentiation. Topiramate increased paired-pulse inhibition, whereas acetazolamide had no effect. Both drugs dose-dependently blocked the lengthening of the duration of epileptiform activity compared to vehicle controls. These results indicate that topiramate has an anticonvulsant-related effect (increase in paired-pulse inhibition), which may contribute to its antiepileptic effect, that is not dependent on its ability to inhibit carbonic anhydrase.

[Reduction of renal uranium uptake by acetazolamide: the importance of urinary elimination of bicarbonate]. / Réduction de la fixation rénale de l'uranium par l'acétazolamide: importance de l'élimination urinaire du bicarbonate.

Acetazolamide was compared with bicarbonate for the treatment of contamination with uranium. Uranium was injected peritoneally in rats, and its distribution was investigated. Acetazolamide was three times more efficient than bicarbonate in reducing the renal content of uranium. On the other hand, it had no effect on hepatic or skeletal content. In this study, renal physiology provides the basis for understanding the mode of action of acetazolamide and bicarbonate. In this context, it is of interest to determine the alkalinity of the urine, with the aim of knowing whether bicarbonate is present to mobilize uranium.