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PubMed1998

Episodic ataxia and channelopathies.

Clinical details are given of different types of episodic ataxia: type 1, with myokymia, and attacks which usually last a few minutes, and may occur several times a day, and treatment with acetazolamide can reduce the number of attacks; type 2, with interictal nystagmus, and attacks which last for several hours to a day or more, and treatment with acetazolamide is very effective; paroxysmal choreoathetosis with episodic ataxia, with attacks lasting for about 20 min and occurring at varying intervals; and familial hemiplegic migraine, with transient hemiplegia presenting during the aura of a migraine headache, the symptoms improving on treatment with acetazolamide. Their inheritance is of dominant type; and the gene for type 1 is mapped to chromosome 12p near to a cluster of potassium channel genes, and that for type 2 and for familial hemiplegic migraine to chromosome 19p near to calcium channel genes. The differential diagnosis from other conditions with a periodic symptomatology is discussed, especially from a number of metabolic disorders. Treatment is effective for many of these, and the treatment of the episodic ataxias with acetazolamide can sometimes have a dramatic effect. The possible role of the channelopathies in the causation of some periodic neurological disorders is considered; with the expectation that further research will improve the identification of specific diseases, and lead to more effective treatment.

Acetazolamide↗
PubMed1998

Blood flow differences between leuko-araiosis with and without lacunar infarction.

BACKGROUND: The present study was designed to find the differences in regional cerebral blood flow and cerebrovascular acetazolamide reactivity between leuko-araiosis with and without lacunar infarction. METHODS: Fifteen cases of leuko-araiosis with lacunar infarction, 15 cases of leuko-araiosis without lacunar infarction and 15 age-matched controls in which leuko-araiosis and cerebrovascular diseases are absent (control group) were studied. The regional cerebral blood flow was measured using the stable xenon computed tomography method before and 20 minutes after intravenous injection of 17 mg/kg acetazolamide. RESULTS: The blood flows in the leuko-araiosis area and the lacunar area were significantly lower than the blood flow in the cerebral white matter. The blood flows in the cerebral cortex and the cerebral white matter were significantly lower in the leuko-araiosis with lacunar infarction group than in the leuko-araiosis without lacunar infarction group and the control group. The cerebrovascular acetazolamide reactivity in the leuko-araiosis area and the lacunar area was significantly lower than that in the cerebral white matter. The cerebrovascular acetazolamide reactivity in the cerebral cortex and the cerebral white matter was significantly lower in the leuko-araiosis with lacunar infarction group than in the leuko-araiosis without lacunar infarction group and the control group. CONCLUSIONS: The degree of arteriolosclerosis is considered to be more severe and the rate of association of hypertension was higher in leuko-araiosis with lacunar infarction than in leuko-araiosis without lacunar infarction.

Acetazolamide↗
PubMed1994

Simultaneous assessment of vasoreactivity using transcranial Doppler ultrasound and cerebral blood flow in healthy subjects.

Blood flow velocities in both middle cerebral arteries and regional cerebral blood flow in their perfusion territories were measured simultaneously in 36 healthy subjects. In 20 subjects, the measurements were first performed under basal conditions and then repeated 15-20 min after an intravenous injection of 1 g of acetazolamide. Reproducibility of simultaneous blood flow and velocity measurements was tested by examining 16 subjects on two occasions under basal conditions with an interval of 20 min. Relatively good reproducibility was found for repeated measurements of velocity and blood flow, being best when side-to-side asymmetry was assessed. The increase in blood flow velocities after acetazolamide was symmetrical (right side, 34.2%; and left side, 35.5%), and the velocity increase was significantly correlated with basal values. The increase in cerebral blood flow was also symmetrical (right side, 29.8%; left side, 30.1%) but not correlated with basal flow values. No significant relationship was found between velocity increase and increase in regional cerebral blood flow. This finding is probably not only due to methodological inaccuracies but may suggest that acetazolamide has an effect on the diameter of the middle cerebral artery or on the magnitude of this artery's perfusion territory. This study supports the use of acetazolamide for assessing cerebral vasoreactivity following the definition of lower limits for velocity and flow increase and for asymmetry of the response.

Acetazolamide↗
PubMed2000

Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro.

Acidification of the extracellular milieu of malignant tumors is reported to increase the invasive behavior of cancer cells. In normal tissues, production of acid is catalyzed by carbonic anhydrases (CAs), some of which are known to be overexpressed in certain cancers. To investigate the functional role of CA activity in such cancer cells, we analyzed the effect of acetazolamide, a potent CA inhibitor, on the invasive capacity of four renal carcinoma cell lines (Caki-1, Caki-2, ACHN, and A-498). We found that 10 microM acetazolamide inhibited the relative invasion rate of these cell lines between 18-74%. The Caki-2 and ACHN cell lines displayed the highest responsiveness, and their responses clearly depended on the acetazolamide concentration in the culture medium. Immunocytochemical and Western blotting results identified the presence of CA isoenzyme II in the cytoplasm of all four cell lines and CA XII on the plasma membrane in three of four cell lines. Because acetazolamide alone reduced invasiveness of these cancer cells in vitro, we conclude that the CAs overexpressed in these renal cancer cells contribute to invasiveness, at least in vitro, and suggest that CA inhibitors may also reduce invasiveness in other tumors that overexpress one or more CAs.

Acetazolamide↗
PubMed2000

Medical treatment in Ménière's disease: avoiding vestibular neurectomy and facilitating postoperative compensation.

The efficacy of medical treatment in preventing the need for vestibular neurectomy (VN) in patients with disabling Ménière's disease, and in facilitating postoperative compensation of equilibrium after VN, was investigated. Ninety-five patients with classic symptoms of unilateral incapacitating Ménière's disease were included. Patients were treated with either 16 mg betahistine three-times daily (n = 49) or 125 mg acetazolamide once-daily (n = 46) for 6 months. The study showed that marked benefit was achieved in 51 of the 95 patients, of whom significantly more were in the betahistine group than in the acetazolamide group [32 (65%) vs 19 (41%); p < 0.05]. Twenty-seven patients in the acetazolamide group and 17 in the betahistine group experienced no benefit from medical treatment and therefore underwent VN. Twelve patients in the betahistine group and 6 in the acetazolamide group eventually experienced a relapse and thus also underwent VN. Therefore 62 patients in total underwent VN. Following surgery, patients were given medical treatment in an attempt to facilitate vestibular compensation; 28 received betahistine (16 mg three-times daily) and 34 received cinnarizine (25 mg three-times daily) for 3 months. The patients treated with betahistine had a shorter period of disability and significantly better results on rotatory testing. In conclusion we recommend the use of betahistine in patients who have undergone VN.

Acetazolamide↗
PubMed1988

Altitude insomnia: studies during an expedition to the Himalayas.

During an expedition to the Himalayas, we studied the sleep and respiration of six climbers. Three ingested acetazolamide (500 mg) daily throughout the climb and the other three ingested placebo. At high altitude (4,150-4,846 m), each subject ingested temazepam (10 mg) for one night and placebo for another. Acetazolamide improved sleep above 2,750 m, but it is uncertain whether this was due to sedation or to improvements in arterial oxygen saturation. Sleep was markedly disturbed in all subjects above 4,000 m. Temazepam improved sleep, and in subjects taking acetazolamide, it reduced sleep-onset latencies and increased sleep efficiency close to that of sea level values. These observations suggest that the prophylactic use of acetazolamide is likely to improve sleep in climbers and that a low dose of a benzodiazepine such as temazepam (10 mg) may be beneficial at high altitude. Studies are now needed to exclude any possibility of respiratory impairment at altitude before a firm recommendation can be made regarding the routine use of this hypnotic.

Acetazolamide↗
PubMed1997

Predictability of extracranial/intracranial bypass function: a retrospective study of patients with occlusive cerebrovascular disease.

OBJECTIVE: When the efficacy of extracranial/intracranial bypass surgery is discussed, can we include the patients with extensive collateral circulation through the bypass and those with poor collateral circulation in the same group? The bypass function should be determined not by the patency of the bypass but by the extent of collateral circulation through the bypass. We retrospectively analyzed our patients to determine whether the extent of bypass flow can be predicted from the results of preoperative studies. METHODS: In 51 hemispheres of 44 consecutive patients who underwent extracranial/intracranial bypass surgery, correlation between the extent of bypass flow and the preoperative results of angiographic and stimulated cerebral blood flow studies were investigated. RESULTS: The bypass function is highly predictable with the aid of preoperative studies. In 11 hemispheres that showed both retrograde spontaneous circulation via leptomeningeal anastomoses and decreased reactivity to acetazolamide of cerebral blood flow in an area distal to the arterial lesion, collateral circulation through the bypass developed well and reactivity to acetazolamide improved. In all of 13 hemispheres that showed normal reactivity to acetazolamide, the bypass was patent but the collateral circulation did not develop well. In only 4 of 24 hemispheres with spontaneous antegrade circulation distal to the lesion was there satisfactory collateral circulation through the bypass. CONCLUSION: Our results indicate that improvement of the hemodynamic status by bypass surgery should be expected only in patients with both spontaneously developed leptomeningeal anastomoses and decreased reactivity to acetazolamide.

Acetazolamide↗
PubMed1997

Visualization of frontal postural hypoperfusion in patients with Takayasu arteritis with upright 99Tcm-HMPAO brain SPET.

Takayasu arteritis is a chronic inflammatory angiopathy involving the cerebral arteries. We performed upright and supine 99Tcm-HMPAO brain single photon emission tomography (SPET) to investigate the cerebral perfusion pattern in eight patients with Takayasu arteritis, and we compared the results with those acquired using 123I-IMP and acetazolamide in six patients. SPET images were evaluated visually and semi-quantitatively. Hypoperfusion was visually detected in all eight patients during the provocative upright test with 99Tcm-HMPAO, and in three of six tested using acetazolamide and 123I-IMP. Semiquantitative analysis revealed that the mean cortical-to-cerebellar ratio in the upright position was significantly changed compared to that in the supine position in the right frontal area (from 0.86 +/- 0.07 to 0.91 +/- 0.09; P < 0.05). Change was also seen in the left frontal area (from 0.85 +/- 0.08 to 0.91 +/- 0.08; P < 0.05). No significant change was seen in other cortical areas with the upright test or in any areas with the acetazolamide test. We postulate that reduced arterial compliance may cause frontal postural hypoperfusion in patients with Takayasu arteritis due to poor functioning of autoregulation and arterial stenosis or occlusion. We conclude that the provocative upright test with 99Tcm-HMPAO brain SPET can detect abnormal patterns of cerebral perfusion in patients with Takayasu arteritis that might be missed by brain SPET using 123I-IMP and acetazolamide.

Acetazolamide↗
PubMed1996

Cerebral blood flow reserve in patients with syndrome X.

BACKGROUND: Patients with syndrome X frequently show disorders of oesophageal motility, bronchial reactivity or impaired vasodilator capacity of peripheral vascular beds. For these reasons, it has been suggested that syndrome X may represent a generalized abnormality of vascular and non-vascular smooth muscle function, rather than an isolated coronary problem. OBJECTIVE: To measure the cerebral blood flow and cerebrovascular vasodilator reserve in syndrome X patients and in controls. METHODS: We measured the cerebral blood flow and cerebrovascular reserve in 16 patients with syndrome X [11 women, aged 59.5 +/- 10.8 years (mean +/- SD)] and in 16 age-matched healthy volunteers. No patients had evidence of stenoses of carotid and vertebral arteries on Doppler sonography. Cerebral blood flow was measured by the 133Xe inhalation method, using the initial slope index as the cerebral blood flow index. After a baseline measurement, a second cerebral blood flow measurement was performed 20 min after administration of 10 mg/kg acetazolamide intravenously. Acetazolamide is known to be a potent cerebral vasodilator. The percentage increase in cerebral blood flow after acetazolamide administration was considered an index of cerebrovascular vasodilator reserve. RESULTS: Under basal conditions, both regional and global cerebral blood flow were nearly identical in the control group and in the patient group (initial slope index 50.2 +/- 3.8 versus 50.3 +/-6.2, NS). After acetazolamide administration, the cerebral blood flow increase was 29.0 +/- 14% in the patient group and 29.5 +/- 11% in the control group (NS). CONCLUSIONS: Our data show that cerebral blood flow and cerebrovascular vasodilator reserve were preserved in a series of patients with syndrome X. These results are not consistent with the hypothesis of a diffuse smooth muscle disorder.

Acetazolamide↗
PubMed2003

Heterogeneity of cerebral blood flow in symptomatic patients undergoing carotid endarterectomy.

There is still controversy concerning which patients with asymptomatic carotid stenosis or symptomatic moderate stenosis are likely to benefit from carotid endarterectomy. The surgical candidates for carotid endarterectomy should have a high risk for stroke, but a low risk for operative complications. Therefore, new effective patient selection strategies, including haemodynamic testing, schemes of risk stratification and pre-operative cardiac testing, are under investigation. To improve haemodynamic assessment of patients with carotid artery stenosis, we evaluated a novel global cerebral blood flow (CBF) heterogeneity index at rest and after acetazolamide injection in patients undergoing carotid endarterectomy. CBF heterogeneity index was measured in 15 patients by using basal and acetazolamide enhanced 99mTc-HMPAO SPET both before and 1 month after surgery. CBF heterogeneity index was calculated as the coefficient of variation of a total of 44 cerebral regions representing mainly both ipsi- and contralateral grey matter. A high linear correlation was observed between CBF heterogeneity index and ipsilateral carotid stenosis degree (r=0.74, P=0.003). Before surgery, CBF heterogeneity index increased significantly after acetazolamide injection when compared to the basal condition (from 7.0+/-1.5 to 8.3+/-1.7%, P=0.008). This response disappeared after carotid endarterectomy. When compared to pure asymmetry of CBF (ipsi/contralateral CBF ratio), the CBF heterogeneity index seemed to reflect, more sensitively, the haemodynamic effects of carotid endarterectomy. The CBF heterogeneity index after acetazolamide injection is a sensitive marker of the haemodynamic consequences of carotid artery stenosis and its operative treatment.

Acetazolamide↗
PubMed1996

Effects of sodium lactate on ventilation and acid-base balance in healthy humans.

Sodium lactate inhibits ventilation when infused in healthy human subjects. This effect has been attributed to lactate-induced metabolic alkalosis. In order to further delineate the mechanisms responsible for this depression of ventilation, healthy humans were infused with sodium lactate with or without acetazolamide. Sodium lactate increased blood pH from 7.37 +/- 0.02 to 7.47 +/- 0.01 and induced a sustained urinary excretion of bicarbonate. PO2 of arterialized blood decreased by 10.3 +/- 2.1 mmHg, indicating an inhibition of ventilation. Acetazolamide decreased lactate-induced alkalinisation of blood (pH after lactate + acetazolamide 7.42 +/- 0.02), but did not prevent the drop in PO2. Acetazolamide alone tended to stimulate ventilation, as indicated by an increase in PO2. These results indicate that sodium lactate inhibits ventilation independently of changes in systemic blood pH. Alkalinization of the cerebrospinal fluid, or other central effects of lactate, is probably responsible for this ventilatory depression.

Acetazolamide↗
PubMed1979

CO2 along the proximal tubules in the rat kidney.

The proximal intratubular pH of the rat kidney was measured in vivo with an antimony electrode system. PCO2 and bicarbonate concentration of the proximal tubular fluid were determined with an ultramicro equilibration system. The tubular fluid to plasma inulin concentration ratio was evaluated by a microscope fluorometric method. The acid-base parameters and the inulin concentrations were determined under control conditions and during acetazolamide treatment. The intratubular PCO2 was higher than the PCO2 of the systemic arterial blood under control conditions and the difference in PCO2 was increased during acetazolamide treatment. In acetazolamide treated rats the rate of fractional bicarbonate reabsorption was decreased in the early part of the proximal tubule, while it was of about the same in the middle and late parts as compared with control rats. The total bicarbonate reabsorption in the proximal tubule was reduced by 50% due to the carbonic anhydrase inhibition. It seems possible that the bicarbonate is still reabsorbed as CO2 after carbonic anhydrase inhibition, as hydrogen ion secretion is not totally stopped by this treatment. The increase in intratubular PCO2 after acetazolamide treatment is assumed to be due to an inhibition of the carbonic anhydrase facilitating effect on outward diffusion of CO2 from the tubular lumen across the cell wall.

Acetazolamide↗
PubMed1984

Evidence for bicarbonate-dependent lithium reabsorption in dog kidneys.

To examine whether lithium is reabsorbed along a transcellular or a paracellular route, experiments were performed in anesthetized volume-expanded dogs under conditions of constant glomerular filtration rate (GFR). Quabain, in doses inhibiting about 80% of Na, K-ATPase, and ethacrynic acid, another inhibitor of transcellular NaCl reabsorption, did not inhibit lithium or bicarbonate reabsorption. Lithium reabsorption increased in proportion to plasma concentration of lithium (PLi) up to 12 mM, suggesting a passive transport of lithium. During ouabain administration acetazolamide halved bicarbonate reabsorption, the main driving force for paracellular reabsorption, and halved the reabsorption of lithium. The reabsorbate concentration of lithium, calculated from data obtained before and after acetazolamide infusion, was almost equal to PLi. Mannitol, which reduces paracellular osmotic transport without affecting bicarbonate reabsorption, reduced lithium and chloride reabsorption in the same proportion as acetazolamide (r = 0.87). Combined acetazolamide and mannitol administration reduced fractional lithium reabsorption to 0.09 +/- 0.02. These data indicate that lithium is not actively transported but reabsorbed passively along a paracellular route by osmotic forces provided by transcellular NaHCO3 reabsorption.

Acetazolamide↗
PubMed1976

The effect of acetzolamide on Ion transport across isolated sheep rumen epithelium.

1. The net fluxes of sodium and chloride from the lumen to the blood side of isolated sheep rumen epithelium were reduced by treatment of both sides of the epithelium with acetazolamide. 2. The changes in the net fluxes of sodium and chloride were significantly correlated and showed recovery after removal of acetazolamide. 3. The net flux of potassium from blood to lumen side of the epithelim was not affected by treatment with acetazolamide. 4. It is suggested that acetazolamide blocks coupled sodium and chloride transport which may be mediated through 'low-activity' carbonic anhydrase enzymes.

Acetazolamide↗
PubMed2000

Efficacy and harm of pharmacological prevention of acute mountain sickness: quantitative systematic review.

OBJECTIVE: To quantify efficacy and harm of pharmacological prevention of acute mountain sickness. DATA SOURCES: Systematic search (Medline, Embase, Cochrane Library, internet, bibliographies, authors) in any language, up to October 1999. STUDY SELECTION: Randomised placebo controlled trials. DATA EXTRACTION: Dichotomous data on efficacy and harm from 33 trials (523 subjects received 13 different interventions, 519 a placebo). DATA SYNTHESIS: At above 4000 m the mean incidence of acute mountain sickness with placebo was 67% (range 25% to 100%); incidence depended on the rate of ascent, but not on the altitude or the mode of ascent. Across all ascent rates, dexamethasone 8-16 mg prevented acute mountain sickness (relative risk 2.50 (95% confidence interval 1.71 to 3.66); number needed to treat (NNT) 2.8 (2.0 to 4.6)), without evidence of dose responsiveness. Acetazolamide 750 mg was also efficacious (2.18 (1.52 to 3.15); NNT 2.9 (2.0 to 5.2)), but 500 mg was not. In two trials, adverse reaction (including depression) occurred after dexamethasone was stopped abruptly (4.45 (1.08 to 18); NNT 3.7 (2.5 to 6.9)). With acetazolamide, paraesthesia (4.02 (1.71 to 9.43); NNT 3.0 (2.0 to 6.0)) and polyuria (4.24 (1.92 to 9.37); NNT 3.6 (2.5 to 6.2)) were reported. Data were sparse on nifedipine, frusemide (furosemide), dihydroxyaluminium-sodium, spironolactone, phenytoin, codeine, phenformin, antidiuretic hormone, and ginkgo biloba. CONCLUSIONS: At above 4000 m, with a high ascent rate, fewer than three subjects need to be treated with prophylactic dexamethasone 8-16 mg or acetazolamide 750 mg for one subject not to experience acute mountain sickness who would have done so had they all received a placebo. Acetazolamide 500 mg does not work.

Acetazolamide↗
PubMed1977

Phosphaturic effect of furosemide: role of PTH and carbonic anhydrase.

The first objective of this study was to examine the effects of furosemide on renal phosphate excretion in the presence and absence of a constant level of parathyroid hormone (PTH) while extracellular fluid volume was held constant. In the absence of PTH, furosemide did not significantly increase fractional phosphate excretion (FEP%, 4.2 +/- 2.7 to 6.2 +/- 1.9%; five dogs). In the presence of PTH, furosemide increased FEP% from 23.4 +/- 3.7 to 33.8 +/- 6.0% (P less .025; five dogs). Thus, the phosphaturia induced by furosemide was dependent on the presence of PTH. The second objective was to evaluate the hypothesis that furosemide exerts its phosphaturic effect through carbonic anhydrase inhibition, and therefore we tested for additivity of the phosphaturic effect of furosemide, and acetazolamide. In the presence of a constant level of PTH, acetazolamide increased FEP % from 24.5 +/- 1.8% to 40.7 +/- 5.1% P less than .025, five dogs. The subsequent administration of furosemide did not further increase FEP%, delta 3.3 +/- 8.9%; NS. Thus, the phosphaturic effect of furosemide was not additive to that of acetazolamide, indicating that acetazolamide and furosemide may share similar mechanisms for inhibiting phosphate reabsorption.

Acetazolamide↗
PubMed1982

Specialized function of carbonic anhydrase-rich and granular cells of turtle bladder.

The mucosal surface of the turtle bladder consists of two major cell types, carbonic anhydrase-rich (CA) and granular (G) cells. These cells types may have specific transport functions. To separate and study these cells, they were removed from the bladder by collagenase digestion and then separated into two distant subpopulations by Ficoll discontinuous density-gradient centrifugation. By morphological criteria the lighter subpopulation (band II) consists primarily of CA cells and the denser population (band III) G cells. The distribution of two enzymes important for H+ transport, CA and glucose-6-phosphate dehydrogenase (G-6-PD), and the effect of specific transport inhibitors, acetazolamide and ouabain, on O2 consumption of these cells was examined. The CA activity of band II cells was 4.5 times greater than that of band III cells. The G-6-PD activity of band II cells was 2.2 times greater than that of band III cells. The rate of O2 consumption of band II cells, 4.73 microliters.mg protein-1.h-1, was reduced 40% by 5 X 10(-5) M acetazolamide but not by ouabain. Band III O2 consumption, 3.43 microliters.mg protein-1.h-1, was reduced 30% by 10(-4) M ouabain but not by acetazolamide. On the basis of the distribution of CA and G-6-PD and the effect of acetazolamide and ouabain on O2 consumption, we propose that CA cells are primarily responsible for H+ transport and G cells for Na+ transport.

Acetazolamide↗
PubMed1989

Electrophysiology of collecting duct H+ secretion: effect of inhibitors.

Segments of the outer medullary collecting duct were isolated from the inner stripe of the rabbit kidney (OMCDi), perfused in vitro, and impaled across their basolateral membranes with voltage-recording microelectrodes. The disulfonic stilbene 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS) (10(-4) M) and the carbonic anhydrase inhibitor acetazolamide (10(-4) M) depolarized the lumen-positive transepithelial voltage (VT) toward 0 mV when added to the bath solution. Concurrently, the basolateral membrane voltage (Vbl) hyperpolarized. The hyperpolarization of Vbl, which averaged 19.3 +/- 2.9 mV (n = 11) for SITS and 22.7 +/- 3.5 mV (n = 11) for acetazolamide, was not due to an alteration in the ionic selectivity of the basolateral membrane, which was highly Cl- selective. The hyperpolarization of Vbl could best be explained by a decrease in the intracellular [Cl-], and the associated shift in the emf for Cl- (ECl) across the basolateral membrane. The decrease in intracellular [Cl-] could be attributed to inhibition of a Cl-HCO3 antiporter in the basolateral membrane. SITS appeared to inhibit this antiporter directly, whereas the effect of acetazolamide was indirect, probably secondary to a decrease in the intracellular [HCO3-]. Finally, both SITS and acetazolamide induced or unmasked an electroneutral K+-coupled transport system in the basolateral membrane.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗