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PubMed1979

The early limb deformity caused by acetazolamide.

Histologic sections were made of the forelimbs of day 10 to 12.5 embryos removed 3, 16, 30, 36, 42, 45, 63 and 75 hours after the intraperitoneal injection of acetazolamide into C57Bl/6J pregnant females. A postaxial deformity was first visible in the right forelimb of day 10.9 embryos 36 hours after the second dose of acetazolamide 1,000 mg/kg on day 9 of gestation. The deformity was a postaxial deficiency of mesenchyme tissue without any evidence of cell necrosis. The deformity was present before aggregation of mesenchyme cells occurs as the first step in chrondrogenesis. The pattern of cell orientation in the adjacent mesenchyme aggregate of a deformed day 12.5 forelimb was normal. This means that the primary effect of acetazolamide is not on the formation of precartilage aggregates in the postaxial region, but involves other aspects of early limb development.

Acetazolamide↗
PubMed1983

Assessment of adult skeletons to detect prenatal exposure to acetazolamide in mice.

A skeletal variant assay system (SVAS) consisting of a group of 88 spontaneously occurring qualitative variations of the adult mouse skeleton was applied to CD-1 animals that had been exposed in utero to 0, 200, or 1,000 mg/kg/day of the sodium salt of acetazolamide dissolved in distilled water, presented by SC injection of the dam during day 8 or days 9-11 of gestation. Two separate series of experiments were performed, and skeletons were examined at postnatal 62 +/- 2 days. Variation occurred in 62 and 67 characters in the two series. Frequencies of occurrence differed from untreated (UNTD) and vehicle-treated (VEH) values of substantial numbers of variants in a dose related manner for both series in both treatment regimes as did the number of variants which showed significantly different frequencies (P less than .01) in comparisons of experimental with either UNTD or VEH. At the high doses 12 and 16 variants occurred with significantly different frequencies from UNTD in day 8 treatments in the two series, and 15 and 19 variants differed in the days 9-11 treated group. Contrasting high-dose animals with appropriate vehicle controls revealed differences in 13 and 12 variants in day 8 treatment groups and in 18 and 15 variants in days 9-11 groups. Agreement between the two series was good, especially in the D9-11 treatments. Several variants differed significantly from both UNTD and VEH in both series of experiments. Among these were a number which appeared more or less specific to acetazolamide exposure. They include: day 8 treatments--accessory parietal, frontal extension, and 27 presacral vertebrae; day 9-11 treatments--sacral fusions in dorsal processes and vertebral bodies, and caudal fusions and malformations; both sets of treatments--lumbar fusions, and fusions of the transverse processes of the sacral vertebrae. Other importantly affected variants, also seen in exposure to other compounds include: day 8 treatments--abnormal metoptic roots; day 9-11 treatments--accessory mental foramen, foramina transversaria imperfecta of the atlas, arch foramen of the fifth cervical (C) vertebra, malformed sternebrae, fossa olecrani perforata, and fewer than 30 caudal vertebrae; both treatment regimes--parted frontals, accessory transverse foramina in C3-C6, reduced articular processes on the thoracic vertebrae, and 14 ribs. By all criteria applied, the SVAS is able to detect prenatal exposure to acetazolamide in adult skeletons even in the absence of any gross morphological abnormalities.

Acetazolamide↗
PubMed1985

Potentiation of acetazolamide induced ectrodactyly in Wistar rats by vasoactive agents and physical clamping of the uterus.

The vasoactive agents serotonin, ergotamine, and nicotine potentiate acetazolamide induced forelimb ectrodactyly (missing digits) in Wistar rats. These vasoactive agents administered alone do not produce forelimb ectrodactyly and are not known to be inhibitors of carbonic anhydrase. Additionally, physical clamping of the uterine horns in addition to oral acetazolamide administration increases the frequency of forelimb ectrodactyly, suggesting that decreased uterine blood flow can potentiate acetazolamide teratogenesis. Since the vasoactive agents used in this study are reported to possess uterine vasoconstrictive activity, a decrease in uterine blood flow is a plausible mechanism for the potentiative ability of these agents.

Abnormalities, Drug-Induced↗
PubMed1991

Time-response and dose-response to acetazolamide in the WB/ReJ and C57BL/6J mouse strains: genetic interaction in the ectrodactyly response.

The WB/ReJ and C57BL/6J strains were compared in their time and dose responses to acetazolamide administered in a single subcutaneous injection regime. WB/ReJ has a genetically determined, high-frequency, transient fetal edema that has maximum expression on day 14 and is resolved by day 18. Acetazolamide, at 1,000 mg/kg, appears to induce edema in WB/ReJ with a time of response on days 9 and 10, and the induced edema follows the same time course of appearance and disappearance as the spontaneous trait. The dose-response analysis is not interpretable in the WB/ReJ and C57BL/6J strains and their reciprocal F1 fetuses because there was significant response only at the highest dose (2,000 mg/kg) used in this study. The time of ectrodactyly response is maximal on day 9 in both WB/ReJ and C57BL/6J strains. The dose-response analysis demonstrates that, for the usual measure of total fetuses with ectrodactyly (or penetrance), the Wb/ReJ and C57BL/6J strains and the WB/ReJ x C57BL/6J F1 (WB.B6F1) have the same slope of the dose-response curve and the strain difference in response can be interpreted as a difference in dosage tolerance. The tolerance of WB/ReJ is twofold greater than that of C57BL/6J. This overdominance of relative resistance to acetazolamide ectrodactyly supports the general finding of directional dominance of relative resistance among genetically different strain pairs. The median effective dose for penetrance of the ectrodactyly response of the reciprocal B6.WBF1 embryo is similar to the WB.B6F1, but the slope of the dose-response curve is significantly different, and a different teratogenic mechanism of response may be involved. Ectrodactyly was predominantly right sided in all genotypes, and, in bilaterally affected fetuses, the right forelimb was more severely affected. An unexpected difference between WB/ReJ and C57BL/6J was found when the laterality of ectrodactyly was analyzed further. There is a significant increase with dosage in bilaterally affected fetuses (a measure of expressivity) in C57BL/6J but not in WB/ReJ, even though the dose-response of total affected fetuses (penetrance) is similar in both strains. In C57BL/6J, the left and right forelimbs are correlated in their responses with the left, requiring approximately a threefold greater dose. The left and right forelimbs are symmetrical in response, and the difference can be interpreted in terms of a developmental (or teratogenic) gradient. In WB/ReJ, the right forelimb has the same dose response as C57BL/6J and requires a twofold greater dose than the right forelimb of C57BL/6J, but the left forelimb has a very flat slope and is not correlated with the response of the right.(ABSTRACT TRUNCATED AT 400 WORDS)

Abnormalities, Drug-Induced↗
PubMed1991

Potentiating effect of caffeine on the teratogenicity of acetazolamide in C57BL/6J mice.

Pregnant C57BL/6J mice were treated with 0 or 50 mg of caffeine (CAFF) per kg, and 0, 200 mg/kg (L) or 1,000 mg/kg (H) of acetazolamide (ACZM) during day 9 of gestation (9DPC). Individual fetuses were examined for gross morphological abnormalities and skeletal variations. The increase in fetal malformations seen, especially right forelimb electrodactyly, was augmented at both dose levels of acetazolamide by concomitant exposure to caffeine. Both frequency and severity of ectrodactyly were potentiated by caffeine. Skeletal examination revealed a reduction of the number of ossified cervical and caudal vertebral centra among litters exposed to ACZM at either dose. In either case (ACZM-H, ACZM-L) that effect was augmented by co-administration of CAFF. The first cervical vertebra (C1) appeared to provide the most sensitive index of teratogenic exposure. This study provides evidence that a subteratogenic dose of caffeine can potentiate the teratogenic effect of acetazolamide in C57BL/6J mice when dams are treated on day 9 of gestation. In addition, skeletal examination provided evidence that simultaneous treatment with both agents delayed fetal development. Many litters exposed to ACZM or both agents displayed a reduction in skeletal ossification even in the absence of gross morphological abnormalities, suggesting that ossification can be used as an indicator of prenatal exposure to potentially harmful substances in the C57BL/6 mouse strain.

Abnormalities, Drug-Induced↗
PubMed1993

Penetrance and expressivity of acetazolamide-ectrodactyly provide a method to define a right-left teratogenic gradient that differs between the C57BL/6J and WB/ReJ mouse strains.

Penetrance or the frequency of embryos with any degree of forelimb ectrodactyly is the usual method to describe the forelimb ectrodactyly response of mouse embryos to acetazolamide. A digit score for number of small or absent digits for the separate right and left forelimb response to acetazolamide provides a measure of expressivity or the severity of response. We examine the relationship between expressivity and penetrance using right and left forelimb data from a previously reported dose-response analysis of the C57BL/6J and WB/ReJ strains to acetazolamide. The data show that expressivity and penetrance are highly correlated for the separate right and left forelimbs for both strains. In C57BL/6J, the dose-response analyses of both expressivity and penetrance of the separate right and left forelimbs demonstrate a teratogenic gradient, decreasing from right to left, that depends on the symmetrical ectrodactyly response of the right and left forelimbs. In WB/ReJ, the right forelimb is also more sensitive than the left, but the dose-response analyses of both penetrance and expressivity show the two forelimbs are asymmetrical in their ectrodactyly response and that there is not a simple teratogenic gradient in this strain. In WB/ReJ, the left forelimb is resistant at even the highest non-lethal doses. The high correlation between expressivity and penetrance for the separate forelimbs of both C57BL/6J and WB/ReJ suggests that this right-left difference between the two strains may not be a property of the limbs themselves but may be an intrinsic genetic difference between the two types of embryos perhaps in the amount of teratogen to which the embryos are exposed.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed2005

Differentiating hemodynamic compromise by the OEF response to acetazolamide in occlusive vascular disease.

Identification of increased stroke risk in a population of symptomatic patients with occlusive vascular disease (OVD) is presently accomplished by measurement of oxygen extraction fraction (OEF) or cerebrovascular reserve (CVR). However, many regions identified by compromised CVR are not identified by OEF. Our aim was to determine whether the response of OEF to acetazolamide, namely, oxygen extraction fraction response (OEFR) would identify those hemispheres in hemodynamic compromise with normal OEF. Nine patients symptomatic with transient ischemic attacks and strokes, and with occlusive vascular disease were studied. Anatomical MRI scans and T2-weighted images were used to identify and grade subcortical white matter infarcts. PET cerebral blood flow (CBF) and OEF were measured after acetazolamide. The relationship between CVR and oxygen extraction fraction response (OEFR) showed that positive OEFR occurred after acetazolamide despite normal baseline OEF values. The two hemispheres with positive OEFR were also associated with severe (> 3 cm) subcortical white matter infarcts. We found that the OEFR was highly correlated with CVR and identified hemispheres that were hemodynamically compromised despite normal baseline OEF.

Acetazolamide↗
PubMed1994

Effect of acetazolamide on early ischemic cerebral edema in gerbils.

Acetazolamide was given in the early stage of ischemic cerebral edema produced by unilateral permanent carotid occlusion in gerbils. The animals were studied 1, 4, and 6 hours after ischemia. The tissues were examined for water and electrolyte concentrations and ischemic areas were visualized by 2,3,5-triphenyltetrazolium chloride (TTC) and H-E staining. Acetazolamide injected just after occlusion showed a positive effect in reducing edematous changes. Later administration of the drug had neither positive nor harmful effect on the ischemic brains. Thus, acetazolamide seems to be useful for cerebrovascular response studies in the early stage of a brain lesion.

Acetazolamide↗
PubMed1995

A protein is involved in accessibility of the inhibitor acetazolamide to the carbonic anhydrase(s) in the cyanobacterium Synechocystis PCC 6803.

A gene, zam (for resistance to acetazolamide), controlling resistance to the carbonic anhydrase inhibitor acetazolamide, is described. It has been cloned from a spontaneous mutant, AZAr-5b, isolated from the cyanobacterium Synechocystis PCC 6803, for its resistance to this drug (Bédu et al., Plant Physiol 93: 1312-1315, 1990). This mutant, besides its resistance to acetazolamide, displayed an absence of catalysed oxygen exchange activity on whole cells, suggestive of a deficiency in carbonic anhydrase activity. The gene was isolated by screening a genomic library of AZAr-5b, and selecting for the capacity to transfer the AZAr phenotype to wild-type cells. A system leading to forced homologous recombination in the host chromosome, using a platform vector, was devised in order to bypass direct selection difficulties. The putative encoded protein, 782 amino acids long, showed some homology with four eukaryotic and prokaryotic proteins involved in different cellular processes, one of them suppressing a phosphatase deficiency. The mutated allele of AZAr-5b showed an in-frame 12 nucleotide duplication, which should not interfere with translation, and might result from transposition of a mobile element. Integration into a wild-type genome of either the spontaneous mutated allele or one inactivated by insertional mutagenesis conferred the character of resistance, but not the deficiency in oxygen exchange, indicating that the two phenotypic aspects of AZAr-5b corresponded to two independent mutations. A working hypothesis explaining the phenotypes of the mutants is that the presence of the Zam protein would be necessary for the inhibitor to reach (one of) the two carbonic anhydrases present in this strain. This, however, would be a secondary action, the physiological role of the protein still being cryptic.

Acetazolamide↗
PubMed1985

Oxygen uptake and carbon dioxide elimination after acetazolamide in the critically ill.

Acetazolamide, which reversibly inhibits carbonic anhydrase, is a useful diuretic in alkalotic and over-hydrated patients. In two earlier investigations we have consistently found increases in the arterial and venous oxygen saturation and tension when patients were treated with acetazolamide 15 mg . kg-1. A plausible explanation of this phenomenon is that acetazolamide diminishes oxygen consumption. In the present study we measured oxygen uptake in 10 critically ill patients. We found a minor and statistically insignificant decrease in oxygen consumption. Nevertheless SVO2 increased from 0.77 to 0.83 and PVO2 from 5.9 kPa to 6.8 kPa. It is still not possible from this investigation to determine the origin of the improvement in blood oxygenation. The inhibition of carbonic anhydrase caused a CO2 retention of 5.8% of the total CO2 production. An increase in body stores of CO2 of this magnitude is without clinical significance.

Acetazolamide↗
PubMed1985

Attenuation of cisplatinum-induced nephrotoxicity in the rat by high salt diet, furosemide and acetazolamide.

The influence of variations in sodium chloride diet, furosemide and acetazolamide on nephrotoxicity induced by cisplatinum have been investigated in the rat by measuring serum creatinine concentrations 5 days after cisplatinum (5 mg/kg, ip) administration. Sodium chloride depletion enhanced, while sodium chloride loading minimized changes in renal function. Increases in urine flow rate following a dextrose water load failed to alter the nephrotoxic response. Both furosemide and acetazolamide, given 30 min before cisplatinum, attenuated the nephrotoxic response. In contrast, neither sodium chloride loading, furosemide, nor acetazolamide influenced the change in renal function when given 30 min after cisplatinum. These observations indicate that renal damage due to cisplatinum can be modified by alterations in dietary salt and by diuretics and that the extent of ultimate renal damage is dependent on factors occurring immediately after cisplatinum administration.

Acetazolamide↗
PubMed1983

Correction of CSF HCO-3 after its experimental increase in normocapnia: inhibition by acetazolamide.

In anaesthetized normocapnic dogs CSF [HCO-3] was increased to ca 33 mmol/l by perfusing the brain ventricles for 45 min with a mock CSF containing a high [HCO-3] which in addition contained 2.5 mg/ml acetazolamide to inhibit central carbonic anhydrase. In dogs with normal plasma [HCO-3], CSF [HCO-3] fell by 5.4 mmol/l in 2 h following the end of the perfusion. Lowering plasma [HCO-3] to 11 mmol/l by infusing HCl intravenously increased the CSF [HCO-3] fall to 7.5 mmol/l. Increasing plasma [HCO-3] to 36 mmol/l completely impeded the fall in CSF [HCO-3]. It is concluded that in these experiments clearing of HCO-3 from the CSF is critically dependent on plasma [HCO-3]. When the data are compared to those of comparable experiments without intraventricular administration of acetazolamide (Weyne et al. 1982), they indicate that acetazolamide impedes clearing of HCO-3 from CSF at high and at normal plasma [HCO-3] but not at low plasma [HCO-3]. The experiments therefore suggest a dual contribution for the clearing of HCO-3 from the CSF after its experimental increase: diffusion along the CSF-plasma gradient for HCO-3 and a carbonic anhydrase dependent clearing of HCO-3.

Acetazolamide↗
PubMed1979

[Timolol and acetazolamide in the treatment of increased intraocular pressure (author's transl)].

Twenty-four patients with open-angle glaucoma were tested to see if, and to what extent, timolol and acetazolamide produced a supplementary reduction of intraocular pressure. Twelve patients were treated with timolol eye drops, 0.5% b.d over a period of one week and then received one dose i.v. acetazolamide 250 mg which produced a statistically significant drop in intraocular pressure. Twelve patients with open-angle glaucoma who had been treated with acetazolamide 500 mg t.d.s. orally over a period of one week, received one drop of timolol 0.25% which produced a statistically significant additional effect. These results are discussed on the basis of the mode of action of the applied medications.

Acetazolamide↗
PubMed1991

Acetazolamide reactivity on cerebral blood flow in patients with subarachnoid haemorrhage.

Cerebral vasodilatory capacity was evaluated by acetazolamide-activated N-isopropyl-p-[123I]iodoamphetamine (123I-IMP) single photon emission computed tomography (SPECT) in 42 patients with subarachnoid haemorrhage (SAH). A low perfusion area was present in the corresponding region of haematoma seen on the CT and continued to be noted throughout the time courses. Deteriorated acetazolamide reactivity affected by surgical intervention was seen in 100% of the patients who underwent aneurysm repair in the 1st postoperative week, 92% in the second week, 73% in the third week, and 47% in the fourth week. Three patients with acute diffuse brain swelling seen on CT showed intracranial non-filling of 123I-IMP on SPECTs performed on Day 6, and all three died by Day 10. Some low perfusion areas, due to probable vasospasm, were present in 77% of Hunt and Hess grades I and II patients and in 100% of grades III, IV, and V patients throughout their time courses. Overall, low perfusion areas, due to probable vasospasm, were seen in 10 patients (31%) of 32 who underwent SPECT between Day 4 and 8,23 (77%) of 30 between Day 9 and 14, 21 (72%) of 29 between Day 15 and 21, and 11 (48%) of 23 between Day 22 and 28. The results suggest acetazolamide-activated 123I-IMP study is of value in evaluating changes in vasodilatory capacity in SAH patients in the acute and subacute stages.

Acetazolamide↗
PubMed2000

A comparative study of simple methods to quantify cerebral blood flow with acetazolamide challenge by using iodine-123-IMP SPECT with one-point arterial sampling.

The aim of this study was to compare the accuracy of simplified methods for quantifying rCBF with acetazolamide challenge by using 123I-N-isopropyl-p-iodoamphetamine (IMP) and SPECT with one-point arterial sampling. After acetazolamide administration we quantified rCBF in 12 subjects by the following three methods: (a) the modified microsphere method, (b) the IMP-autoradiographic (ARG) method based on a two-compartment one-parameter model, and (c) the simplified method based on a two-compartment two-parameter model (functional IMP method). The accuracy of these methods was validated by comparing rCBF values with those obtained by the standard method: the super-early microsphere method with continuous withdrawal of arterial blood. On analyzing rCBF in each flow range (0-0.25, 0.25-0.5, 0.5-0.75 and more than 0.75 ml/g/min), rCBF values obtained by both methods (a) and (c) showed significant correlations (p < 0.01) with those obtained by the standard method in every range, but rCBF values obtained by method (b) did not significantly correlated in the high flow range (0.5-0.75 and more than 0.75 ml/g/min). Method (c) was found to be the most accurate, even though it needs two serial SPECT scans. When requiring one SPECT scan, method (a) was considered to be superior to method (b) because of its accuracy, especially in high flow regions loaded with acetazolamide.

Acetazolamide↗
PubMed1997

Effect of acetazolamide on cerebral blood flow and tympanic temperature in healthy subjects and patients with subacute subarachnoid haemorrhage.

The influence of the increased cerebral blood flow (CBF) induced by acetazolamide on tympanic temperature (Tty) was examined in three healthy male volunteers and in five patients with subacute subarachnoid haemorrhage (SAH). The CBF was estimated by means of stable xenon-enhanced computed tomography before and after the administration of acetazolamide. The Tty was recorded continuously in both ears using thermistor thermometers. In all subjects, CBF increased ranging from 11% to 108% after acetazolamide administration. In all the healthy subjects and in two patients with mild SAH, Tty was higher than the oesophageal temperature (Toes) and Tty decreased bilaterally, ranging from 0.07 to 0.35 degree C as CBF increased. Three patients with severe SAH were febrile, their Toes exceeding Tty and their Tty rose by 0.30 to 0.53 degree C with increased CBF. These observations suggest that Tty follows brain temperature which changes with an increase in CBF in euthermic subjects as well as in febrile subjects.

Acetazolamide↗
PubMed1998

Effects of the carbonic anhydrase inhibitor acetazolamide on splanchnic blood flow in anaesthetized rats.

The aim of the present study was to evaluate whether inhibition of the enzyme carbonic anhydrase with acetazolamide interfered with pancreatic islet and whole splanchnic blood perfusion in rats. Carbonic anhydrase is present both in the endocrine cells and, in particular, the endothelium of the pancreatic islet. Thiobutabarbital-anaesthetized, male Sprague-Dawley rats were used in all experiments, and acetazolamide (50 mg/kg body weight) was given to untreated control rats or rats pretreated with glucose, i.e. to normoglycaemic and hyperglycaemic animals. No acetazolamide-induced effects on blood glucose or serum insulin concentrations, mean arterial blood pressure, whole pancreatic or islet blood flow were seen in any of the animals. There were no effects on duodenal or colonic blood flow recorded in the control rats, whereas an increase in duodenal blood flow (P<0.02) was observed in the hyperglycaemic animals. A tendency to an increase was seen in colonic blood flow in hyperglycaemic animals, although this was not statistically significant (P = 0.069). Inhibition of carbonic anhydrase seems to induce only minor effects on pancreatic blood flow, while duodenal blood flow is slightly enhanced in hyperglycaemic animals.

Acetazolamide↗