The effects of inhibition of carbonic anhydrase with dichlorphenamide on ventilatory control at rest and on exercise in normal subjects.
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Adult↗
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[Modification of ERG produced by dichlorphenamide].
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Animals↗
Distribution of 5,5-dimethyl-2,4-oxazolidinedione (DMO) in intraocular fluids. V. Effect of plasma level, probenecid, and dichlorphenamide on time course.
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Animals↗
The role of the hydrophobicity of the substituted groups of dichlorphenamide in the development of carbonic anhydrase inhibition.
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Carbonic Anhydrase Inhibitors↗
Patient tolerance to carbonic anhydrase inhibitors.
We evaluated carbonic anhydrase inhibitors in a crossover study with a placebo and random allocation of treatment administration. Drugs evaluated included acetazolamide tablets and Sequels, dichlorphenamide, ethoxzolamide, methazolamide, and an ascorbic acid placebo. The best tolerated drug was acetazolamide Sequels. Methazolamide was next. The least tolerated drugs were ethoxzolamide, acetazolamide tablets, and dichlorphenamide.
Acetazolamide↗
Ocular hypotensive effects of carbonic anhydrase inhibitors in normotensive and glaucomatous Beagles.
Four carbonic anhydrase inhibitors (acetazolamide, dichlorphenamide, ethoxzolamide, and methazolamide) cause ocular hypotony in normotensive and glaucomatous Beagles. Four dosages of acetazolamide and methazolamide and three dosages of dichlorphenamide and ethoxzolamide were evaluated. The extent of ocular hypotony after these carbonic anhydrase inhibitors was usually greater in glaucomatous Beagles than it was in normotensive Beagles.
Acetazolamide↗
Teratogenesis of acetazolamide in the CBA/J and SWV strains of mice. I. Teratology.
SWV mice were totally resistant to the teratogenic and embryolethal actions of acetazolamide. The time of maximal sensitivity to acetazolamide-induced ectrodactyly in the CBA/J strain was the middle of day 10; the dose response at this time was studied. Comparison of the responses of the two strains and reciprocal hybrids indicated that sensitivity is a property of the embryo and is not maternally mediated. SWV mice were also resistant to dichlorphenamide which suggests they may be resistant to many or even all teratogenic carbonic anhydrase inhibitors.
Abnormalities, Drug-Induced↗
Role of physiological HCO3-buffer on intracellular pH and histamine release in rat peritoneal mast cells.
The purpose of this study was to examine how intracellular pH (pHi) regulation and histamine release are affected by HCO3- in rat peritoneal mast cells. The pHi was measured using the pH-sensitive dye 2', 7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF). We observed a pHi of 6.88+/-0.012 (n=24) in resting mast cells exposed to a HEPES buffer (pH 7.4), but a sustained drop of 0.21 pH units to 6.67+/-0.015 (n=23) when we exposed the mast cells to a HEPES/HCO3- buffer equilibrated at all time with 5% CO2 (pH 7.4). This fall in pHi is inhibited by the carbonic anhydrase inhibitor dichlorphenamide and is Na+-independent, indicating the involvement of Na+-independent Cl-/HCO3- exchange activity. Furthermore removal of external Cl- in the presence but not in the absence of HCO3- reversed the Cl-/HCO3- exchange and induced an alkaline load. The recovery from this alkaline load was dependent on external Cl- but independent of Na+. Both the alkalinization and the recovery were inhibited by the anion transport inhibitor 4, 4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS). In addition, 36Cl- uptake measurements confirm the presence of a Cl-/HCO3- exchanger. Histamine release stimulated by antigen and compound 48/80 was substantially reduced in the presence of HEPES/ HCO3- buffer (pHo 7.4, pHi 6.66). Histamine release was increased, however, when pHi was clamped to 6.66 in HCO3--free media (pHo 6.9). We conclude that: (1) Na+-independent Cl-/HCO3- exchange determines steady-state pHi in rat peritoneal mast cells; and (2) the reduction in histamine release observed in the presence of HCO3- is not due to its effect on pHi per se, but rather on other changes in ion transport.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Delayed protein digestion in the alligator following carbonic anhydrase inhibition.
Small alligators were injected with a carbonic anhydrase (CA) inhibitor (dichlorphenamide) and a day later they were fed large amounts of lean beef. The rate of protein digestion was determined and compared with that in controls fed the same amount. The controls began digestion at once, while in the CA-inhibited ones, digestion was blocked for over 10 hr. The inhibitor decreased gastric HCl production to one-third that in controls and delayed activation of pancreatic and intestinal proteases. After 15 hr, digestion began in the inhibited group and proceeded to completion. Once digestion began, further injections of the inhibitor could not block it. It seems that CA inhibition blocks digestion (for a time) by reducing HCl synthesis. NaHCO3 to neutralize the acid chyme in the intestine, was derived from that in the plasma.
Acetazolamide↗
Carbonic anhydrase inhibitors are antiarthritic in the rat.
Adjuvant-induced arthritis in rats was attenuated by the therapeutic administration of carbonic anhydrase inhibitors. Female Lewis rats with established disease were treated daily (day 18 through day 50) with various carbonic anhydrase inhibitors; oedema and joint integrity (X-ray) were determined post-treatment. Acetazolamide, ethoxzolamide, methazolamide, and dichlorphenamide reduced paw oedema and attenuated the deterioration of the joints of rats with adjuvant arthritis. However, no carbonic anhydrase inhibitor tested possessed significant, acute, anti-inflammatory activity in the carrageenan-paw oedema test. The activity of carbonic anhydrase inhibitors in the chronic model of inflammation may be due to their reported inhibition of bone resorption.
Acetazolamide↗
[Minimally inflammatory cataract surgery].
BACKGROUND: Cataract surgery leads to a more or less intensive postoperative inflammation due to breakdown of the blood-aqueous barrier. In a prospective, randomized and controlled clinical trial, we examined aqueous flare as well as intraocular pressure and visual acuity after a minimally invasive cataract surgical procedure under different anti-inflammatory treatment. PATIENTS AND METHOD: In 150 patients (39-88 years of age) without glaucoma or pre-existing deficiencies of the blood-aqueous barrier, phacoemulsification through a clear-corneal tunnel incision with implantation of a 5 mm PMMA posterior chamber intraocular lens was performed. Patients were randomly assigned to one of 5 treatment groups, each consisting of 30 patients: 1) preservative-free diclofenac 0.1% eyedrops (DICpf) pre- and postop.; 2) diclofenac 0.1% eyedrops with preservative (DICp) pre- and postop.; 3) DICpf only postop.; 4) DICpf pre- and postop. in combination with dexamethasone-21-dihydrogenphosphate 0.1% eyedrops (DEXA); 5) DEXA postoperatively. For prevention of postoperative intraocular pressure (IOP) elevation, carbachol 0.01% (for intraocular application) was injected into the anterior chamber intraoperatively, and dichlorphenamide (50 mg/d per os) was applied until day 1 postoperatively. - Aqueous flare (laser flare-cell meter FC-1000), IOP (Gold-mann applanation tonometer) and best-corrected visual acuity were determined on the day before surgery as well as 6 hrs (only flare and IOP), 1 day, 3 and 7 days postoperatively. RESULTS: Aqueous flare (photon counts/ms) in treatment group 1 increased from 10.8 +/- 1.7 (means +/- SE) preoperatively to only 14.7 +/- 3.1 in the afternoon of the day of surgery. Already on day 1 postoperatively, the flare decreased to 9.3 +/- 0.9, and remained relatively constant on days 3 and 7 after surgery. The flare in group 3 (DICpf only postop.) was significantly higher (p = 0.03; ANOVA) than in group 1. There were no other significant group differences concerning flare (group 1 vs. 3;1 vs. 4;4 vs. 5). -IOP (mm Hg) dropped from 16.3 +/- 0.2 preoperatively to 15.8 +/- 0.6 already 6 hrs postoperatively (group means). On days 1 and 3, the IOP continued to drop to 13.2 +/- 0.3 and 12.7 +/- 0.3, respectively. Not before day 7, the IOP tended to increase again (14.2 +/- 0.3). The IOP showed no significant group differences. - Visual acuity increased from 0.25 +/- 0.01 preoperatively to 0.73 +/- 0.02 already on day 1 postoperatively (group means). On days 3 and 7, the acuity amounted to 0.83 +/- 0.24 and 0.92 +/- 0.02, respectively. DISCUSSION: Under the conditions of the present study (with specific pharmacological therapy and patient selection), clear-corneal phacoemulsification leads to an extremely low and short-lasting intraocular inflammation, especially under pre- and postoperative treatment with preservative-free diclofenac eyedrops. Thus, the aim of minimally inflammatory cataract surgery (MICS) is realized. As secondary phenomenon, a postoperative IOP increase, often observed in the early postoperative period, is lacking, and the visual acuity rises very fast postoperatively.
Adult↗
Long-term management of a glaucomatous eye in a dog treated with medical therapy alone.
An acute open angle glaucoma of the right eye was diagnosed in an 8-year-old male Yorkshire terrier which was presented with anorexia, depression, and trembling. Abnormal findings of the right eye on admission included elevated intraocular pressure (IOP; 40 mmHg), the presence of fibrin and flare in the anterior chamber, and immature cataract. Morphological abnormalities of the iridocorneal angle were not detected, and an open angle was seen in the eye. Although an elevated IOP was observed at one year after admission, lowering IOP (< or = 24 mmHg) was maintained with medical therapy using dichlorphenamide (DCPA) and timolol maleate, DCPA alone, or no-treatment for 1973 days. This case suggests that lower IOP can be maintained with medical therapy alone for a long period in a patient with open angle glaucoma.
Adrenergic beta-Antagonists↗
[The broncholytic effect of carboanhydrase inhibitors in subjects with healthy lungs (author's transl)].
Carboanhydrase inhibitors are said to have a positive effect on respiratory insufficiency. We examined this, especially regarding the bronchial system. Actions and reactions of the human bronchial system can be followed by measurement of the anatomical dead space breath by breath. We have developed a new method which was tested by classical broncho-effective substances. Our experiments show in case of two men with healthy lungs that the three carboanhydrase inhibitors acetazolamide, methazolamide, and dichlorphenamide have a pronounced broncholytic effect. The effect is greater than that of fenoterol. In addition the bronchial peristalsis and the bronchial compliance are increased. In contrast to fenoterol carboanhydrase inhibitors have no cardiac side effect.
Acetazolamide↗
Gas-phase behaviour of negative ions produced from thiazidic diuretics under electrospray conditions.
A systematic mass spectrometric study of 10 thiazidic diuretics and related compounds was undertaken by mass spectrometry (MS) with electrospray ionization in the negative ion mode. Collisional dissociation 'in-source' (CID-MS) and in a low-pressure collision cell (CID-MS/MS) were compared in both excitation regions. Spectra obtained by CID-MS and by CID-MS/MS were matched. Using the two methods, loss of HCl and consecutive dissociations from 2HCl losses were exhibited from compounds such as methyclothiazide and trichlormethiazide but not from other thiazidic diuretics that contain chlorine substituents in the aromatic moiety. However, deprotonated dichlorphenamide gave rise to loss of HCl by CID-MS and CID-MS/MS. For other diuretics such as hydroflumethiazide and hydrochlorothiazide, the loss of HCN and [HCN + SO(2)] was relevant. Reaction mechanisms were checked by means of deuterium-hydrogen exchange, which showed that deprotonation took place regioselectively on the heterocyclic moiety. The cleavage pathways require molecular isomerization forming ion-dipole complexes prior to decompositions, allowing long-distance proton transfer for neutral elimination. Identifications of the most specific fragmentations presented in this paper were applied to the screening and unambiguous identification of diuretics for horse doping control.
Benzothiadiazines↗
Channelopathies.
In patients with mutations in the genes that encode the chloride, sodium, and calcium channels in skeletal muscle, there is abnormal function of the muscle membrane, which can cause myotonia or attacks of weakness. Mutations in the chloride and sodium channels can lead to myotonia, which typically begins in early childhood. Mexiletine is usually effective in controlling myotonia in these patients. Mexiletine is also effective in preventing attacks of cold-provoked muscle paralysis in patients with paramyotonia congenita, a sodium channel disorder. Certain mutations in the sodium channel cause attacks of hyperkalemic periodic paralysis; these attacks are often controlled with thiazide diuretics. Mutations in the skeletal muscle calcium channel cause periodic attacks of weakness, but hypokalemia (not hyperkalemia) occurs during these episodes. The carbonic anhydrase inhibitors acetazolamide and dichlorphenamide prevent attacks of hypokalemic periodic paralysis, although the mechanism by which they produce this protective effect remains a mystery. Interestingly, the hypokalemic attacks with periodic weakness that occur in some thyrotoxic patients are made worse by acetazolamide. This undesirable response to treatment emphasizes that not all disorders associated with hypokalemic periodic paralysis will benefit from carbonic anhydrase inhibitor therapy. DNA analysis to search for a mutation in the genes that encode for chloride, sodium, or calcium channels in skeletal muscle is helpful to establish the diagnosis. Some patients may eventually require provocative testing, however, to evaluate the attack of weakness and to reach a final diagnosis. Fortunately, there are effective treatments for the channelopathies that affect the skeletal muscle membrane.
Journal Article↗
[3H]acetazolamide binding to carbonic anhydrase in normal and transformed cells.
The binding of [3H]acetazolamide (AZ), a carbonic anhydrase (CA) inhibitor, to soluble and particulate forms of CA was investigated. Sources for the assays were purified CA II, adult rat cortical, oligodendrocyte and neuronal enriched preparations; cultured murine glial cells, rat C-6 glioma, rat hepatoma and human glioblastoma cells. CA enzyme activity in the same preparations was also assayed by following change in pH during incubation. A gel permeation chromatographic method was developed to assess [3H]AZ binding to soluble CA, while glass fiber filter vacuum filtration was used for particulate CA binding. Saturable specific binding of [3H]AZ to rat cortical soluble and particulate CA preparations was demonstrated. Computer-assisted data analysis estimated the binding parameters of [3H]AZ to soluble rat cortical CA to be Bmax = 0.38 +/- 0.13 pmol/mg protein and Kd = 34.7 +/- 17.5 nM. The rat cortical particulate fraction Bmax was 2.05 +/- 0.28 pmol/mg protein with a Kd of 107.1 +/- 24.2 nM. Purified bovine CA-II bound 1.15 +/- 0.19 pmol [3H]AZ/mg protein with a Kd of 54.0 +/- 3.4 nM. The pH optima for [3H]AZ binding to soluble and particulate CA was between 6.5 and 7.5. Binding was linear with respect to protein up to 1.0 mg/mL. The particulate fraction bound 3-4 times more [3H]ligand per unit protein than the soluble fraction. Interestingly, no detectable CA enzyme activity or [3H]AZ binding was observed in the soluble or particulate fractions of human glioblastoma, rat C-6 glioma or rat hepatoma cells. Binding of [3H]AZ to other soluble enzymes or proteins was negligible. In competition binding experiments, a rank order of inhibition of [3H]AZ binding to rat cortical CA by established CA inhibitors was: dichlorphenamide greater than acetazolamide greater than or equal to benzolamide greater than methazolamide greater than hydrochlorothiazide greater than or equal to sulfanilamide. [3H]AZ binding was not affected by other classes of pharmacologic characterizing agents. The binding of [3H]AZ to the CA enzyme molecule is highly specific and sensitive and may prove useful in vitro or in situ as a probe for this enzyme.
Acetazolamide↗
Diuretic screening in human urine by gas chromatography-mass spectrometry: use of a macroreticular acrylic copolymer for the efficient removal of the coextracted phase-transfer reagent after derivatization by direct extractive alkylation.
A simple and efficient procedure has been developed for the derivatization of diuretic agents in human urine by direct extractive alkylation and their detection by gas chromatography-mass spectrometry. The procedure is an improvement over previous extractive alkylation methods because of the development of a simple clean-up step using a macroreticular acrylic copolymer (SM-7 resin) to remove the coextracted phase-transfer reagent from the organic phase after derivatization. With 1 ml of sample the method gives detection limits in the range 10-50 ng/ml for acetazolamide, probenecid, dichlorphenamide, hydroflumethiazide, furosemide, chlorthalidone, bumetanide, hydrochlorothiazide, quinethazone, bendroflumethiazide, metolazone and cyclopenthiazide.
Acrylic Resins↗
Carbonic anhydrase inhibitors ameliorate the symptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels.
Carbonic-anhydrase inhibitors are effective in channelopathies possibly by opening the Ca2+-activated-K+ channels. However, the in vivo effects of these drugs in K+-deficient rats, the animal model of familial hypokalaemic periodic paralysis(hypokalaemic-PP), are currently unknown. Measures of insulin-responses, serum electrolytes levels and patch-clamp experiments were therefore performed in K+ -deficient rats treated in vivo with dichlorphenamide (DCP), ethoxzolamide (ETX), hydrochlorthiazide (HCT), methazolamide (MTZ), bendroflumethiazide (BFT) and acetazolamide (ACTZ). Ten days treatments of K+-deficient rats with DCP, BFT, ETX and ACTZ (5.6 mg/kg per day) restored the serum [K+] to control values and prevented the insulin-induced paralysis. In ex vivo experiments, the carbonic-anhydrase inhibitors enhanced the activity of Ca2+-activated-K+ channels with the order of efficacy: ACTZ>BFT>ETX>DCP. In contrast, HCT and MTZ failed to stimulate the Ca2+-activated-K+ channels and to prevent the hypokalaemia and paralysis. At the concentration of 1mg/kg per day, all these drugs failed to ameliorate the hypokalaemic-PP symptoms. The activation of Ca2+-activated-K+ channel in addition to the mild diuretic effect explained the efficacy of ACTZ and DCP in K+ -deficient rats and in familial hypokalaemic-PP.
Adenosine Triphosphate↗