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The Korean Journal of Internal Medicine Sep 2018Adverse drug reactions can cause considerable discomfort. They can be life-threatening in severe cases, requiring or prolonging hospitalization, impeding proper...
Adverse drug reactions can cause considerable discomfort. They can be life-threatening in severe cases, requiring or prolonging hospitalization, impeding proper treatment, and increasing treatment costs considerably. Although the incidence of severe cutaneous adverse reactions (SCARs) is low, they can be serious, have permanent sequelae, or lead to death. A recent pharmacogenomic study confirmed that genetic factors can predispose an individual to SCARs. Genetic markers enable not only elucidation of the pathogenesis of SCARs, but also screening of susceptible subjects. The human leukocyte antigen (HLA) genotypes associated with SCARs include HLA-B*57:01 for abacavir (Caucasians), HLA-B*58:01 for allopurinol (Asians), HLA-B*15:02 (Han Chinese) and HLA-A*31:01 (Europeans and Koreans) for carbamazepine, HLA-B*59:01 for methazolamide (Koreans and Japanese), and HLA-B*13:01 for dapsone (Asians). Therefore, prescreening genetic testing could prevent severe drug hypersensitivity reactions. Large-scale epidemiologic studies are required to demonstrate the usefulness and cost-effectiveness of screening tests because their efficacy is affected by the genetic differences among ethnicities.
Topics: Drug Eruptions; Genetic Markers; HLA-B Antigens; Humans; Pharmacogenetics
PubMed: 29921043
DOI: 10.3904/kjim.2018.126 -
American Journal of Ophthalmology Case... Mar 2020To report a rare case of intraoperative suprachoroidal hemorrhage during Xen gel stent implantation with accompanying surgical video and subsequent 6-month follow-up.
PURPOSE
To report a rare case of intraoperative suprachoroidal hemorrhage during Xen gel stent implantation with accompanying surgical video and subsequent 6-month follow-up.
OBSERVATIONS
Our patient required incisional glaucoma surgery after inadequate pressure reduction with four classes of topical medication, methazolamide, and selective laser trabeculoplasty. The patient underwent Xen gel stent implantation and developed an intraoperative suprachoroidal hemorrhage, which was managed in the operating room. The patient recovered his baseline visual acuity with a functioning bleb out to 6 months postoperatively.
CONCLUSIONS AND IMPORTANCE
Micro-invasive glaucoma surgeries offer a new repertoire of surgical options, purportedly with safer and less invasive techniques. Xen gel stent implantation may be a promising alternative to traditional trabeculectomies and tube shunt implants, providing similar IOP lowering results with potentially lower risk for complications. However, rare and severe complications such as suprachoroidal hemorrhage may still occur. Recognizing a suprachoroidal bleed, particularly intraoperatively, will still be necessary to help minimize the potential vision threatening sequelae often associated with this severe complication.
PubMed: 32025590
DOI: 10.1016/j.ajoc.2020.100600 -
Journal of Cataract and Refractive... Jul 2023A 62-year-old woman with mild myopia presented to her local optometrist for a routine examination and was found to have intraocular pressure (IOP) of 30 mm Hg in both...
A 62-year-old woman with mild myopia presented to her local optometrist for a routine examination and was found to have intraocular pressure (IOP) of 30 mm Hg in both eyes and cupped nerves. She had a family history of glaucoma in her father. She was started on latanoprost in both eyes and was referred for a glaucoma evaluation. On initial evaluation, her IOP was 25 mm Hg in the right eye and 26 mm Hg in the left eye. Central corneal thickness measured 592 µm in the right eye and 581 µm in the left eye. Her angles were open to gonioscopy without any peripheral anterior synechia. She had 1+ nuclear sclerosis with a corrected distance visual acuity (CDVA) of 20/25 in the right eye and 20/30- in the left eye and uncorrected near visual acuity of J1+ in each eye. Her nerves were 0.85 mm in the right eye and 0.75 mm in the left eye. Optical coherence tomography (OCT) showed retinal nerve fiber layer thinning and a dense superior arcuate scotoma into fixation in her right eye, and superior and inferior arcuate scotomas in her left eye (Figures 1 and 2JOURNAL/jcrs/04.03/02158034-202307000-00019/figure1/v/2023-06-26T195222Z/r/image-tiffJOURNAL/jcrs/04.03/02158034-202307000-00019/figure2/v/2023-06-26T195222Z/r/image-tiff, Supplemental Figures 1 and 2, available at http://links.lww.com/JRS/A882 and http://links.lww.com/JRS/A883). She was successively trialed on fixed combination brimonidine-timolol, dorzolamide, and netarsudil, in addition to her latanoprost, but her IOP remained in the mid- to upper 20s in both eyes. The addition of acetazolamide lowered the pressure to 19 mm Hg in both eyes, but she tolerated it poorly. Methazolamide was also attempted with similar side effects. We elected to perform left eye cataract surgery combined with 360-degree viscocanaloplasty and insertion of a Hydrus microstent (Alcon Laboratories, Inc.). Surgery was uncomplicated with IOP of 16 mm Hg on postoperative day 1 with no glaucoma medications. However, by postoperative week 3, IOP returned to 27 mm Hg, and despite restarting latanoprost-netarsudil and finishing her steroid taper, IOP remained at 27 mm Hg by postoperative week 6. Brimonidine-timolol was added back to her left eye regimen and at postoperative week 8, IOP had elevated to 45 mm Hg. Maximizing her therapy with the addition of topical dorzolamide and oral methazolamide brought her IOP back down to 30 mm Hg. At that point, the decision was made to proceed with trabeculectomy of the left eye. The trabeculectomy was uneventful. However, postoperative attempts to augment filtration were rendered less successful by extremely thick Tenon layer. At her most recent follow-up the pressure in the left eye was mid-teens with brimonidine-timolol and dorzolamide. Her right eye IOP is in the upper 20s on maximum topical therapy. Knowing her postoperative course in the left eye, how would you manage the right eye? In addition to currently available options, would you consider a supraciliary shunt such as the MINIject (iSTAR) if such a device were U.S. Food and Drug Administration (FDA)-approved?
Topics: Humans; United States; Female; Adolescent; Middle Aged; Glaucoma, Open-Angle; Latanoprost; Methazolamide; Timolol; Glaucoma; Treatment Outcome
PubMed: 37390324
DOI: 10.1097/j.jcrs.0000000000001221 -
Scientific Reports Oct 2016Subarachnoid hemorrhage (SAH) results in significant nerve dysfunction, such as hemiplegia, mood disorders, cognitive and memory impairment. Currently, no clear measures...
Subarachnoid hemorrhage (SAH) results in significant nerve dysfunction, such as hemiplegia, mood disorders, cognitive and memory impairment. Currently, no clear measures can reduce brain nerve damage. The study of brain nerve protection after SAH is of great significance. We aim to evaluate the protective effects and the possible mechanism of methazolamide in C57BL/6J SAH animal model in vivo and in blood-induced primary cortical neuron (PCNs) cellular model of SAH in vitro. We demonstrate that methazolamide accelerates the recovery of neurological damage, effectively relieves cerebral edema, and improves cognitive function in SAH mice as well as offers neuroprotection in blood- or hemoglobin-treated PCNs and partially restores normal neuronal morphology. In addition, western blot analyses show obviously decreased expression of active caspase-3 in methazolamide-treated SAH mice comparing with vehicle-treated SAH animals. Furthermore, methazolamide effectively inhibits ROS production in PCNs induced by blood exposure or hemoglobin insult. However, methazolamide has no protective effects in morality, fluctuation of cerebral blood flow, SAH grade, and cerebral vasospasm of SAH mice. Given methazolamide, a potent carbonic anhydrase inhibitor, can penetrate the blood-brain barrier and has been used in clinic in the treatment of ocular conditions, it provides potential as a novel therapy for SAH.
Topics: Animals; Apoptosis; Blood-Brain Barrier; Brain Edema; Caspase 3; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Gene Expression Regulation; Male; Methazolamide; Mice; Mice, Inbred C57BL; Neurons; Reactive Oxygen Species; Subarachnoid Hemorrhage; Vasospasm, Intracranial
PubMed: 27731352
DOI: 10.1038/srep35055 -
Cureus Feb 2022Stevens-Johnson syndrome (SJS) is a potentially life-threatening cutaneous disorder that is characterized by skin erosions. It lies on a spectrum of varying severity...
Stevens-Johnson syndrome (SJS) is a potentially life-threatening cutaneous disorder that is characterized by skin erosions. It lies on a spectrum of varying severity with toxic epidermal necrolysis (TEN) being the most severe form. An overlap of the syndromes is known as SJS/TEN. These disorders are most often caused by a drug reaction, with anti-epileptic drugs and sulfonamide drugs as the common offending agents. Rarely, the syndrome can be due to a reaction to carbonic anhydrase inhibitors such as methazolamide. When present in association with methazolamide, the syndrome has only been known to occur in patients of Asian descent with human leukocyte antigen (HLA) mutations. We present a case of methazolamide-associated Stevens-Johnson syndrome in a patient of Caucasian descent.
PubMed: 35155038
DOI: 10.7759/cureus.21864 -
Drug Metabolism Letters 2017Drug therapy is occasionally accompanied by an idiosyncratic severe toxicity, which occurs very rarely, but can lead to patient mortality. Methazolamide, an...
OBJECTIVE
Drug therapy is occasionally accompanied by an idiosyncratic severe toxicity, which occurs very rarely, but can lead to patient mortality. Methazolamide, an anti-glaucomatous agent, could cause severe skin eruptions called Stevens-Johnson syndrome/toxic epidermal necrolyis (SJS/TEN). Its precise etiology is still uncertain. In this study, the metabolism of methazolamide was investigated in immortalized human keratinocytes to reveal the possible mechanism which causes SJS/TEN.
METHODS
The metabolism of methazolamide was studied using immortalized human keratinocytes, HaCaT cells. HPLC was used to isolate a metabolite from the culture medium. Mass spectrometry (LCMS/ MS) was employed for its characterization. Three typical chemical inducers were assessed for the inducibility of cytochrome P450, and methimazole was used as the inhibitor of flavin-containing monooxygenase (FMO).
RESULTS
A sulfonic acid, N-[3-methyl-5-sulfo-1,3,4-thiadiazol-2(3H)-ylidene]acetamide (MSO) was identified as the final metabolite. Dexamethasone and β-naphthoflavone behaved as an inducer of cytochrome P450 in the metabolism, but isoniazid did not. The effect of methimazole was not consistent. We did not detect any glucuronide nor any mercapturic acid (N-acetylcysteine conjugate).
CONCLUSION
N-[3-methyl-5-sulfo-1,3,4-thiadiazol-2(3H)-ylidene]acetamide (MSO) is not considered to be a direct product of an enzymatic reaction, but rather an auto-oxidation product of N-[3-methyl-5- sulfe-1,3,4-thiadiazol-2(3H)-ylidene]acetamide, a chemically unstable sulfenic acid, which is produced by cytochrome P450 from the β-lyase product of cysteine conjugate of methazolamide. MSO is considered to be susceptible to glutathione and to return to glutathione conjugate of methazolamide, forming a futile cycle. A hypothetical scenario is presented as to the onset of the disease.
Topics: Acetylcysteine; Carbonic Anhydrase Inhibitors; Cell Line; Chromatography, High Pressure Liquid; Cysteine; Cytochrome P-450 Enzyme System; Dexamethasone; Glaucoma; Glucuronides; Humans; Isoniazid; Keratinocytes; Lyases; Methazolamide; Methimazole; Oxidation-Reduction; Oxygenases; Stevens-Johnson Syndrome; Sulfenic Acids; Sulfonic Acids; Tandem Mass Spectrometry; beta-Naphthoflavone
PubMed: 28137210
DOI: 10.2174/1872312811666170127160931 -
IUCrJ Sep 2016Carbonic anhydrases (CAs; EC 4.2.1.1) catalyze the interconversion of CO and HCO, and their inhibitors have long been used as diuretics and as a therapeutic treatment...
Carbonic anhydrases (CAs; EC 4.2.1.1) catalyze the interconversion of CO and HCO, and their inhibitors have long been used as diuretics and as a therapeutic treatment for many disorders such as glaucoma and epilepsy. Acetazolamide (AZM) and methazolamide (MZM, a methyl derivative of AZM) are two of the classical CA inhibitory drugs that have been used clinically for decades. The jointly refined X-ray/neutron structure of MZM in complex with human CA isoform II (hCA II) has been determined to a resolution of 2.2 Å with an of ∼16.0%. Presented in this article, along with only the second neutron structure of a clinical drug-bound hCA, is an in-depth structural comparison and analyses of differences in hydrogen-bonding network, water-molecule orientation and solvent displacement that take place upon the binding of AZM and MZM in the active site of hCA II. Even though MZM is slightly more hydrophobic and displaces more waters than AZM, the overall binding affinity () for both of the drugs against hCA II is similar (∼10 n). The plausible reasons behind this finding have also been discussed using molecular dynamics and X-ray crystal structures of hCA II-MZM determined at cryotemperature and room temperature. This study not only allows a direct comparison of the hydrogen bonding, protonation states and solvent orientation/displacement of AZM and MZM, but also shows the significant effect that the methyl derivative has on the solvent organization in the hCA II active site.
PubMed: 28461893
DOI: 10.1107/S2052252516010514 -
Aging Cell Aug 2018Mounting evidence suggests that mitochondrial dysfunction plays a causal role in the etiology and progression of Alzheimer's disease (AD). We recently showed that the...
Mounting evidence suggests that mitochondrial dysfunction plays a causal role in the etiology and progression of Alzheimer's disease (AD). We recently showed that the carbonic anhydrase inhibitor (CAI) methazolamide (MTZ) prevents amyloid β (Aβ)-mediated onset of apoptosis in the mouse brain. In this study, we used MTZ and, for the first time, the analog CAI acetazolamide (ATZ) in neuronal and cerebral vascular cells challenged with Aβ, to clarify their protective effects and mitochondrial molecular mechanism of action. The CAIs selectively inhibited mitochondrial dysfunction pathways induced by Aβ, without affecting metabolic function. ATZ was effective at concentrations 10 times lower than MTZ. Both MTZ and ATZ prevented mitochondrial membrane depolarization and H O generation, with no effects on intracellular pH or ATP production. Importantly, the drugs did not primarily affect calcium homeostasis. This work suggests a new role for carbonic anhydrases (CAs) in the Aβ-induced mitochondrial toxicity associated with AD and cerebral amyloid angiopathy (CAA), and paves the way to AD clinical trials for CAIs, FDA-approved drugs with a well-known profile of brain delivery.
Topics: Acetazolamide; Amyloid beta-Peptides; Carbonic Anhydrase Inhibitors; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Methazolamide; Mitochondria; Tumor Cells, Cultured
PubMed: 29873184
DOI: 10.1111/acel.12787 -
Investigative Ophthalmology & Visual... Apr 2009Bicarbonate transport plays a role in aqueous humor (AH) secretion. The authors examined bicarbonate transport mechanisms and carbonic anhydrase (CA) in porcine...
PURPOSE
Bicarbonate transport plays a role in aqueous humor (AH) secretion. The authors examined bicarbonate transport mechanisms and carbonic anhydrase (CA) in porcine nonpigmented ciliary epithelium (NPE).
METHODS
Cytoplasmic pH (pH(i)) was measured in cultured porcine NPE loaded with BCECF. Anion exchanger (AE), sodium bicarbonate cotransporter (NBC), and CA were examined by RT-PCR and immunolocalization. AH secretion was measured in the intact porcine eye using a fluorescein dilution technique.
RESULTS
Anion exchanger AE2, CAII, and CAIV were abundant in the NPE layer. In cultured NPE superfused with a CO(2)/HCO(3)(-)-free HEPES buffer, exposure to a CO(2)/HCO(3)(-)-containing buffer caused rapid acidification followed by a gradual increase in pH(i). Subsequent removal of CO(2)/HCO(3)(-) with HEPES buffer caused rapid alkalinization followed by a gradual decrease in pH(i). The rate of gradual alkalinization after the addition of HCO(3)(-)/CO(2) was inhibited by sodium-free conditions, DIDS, and the CA inhibitors acetazolamide and methazolamide but not by the Na-H exchange inhibitor dimethylamiloride or low-chloride buffer. The phase of gradual acidification after removal of HCO(3)(-)/CO(2) was inhibited by DIDS, acetazolamide, methazolamide, and low-chloride buffer. DIDS reduced baseline pH(i). In the intact eye, DIDS and acetazolamide reduced AH secretion by 25% and 44%, respectively.
CONCLUSIONS
The results suggest the NPE uses a Na(+)-HCO(3)(-) cotransporter to import bicarbonate and a Cl(-)/HCO(3)(-) exchanger to export bicarbonate. CA influences the rate of bicarbonate transport. AE2, CAII, and CAIV are enriched in the NPE layer of the ciliary body, and their coordinated function may contribute to AH secretion by effecting bicarbonate transport into the eye.
Topics: 4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; Acetazolamide; Animals; Aqueous Humor; Bicarbonates; Biological Transport, Active; Carbonic Anhydrases; Cells, Cultured; Chloride-Bicarbonate Antiporters; Ciliary Body; Epithelial Cells; Fluoresceins; Fluorescent Dyes; Hydrogen-Ion Concentration; Reverse Transcriptase Polymerase Chain Reaction; Sodium-Bicarbonate Symporters; Swine
PubMed: 19011010
DOI: 10.1167/iovs.08-2487 -
Experimental and Therapeutic Medicine Oct 2016The aim of the present study was to observe the clinical efficacy and safety of recombinant tissue plasminogen activator (rt-PA) combined with compound anisodine in...
The aim of the present study was to observe the clinical efficacy and safety of recombinant tissue plasminogen activator (rt-PA) combined with compound anisodine in treating central retinal artery occlusion (CRAO). Forty-eight patients diagnosed with CRAO were randomly divided into a treatment group (24 cases) and a control group (24 cases). For the control group, nitroglycerin, 654-2, methazolamide, puerarin and compound anisodine were used for the treatment, along with oxygen, massage and other conventional treatments. Besides conventional therapy, the treatment group was also given intravenous rt-PA thrombolysis. Visual acuity, fundus oculi, visual field changes were taken as indicators for efficacy evaluation. It was found that the total effective rate of the control group was 70.83%, while that for the treatment group was 91.67%, and the comparative difference between the two groups was of statistical significance (p<0.05). The visual field defect of the control group after treatment was approximately 74.26±12.91%, and the visual field defect of the treatment group after treatment approximately 35.08±16.33%; thus, the comparative difference was statistically significant (p<0.01). The comparative difference of the original contents of fibrous protein in blood in the treatment group before and after treatment was statistically significant (p<0.01). In conclusion, the result show that intravenous thrombolysis with rt-PA combined with compound anisodine is safe and effective in treating CRAO, which can significantly improve the prognosis of patients.
PubMed: 27698763
DOI: 10.3892/etm.2016.3681