Genetic markers of severe cutaneous adverse reactions

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.

Angle Closure and the Acute Rise of Intraocular Pressure after Administration of Methazolamide

PURPOSE: To report a case involving an unexpected increase in intraocular pressure (IOP) and acute angle closure after oral administration of methazolamide. CASE SUMMARY: A 38-year-old male visited the emergency department complaining of decreased visual acuity (VA) and ocular pain. These symptoms developed after he took two tablets of 50 mg methazolamide because his IOP was above normal after a short course of systemic steroid treatment. His uncorrected VA dropped to 0.04 and the refractive error was −6.5 diopters in both eyes. The anterior chamber was very shallow, and the IOPs were 46 mmHg in the right eye and 42 mmHg in the left eye. Macular retinal folds were observed in both eyes in infrared fundus images. The patient was instructed not to take methazolamide, which was suspected as the cause of this idiosyncratic drug reaction. He was prescribed topical anti-glaucoma medications and cycloplegics to relieve the acute angle closure, and all symptoms disappeared after these treatments. CONCLUSIONS: Methazolamide is a sulfa derivative like topiramate, which can cause acute angle closure involving edema of the ciliary body and anterior displacement of the lens-iris diaphragm. Clinicians should consider this possible IOP increase before prescribing methazolamide.

Experience of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in a Regional Hospital: 70 Cases in 7 Years / 대한내과학회지

BACKGROUND/AIMS: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe cutaneous adverse reactions that frequently result in fatal outcomes. We investigated cases of SJS and TEN in a regional hospital. METHODS: From 2008 to 2014, SJS and TEN cases were enrolled retrospectively by allergy and dermatology specialists, and their clinical features and severity-of-illness score for TEN (SCORTEN) were assessed. RESULTS: During the 7-year study period, 56 SJS and 14 TEN cases were recruited. The majority (71%) were 40-70 years of age (mean age of male and female patients, 55 and 54 years, respectively). Regarding drugs, anticonvulsants (42.8%) were the most frequently causative, followed by carbonic anhydrase inhibitors (20.0%), antimicrobials (15.7%), allopurinol (7.1%), and non-steroidal anti-inflammatory drugs (7.1%). No fatal case of SJS was seen. However, 7 of the 14 patients with TEN died (50%; mean age, 67 years; 1 of 5 [20%] males and 6 of 9 females [66.7%]). The mortality rate was reflected in the SCORTEN values. Vancomycin, allopurinol, methazolamide (two cases each) and megestrol (one case) were the causative drugs in the seven fatal TEN cases. Treatment modality did not affect the likelihood of death due to TEN. CONCLUSIONS: The causative drugs of, and frequency of mortality due to, SJS and TEN should be recognized by physicians. Elderly females with TEN are at high risk of mortality. SCORTEN values reflect the mortality rate of TEN patients. Early recognition and proper management of SJS and TEN may reduce the mortality rate.

Methazolamide-induced toxic epidermal necrolysis confirmed by lymphocyte activation test

Among various dermatological entities, toxic epidermal necrolysis (TEN) is a rare but potentially fatal delayed hypersensitivity reaction to numerous medications. A 38-year-old male presented with systemic hypersensitivity reaction, such as high fever, pain in the eyes, and diffuse pruritic erythematous maculopapular eruptions with multiple targetoid plaques that became vesicular and bullous. Oral mucosa and conjunctivae were involved. The first sign appeared about 1 week after taking methazolamide (50 mg twice a day) for the management of glaucomatous eyes. Although methazolamide was discontinued, blistering and skin denudation progressed to affect up to 80% of the body surface area and a positive Nikolsky sign was noted. High fever also persisted. Skin lesions started to improve after 2 weeks of management and fever subsided. Cutaneous lesions improved with minimal permanent sequele 2 months later. HLA-B*5901 was found by high-resolution genotyping. The lymphocyte activation test performed 6 months after remission showed a positive response to methazolamide challenge. This is the first case of methazolamide-induced TEN in which methazolamide was confirmed as a culprit drug by the lymphocyte activation test.

Five Cases of Stevens-Johnson Syndrome May Be Associated with Methazolamide Treatment / 대한피부과학회지

Recently, Stevens-Johnson syndrome associated with methazolamide has been reported in Koreans, more frequently. Methazolamide is a carbonic anhydrase inhibitor commonly used for lowering intraocular pressure in glaucoma and other ophthalmologic diseases. We reported five cases of Stevens-Johnson syndrome induced by methazolamide. All patients showed atypical clinical manifestations, compared to classical Stevens-Johnson syndrome. Methazolamide induced Stevens-Johnson syndrome showed scattered or confluent maculopapular eruptions initially, which are similar to morbiliform drug eruption with mild lip erosion and palmar erythema. Even though there was no skin erosion initially, it showed rapid progression to severe erosion on the trunk and palmoplantar erythema within 5 to 7 days. Therefore, our data indicated that methazolamide induced Stevens-Johnson syndrome should be checked for a patient who has a history of ophthalmologic treatment with a drug eruption like skin lesion.

A Case of Paclitaxel-induced Maculopathy Treated with Methazolamide

A 54-year-old female patient who had been undergoing anti-cancer chemotherapy and radiotherapy for seven years after surgery for left breast cancer visited our clinic for visual disturbance in the right eye at nine months after paclitaxel administration. The best-corrected visual acuity was 0.5 in the right eye and 1.0 in the left eye. The patient was diagnosed with maculopathy due to paclitaxel administration based on the finding of cystoid macular edema in the right eye on fundus examination and optical coherence tomography; however, no leakage was detected on fluorescein angiography. Thus, drug replacement was planned. On the other hand, no abnormal finding was observed in the left eye. However, as the anti-cancer effect of paclitaxel is significant, replacing paclitaxel with another agent was not warranted; therefore, maintenance therapy with methazolamide was performed before and after administering the anti-cancer agent. Aggravation of cystoid macular edema was prevented, and vision improvement was achieved by oral maintenance therapy with methazolamide. In addition, the same fundus findings as shown in the right eye were detected in the left eye at 16 months after paclitaxel administration. After administering methazolamide, macular thickness was reduced, and vision was improved in the left eye. Paclitaxel administration was discontinued due to cutaneous metastasis from the breast cancer, and another anti-cancer agent was then administered. No subsequent cystoid macular edema has occurred.

Comparison of Methazolamide and Acetazolamide for Prevention of Acute Mountain Sickness in Adolescents

PURPOSE: Acute mountain sickness (AMS) commonly occurs when unacclimatized individuals ascend to altitudes above 2500 m. Acetazolamide, a carbonic anhydrase inhibitor (CAI), is recommended for AMS prophylaxis, but may have adverse effects such as paresthesia. Methazolamide has the same pharmacologic effect, but diffuses more rapidly into tissue and is more potent than acetazolamide. But, little is known about methazolamide as an AMS prophylactic agent. This study was conducted to prospectively compare metazolamide with acetazolamide for its preventive effect for AMS in adolescents. METHODS: Nineteen adolescents aged 13~18 years attempting an ascent of Mt. Kalapatar (5500 m) were randomly divided to receive acetazolamide (n=10) or methazolamide (n=9). Oxygen saturation (SpO2) and pulse rate were measured at each altitude. The incidence of AMS was calculated using the Lake Louise questionnaire. Difference in incidence between two groups was analyzed using generalized estimating equation. Difference in Lake Louise scores (LLS) was analyzed using linear mixed model testing. RESULTS: Overall incidence of AMS was 68.4%. Fatigue or malaise was the most frequent symptom (94.7%) followed by headache (84.2%). SpO2 decreased as the altitude increased (p<0.001). There was no difference in SpO2 and pulse rate between the two groups (p=0.44). There was no difference in LLS (p=0.22) and incidence of AMS (p=0.07) between the two groups with increasing altitude. Paresthesia was less common in the methazolamide group, but was not statistically different (p=0.35). CONCLUSION: Methazolamide is equally effective as acetazolamide in preventing AMS among adolescents.

Epidermal Necrolysis due to Methazolamide Treatment in Glaucomatous Patients / 대한피부과학회지

Epidermal necrolysis (EN) is a rare, but potentially life threatening disease, characterized by epidermal necrosis and sub-epidermal detatchment, and is predominantly medication-induced. Methazolamide is a sulfonamide derivative and carbonic anhydrase inhibitor used for lowering of intraocular pressure in glucomatous patients. Common side effects of methazolamide include metabolic acidosis, hypokalemia, tinnitus, transient myopia, and renal calculi; however, EN caused by methazolamide is very rare. We report on two cases of EN induced by methazolamide treatment and review previously published cases.

Methazolamide-induced Stevens-Johnson Syndrome

PURPOSE: To report three consecutive cases of methazolamide-induced Stevens-Johnson syndrome. CASE SUMMARY: We describe three patients who were all prescribed methazolamide for treatment of ophthalmologic conditions. A 29-year-old man and a 47- year-old woman were prescribed methazolamide (100 mg/day) for the treatment of central serous chorioretinopathy (CSCR). A 66-year-old woman was prescribed methazolamide (100 mg/day) for acute glaucoma of the left eye for approximately two weeks. After taking the methazolamide, three patients were showed the pururitic maculopapular rashes on the whole body and the vesicular eruptions of the oral mucosa and conjunctiva. On the basis of medication histories, characteristic skin lesions and mucosal involvement, we diagnosed all three patients with methazolamide-induced Stevens-Johnson syndrome. All three patients were hospitalized and treated with intravenous steroids and antihistamines. Two of the three cases showed conjunctival pseudomembranes. In two cases, the skin lesions worsened during the first week of treatment, and then resolved without complications over the next two to three weeks. The condition of the 47-year-old female patient deteriorated rapidly to toxic epidermal necrolysis due to sensitivity to sulfa antibiotics. HLA- A24, B59 and Cw1 were detected in all three cases. CONCLUSIONS: In 2008, domestic production of acetazolamide was halted in Korea. Because of this, methazolamide is expected to be prescribed by ophthalmologists more commonly than in previous years. Complete medical histories should be taken before prescribing methazolamide to patients. HLA typing should be conducted whenever possible to screen patients before prescription of methazolamide.

Toxic Epidermal Necrolysis and Stevens-Johnson Syndrome Caused by Topical Ophthalmic Use of Dorzolamide / 대한피부과학회지

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are the potentially life-threatening, acute hypersensitivity reaction to inciting drugs. These diseases have been often associated with systemic carbonic anhydrase inhibitor such as acetazolamide or methazolamide in Korean and Japanese patients. Dorzolamide is a recently developed topical carbonic anhydrase inhibitor with few significant systemic adverse effects. To the best of our knowledge, there have been only a few reports of SJS or TEN caused by topical dorzolamide in the literature. We herein present two cases of TEN and one case of SJS related with topical use of dorzolamide. It should be emphasized that although rarely, topical dorzolamide may cause serious sulfonamide hypersensitivity such as SJS or TEN in the susceptible patient through the systemic absorption.

Two Cases of HLA-B59(+) Stevens-Johnson Syndrome (SJS)-Toxic Epidermal Necrolysis (TEN) Associated with Methazolamide Treatment / 대한피부과학회지

Methazolamide is a sulfonamide derivative and carbonic anhydrase inhibitor used to lower intraocular pressure in glaucomatous eyes. Stevens-Johnson syndrome (SJS)-toxic epidermal necrolysis (TEN) associated with methazolamide treatment has been reported in Korean and Japanese patients. We report two cases of SJS-TEN associated with methazolamide treatment. The result of HLA typing of our two patients was a positive reaction for HLA-B59, which is specific to Koreans and Japanese. This suggests a possible relationship between genetic background and SJS-TEN associated with methazolamide treatment. Therefore, methazolamide should be prescribed with caution to Korean or Japanese patients.

A Clinical Observation of the Patients with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Jeju Island / 대한피부과학회지

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, acute life-threatening, hypersensitivity reaction usually to certain medications. Although SJS and TEN occur at an estimated incidence of 0.4 and 1.2 cases per million per year, these conditions have occurred, not infrequently, on Jeju island. OBJECTIVE: We performed this study to evaluate the clinical characteristics of the 15 patients diagnosed as SJS and TEN in Jeju island. METHODS: The retrospective clinico-epidemiologic analysis of 10 months' data of 15 inpatients, including 5 SJS patients, 8 SJS/TEN overlap patients and 2 TEN patients, was conducted through the available medical records. RESULTS: 1. Mean time of onset of clinical disease following the institution of a new drug was 10.1 days. Mean duration of drug exposure was 9.3 days. There were 4 cases showing positive response to skin test. The most common culprit drugs were anti-glaucoma agents (26.7%) such as methazolamide or acetazolamide, and anti-convulsants (26.7%) including valproic acid. 2. The clinical outcome was as follows; recovery in 13 patients, transfer in one patient, and expire in one. Time from appearance of first skin lesions to the initiation of therapy (time to treat) in 15 patients was 3.5 days; time from start of hospital treatment to interruption of further progression (time to arrest), 4.1 days; time to heal, 14.1 days; length of hospital stay, 20.6 days. The four patients with delayed withdrawal of drugs represented a longer time to treat (4.8 days), time to arrest (4.5 days), time to heal(15 days), and length of hospital stay (26.5 days) than those in the 11 patients with early withdrawal. 3. The fraction of patients corresponding to risk factors of SJS or TEN was as follows; elder (>60 years old) (46.6%), widespread lesions (>10%) (66.6%), lymphopenia (66.6%), leukopenia (40%), neutropenia (26.7%), thrombocytopenia (20%), abnormal BUN/Cr (20%), abnormal liver function (46.7%), symptoms of respiratory tract (53.3%), sepsis (13.3%). There were conjunctivitis (66.6%), keratitis (60%), gastroenterologic complications (40%), anxiety disorder (13.3%), and urologic complications (13.3%) in the accompanied systemic complications at first visit. 4. The analysis of a medication history in 15 patients showed 10 cases of prescribed medication and 5 female cases of non-prescribed medication. The patients taking prescribed medication were younger (47.3 years old) than the cases of non-prescribed medication (68 years old). Four cases among the patients with non-prescribed medication at the pharmacy corresponded to the prescription drugs. CONCLUSION: In Jeju island, the incidence of SJS and TEN seems to be higher than that in the published literatures. Along with the habitual pattern of too frequent, prolonged medication by elder patients, the territorial trait of seeing a pharmacist for the disease care at first, and the pharmacists practicing medicine like a physician instead of dispensing a prescription, might contribute to this higher incidence. Anti-glaucoma ophthalmics and anti-convulsants might be the principal causative drugs leading to SJS or TEN in Jeju island.

A Case of Stevens-Johnson Syndrome Caused by Acetazolamide / 대한피부과학회지

A 53-year-old man having glaucoma treated with acetazolamide. After 7 days, he developed diffuse erythematous papules on both forearms and hands with multiple erosive lesions on his lips and genitalia. In the diagnosis of Stevens-Johnson syndrome, he was treated with systemic prednisolone with no sequale. Acetazolamide, which is a kind of sulfa drug and carbonic anhydrase inhibitor is commonly prediscribed by ophthalmologists. However severe side effects such as Stevens-Johnson syndrome has been overlooked. Moreover, according to recent research, HLA-B59 was known to be detected in Stevens-Johnson syndrome caused by methazolamide, which is analogous to acetazolamide. For these reasons, we emphasized the possibility of adverse drug reaction due to acetazolamide and the need caution about genetic risk factor through HLA typing.

Four cases of Stevens-Johnson Syndrome associated with Methazolamide Treatment / 대한피부과학회지

Methazolamide is a carbonic anhydrase inhibitor commonly used for lowering intraocular pressure in glaucoma and other ophthalmologic diseases. Carbonic anhydrase inhibitors are sulfonamide derivatives that are known to cause many adverse side effects, including dermatologic reactions. Recently, Stevens-Johnson syndrome (SJS) associated with methazolamide treatment has been reported in Japanese and Japanese Americans, and it suggested a relationship between genetic background and methazolamide-induced SJS. We report four cases of SJS induced by methazolamide. Methazolamide should be prescribed with caution in patients of Japanese or Korean descent.

Association of HLA Type with Stevens-Johnson Syndrome Induced by Methazolamide Treatment

There have been reports between Stevens-Johnson syndrome (SJS)induced by methazolamide treatment and genetic background especially in Japanese and Korean descent.We report 6 cases of SJS and the results of HLA (human leukocyte antigen)typing that suggest a relationship between genetic background and SJS induced by methazolamide treatment. We observed 6 patients as the subjects of this research, who had been suffering from SJS induced by methazolamide treatment at the Department of Ophthalmology, Catholic University.SJS appeared about 2 weeks after the patient started taking methazolamide (100 or 200 mg/d).After 15~30 days of treatment, they recovered with no serious complication.The results of HLA typing carried out 6 patients that all of the patients had HLA-A2, 5 patients were HLA-Cw1 and HLA-B59. Methazolamide should be carefully prescribed in patients of Japanese or Koreans descent and should not prescribe sulfonamide in SJS patients. A further systematic research on more cases is required to explaining ethnic peculiarity of the syndrome.

Three Cases of Stevens-Johnson Syndrome Associated with Methazolamide Treatment

There have been recent reports on the increasing number of Stevens-Johnson syndrome cases resulting from methazolamide and its relatively higher incidence in Japanese and Korean than any other people. The objective of this study is to examine its developement potential in Korean people.We observed three patients as the subjects of this research, who had been suffering from skin eruption during glaucoma treatment in the Department of Ophthalmology Catholic University, College of Medicine. All of them, for lowering IOP, took methazolamide 50mg a day for more than two weeks, but they had no history of systemic disease but glaucoma or hypersensitivity induced by other medications. With regard to their skin, vesicular eruption came out in their whole body and particularly oral mucosa severely. Also, systemic symptom such as slight fever and general malaise was accompained . However, by quitting the use of methazolamide and medicating corticosteriods instead, they recovered with no serious complication.It can be concluded, therefore, that they had Stevens-Johnson syndrome mainly by methazolamide based on the condition of their skin eruptionand the fact that they got well again by stopping the use of methazolamide on which they chiefly relied. However, a further systematic research on more cases os required with a view to elucidating confirmatory diagnosis and ethnic pecularity of the syndrome.

Carotid body chemoreception: the importance of CO2-HCO3- and carbonic anhydrase. (review)

The current hypotheses of carotid body (CB) chemoreception regard the glomus cells as the initial site of stimulus transduction. The consensus is that the transduction of chemical stimulus is coupled with the release of transmitter(s) from the glomus cells, which in turn generates action potentials in the afferent nerve terminals. Carbonic anhydrase (CA) is present in the glomus cells of the CB. Inhibition of CA activity in the CB in situ reduces the carotid chemosensory responses to CO2 and to O2, suggesting a common mechanism of chemosensing for both stimuli. However, CA inhibitors also block the red blood cell enzyme. Thus, the CO2 hydration reaction does not come to completion within the transit time of the blood from the lung to the CB. A steady-state reaction is not reached until later and so the PCO2 and pH levels in arterial blood samples are not the same as those sensed by the CB. Experiments in vitro using cat CB perfused and superfused with cell-free solutions, which had been pre-equilibrated with respiratory gases, strongly support the proposition that the CA activity in CB cells is essential for the speed and amplitude of the initial response to CO2 and for its subsequent adaptation. The immediate response to hypoxia also is delayed, but the late steady-state was less dependent on CA activity. In the nominal absence of CO2-HCO3- from the perfusate, hypoxic chemoreception persisted and its magnitude is not affected by CA inhibition, except for a delay which may be due to the initial alkaline pH of the glomus cells. Recent experiments performed in isolated glomus cells and in the whole CB show that hypoxia does not modify significantly the intracellular pH. By its simple catalytic function, CA can speed up the approach of the CO2 hydration reaction to equilibrium. However, CA may also contribute in the steady-state to the regulation of pHi by providing a continuous supply of H+ and HCO3-. Furthermore, CA performs a facilitatory role in the physiological chemosensory responses to CO2 and O2 in the presence of extracellular CO2-HCO3-. This role is likely to be related to the ion exchanger function and then to pHi regulation in the chemoreceptor cells