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PubMedDate not supplied

Efficacy and safety of transdermal methimazole in the treatment of cats with hyperthyroidism.

The objective of this study was to determine whether transdermal methimazole was as safe and effective as oral methimazole for the control of hyperthyroidism in cats. Forty-seven cats with newly diagnosed hyperthyroidism were randomized to receive either transdermal methimazole in pluronic lecithin organogel (PLO; applied to the inner pinna), or oral methimazole (2.5 mg q12h for either route). Cats were evaluated at weeks 0, 2, and 4 with a physical exam, body weight determination, CBC, biochemical panel, urinalysis, measurement of total levothyroxine (T4) concentration, indirect Doppler blood pressure determinaiton, and completion of an owner questionnaire. Data between the 2 groups and over time were compared by nonparametric methods. Forty-four cats followed the protocol (17 oral and 27 transdermal). Significantly more cats treated with oral methimazole had serum T4 concentrations within the reference range after 2 weeks (14 of 16 cats) compared to those treated by the transdermal route (14 of 25; P = .027). This difference was no longer significant by 4 weeks of treatment (9 of 11 for oral versus 14 of 21 for transdermal), possibly because of inadequate numbers evaluated by 4 weeks. Cats treated with oral methimazole had a higher incidence of gastrointestinal (GI) adverse effects (4 of 17 cats) compared to the cats treated with transdermal methimazole (1 of 27; P = .04), but no differences were found between groups in the incidence of neutropenia, hepatotoxicity, or facial excoriations. Although the overall efficacy of transdermal methimazole is not as high as that of oral methimazole at 2 weeks of treatment, it is associated with fewer GI adverse effects compared to the oral route.

Administration, Cutaneous↗
PubMed2002

Bioavailability of transdermal methimazole in a pluronic lecithin organogel (PLO) in healthy cats.

The antithyroid drug methimazole is widely used for the medical management of feline hyperthyroidism. Recently, custom veterinary pharmacies have offered methimazole in a transdermal gel containing pluronic and lecithin (PLO), with anecdotal evidence of efficacy. The purpose of this study was to determine the bioavailability, relative to i.v. and oral routes of administration, of transdermal methimazole in a PLO gel in cats. Six healthy adult cats were assigned to receive 5 mg of methimazole by the i.v., oral, or transdermal routes, in a randomized triple crossover protocol with 1 week washout between doses. Blood samples were taken for high performance liquid chromatography (HPLC) determination of serum methimazole, at 0, 5, 15, 30, 60 min, and 2, 4, 6, 12 and 24 h after dosing. Methimazole absorption following transdermal administration was poor and variable, with only two of six cats achieving detectable serum methimazole concentrations at any time point following transdermal administration. Area under the concentration-time curve (AUC), maximum concentration (Cmax), and absolute bioavailability were all significantly lower for the transdermal route (0.39 +/- 0.63 microg h/mL, 0.05 +/- 0.09 microg/mL, and 11.4 +/- 18.7%, respectively) than for either i.v. (7.96 +/- 4.38 microg h/mL, 3.34 +/- 2.00 microg/mL, 100%) or oral routes (2.94 +/- 1.24 microg h/mL, 0.51 +/- 0.15 microg/mL, 40.4 +/- 8.1%). The results of this study indicate generally low to undetectable bioavailability of methimazole in a lecithin/pluronic gel given as a single transdermal dose to healthy cats, although one individual cat did achieve nearly 100% transdermal bioavailability relative to the oral route.

Administration, Cutaneous↗
PubMed2006

The effects of methimazole on development of the fathead minnow, Pimephales promelas, from embryo to adult.

The importance of thyroid hormones in regulating early developmental processes of many amphibian and fish species is well known, but the impacts of exposure to disrupters of thyroid homeostasis during the embryo-larval-juvenile transitions are unclear. To investigate these impacts, fathead minnows, Pimephales promelas, were exposed to a model thyroid axis disrupter, methimazole, an inhibitor of thyroid hormone synthesis, at control (0), 32, 100, and 320 mug/l, starting at <24-h postfertilization, for 28, 56, and 83/84 days postfertilization (dpf). Thyroid disruption was evident at 28 dpf, when survival was significantly reduced by 32 or 100 mug/l methimazole concomitant with a reduced thyroxine (T(4)) content. However, the T(3) content of these fish was similar to that of control fish, and body mass was unaffected (as in all groups), suggesting compensatory mechanisms overcame reduced T(4) synthesis. At the highest concentration of methimazole (320 mug/l), activation of feedback mechanisms on the hypothalamic-pituitary-thyroid axis was suggested by the normal T(4) content after 28 dpf exposure to methimazole, although triiodothyronine (T(3)) content of these fish was significantly reduced. The generally less pronounced disruption of thyroid hormone homeostasis after 56 days exposure to methimazole also suggests compensatory mechanisms in juvenile/adult fish that may regulate T(4) content, despite exposure to methimazole at 32 or 100 mug/l (in fish held in 320 mug/l methimazole, the T(4) content was significantly higher than in controls). Whole body T(3) content at 56 dpf was significantly depressed only in fish held in 100 mug/l methimazole. By 83/84 dpf, length, body mass, and thyroid hormone concentrations were similar in all experimental groups and controls, indicating that adult fish may achieve regulation of their thyroid axis despite prolonged exposures to thyroid disruptors throughout early development.

Animals↗
PubMedDate not supplied

The effect of methimazole on thyroid uptake of pertechnetate and radioiodine in normal cats.

Many hyperthyroid cats referred for thyroid imaging and 131I therapy are concurrently or recently receiving antithyroid medications. The effect of the antithyroid drug, methimazole, on thyroid uptake of 99mTcO4 and 123I was evaluated in 8 normal cats. Quantitative analysis was used to determine the normal percent dose uptake of 99mTcO4 and 123I, the change in thyroid:salivary ratios (T:S) of 99-TcO4 over time, and the duration of the methimazole effect on thyroid uptake of 123I. Methimazole was administered to 5 cats for 3 weeks in which a hypothyroid state was obtained; 3 cats served as non-treatment controls. 99mTcO4 and 8 and 24 hour 123I imaging was repeated after 3 weeks of methimazole therapy (time of maximum T4 suppression). Methimazole was then discontinued and 123I images and serum T4 concentrations were repeated at 1, 4, 9, 15, and 24 days post withdrawal. The percent dose uptake of 99mTcO4 increased throughout the acquisition period with maximum uptake occurring 4 hour post injection. The baseline 20 min. T:S ratio for controls and treatment cats were 0.79 +/- 0.08 and 0.81 +/- 0.05 respectively; with a peak value of 1.29 +/- 0.23 and 1.31 +/- 0.18 at 4 hours. The baseline T:S ratios were not significantly different from 20 minutes to 2 hours, however they were significantly elevated at 4 hours post injection. Baseline, 8 and 24 hour percent dose uptake of 123I were 2.1 +/- 0.42% and 7.04 +/- 1.24%, respectively. There was a significant increase in the T:S ratio in the treatment group at all time points. The 8 hour percent dose uptake of 123I at 1, 4, and 9 days post methimazole withdrawal were significantly increased and peaked at 4 days. The 24 hour uptake was significantly increased at 4 and 9 days, with peak uptake at 9 days post-methimazole withdrawal. The 123I percent dose uptake decreased to baseline values by day 15 post withdrawal. Radioiodine uptake is not inhibited by methimazole treatment in normal cats, and is significantly enhanced after recent withdrawal. This finding is supportive of a "short term rebund effect" with maximal enhanced uptake between 4 and 9 days after discontinuing antithyroid drugs. The increased uptake of 99mTcO4 may also affect the interpretation of 99mTcO4 thyroid scintigraphy for 2-3 weeks.

Animals↗
PubMed1996

Effects of methimazole in the early and established phases of NG-nitro-L-arginine methyl ester hypertension.

In the present study we evaluated the effects of methimazole, an antithyroid drug, on blood pressure and other variables in the early and established phases of hypertension induced by the inhibition of nitric oxide synthesis with the oral administration of NG-nitro-L-arginine methyl ester (L-NAME), 75 mg/100 ml in the drinking water. Moreover, we also evaluated the acute pressor effect of L-NAME on systemic blood pressure in control and rats treated chronically with methimazole, administered via drinking water (30 mg/100 ml). Oral administration of methimazole maintained the blood pressure of L-NAME-treated rats at normal levels 25 days after induction of hypertension. However, after 25 days of methimazole treatment in rats made hypertensive with L-NAME (for 25 days), high blood pressure was similar in methimazole-treated and non-treated L-NAME rats, despite the fact that a hypothyroid state had been achieved in the methimazole-treated rats. Acute intravenous injection of L-NAME caused a similar increase in mean arterial pressure in control and methimazole-treated rats at the lowest dose; however, smaller pressor responses were observed with increasing doses in hypothyroid rats. These results clearly demonstrate that hypothyroidism induced by methimazole prevents, but does not reverse, L-NAME hypertension and reduces the acute pressor responsiveness to L-NAME administration.

Administration, Oral↗
PubMed2003

Efficacy and safety of once versus twice daily administration of methimazole in cats with hyperthyroidism.

OBJECTIVE: To determine whether once daily administration of methimazole was as effective and safe as twice daily administration in cats with hyperthyroidism. DESIGN: Randomized, nonblinded, clinical trial. ANIMALS: 40 cats with newly diagnosed hyperthyroidism. PROCEDURE: Cats were randomly assigned to receive 5 mg of methimazole, PO, once daily (n = 25) or 2.5 mg of methimazole, PO, twice daily (15). A complete physical examination, including measurement of body weight; CBC; serum biochemical analyses, including measurement of serum thyroxine concentration; and urinalysis were performed, and blood pressure was measured before and 2 and 4 weeks after initiation of treatment. RESULTS: Serum thyroxine concentration was significantly higher in cats given methimazole once daily, compared with cats given methimazole twice daily, 2 weeks (3.7 vs 2.0 micro +/- g/dL) and 4 weeks (3.2 vs 1.7 microg/dL) after initiation of treatment. In addition, the proportion of cats that were euthyroid after 2 weeks of treatment was lower for cats receiving methimazole once daily (54%) than for cats receiving methimazole twice daily (87%). Percentages of cats with adverse effects (primarily gastrointestinal tract upset and facial pruritus) were not significantly different between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that once daily administration of methimazole was not as effective as twice daily administration in cats with hyperthyroidism and cannot be recommended for routine use.

Administration, Oral↗
PubMed2001

Methimazole interferes with the progression of experimental autoimmune myocarditis in rats.

In order to ascertain whether methimazole, a drug commonly used for the treatment of hyperthyroidism, interferes with the progression of autoimmune-mediated myocardial injury, we investigated the effect of methimazole on experimental autoimmune myocarditis (EAM) in rats. EAM was induced by immunization with porcine cardiac myosin. Methimazole administration markedly slowed the body weight growth in both normal and EAM rats, but did not induce morphologic change of cardiac tissue in normal rats. In EAM rats, macroscopic examination revealed discoloration of the cardiac surface, and histopathological examination by light microscopy showed extensive myocardial necrosis, infiltration by inflammatory cells and myocardial fibrosis. In the EAM rats treated with methimazole, the discolored areas on the cardiac surface were markedly diminished in size, and the myocardial necrosis, cellular infiltration and fibrosis were significantly less severe. To identify the mechanism responsible of this effect, we investigated the change of regulatory lymphocyte subsets in peripheral blood using an immunofluorescence technique with a flow cytometer. A decrease in the helper/suppressor T cell ratio as a result of the increased proportion of suppressor T cells and a decrease in the proportion of B cells were observed in normal rats after methimazole administration, and similar findings were made in the EAM rats treated with methimazole. These results indicate that methimazole interferes with the progression of EAM, and immunosuppression may, at least in part, be involved in the inhibitory effect of methimazole on EAM in rats.

Animals↗
PubMed1985

Early development in the caudate and thyroid of methimazole-treated rats.

Rat pups were made hypothyroid by administration of the antithyroid agent, methimazole, to pregnant and lactating dams from gestational day 17 to postnatal day 10. Dendritic branching of caudate neurons in methimazole-treated pups was decreased 30 to 40 percent between 1 and 28 days of age. Perinatal methimazole treatment produced a pattern of developmental deficit or prolonged delay in the growth of dendrites of caudate interneurons. The antithyroid effect was also apparent in morphometric changes in the thyroid gland of methimazole-treated rats. Functional tissue was present at all ages examined. Colloid storage in the thyroid was decreased during methimazole administration compared with colloid storage after methimazole was discontinued. Both during and after methimazole administration the size of thyroid follicular cell nuclei in methimazole-treated pups was significantly greater than that of thyroid nuclei in control animals. Changes in dendritic branching, body weight and thyroxine levels lasted into adult life but recovery toward control levels was seen in adults. These changes in offspring following maternal administration of a goitrogen were demonstrated at an exposure level well below complete thyroid suppression.

Animals↗
PubMed1993

Methimazole as a protectant against cisplatin-induced nephrotoxicity using the dog as a model.

The protective effect of methimazole, a commonly used antithyroid drug, on cisplatin-induced nephrotoxicity was studied. Eight dogs received 80 mg/m2 cisplatin i.v. without saline prehydration. Dogs were randomized into two groups of four dogs each: one group received 40 mg/kg methimazole i.p. at 30 min prior to and 4 h after cisplatin delivery, and the other group received saline placebo i.p. Methimazole protected dogs against the in vivo nephrotoxicity elicited by cisplatin as evidenced by clinicopathologic and histopathologic indices. Protection was not complete, as methimazole-treated animals developed mild histopathologic renal changes. Measures of renal oxidative stress did not differ between the two groups at day 5 following cisplatin treatment. No difference was noted for serum thyroxine concentrations before or after therapy in either group; however, serum levels of 3,5,3'-triiodothyronine were significantly higher on day 5 in both groups of dogs receiving cisplatin, regardless of whether they received methimazole or not. Methimazole as used in this study was found to be well tolerated in dogs over the short term, with no significant clinical or clinicopathologic toxicity being observed. The results of this study support the additional evaluation of methimazole as a protectant against cisplatin-induced nephrotoxicity using the dog as a model.

Animals↗
PubMed1992

Methimazole treatment reduces cardiac hypertrophy and mortality without a concomitant reduction in blood pressure in established Goldblatt two-kidney one clip hypertension.

The effects of methimazole, an antithyroid drug, on blood pressure and other parameters were evaluated in the established phase of Goldblatt two-kidney one clip (G2K-1C) hypertension. Methimazole was administered via drinking water for five weeks, starting five weeks after hypertension had been induced. After this period of treatment, similarly high blood pressures were observed in methimazole-treated and non-treated G2K-1 C rats, despite the fact that a hypothyroid state had been achieved in methimazole-treated rats. Methimazole-treated G2K-1 C rats showed reductions in heart rate, ventricular weight, ventricular/body weight ratio and mortality in comparison with rats not treated with methimazole. These results clearly demonstrate that hypothyroidism induced by methimazole: a) does not reverse G2K-1 C hypertension, but b) improves the rate of survival and c) reduces relative cardiac hypertrophy, possibly by the reduction in cardiac work observed in Goldblatt hypothyroid rats.

Animals↗
PubMed1987

The behavioral effects of perinatal methimazole administration in Swiss Webster mice.

Methimazole was tested for use as a positive control agent in behavioral studies of mice. Continuous administration of the antithyroid agent via drinking water (0.1 mg/ml) from Day 16 of pregnancy through Day 10 postpartum produced developmental delays in mice offspring. Ten methimazole and 12 untreated litters were studied. Developmental milestones were unaltered; i.e., time of pinna detachment, incisor eruption, eye opening, vaginal patency, and testicular descent were not different between groups. Mean body weights of methimazole offspring were consistently reduced, but significant differences were isolated to a few days in the preweaning period and a few weeks during the postweaning period. There was no enduring effect. All preweaning tests showed some significant treatment-related changes; methimazole pups were developmentally delayed. Surface righting time was increased while time pivoting and the number of quadrants traveled were decreased in methimazole pups. Negative geotaxis showed significant treatment-related increases in the time to orient 180 degrees uphill, the percentage of pups orienting 180 degrees uphill, and the percentage of pups orienting less than 180 degrees. Ontogeny of swimming ability also showed significant delays. The only postweaning test evaluated, time on a rotating rod, showed no treatment-related effects. Brain weights Postnatal Day (PND) 120 were not different between groups. In this study, methimazole produced developmental delays in mice that were detectable by behavioral tests. Thus, methimazole has potential as a positive control agent for mice, not only to validate preweaning test sensitivity, but also to validate a laboratory's ability to perform preweaning behavioral studies.

Aging↗
PubMedDate not supplied

Methimazole treatment of 262 cats with hyperthyroidism.

The efficacy and safety of the antithyroid drug methimazole were evaluated over a 3-year period in 262 cats with hyperthyroidism. In 181 of the cats, methimazole was administered for 7 to 130 days (mean, 27.7 days) as a preoperative preparation for thyroidectomy. The remaining 81 cats were given methimazole for 30 to 1,000 days (mean, 228 days) as sole treatment for the hyperthyroid state. After 2 to 3 weeks of methimazole therapy (10 to 15 mg/d), the mean serum thyroxine (T4) concentration decreased significantly (P less than 0.001) from a pretreatment value of 12.1 micrograms/dl to 2.1 micrograms/dl. The final maintenance dose needed to maintain euthyroidism in the 81 cats that were given methimazole as sole treatment for hyperthyroidism ranged from 2.5 to 20 mg/d (mean, 11.9 mg/d). Clinical side effects developed in 48 (18.3%) cats (usually within the first month of therapy), which included anorexia, vomiting, lethargy, self-induced excoriation of the face and neck, bleeding diathesis, and icterus caused by hepatopathy. Mild hematologic abnormalities developed in 43 (16.4%) cats (usually within the first 2 months of treatment), which included eosinophilia, lymphocytosis, and slight leukopenia. In ten (3.8%) cats, more serious hematologic reactions developed including agranulocytosis and thrombocytopenia (associated with bleeding). These hematologic abnormalities resolved within 1 week after cessation of methimazole treatment. Immunologic abnormalities associated with methimazole treatment included the development of antinuclear antibodies in 52 of 238 (21.8%) cats tested and red cell autoantibodies (as evidenced by positive direct antiglobulin tests) in three of 160 (1.9%) cats tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Effect of methimazole-induced hypothyroidism on multiple opioid receptors in rat brain regions.

The effect of chronic administration of methimazole (0.05% w/v) in drinking water for 32 days to male Sprague-Dawley rats on the binding of opioid ligands, 3H-Tyr-D-Ala-Gly-MePhe-Gly-ol (DAGO, mu-receptors), 3H-Tyr-D-Ser-Gly-Phe-Leu-Thr (DSTLE, delta-receptors) and 3H-ethylketocyclazocine (EKC, kappa-receptors) to membranes of brain regions was determined. Chronic administration of methimazole to rats decreased their rate of body weight gain, colonic temperature, systolic blood pressure and heart rate in comparison to vehicle-treated rats. Administration of methimazole also decreased the serum concentration of triiodothyronine (total T3) and T4 when compared to vehicle-treated rats. The binding of 3H-DAGO to membranes of amygdala, pons and medulla, striatum, midbrain and cortex of methimazole-treated rats was greater than vehicle-treated rats, however, the binding to membranes of hypothalamus in the two treatment groups did not differ. The binding of 3H-DSTLE in amygdala and hypothalamus of methimazole-treated rats did not differ but it was significantly greater in pons and medulla, midbrain, cortex and striatum of methimazole-treated rats than vehicle-treated rats. The binding of 3H-EKC to membranes of pons and medulla was lower and of striatum and cortex of methimazole-treated rats was significantly greater than vehicle-treated rats, but the binding to membranes of amygdala, hypothalamus, and midbrain of the two treatment groups did not differ. The results indicate that brain, mu-, delta- and kappa-opioid receptors are differentially altered in hypothyroidism.

Animals↗
PubMed1975

Relation between thyroid iodine content and the accumulation and oxidation of [35-S] Methimazole in the rat.

The thyroid accumulation and oxidation of a single intraperitoneal dose of [35-S] methimazole has been studied in iodine-deficient, normal and iodine-treated rats. A highly significant positive linear correlation was found between the thyroid oxidation of methimazole to sulfate and intrathyroidal iodine content. A single dose of potassium iodide given intraperitoneally (ip) to rats 1 h before administration of [35-S] methimazole (1 mg/kg ip) increased the thyroid accumulation and oxidation of methimazole. Conversely, the thyroids of rats maintained on a low iodine diet for 21 days showed a markedly reduced capacity to accumulate and oxidize methimazole. The level of oxidation found in the iodine-deficient, normal and iodide-treated groups was 0.21, 4.15 and 12.6 nmol sulfate/g thyroid respectively. The animals maintained on the low iodine diet for 21 days showed significant increases in thyroid weight and thus the decrease in methimazole oxidation occurred in spite of increased stimulation by endogenous TSH. These results show that the intrathyroidal iodine content is a critical factor in the metabolism of methimazole in the thyroid.

Animals↗
PubMed2006

Effect of Graves' disease and methimazole on warfarin anticoagulation.

OBJECTIVE: To describe a case of Graves' disease treated with methimazole and examine the influence of thyroid hormone alteration on warfarin anticoagulation. CASE SUMMARY: A 54-year-old man presented to the emergency department with palpitations, fatigue, weight loss, and anxiety attacks. He was taking no medications at that time. An electrocardiogram showed new onset atrial fibrillation. His thyroid profile was consistent with hyperthyroidism. The patient was admitted to the intensive care unit and started on methimazole 30 mg/day, metoprolol, enoxaparin, and warfarin 5 mg/day. Postdischarge doses of warfarin and methimazole were adjusted over the next several months based on thyroid panel results indicative of hypothyroidism. Postdischarge changes in methimazole dose caused alterations in thyroid function and intensity of anticoagulation as measured by international normalized ratio. DISCUSSION: Interactions between warfarin and drugs that alter thyroid hormone concentrations have been reported; however, the extent and significance of the interaction between methimazole and warfarin have been inadequately described. Thyroid hormone concentrations influence the metabolic rates of proteins and, thus, can alter the amount of vitamin K-dependent clotting factors, which in turn can alter the extent of inhibition by warfarin. This may lead to changes in the intensity of anticoagulation and thereby increase the risk of thromboembolic or hemorrhagic events. CONCLUSIONS: Changes in thyroid hormone concentrations have the potential to significantly alter the extent of warfarin-induced anticoagulation. Clinicians must be aware of the need for close anticoagulation monitoring and dosage adjustment in patients receiving concomitant warfarin and methimazole. The full extent of this interaction may be delayed following a change in methimazole dose.

Anticoagulants↗
PubMed1983

Comparative bioavailability of carbimazole and methimazole.

In this study we investigated the oral bioavailability of therapeutic doses of two antithyroid drugs, methimazole and carbimazole, in seven euthyroid subjects. To increase the statistical power deuterium-labeled methimazole was given orally as an internal standard together with the tested drugs. Using a recently described highly sensitive gas chromatographic-mass spectrometric assay for methimazole we found that intake of 15 mg carbimazole resulted in plasma concentrations of methimazole and pharmacokinetic data comparable to intake of an equimolar amount of methimazole, i. e., 9.2 mg. Maximum concentrations of 163 and 149 ng/ml, respectively, were reached in both instances at 0.9 h after intake of 15 mg carbimazole and 10 mg methimazole. The plasma half-life was 5.7 and 5.4 h, respectively. In contrast to previous suggestions the interindividual differences in pharmacokinetics were small. In conclusion, carbimazole was rapidly and totally bioactivated to methimazole, and the drugs should be regarded as equipotent when compared on a molar basis.

Administration, Oral↗
PubMedDate not supplied

Effect of methimazole and fish oil treatment on gentamicin nephrotoxicity in rats.

Gentamicin, a nephrotoxic aminoglycoside antibiotic, was injected into adult male albino rats, alone or together with methimazole and fish oil. The effects on renal and liver functions and renal thiol status were studied. Gentamicin was administered as two i.p. injections (40 mg/kg body weight) for 3, 7 and 10 consecutive days. The animals were sacrificed 12 hours after the last injection. In gentamicin-treated rats, for 7 and 10 days, blood urea nitrogen (BUN) and serum creatinine concentrations and urinary N-acetyl-beta-D-glucosaminidase (NAG) activity were significantly increased compared with saline-treated controls. Administration of methimazole (20 mg/kg) and fish oil (5 ml/kg) together with gentamicin partially protected against the nephrotoxicity induced by gentamicin by returning the urea and creatinine concentrations and urinary NAG activity to normal levels, despite having higher kidney gentamicin concentrations, especially with methimazole. Rats given gentamicin alone for 3 days exhibited no elevation of BNU, serum creatinine and urinary NAG values. However, these rats exhibited an increase in nonprotein disulfide concentrations and a decrease in renal protein thiol and protein disulfide concentrations, as opposed to rats given gentamicin and methimazole and rats given gentamicin and fish oil. These results show that methimazole and fish oil were effective antagonists of gentamicin-induced nephrotoxicity. Methimazole did not inhibit gentamicin renal uptake but may protect against gentamicin-induced nephrotoxicity by acting as an antioxidant within the kidneys. On the other hand, fish oil may protect against gentamicin-induced nephrotoxicity by counteracting the biochemical alterations induced by the drug in the renal cortex. We conclude that methimazole and fish oil may be compounds for reducing gentamicin-toxic side effects, including nephrotoxicity, without compromising its antibiotic activity.

Animals↗
PubMed2007

Methimazole-induced cell death in rat olfactory receptor neurons occurs via apoptosis triggered through mitochondrial cytochrome c-mediated caspase-3 activation pathway.

The administration of methimazole is known to induce cell death in rat olfactory receptor neurons (ORNs). We investigated whether this injury occurs via apoptosis or through necrosis and whether it involves the extrinsic or intrinsic pathway. Rats were intraperitoneally injected with vehicle (control) or 300 mg/kg methimazole. The experimental animals were also administered vehicle or a caspase-3 or caspase-9 inhibitor 30 min earlier. The administration of methimazole induced cell death predominantly in the mature ORNs and partially reduced olfactory sensitivity in the rats; the injured cells were TUNEL-positive and showed a nuclear staining pattern. This insult induced cytochrome c release from the mitochondria and a significant increase in the immunoreactivity of activated caspase-3 and caspase-9 as well as that of cleaved poly-ADP-ribose-polymerase; in addition, it caused a significant increase in the fluorogenic activity of caspase-3 and caspase-9. However, it did not affect the immunoreactivity of activated caspase-8 or the fluorogenic activity of caspase-8. Pretreatment with a caspase-3 or caspase-9 inhibitor nearly completely prevented the morphologic, biochemical, and functional changes induced by methimazole. These findings suggest strongly that methimazole-induced cell death in rat ORNs is predominantly apoptosis; moreover, the majority of this apoptotic cell death is triggered through mitochondrial cytochrome c-mediated caspase-3 activation pathway, and both caspase-3 and caspase-9 inhibitors can prevent methimazole-induced cell death in the ORNs.

Animals↗