Sertraline-induced liver injury
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A 66-year-old female patient received oral sertraline (initial dose 25 mg once daily, gradually increased to 100 mg once daily on day 10), zopiclone (7.5 mg once per night), lorazepam (0.5 mg thrice daily), and amlodipine (2.5 mg once daily) following the doctor′s advice due to recurrent depressive disorder, sleep disorder, and hypertension. Before administration, the patient′s serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyl transpeptidase (γ-GT) were 21 U/L, 16 U/L and 50 U/L, respectively. On day 16 after the medication, the patient′s serum levels of AST, ALT, and γ-GT were 114 U/L, 134 U/L, and 192 U/L, respectively, but the treatment protocol was not adjusted. On day 21 after the medication, her serum levels of AST, ALT, and γ-GT turned to be 178 U/L, 242 U/L, and 362 U/L, respectively. Then hepatoprotective drugs were given, sertraline was discontinued by gradual reduction (oral escitalopram 5 mg once daily was added when sertraline was reduced to 25 mg once daily, but escitalopram was changed to oral mirtazapine 15 mg at bedtime finally due to the patient′s leg discomfort), and the other drugs were continued. The liver function of the patient gradually improved and her serum levels of AST, ALT, and γ-GT were 35 U/L, 36 U/L, and 108 U/L, respectively about 50 days after sertraline withdrawal.
Key words:
Sertraline; Drug-related side effects and adverse reactions; Liver diseasesKeywords:
Sertraline
Escitalopram
Bedtime
Liver function
Lorazepam
Mirtazapine
Carvedilol (DQ-2466) is a new β-blocker with vasodilating properties. In order to investigate the hemodynamics and safety of carvedilol after single oral administration, in a placebo controlled manner, each group of 5 healthy male volunteers was treated with ascending doses of 20, 40, or 60 mg. The following results were obtained: (1) Both systolic and diastolic blood pressures at rest decreased significantly from 2 hr to 24 hr after administration of carvedilol at each dose level (P<0.05-0.001). Maximum decreases of systolic and diastolic blood pressures were achieved at 3-4 hr after administration. The changes of systolic blood pressure (SBP Δ%) were 4. 2, 14. 6, 16. 2, and 16. 6% in placebo, 20, 40, and 60 mg group, respectively, at 3 hr after dosing. The changes of diastolic blood pressure (DBP Δ%) were 0.5, 16. 1, 13. 3, and 18. 8% in placebo, 20, 40, and 60 mg group, respectively, at 4 hr after dosing. There was no significant difference in the changes of pulse rate (PR Δ%) at rest between carvedilol administration group and placebo admistration group.(2) Stroke index (SI) and cardiac index (CI), which were determined by echocardiography, were not affected in the 20 mg group.SI and CI slightly decreased in the 40 mg group in comparison with the placebo group.There was a tendency of decrease in these parameters in the 60 mg group.Total peripheral vascular resistance (TPVR) decreased significantly at 4 and 29 hr after 20 mg dosing.(3) The increase of systolic blood pressure on treadmill exercise was significantly reduced with dose-dependency in carvedilol administration groups for 9 hr after dosing.(4) There were no abnormal laboratory findings. No subjective symptoms were observed in the placebo and the 20 mg group.One of 5 subjects in the 40 mg group 4 of 5 subjects in the 60 mg group showed slight dizzy feeling, heavy-headedness, nausea, and dizziness.(5) In conclusion, carvedilol appears to maintain marked hypotensive effects up to 24 hr after single oral administration of 20 mg, which was the lowest dose in this study. At less than 40 mg, there were no clinically significant subjective symptoms. This suggests that maximum daily dose should be less than 40 mg in the future investigation for multiple dosing.
Carvedilol
Beta blocker
Pulse pressure
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Background: The aim of the study was to understand the influences of withdrawal or dose reduction of pioglitazone in patients with type 2 diabetes. Methods: We retrospectively picked up patients who had undergone withdrawal or daily dose reduction of pioglitazone after a continuous prescription for 3 months or longer between January 2010 and March 2014. We compared the data before the withdrawal or dose reduction of pioglitazone with the data at 3 or 6 months after those by a chart-based analysis. Results: Among 713 patients taking pioglitazone at least once during the studied period, 20 patients had undergone withdrawal of pioglitazone (group A) and 51 patients had undergone daily dose reduction (group B). The mean pioglitazone dose at baseline was 23 mg in subjects of group A, and 30 mg in group B. The number of subjects who had taken high-dose metformin (>= 1,000 mg) and dipeptidyl peptidase-4 (DPP-4) inhibitors increased after the withdrawal or dose reduction of pioglitazone in both groups. Although no significant change was observed in plasma glucose and HbA1c levels, body weight significantly decreased at 3 and 6 months after the dose reduction in group B. The same tendency was observed in group A. Serum high-density lipoprotein-cholesterol (HDL-C) levels significantly decreased at 3 and 6 months after the withdrawal in group A. The serum alanine aminotransferase levels significantly increased 3 months after the withdrawal in group A. Conclusions: Present study demonstrated that the withdrawal of pioglitazone exacerbated serum HDL-C and liver function in patients with type 2 diabetes, although glycemic control could be maintained by using high-dose metformin or DPP-4 inhibitors. J Clin Med Res. 2016;8(8):585-590 doi: http://dx.doi.org/10.14740/jocmr2611w
Pioglitazone
Longitudinal Study
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A 67-year-old female presented to the emergencydepartment with a 2-week history of progressivenausea, vomiting, abdominal pain, muscle cramps,and dehydration with an associated 3.6 kg weightloss. The patient had amedical history significantfor hypertension, hyperc-holesterolemia, myocardialinfarction, quadruple coro-nary artery bypass, asthma,and osteoarthritis. Medica-tions included enteric-coated acetylsalicylic acid81 mg daily, cilazapril 5 mgdaily, diltiazem CD 240 mgdaily, rosuvastatin 80 mgdaily, ezetimibe 10 mg daily,venlafaxine XL 75 mg daily,Advair (salmeterol/fluticasone) inhaler 250 mcg 1puff twice daily, Didrocal (calcium carbonate oretidronate) 1 tablet daily, glucosamine 1500 mgdaily, and ranitidine 150 mg twice daily. Vital signsat presentation included blood pressure 132/60mm Hg, heart rate 72 beats/minute, respiratoryrate 16 breaths/minute, and oxygen saturation 96%on room air. Abnormal findings on initial physicalexam indicated a mildly tender abdomen in all 4quadrants and reduced skin turgor, but the remain-der of the physical exam was unremarkable. Base-line laboratory tests indicated the following abnor-mal results: potassium 5.9 mmol/L, blood ureanitrogen 40.3 µmol/L, serum creatinine 1035µmol/L, creatine kinase (CK) 30,509 U/L, urinarymyoglobin >30,000 mcg/L, aspartate aminotrans-ferase 539 U/L, alanine aminotransferase 393 U/L,lactate dehydrogenase 1239 U/L. Urinalysis waspositive for red blood cellsand protein, and was nitritenegative, and a 12-leadelectrocardiogram indi-cated normal sinus rhythmwith no ischemic changes. Further history regard-ing the use of cholesterol-lowering agents revealedthe patient was initiated onsimvastatin 40 mg daily fol-lowing a myocardial infarc-tion 9 years previously, andwas switched to atorvas-tatin 20 mg daily 1 year later. The atorvastatin dosewas increased gradually over 4 years to 80 mg daily,but failed to achieve target low-density lipoproteincholesterol (LDL-C). Three years prior to presen-tation, ezetimibe 10 mg daily was added, whichresulted in an LDL-C reduction to 2.4 mmol/L.However, 7 months prior to presentation, atorvas-tatin 80 mg daily and ezetimibe 10 mg daily hadbeen inadequately controlling her cholesterol(LDL-C 2.9 mmol/L) and as a result atorvastatinwas switched to rosuvastatin 40 mg daily. Twomonths later, again due to inability to reach targetLDL-C, the dose of rosuvastatin was increased to
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In 9 clinics 177 patients (68 men and 109 women) aged 23-69 years with primary hypercholesterolemia (TC above 6.5 mmol/L) were treated with lovastatin for 12 weeks. The treatment was started with 20 mg daily. The dose was doubled every 4 weeks, if the total serum cholesterol level did not fall below 5.2 mmol/L. For 4 weeks before treatment with lovastatin all patients received placebo. After the first 4 weeks of therapy the mean TC level decreased significantly (from 8.09 mmol/L to 6.54 mmol/L) by 18.5%. In comparison with the results after placebo (the starting value), after the 8 weeks of the therapy the TC level reduction reached 22.4% and after 12 weeks 23.5%. The mean LDL cholesterol decreased by 26.1%, 30.8% and 32.9% after 4.8 and 12 weeks of lovastatin treatment respectively. An increase in HDL cholesterol by 5.9%, 6.0% and 7.6% and decrease in triglyceride level by 10.7%, 14.9% and 14.0% respectively was also observed. In 6 patients on lovastatin treatment symptoms of acute pancreatitis in 1 case, a cataract in 1 case and aggravation of coronary insufficiency in 4 cases were noticed. These symptoms in the light of our knowledge of the mechanism of action of the drug used and of its side effects described in other trials, may be considered of independent on lovastatin. The treatment was discontinued in 5 cases (because of gastrointestinal intolerance in 2 patients, of aggravation of coronary insufficiency in 2 patients and of pain in the right hypochondrium in 1 patient who himself decided to stop the therapy).(ABSTRACT TRUNCATED AT 250 WORDS)
Lovastatin
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Two hundred and ten patients (119 men and 91 women, mean age 54) with primary hypercholesterolemia (97% with total serum cholesterol greater than 240 mg/dl) were treated with lovastatin during 12 weeks in a placebo-controlled multicenter trial (10 cities and 21 investigators). All patients remained under an isocaloric low-fat, low-cholesterol diet throughout the study, and received placebo on a single-blind basis for the first 4 weeks (pretreatment period). Serum total cholesterol (TC), triglycerides (TG) and HDL-cholesterol (HDL-C) were measured at the beginning (week-4) and again at week 12. TC was also measured at weeks 0, 4, 8 and 12, while LDL-cholesterol (LDL-C) was calculated by a modification of Friedewald's formula. At the 5 clinic visits vital signs and body weight were recorded, and patients were questioned about adverse experiences. Safety laboratory tests (complete blood count, serum creatinine and creatinine phosphokinase, fasting plasma glucose, serum bilirubin, transaminases and alkaline phosphatase) plus a resting electrocardiogram (EG) and a complete (slit lamp) ophthalmologic examination were also carried out at weeks-4 and 12. During the treatment period lovastatin dosage was adjusted from 20 mg/day to 40 or 80 mg/day, if the TC value was greater than 200 mg/dL, with the resulting mean daily increasing doses of 28 mg (weeks 0-4), 37 mg (weeks 4-8), and 55 mg (weeks 8-12).(ABSTRACT TRUNCATED AT 250 WORDS)
Lovastatin
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An adequate propranolol dose to reduce 25% the initial heart rate was searched in 19 children with portal hypertension. 13 were pre-hepatic and 6 hepatic hypertension, mean age: 6.96 +/- 3.48 years, range: 2-14 years. Treatment was started with 0.5 mg/kg/day increasing 0.25 mg/kg/day every third day, needing an average of 26 +/- 13 days (range: 6-54 days) to obtain the response. Daily dose ranged from 1 to 5.25 mg/kg/day (mean: 2.69 +/- 1.16). The highest daily dose was 175 mg, the lowest 23.4 mg (mean: 58.27 +/- 36.6 mg/day). Some parameters were evaluated before and after achieving the dose. There was a significant reduction of mean blood pressure (p < 0.01) and peripheral venous pressure (p < 0.05) in 68.4% of patients. A significant elevation (p < 0.001) of 24 hour urinary catecholamine levels occurred in 94.7%. Side effects were minimal. Propranolol could be considered a safe pharmacological option in these patients.
Mean blood pressure
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To analyze retrospectively data on lipid lowering efficacy, tolerability and safety of different doses of simvastatin in patients with primary hyperlipidemia.Thirty five patients (mean age 54.9-/+8.5 years, 15 men, 20 women) received simvastatin for 3-6 months in doses 10 (n=12), 20 (n=8), 40 (n=10) and 80 (n=5) mg/day. Average lowering of low density lipoprotein cholesterol was 28.9, 37.6, 39.7, and 46.2% on doses 10, 20, 40 and 80 mg/day, respectively. Elevation of activity of transaminases (AST and ALT) above 3 upper limits of normal (ULN) accompanied by right upper quadrant pain occurred in 1 patient and the drug (10 mg/day) was stopped. Symptomless elevation of AST and ALT activities above 2 ULN was registered in 2 other patients receiving 10 and 20 mg/day. The dose of 80 mg/day was well tolerated - none of 5 patients had symptoms of myopathy or elevated creatinekinase activity.
Tolerability
Hyperlipidemia
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Objective Arhalofenate is a novel antiinflammatory uricosuric agent. The objective of this study was to evaluate its antiflare activity in patients with gout. Methods This was a 12‐week, randomized, double‐blind, controlled phase IIb study. Eligible patients had had ≥3 flares of gout during the previous year, had discontinued urate‐lowering therapy and colchicine, and had a serum uric acid (UA) level of 7.5–12 mg/dl. Patients were randomly assigned at a 2:2:2:2:1 ratio to receive 600 mg arhalofenate, 800 mg arhalofenate, 300 mg allopurinol, 300 mg allopurinol plus 0.6 mg colchicine, or placebo once a day. The primary outcome measure was the flare incidence (number of flares divided by time of exposure). The serum UA level was a secondary outcome measure. Results A total of 239 gout patients were randomized and took at least 1 dose of study medication. The primary outcome measure comparing flare incidence between 800 mg arhalofenate and 300 mg allopurinol was achieved, with a 46% decrease in the 800 mg arhalofenate group (0.66 versus 1.24; P = 0.0056). Treatment with 800 mg arhalofenate was also significantly better than placebo ( P = 0.049) and not significantly different from treatment with 300 mg allopurinol plus 0.6 mg colchicine ( P = 0.091). Mean changes in serum UA level were −12.5% with 600 mg arhalofenate and −16.5% with 800 mg arhalofenate ( P = 0.001 and P = 0.0001, respectively, versus −0.9% with placebo). There were no meaningful differences in adverse events (AEs) between groups, and there were no serious AEs related to arhalofenate. Urinary calculus occurred in 1 patient receiving 300 mg allopurinol. No abnormal serum creatinine values >1.5‐fold the baseline value were observed in the arhalofenate‐treated groups. Conclusion Arhalofenate at a dosage of 800 mg decreased gout flares significantly compared to allopurinol at a dosage of 300 mg. Arhalofenate was well tolerated and appeared safe. Arhalofenate is the first urate‐lowering antiflare therapy.
Allopurinol
Colchicine
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Background:Bezafibrate has been reported to be useful in the treatment of liver dysfunction. Previously we reported that bezafibrate has also choleretic action. Bezafibrate drives this choleretic action along with biliary excretion of glutathione(GSH). Since ezetimibe has also been reported to be effective against fatty liver, we evaluated the effects of bezafibrate and ezetimibe as combination therapy in patients with dyslipidemia complicated by liver dysfunction. Methods:The study included 20 patients (13 men and 7 women). All patients received bezafibrate(400 mg administered as two 200 mg doses, one each in the morning and evening)and ezetimibe(10 mg at bedtime)administered daily over a period of 6 months. Eight of these 20 patients were previously on statin treatment and switched to the combination treatment. Results:Mean AST was 48 IU/L before combination treatment and decreased to 32 IU/L after 6 months of treatment, with significant decreases evident after 4 and 6 months. Mean ALT level was 63 IU/L before treatment and decreased to 34 IU/L, with a significant decrease evident from 1 month onward. Mean γ-GTP was 63 IU/L before treatment and decreased to 44 IU/L, with a significant decrease evident from 2 months onward. Mean TG levels were significantly decreased after 1 month of treatment, with a 46.3% decrease after 6 months. Mean HDL-C levels increases significantly at 2 months and 6 months, with a 24.8% increase after 6 months. In the 8 patients who were switched from statin monotherapy to bezafibrate plus ezetimibe combination therapy, mean levels of AST, ALT, and γ-GTP decreased, although not significantly. Mean HDL-C increased by 29.1% after 6 months, with significant increases after 5 and 6 months. Conclusion:Combination therapy using bezafibrate and ezetimibe is useful in the treatment of the patients with dyslipidemia complicated by liver dysfunction.
Bezafibrate
Ezetimibe
Choleretic
Combination therapy
Dyslipidemia
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Background:Previous studies indicated that a recently approved synthetic HMG-CoA reductase inhibitor, ato- rvastatin, reduces LDL cholesterol and triglyceride. To assess the efficacy on the level of serum LDL cholesterol and other lipoprotein fractions and its safety, we investigated 59 patients for lipid and side effect profile. Method:In patients with hypercholesterolemia, who showed 12-hours fasting serum LDL cholesterol >145 mg/dl and <250 mg/dl and triglyceride levels <400 mg/dl were enrolled to diet therapy for 4 weeks. After 4 weeks of diet therapy, serum lipid profile were reevaluated and patients with LDL cholesterol ≥130 mg/dl were as-signed to receive 10 mg dose of atorvastatin once daily for 4weeks. After 4 weeks of drug therapy, serum lipid profile were rechecked, if showed LDL cholesterol level≥130 mg/dl, assigned to receive 20 mg dose of atorva-statin once daily until 8 weeks. Result:Of the 59 patients were assigned to receive atorvastatin therapy, 52 pati-ents completed the study. Among lipid profiles, total cholesterol, triglyceride, LDL-cholesterol and apolipoprotein B levels showed significant reduction with mean reduction rate of 28%, 13%, 38%, 32% respectively after 4 weeks and 31%, 13%, 41% and 34% respectively after 8 weeks. HDL-Cholesterol and lipoprotein (a level did not show significant change after 8 weeks of therapy. Nine patients had mild adverse events, such as elevated ALT, epigastric pain, insomnia, thumb pain. postural hypotension, palpitation and constipation. Only three patie-nts of fifty-nine withdrew from the study due to adverse events related to drug treatment. Conclusion:The atorvastatin was highly effective and generally well tolerated with an acceptable safety profile in patients with primary hypercholestelemia. (Korean Circulation J 1999;29(2 :928-936
Lipid Profile
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