M. Winiarska

39 INTERACTION OF DULOXETINE HYDROCHLORIDE WITH WARFARIN CAUSING PERSISTENT, SEVERE ELEVATION OF INTERNATIONAL NORMALIZED RATIO.

To report interaction of Cymbalta (duloxetine hydrochloride) with warfarin leading to persistent, severe elevation of an INR. A 44 year old woman, homozygous for the factor V Leiden mutation, receiving warfarin (10 mg/day) for 1 year after an ischemic stroke, with a stable INR (2.17 ± 0.51) for the year, was evaluated by us 30 days after development of petechiae-purpura (day 94, Fig. 1). Serial measures were taken for INR and liver function tests (LFTs), and plasma warfarin was measured on day 85. Measures were taken on day 94 for fibrinogen, vitamin K-dependent clotting factors, and with repeat measures of factors II and X on day 98 (Fig. 1). No drugs taken daily over the previous year were changed (warfarin, atorvastatin, lamotrigine, topiramate, clorazepam, albuterol); however, Cymbalta (30 mg/day), a selective serotonin and norepinephrine reuptake inhibitor (SSNRI), was added by the psychiatrist at day 0 and was continued until day 94. Having unexpectedly high INR (5.0) on day 55, warfarin was stopped, but Cymbalta was continued. Despite cessation (documented by pill count) of warfarin, INR continued to rise to > 19 on day 85, when plasma warfarin level was 5.3 μg/mL (therapeutic range 2-8 μg/mL), 30 days after the last warfarin dose. INR was briefly reduced to 2.7 only by vitamin K (IV) on day 85. On day 94, with INR 6.4, 39 days after stopping warfarin, factors II, VII, and X had low values; LFTs and fibrinogen remained normal. On day 94, duloxetine was stopped, and by day 98, INR had fallen to 1.2, with factor II increasing to 48% and factor X to 54%. On day 105, INR was 0.9. The metabolism of warfarin involves several CY P450 isoenzymes (CY P 1A2, 2D6, 2C9, 2C19, and 3A4). Duloxetine inhibits CYP1A2 and CYP2D6 and could potentially interact with warfarin. Duloxetine is also highly protein bound in plasma (> 90%) and when given with warfarin, another highly protein-bound drug, could displace warfarin, possibly resulting in a toxic effect. Our case emphasizes the need to closely monitor for the toxic drug interactions between the 2 drugs.

41 ROSUVASTATIN ACCEPTABILITY, EFFICACY, AND SAFETY IN HYPERCHOLESTEROLEMIC PATIENTS UNABLE TO TOLERATE OTHER STATINS.

Statins as a class are well tolerated. We assessed acceptability, efficacy, and safety of rosuvastatin in 57 euthyroid patients with primary high LDL cholesterol (LDLC) who, serially, could not tolerate most other statins or cholesterol-lowering drugs, primarily because of myocitis. Of the 57 patients, 44 could not tolerate atorvastatin, 27 simvastatin, 15 pravastatin, 7 fluvastatin, 2 lovastatin, 1 Vytorin, 10 WelChol, 5 Zetia, 2 TriCor, and 2 Niaspan. Rosuvastatin (5 mg/day)-diet was given to 24 patients (3 men, 21 women, 21 white, 3 black, 3 type 2 diabetics, mean ± SD age 61 ± 9 years, BMI 31.7 ± 4.2, LDLC 179 ± 32 mg/dL). On rosuvastatin 5 mg-diet for a median of 5 months, weight fell 3.0 ± 7.7 lb (p = .016), LDLC fell 76 ± 35 mg/dL (p < .0001) to 103 ± 31 mg/dL, with median percent change -47%. Adjusted for changes in body weight, decrements in LDLC remained significant, LS mean ± SE -75 ± 8 mg/dL, p < .0001. None of the 24 patients discontinued the 5 mg rosuvastatin, muscle symptoms were minor to absent, and there were no untoward changes in liver function tests (

4 SUCCESS OF METFORMIN-PIOGLITAZONE IN RESOLVING ENDOCRINOPATHY AND INSULIN RESISTANCE-HYPERINSULINEMIA IN 40 WOMEN WITH POLYCYSTIC OVARY SYNDROME NOT OPTIMALLY RESPONSIVE TO METFORMIN ALONE.

3 times the laboratory upper normal limit), or in CPK (

74 METFORMIN-DIET AMELIORATES CORONARY HEART DISEASE RISK FACTORS AND FACILITATES RESUMPTION OF REGULAR MENSES IN ADOLESCENTS WITH POLYCYSTIC OVARY SYNDROME.

10 times the laboratory upper normal limit). Rosuvastatin (10 mg/day) was given to 33 patients, 16 men, 17 women, 31 white, 1 black, 1 other, 9 smokers, 4 type 2 diabetics, mean ± SD age 59 ± 10 years, BMI 31.1 ± 5.2, and LDLC 178 ± 53 mg/dL. On therapy for a median of 11 months, body weight fell 3.1 ± 6.8 lb (p = .014), LDLC fell 80 ± 49 mg/dL (p < .0001) to 96 ± 38 mg/dL, median percent change -48%. Adjusted for body weight change, decrements in LDLC remained significant, LS mean ± SE -82 ± 11 mg/dL, p < .0001. None of the 33 patients discontinued the 10 mg rosuvastatin, muscle symptoms were minor to absent, and there were no untoward changes in liver function tests (

2 WEIGHT LOSS IS A FEATURE OF PROTRACTED METFORMIN THERAPY IN WOMEN WITH POLYCYSTIC OVARY SYNDROME.

3 times the laboratory upper normal limit), or in CPK (

40 HEREDITARY THROMBOPHILIAS MEDIATING ARTERIAL THROMBOTIC EVENTS.

10 times the laboratory upper normal limit). Since rosuvastatin is not metabolized by the 3A4 isoenzyme of the cytochrome P450 enzyme system and is < 10% metabolized by the 2C9 isoenzyme, we speculate that its acceptability, efficacy, and safety in hypercholesterolemic patients unable to tolerate other statins are related to reduced interactions with other drugs known to inhibit CYP 450 enzymes. By contrast, atorvastatin, lovastatin, and simvastatin are metabolized through the 3A4 pathway and fluvastatin through 2C9, common pathways for many other drugs, facilitating drug-drug interactions, which may be expressed clinically as muscle symptoms, leading to discontinuance of the statin. Rosuvastatins LDLC lowering potency often facilitates reaching LDLC goals by use of low doses, 5 or 10 mg/day.

19 STROMELYSIN-1 5A/6A AND eNOS T-786C POLYMORPHISMS, MTHFR C677T AND A1298C MUTATIONS, AND CIGARETTE-CANNABIS SMOKING: A PILOT STUDY OF GENE-ENVIRONMENT PATHOPHYSIOLOGICAL ASSOCIATIONS WITH BUERGER'S DISEASE.

In 40 women (36 white, 1 black, 3 other) with polycystic ovary syndrome (PCOS) not optimally responsive to metformin (MET 2.55 g/day) for 1 year, endocrine and menstrual response to MET (2.55 g) with added pioglitazone (PIO 45 mg/day) for 1 year were compared to outcomes on MET alone. Before MET, 35% of women were obese with BMI 30.0 to < 40 and 48% had BMI 40 or higher (severely obese). In the year before MET, the mean ± SD (median) of expected menses was only 23 ± 27% (median 17%), rising to 44 ± 41% (median 33%) after 1 year on MET (p = .002), then rising to 81 ± 30% (median 100%) after 6 months on MET-PIO (p < .0001), 76 ± 33% (median 100%) at 9 months, and 78 ± 35% (median 100%) at 12 months. Before MET, mean ± SD weight was 106 ± 28 kg and median BMI 37.6 kg/m2. After 1 year on MET weight fell (104 ± 28 kg, p = .01) but increased on MET-PIO (106 ± 29 kg, p = .03). On MET for 1 year, median DHEAS fell nonsignificantly (p = .75) from median 224 to 201 μg/dL but then fell to 169 μg/dL on MET-PIO (p = .03). Median sex hormone binding globulin (SHBG) was 25 nmol/L before MET, 20 on MET (p > .1), and rose to 27 on MET-PIO (p < .001). Median fasting serum insulin was 20.2 μU/mL before MET, 20.1 on MET (p > 0.1), but then fell to 13.1 μU/mL on MET-PIO (p < .001). HOMA insulin resistance was 3.90 before MET, 4.76 on MET (p > .1), but then fell to 2.74 on MET-PIO (p < .001). HOMA insulin secretion was 285 before MET, 217 on MET (p > .1), but then fell to 159 on MET-PIO (p < .001). HDL cholesterol, 41 mg/dL before MET, 40 mg/dL on MET (p > .1), rose to 44 mg/dL on MET-PIO (p < .001). In obese and severely obese women with PCOS who do not optimally respond to MET, addition of PIO to MET (despite weight gain) promotes much more regular menses, lowers DHEAS, elevates SHBG, lowers fasting serum insulin, lowers HOMA insulin resistance and HOMA insulin secretion, and elevates HDL cholesterol. Combination of the insulin-sensitizing agents MET and PIO successfully resolves endocrinopathy and insulin resistance-hyperinsulinemia in obese women with PCOS who are not optimally responsive to MET alone.

Rosuvastatin 5 and 10 mg/d: A pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach ldl cholesterol goals with nonstatin lipid-lowering therapies

In 35 postmenarchal adolescent females (17 ± 2 years, range 14-19) with polycystic ovary syndrome (PCOS), in a case-series prospective description, we assessed effectiveness of metformin-diet for 1 year for reduction of weight, insulin, HOMA insulin resistance (IR), cholesterol, triglycerides, and resumption of regular menses. By selection, all 35 girls met the 2003 consensus criteria for diagnosis of PCOS; all 35 had clinical hyperandrogenism, 37% were amenorrheic, and 60% oligomenorrheic. Pretreatment median weight was 82.7 kg, BMI 30.8 kg/m2, and 19 (54%) girls had BMI > the CDC age-gender-specific 95th percentile (overweight). Calories (26% protein, 44% carbohydrate) were targeted to 1,500-1,800/day if BMI was < 25 or to 1,200-1,500/day if BMI was

Sustainability of 8% weight loss, reduction of insulin resistance, and amelioration of atherogenic-metabolic risk factors over 4 years by metformin-diet in women with polycystic ovary syndrome.

25, along with 2,550 mg metformin. After 1 year on metformin-diet, median weight fell from 82.7 to 79.1 kg (p = .009); the median of the percent change was -5%. In 6 girls (17%) weight loss was

Interaction of duloxetine and warfarin causing severe elevation of international normalized ratio

10 kg, in 8 (23%) was 5-10 kg, and in 11 (31%) was 0-5 kg. After 1 year on metformin-diet, fasting serum insulin 16.7 to 13.3 uU/mL (p < .0001), HOMA IR 3.41 to 2.74 (p = .0004), total cholesterol 164 to 151 mg/dL (p = .002), and triglyceride 103 to 85 mg/dL (p = .006). After 1 year on metformin-diet, reduction in insulin was associated with reduction in testosterone, R2 = 20%, p = .008. The percentage of cycles with normal menses rose from a pretreatment median of 8% to 100% after 1 year on metformin-diet, p < .0001. In 19/35 girls (54%) serum progesterone was