Warfarin Dosing According to the Genotype-guided Algorithm is Most Beneficial in Patients With Atrial Fibrillation: A Randomized Parallel Group Trial.

BACKGROUND: Observational studies have indicated potential benefits of CYP2C9- and VKORC1-guided dosing of warfarin but randomized clinical trials have resulted in contradictory findings. One of the reasons for contradiction may be the negligence of possible differences between warfarin indications. This study aims to determine efficacy and safety of genotype-guided and clinically guided dosing of warfarin in atrial fibrillation (AF), deep-vein thrombosis (DVT), and pulmonary embolism (PE) within the first 5 days after the introduction of therapy. METHODS: In this single-center, single-blinded, randomized, controlled trial including patients of both sexes, ≥18 years of age, and diagnosed with AF, DVT, or PE, a total of 205 consecutive patients were allocated into the group where warfarin therapy was genotype-guided pharmacogenetics guided (PHG), and where it was adjusted according to the clinical parameters non pharmacogenetics guided (NPHG). Genotyping of CYP2C9*2, *3, and VKORC1 was performed using the real-time polymerase chain reaction method. The primary outcomes were the percentage of time in the therapeutic international normalized ratio (INR) (2.0-3.0) range and the percentage of patients who achieved a stable anticoagulation defined as the INR (2.0-3.0) range in at least 2 consecutive measurements. RESULTS: In patients with AF, the percentage of time spent in the therapeutic range of INR was higher in the PHG group [mean = 26% (SD 25.0)] than in the NPHG group [mean = 14% (SD 18.6)], [Δ = 12; 95% confidence interval, 0-23; P = 0.040]. There was no significant difference in other 2 indications for warfarin treatment. A stable dose of warfarin was achieved in a statistically higher number of patients in the PHG group 14/30 (47%) than in the NPHG group 7/32 (22%) (odds ratio = 3.13, 95% confidence interval, 0.92-10.98; P = 0.039). CONCLUSIONS: CYP2C9 and VKORC1 genotype-guided dosing of warfarin may be beneficial in patients diagnosed with AF. There is no evidence for such conclusion in patients with DVT and PE.

Amoxicillin-induced aseptic meningitis: case report and review of published cases
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OBJECTIVE: Amoxicillin-induced aseptic meningitis (AIAM) is an extremely rare adverse reaction with only 12 reported cases. The term aseptic meningitis refers to patients who have clinical and laboratory evidence for meningeal inflammation with negative routine bacterial cultures. Since the exact pathogenesis is still unknown and clinical signs and cerebrospinalfluid (CSF) findings vary greatly, AIAM is usually a diagnosis of exclusion. CASE SUMMARY: We report a clinical case of a patient referred to the clinical pharmacology outpatient clinic for consultation on suspected recurrent AIAM and a review of published cases. CONCLUSIONS: This report adds to the evidence-base of AIAM and emphasizes the importance of taking a thorough medication history in individuals with suspected meningitis. Considering the wide utilization of amoxicillin, it is important that healthcare providers are aware of AIAM.
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Clinical pharmacology consultation: a better answer to safety issues of drug therapy during pregnancy?

PURPOSE: drug safety classifications give a very basic estimation of risk and should only be used as general guideline when assessing risk of pregnancy-related drug exposure or planning treatment. We conducted a study to assess the strength of association between both the clinical pharmacologists' risk assessment and the FDA risk categorization, and adverse pregnancy outcomes. METHODS: we retrospectively reviewed records of 1,076 patients consecutively referred to the clinical pharmacology outpatient clinic for pregnancy-related drug exposure (2000-2008). Clinical pharmacologists' risk assessments were reviewed in relation to FDA drug categorization and available pregnancy outcomes. RESULTS: overall, clinical pharmacologists' risk estimation was in agreement with the FDA risk categorization system in only 28% of consulted women, and in only 9% of women with high-risk exposure (FDA DX). Clinical pharmacologists' risk assessment confirming high-risk drug exposure had a better positive predictive value for adverse pregnancy outcomes than the FDA DX categorization (25% vs 14% respectively), while the negative predictive values were similar (92% vs 94% respectively). Clinical pharmacologists' risk assessment was a better predictor of adverse pregnancy outcomes compared with FDA risk categorization (OR 2.11 [95%CI 1.5-3.1; p < 0.001] vs OR 1.52 [95%CI 1.1-2.1; p = 0.014] respectively). CONCLUSIONS: additional evaluation beyond the FDA drug classification is essential for safer and more rational drug use in pregnancy. Clinical pharmacologists who have undergone rigorous medical training are ideally placed to consult on administration of medicines in pregnant women, thus making the prescribing of treatments in that patient category substantially safer and more rational.

No Adverse Effects After Radioiodine Treatment at 3 Weeks of Pregnancy.

Radioactive iodine is used for the treatment of hyperthyroidism. Because it accumulates in the fetal thyroid, its administration during pregnancy may cause severe and potentially irreversible hypothyroidism in neonates, with consequent mental retardation, and it is contraindicated during the whole pregnancy. We present a case of a pregnant woman inadvertently treated with 1 mCi (37 MBq) of I in the earliest period of pregnancy and subsequently gave birth to a male infant without signs or symptoms of hypothyroidism or any other damage. This case illustrates that when radioactive iodine administration happens around the third week of gestation pregnancy outcome can be normal.

Antitumor activity of novel N-sulfonylpyrimidine derivatives on the growth of anaplastic mammary carcinoma in vivo.

PURPOSE: The purpose of this study was to investigate in vivo antitumor activity of newly synthesized N-sulfonylpyrimidine derivatives 1-(p-toluenesulfonyl)cytosine (4H), 1-(p-toluenesulfonyl)cytosine hydrochloride (4HxHCl) and zinc(II) complex of 1-(p-toluenesulfonyl)cytosine (4K). MATERIALS AND METHODS: In order to do that we have used mouse anaplastic mammary carcinoma (AMCa). Tumor cells (10(6)) in a volume of 0.02 ml were transplanted into the thigh of the right hind leg of CBA mice. All compounds were dissolved in distilled water immediately before injecting to animals. RESULTS: Antitumor effect of these compounds depends on drug doses and time interval between tumor transplantation and drug application. Further the efficacy of these compounds depends on number of drug injections, i. e. whether drug was given in single or in multiple doses. Multiple doses of 400 mg/kg of 1-(p-toluenesulfonyl)cytosine (4H) showed good antitumor effect when applied on day 1, 3, 5, 7 and 9 after tumor transplantation. Still good but slightly lower antitumor effect was also achieved when that compound was given in a single dose (1,200 mg/kg) on day 1 after tumor transplantation. The longest period of tumor growth time was obtained after application of 1-(p-toluenesulfonyl)cytosine hydrochloride (4HxHCl) given as a single dose (300 mg/kg) on day 1 or on day 6 after tumor implantation. However, antitumor effect of zinc(II) complex of 1-(p-toluenesulfonyl)cytosine (4K) was very strong when 300 mg/kg was given on day 1 or day 6, while this effect was slightly lower when drug (200 mg/kg/inj) was given on day 1, 3, 5, 7 and 9 or on day 6, 8, 10, 12 and 14. CONCLUSION: In this work it has been found that N-1-sulfonylcytosine derivatives have strong antitumor activity against mouse mammary carcinoma which is a good reason for further research of these compounds both in experimental and preclinical studies.