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The antithrombotic benefits of warfarin are countered by a narrow therapeutic index that contributes to excessive bleeding or cerebrovascular clotting and stroke in some patients. This article reviews the current literature describing warfarin sensitivity genotyping and compares the results of that review to the findings of our study in 189 patients at Mayo Clinic conducted between June 2001 and April 2003. For the review of the literature, we identified relevant peer-reviewed articles by searching the Web of Knowledge using key word warfarin-related adverse event. For the 189 Mayo Clinic patients initiating warfarin therapy to achieve a target international normalized ratio (INR) in the range of 2.0 to 3.5, we analyzed the CYP2C9 (cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex, subunit 1) genetic loci to study the relationship among the initial warfarin dose, steady-state dose, time to achieve steady-state dose, variations in INR, and allelic variance. Results were compared with those previously reported in the literature for 637 patients. The relationships between allelic variants and warfarin sensitivity found in our study of Mayo Clinic patients are fundamentally the same as in those reported by others. The Mayo Clinic population is predominantly white and shows considerable allelic variability in CYP2C9 and VKORC1. Certain of these alleles are associated with increased sensitivity to warfarin. Polymorphisms in CYP2C9 and VKORC1 have a considerable effect on warfarin dose in white people. A correlation between steady-state warfarin dose and allelic variants of CYP2C9 and VKORC1 has been demonstrated by many previous reports and is reconfirmed in this report. The allelic variants found to most affect warfarin sensitivity are CYP2C9*1*1-VKORC1BB (less warfarin sensitivity than typical); CYP2C9*1*1-VKORC1AA (considerable variance in INR throughout initiation); CYP2C9*1*2-VKORC1AB (more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*2-VKORC1AB (much more sensitivity to warfarin than typical); CYP2C9*1*3-VKORC1AA (much more sensitivity to warfarin than typical); and CYP2C9*2*2-VKORC1AB (much more sensitivity to warfarin than typical). Although we were unable to show an association between allelic variants and initial warfarin dose or dose escalation, an association was seen between allelic variant and steady-state warfarin dose. White people show considerable variance in CYP2C9 allele types, whereas people of Asian or African descent infrequently carry CYP2C9 allelic variants. The VKORC1AA allele associated with high warfarin sensitivity predominates in those of Asian descent, whereas white people and those of African descent show diversity, carrying either the VKORC1BB, an allele associated with low warfarin sensitivity, or VKORC1AB or VKORC1AA, alleles associated with moderate and high warfarin sensitivity, respectively.

Background. We describe a heart transplant patient with painful periostitis and exostoses who was receiving long-term therapy with voriconazole, which is a fluoride-containing medication. Elevated plasma and bone fluoride levels were identified. Discontinuation of voriconazole therapy led to improvement in pain and reduced fluoride and alkaline phosphatase levels. Methods. To determine whether voriconazole is a cause of fluoride excess, we measured plasma fluoride levels in 10 adult post-transplant patients who had received voriconazole for at least 6 months and 10 post-transplant patients who did not receive voriconazole. To assess the effect of renal insufficiency on fluoride levels in subjects receiving voriconazole, half were recruited on the basis of a serum creatinine level of ≥1.4 mg/dL on their most recent measurement, whereas the other 5 subjects receiving voriconazole had serum creatinine levels <1.4 mg/dL. All control subjects had serum creatinine levels of ≥1.4 mg/dL. Patients were excluded from the study if they received a fluorinated pharmaceutical other than voriconazole. Results. All subjects who received voriconazole had elevated plasma fluoride levels, and no subjects in the control group had elevated levels (14.32 μmol/L ± 6.41 vs 2.54 ± 0.67 μmol/L; P<.001). Renal function was not predictive of fluoride levels. Plasma fluoride levels remained significantly higher in the voriconazole group after adjusting for calcineurin inhibitor levels and doses. Half of the voriconazole group subjects had evidence of periostitis, including exostoses in 2 patients. Discontinuation of voriconazole therapy in patients with periostitis resulted in improvement of pain and a reduction in alkaline phosphatase and fluoride levels. Conclusions. Voriconazole is associated with painful periostitis, exostoses, and fluoride excess in posttransplant patients with long-term voriconazole use.

[...]concerns have been raised about the physiological consequences of metal release from MoM hip prostheses into the periprosthetic tissue and systemic circulation. Co and Cr concentrations in the serum and hip joint fluid correlate with the degree of MoM implant wear and are increased in individuals with an accumula- tion of metal debris in the periprosthetic tissue. [...]some scientists have suggested that Co and Cr concentrations be routinely measured during the management of patients with MoM hip prosthe- ses.

Background: Exposure to drugs and toxins is a major cause for patients’ visits to the emergency department (ED). Methods: Recommendations for the use of clinical laboratory tests were prepared by an expert panel of analytical toxicologists and ED physicians specializing in clinical toxicology. These recommendations were posted on the world wide web and presented in open forum at several clinical chemistry and clinical toxicology meetings. Results: A menu of important stat serum and urine toxicology tests was prepared for clinical laboratories who provide clinical toxicology services. For drugs-of-abuse intoxication, most ED physicians do not rely on results of urine drug testing for emergent management decisions. This is in part because immunoassays, although rapid, have limitations in sensitivity and specificity and chromatographic assays, which are more definitive, are more labor-intensive. Ethyl alcohol is widely tested in the ED, and breath testing is a convenient procedure. Determinations made within the ED, however, require oversight by the clinical laboratory. Testing for toxic alcohols is needed, but rapid commercial assays are not available. The laboratory must provide stat assays for acetaminophen, salicylates, co-oximetry, cholinesterase, iron, and some therapeutic drugs, such as lithium and digoxin. Exposure to other heavy metals requires laboratory support for specimen collection but not for emergent testing. Conclusions:Improvements are needed for immunoassays, particularly for amphetamines, benzodiazepines, opioids, and tricyclic antidepressants. Assays for new drugs of abuse must also be developed to meet changing abuse patterns. As no clinical laboratory can provide services to meet all needs, the National Academy of Clinical Biochemistry Committee recommends establishment of regional centers for specialized toxicology testing.

No pharmacotherapies have been shown to increase long-term (≥6-month) abstinence rates among smokeless tobacco (ST) users. Available evidence suggests that underdosing may occur with standard dose nicotine replacement therapy (NRT) in ST users. We investigated the effect of high-dose nicotine therapy on tobacco withdrawal symptoms among ST users in a randomized, controlled clinical pilot study. A total of 42 ST users using at least 3 cans or pouches per week were randomized to nicotine patch doses of 63, 42, or 21 mg/day or placebo for 8 weeks. Multiple daily assessments of tobacco withdrawal and nicotine toxicity were obtained with an electronic diary. During the first week of nicotine patch therapy, we observed a dose-response relationship such that higher nicotine patch doses were associated with less decreased arousal (χ2=6.87, p=.009), less negative affect (χ2=3.85, p=.05), and less restlessness (χ2=3.90, p=.048). During the second week, higher nicotine patch doses were associated with less decreased arousal (χ2=6.77, p=.009). Overall, the frequency of nicotine toxicity symptoms did not differ by dose group. Of specific symptoms, nausea was observed to be more frequent in the 63 mg/day dose group compared with placebo (p=.035). In conclusion, high-dose nicotine patch therapy resulted in a greater reduction of tobacco withdrawal symptoms among ST users using at least 3 cans per week. High-dose nicotine patch therapy is safe and well tolerated in this population of tobacco users.

Objectives: To describe a homemade form of smokeless tobacco known as Iqmik used among Alaska Natives residing in western Alaska. Methods: Individual and small-group interviews were conducted with 23 adult Alaska Natives. The major themes from the interview data were summarized. A chemical analysis was conducted of the alkalinity of a sample of fungus ash used to prepare Iqmik. Results: Few adverse health effects of using Iqmik were reported. The alkalinity of the sample of fungus ash was high (pH=10.9). Conclusion: The high alkalinity of Iqmik may contribute to the higher rates of tobacco use in this population.

Objective. To determine the concentration of nicotine and cotinine in maternal blood and neonatal cord blood among pregnant Alaska Native women and to assess the neonates for neurobehavioral effects. Methods. In a nonrandomized, clinical observational pilot trial, 60 pregnant Alaska Native women were enrolled for assessment of Iqmik (a mixture of leaf tobacco and ash) and other tobacco use during pregnancy and at delivery. Neonatal cord blood, nicotine and cotinine concentrations were obtained, and neonatal neurobehavioral effects were assessed using the Lipsitz scale. Results. At delivery, there were 22 subjects who reported using only Iqmik, and 10 who used other tobacco products. Subjects who reported using only Iqmik prior to delivery had higher concentrations of cotinine (167 ± 116 vs. 81 ± 100) in maternal blood (rank sum test, p = 0.036) and higher concentrations of nicotine (8.4 ± 7.3 vs. 4.4 ± 5.1, p = 0.048) and cotinine (153 ± 115 vs. 70 ± 95, p = 0.048) in cord blood compared to subjects who reported using other tobacco products. Neurobehavioral signs as assessed by the Lipsitz score were increased in neonates born to mothers using only Iqmik (3.7 ± 1.8, p = 0.011), or to mothers using other tobacco products (3.4 ± 1.4, p = 0.034) compared to neonates born to women who reported no tobacco use (1.8 ± 1.4). Conclusions. Mothers who use Iqmik and their neonates have higher cotinine concentrations compared to mothers who use cigarettes and/or other forms of tobacco. Neurobehavioral signs occur in neonates born to women who use Iqmik but also in neonates born to mothers who use other forms of tobacco during pregnancy.

Background: Immunoassay-based screening for amphetamines has a variable positive predictive value (PPV) for detecting amphetamine abuse. The lack of immunoassay specificity necessitates confirmatory testing by gas chromatography–mass spectrometry (GC/MS), but the technical complexity and expense of GC/MS limit its availability. Physicians may make decisions regarding patient disposition based on unverified results. In this study we assessed the utility of using dose–response properties to distinguish urine samples containing amphetamines from samples containing cross-immunoreactive species. Methods: Urine was supplemented with known concentrations of amphetamine, methamphetamine, methylenedioxymethamphetamine (MDMA), or pseudoephedrine. Using a series of dilutions, we determined the maximum change in rate over the fractional change in concentration for each compound in the Emit® II amphetamine/methamphetamine immunoassay. Patient urine samples that screened positive for amphetamines were diluted 1:1, 1:10, and 1:20, and maximum slope estimates within the dynamic assay range were determined. An optimal slope cutoff that differentiated samples containing (meth)amphetamine from those containing cross-reacting species was determined by ROC analysis. Results: The slope of the dose response was largest for amphetamine and methamphetamine, followed by MDMA and pseudoephedrine. The optimum slope cutoff for identifying patient specimens containing (meth)amphetamine was 320 (sensitivity, 96%; specificity, 90%; PPV, 92%). High concentrations of less reactive compounds may mask low concentrations of amphetamines. Conclusions: Use of the slope of the dose–response relationship in patient urine specimens can enhance the PPV of presumptive positive immunoassay results but does not exclude the presence of low amphetamine concentrations in samples containing high concentrations of cross-reactive species.

A 65-year-old female with biopsy-confirmed nephrogenic systemic fibrosis (NSF) received a kidney transplantation. Despite good kidney function, her symptoms continued to progress. Deferoxamine was administered intramuscularly at 500 mg/day and later 1000 mg/day after 1 week with no adverse effects. Urine excretion of gadolinium increased from 6.0 μg/day to 11.6 μg/day and subsequently to 13.0 μg/day with 500 mg/day and 1000 mg/day of deferoxamine, respectively. Serum levels, however, remain unchanged from 1.7 ng/ml to 1.4 ng/ml. Although chelation therapy may have a role in the treatment of NSF, deferoxamine is too weak and a stronger chelator is needed.

The ganglionic blocking agent trimethaphan (TMP) is no longer produced. Therefore, a need exists for alternative pharmacological approaches to investigate baroreflex control of the circulation. The aim of the present study was to examine baroreflex-mediated cardiovascular responses during the administration of a muscarinic receptor antagonist (glycopyrrolate; GLY: ) and a selective alpha-2 receptor agonist (dexmedetomidine; DEX: ) and to compare responses to ganglionic blockade with TMP. We hypothesized that combined GLY-: DEX: would inhibit the baroreflex similar to TMP. Ten volunteers participated in two study days and were instrumented with pulse oximeter, nasal cannula, ECG, continuous blood pressure monitoring (Finapres), and I.V. catheter for drug infusions. Each study day consisted of a control condition followed by either combined GLY: -DEX: or TMP on alternating days. A Valsalva maneuver was performed under each condition with every subject and six subjects received bolus phenylephrine (25 mug) during GLY: -DEX: and TMP. Combined GLY: -DEX: increased (P < 0.05) blood pressure (99 +/- 4 mmHg) and heart rate (99 +/- 3 bpm) relative to control condition (BP: 90 +/- 2 mmHg; HR: 64 +/- 3 bpm) and TMP infusion decreased (P < 0.05) blood pressure (79 +/- 3 mmHg) while increasing heart rate (88 +/- 3 bpm). Valsalva maneuver elicited a persistent drop in arterial pressure (no phase IIb recovery) with the absence of a phase IV overshoot during both GLY: -DEX: and TMP conditions. Phenylephrine increased systolic pressure 34 +/- 4 mmHg under GLY: -DEX: and 23 +/- 3 mmHg with TMP (P < 0.05). Heart rate only decreased 1 +/- 2 bpm during GLY: -DEX: and 1 +/- 1 bpm with TMP. Taken together, our results suggest that GLY: -DEX: is a reasonable alternative to TMP for baroreflex inhibition.