Do P-glycoprotein Medications Alter the Risk of Ventriculoperitoneal Shunt in Adults with Hydrocephalus?

Hydrocephalus is a disorder caused by excess fluid accumulation in the brain and results in brain damage with consequent cognitive and physical problems. This condition has no cure; the only treatment is brain surgery. Experimental data indicate that P-glycoprotein (P-gp) plays a crucial role in the pathogenesis of hydrocephalus due to its function in clearing macromolecules from the brain. Numerous medications frequently used are classified as P-gp inducers or inhibitors, and comprehending their effects may aid in attaining improved patient outcomes. Therefore, in this single-center retrospective study, we examined the risk of the need for ventriculoperitoneal shunt placement over 10 years among 4588 adult patients with hydrocephalus not exposed to any P-gp inhibitors/inducers or exclusively exposed to either P-gp inhibitors or inducers. Our analysis shows that patients exposed to P-gp inhibitors had a 3.2 times higher risk of requiring ventriculoperitoneal shunt surgery (P < .0001). In contrast, the relative risk was not significantly affected (P = .07) among those exposed to P-gp inducers. Our findings indicate the need for caution when prescribing P-gp inhibitors to patients with hydrocephalus. Additional studies using larger cohorts are required to confirm whether P-gp inducers in patients with hydrocephalus can mitigate the risk of ventriculoperitoneal shunt.

Magnesium Sulfate Treatment Correlates With Improved Neurological Function in Posterior Reversible Encephalopathy Syndrome (PRES): Report of a Case.

Posterior reversible encephalopathy syndrome (PRES) is a potentially reversible failure of cerebral autoregulation managed by correction of hypertension or underlying medical condition. Nonresponding cases progress to irreversible brain damage. There is some evidence of association of hypomagnesemia with PRES. We describe a case of nonresolving PRES where use of magnesium sulfate led to improvement in neurological function and eventual recovery. Our case highlights the need for a randomized controlled trial to test the efficacy of magnesium in PRES.

Validation and Clinical Utility of the hERG IC50:Cmax Ratio to Determine the Risk of Drug-Induced Torsades de Pointes: A Meta-Analysis.

BACKGROUND: Use of the QT interval corrected for heart rate (QTc) on the electrocardiogram (ECG) to predict torsades de pointes (TdP) risk from culprit drugs is neither sensitive nor specific. The ratio of the half-maximum inhibitory concentration of the hERG channel (hERG IC50) to the peak serum concentration of unbound drug (Cmax ) is used during drug development to screen out chemical entities likely to cause TdP. PURPOSE: To validate the use of the hERG IC50:Cmax ratio to predict TdP risk from a culprit drug by its correlation with TdP incidence. DATA SOURCES: Medline (between 1966 and March 2017) was accessed for hERG IC50 and Cmax values from the antihistamine, fluoroquinolone, and antipsychotic classes to identify cases of drug-induced TdP. Exposure to a culprit drug was estimated from annual revenues reported by the manufacturer. STUDY SELECTION: Inclusion criteria for TdP cases were provision of an ECG tracing that demonstrated QTc prolongation with TdP and normal serum values of potassium, calcium, and magnesium. Cases reported in patients with a prior rhythm disturbance and those involving a drug interaction were excluded. DATA EXTRACTION AND SYNTHESIS: The Meta-Analysis of Observational Studies in Epidemiology checklist was used for epidemiological data extraction by two authors. MAIN OUTCOME AND MEASURE: Negligible risk drugs were defined by an hERG IC50:Cmax ratio that correlated with less than a 5% chance of one TdP event for every 100 million exposures (relative risk [RR] 1.0). RESULTS: The hERG IC50:Cmax ratio correlated with TdP risk (0.312; 95% confidence interval 0.205-0.476, p<0.0001), a ratio of 80 (RR 1.0). The RR from olanzapine is on par with loratadine; ziprasidone is comparable with ciprofloxacin. Drugs with an RR greater than 50 include astemizole, risperidone, haloperidol, and thioridazine. CONCLUSIONS: The hERG IC50:Cmax ratio was correlated with TdP incidence for culprit drugs. This validation provides support for the potential use of the hERG IC50:Cmax ratio for clinical decision making in instances of drug selection where TdP risk is a concern.

Clinical Application and Pharmacodynamic Monitoring of Apixaban in a Patient with End-Stage Renal Disease Requiring Chronic Hemodialysis.

Despite prescribing guidance, limited data exist to describe the use of apixaban in patients with end-stage renal disease (ESRD) requiring hemodialysis (HD). Current apixaban dosing recommendations for this patient population are based largely on a single-dose pharmacokinetic study of eight patients. We describe the clinical application and pharmacodynamic monitoring of apixaban in a 62-year-old 156-kg African-American woman with nonvalvular atrial fibrillation and ESRD requiring hemodialysis who developed calciphylaxis while receiving warfarin therapy. Based on a multidisciplinary clinical judgment decision due to concern for drug accumulation after multiple doses in patients with ESRD receiving HD, she was anticoagulated with apixaban 2.5 mg twice/day, as opposed to 5 mg twice/day as recommended by the package insert. Antifactor Xa monitoring was used, and resultant peak and trough apixaban concentrations were above the upper limit of detection for our clinical laboratory (more than 2.00 IU/ml). On day 7 of her hospitalization, the patient developed gastrointestinal bleeding, and apixaban was discontinued; no further clinical signs of bleeding occurred during her subsequent hospitalization course. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 6) between apixaban exposure and the manifestation of gastrointestinal bleeding. The patient ultimately died 44 days after the acute bleeding event; however, coagulation concerns were not implicated in the patient's death. To our knowledge, this is the first case report that describes apixaban use and associated antifactor Xa monitoring in a patient with ESRD receiving HD, and it provides concern for current apixaban dosing recommendations in this patient population. Further pharmacokinetic and clinical data are likely necessary to better characterize apixaban use in these patients to optimize safety and efficacy.

The metabolic rationale for a lack of cross-reactivity between sulfonamide antimicrobials and other sulfonamide-containing drugs.

Sulfonamide antimicrobials (sulfamethoxazole) contain an arylamine group, oxidized by CYP2C9 to the hydroxylamine with subsequent auto-oxidation to a highly reactive [-nitroso-] intermediate is a necessary (if not sufficient) cause of drug hypersensitivity. Accordingly, xenobiotics that do not contain an arylamine cannot generate this reactive intermediate and do not cross react with sulfonamide antimicrobials. Despite this well-attested observation, product labeling and direct-to-consumer advertising for non-arylamine therapeutic classes of drugs containing the sulfonamido- functional group persist with a warning of the potential for cross-reactivity. It is hoped that by offering an explicit rationale for the lack of cross-reactivity will provide medical practitioners with a level comfort to proceed with prescribing medications such as thiazide diuretics and celecoxib for patients with a history of hypersensitivity to sulfonamide antimicrobials.

To bind or to let loose: effectiveness of sodium polystyrene sulfonate in decreasing serum potassium.

Background. The use of sodium polystyrene sulfonate in decreasing serum potassium has recently been questioned due to the lack of documented effectiveness. Methods. A retrospective cohort analysis of all hospitalized patients who received sodium polystyrene sulfonate over four months was performed. The change in serum potassium was noted over a period of 24 hours. Patients who received any other form of potassium-altering drug or treatment were excluded. Results. The administration of sodium polystyrene sulfonate reduced serum potassium by 16.7% (P < 0.001) as compared to the baseline serum potassium over a period of 24 hours. During this same time, no change in serum creatinine was identified (P = 0.73). In addition, there was no correlation between potassium and creatinine change (r(2) = 0.0004 and P = 0.99). Patients with higher initial serum potassium (≥5.6 mEq/L) reduced their potassium concentration 4% more than those with initial serum potassium of <5.6 mEq/L; however, this reduction did not reach statistical significance (P = 0.32). There was no significant difference in the effectiveness of 15 gm and 30 gm resin preparation (P = 0.54). Thirteen deaths were noted in our cohort, of which one death was due to ischemic colitis. Conclusion. We conclude that sodium polystyrene sulfonate is effective in lowering serum potassium.

Every error a treasure: improving medication use with a nonpunitive reporting system.

BACKGROUND: The fear of reprisal, combined with the additional time required for reporting, are significant disincentives to reporting of medical events. Such considerations provided an incentive for the Upstate Medical University Hospital (Syracuse, New York) to develop monitoring systems to decrease the potential for drug harm. IMPLEMENTING A NONPUNITIVE REPORTING SYSTEM: Previously, a convenient, point-based score card system for punishment and remediation led to underreporting and hindered the identification of safety improvement opportunities in medication use processes. Nursing buy-in was accomplished through careful initial negotiations that emphasized that patients were best served by learning from errors in the medication use process. The revised medication event reporting policy, as established in October 2000 for all staff, severed the link between reporting errors and performance evaluations. RESULTS: Data collected 18 months before the policy change was compared with data collected after the policy change was enacted in October 2000. The number of reports received each month increased from an average of 19 to 102 (p < .001). DISCUSSION: Substantive quality improvements in medication have been achieved by using a systematic approach to the analysis of the markedly increased number of reported medication events following the introduction of a nonpunitive reporting system.

Hospital pharmacology: An alternative model for practice and training in clinical pharmacology.

External pressures continue to be exerted on hospitals to prioritize programs that minimize costs and improve the safety of medication use. Clinical pharmacologists are in an ideal position to provide leadership for such programs. At academic health centers, an added dimension is the exposure of physicians-in-training to the practical application of clinical pharmacology principles. At SUNY Upstate Medical University, the approach is led by a physician with clinical pharmacists and pharmacy practice residents. To align the clinical pharmacists with the overall goals of the program, a faculty promotions track system designed specifically for them has been enacted within the college of medicine. This report summarizes the "hospital pharmacology" program that provides funding for an academic physician-clinical pharmacologist. With this report, the authors hope to outline an alternative practice and training paradigm to potentially address the decline in physicians being trained in and practicing clinical pharmacology since the late 1970s.

Profound metoprolol-induced bradycardia precipitated by acetaminophen-propoxyphene.

Pharmacokinetic studies demonstrate that propoxyphene is a potent inhibitor of cytochrome P450 (CYP) 2D6. Clinically significant sequelae have not been previously reported. We report a case of this inhibition manifested by life-threatening bradycardia in a patient receiving a CYP2D6 substrate, metoprolol. A 48-year-old man came to the emergency department complaining of dizziness 3 hours after ingesting metoprolol, at his usual dose, and 2 tablets of propoxyphene, newly begun postoperatively. Four hours after ingestion of both drugs, the patient was noted to have a ventricular rate of about 30 beats/min with underlying atrial fibrillation. The patient's ventricular response returned to normal within 11 hours of ingestion. We have demonstrated the clinical importance of the interaction between propoxyphene and metoprolol likely resulting from inhibition of hepatic clearance of metoprolol by propoxyphene. Underscoring the clinical relevance of CYP2D6 inhibition by an analgesic of questionable efficacy should proscribe its use.

The cardiovascular toxicity of selective and nonselective cyclooxygenase inhibitors: comparisons, contrasts, and aspirin confounding.

The premature suspension of the Alzheimer Disease Anti-inflammatory Prevention (ADAPT) and the Adenoma Prevention with Celecoxib (APC) trials prompted intense review of the cardiovascular safety profile of selective and nonselective cyclooxygenase (COX) inhibitors. This article reviews the current state of selective COX-2 inhibitors, discusses the mechanistic evidence underlying the cardiovascular risk associated with selective COX-2 inhibition, outlines the pharmacodynamics of aspirin effects on platelets and the interference of propionic acid derivatives (ibuprofen and naproxen) with these effects, and poses that aspirin confounding may have led to the erroneous conclusion of naproxen-associated adverse cardiovascular outcomes in the ADAPT trial. Finally, recommendations regarding selective COX-2 inhibitors and appropriate timing of aspirin coadministration with traditional NSAIDs are proposed in relevance to patient safety and future trial design.

Polymorphisms and the pocketbook: the cost-effectiveness of cytochrome P450 2C19 genotyping in the eradication of Helicobacter pylori infection associated with duodenal ulcer.

The clinical outcome of duodenal ulcer treated with proton pump inhibitor (PPI)-based, anti-Helicobacter pylori (H.p.) regimens varies according to cytochrome P450 2C19 (CYP2C19) genotype. CYP2C19 genotypes differ markedly in peoples of Pacific Rim descent compared with another ethnicity. The authors sought to determine the specific impact that these factors have on the cost-effectiveness of duodenal ulcer management. Their model consisted of two patient cohorts with Helicobacter pylori and duodenal ulcer, trichotomized into CYP2C19 homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs), altering the anti-H.p. regimen in the genotyped cohort only. The authors took the perspective of a third-party payer, and the denominator was ulcer episode prevented. In the reference case, the use of CYP2C19 genotyping prior to initiating anti-H.p. therapy was dominant (costs were saved with each ulcer episode prevented) in all geographic regions of the United States. The subsequent break-even analysis showed a range of 89.20 dollars to 118.96 dollars--from Hawaii to the Midwest, respectively--required to eliminate the cost-savings from each genotype test performed. Using probabilities most unfavorable to genotyping, the variation of peoples with Pacific Rim origins from 0% to 100% altered the cost-effectiveness from 495 dollars to 2125 dollars per ulcer event prevented, respectively. The results suggest that treatment decisions for H.p. infection that are based on a patient's CYP2C19 genotype decreases expenses for health plans implementing testing. This analysis provides an economic basis to support recent calls to expand this technology into routine clinical care to prevent toxicity of narrow therapeutic index drugs.