An open-label, randomized, four-treatment crossover study evaluating the effects of salt form, acetaminophen, and food on the pharmacokinetics of phenylephrine.

Phenylephrine hydrochloride (HCl) is a decongestant available in over-the-counter (OTC) medicines. Previously marketed prescription products contained phenylephrine tannate, an extended-release salt, which allowed dosing every 8-12 h. Given the regulatory history that cold medicines marketed before 1962 had limited supporting clinical data, and with widespread replacement of pseudoephedrine by phenylephrine in OTC products over the last ten years, the need for contemporary studies grew. This exploratory crossover study evaluated effects of salt form, acetaminophen, and food on phenylephrine pharmacokinetics and metabolites in healthy adults. Test treatments were 25 mg phenylephrine tannate (equivalent to 10 mg phenylephrine HCl) combined with 200 mg guaifenesin, fasted; 10 mg phenylephrine HCl combined with 650 mg acetaminophen, fasted; and 10 mg phenylephrine HCl, fed. The reference treatment was 10 mg phenylephrine HCl, fasted. Plasma phenylephrine pharmacokinetics and urine metabolites were determined. Although the tannate salt slowed phenylephrine absorption compared with the HCl salt, terminal concentrations were similar, suggesting that products containing the tannate salt should not be dosed less frequently than those containing the HCl salt. The premise that acetaminophen increases phenylephrine bioavailability by competition for presystemic sulfation was corroborated by increased phenylephrine sulfate in urine. Food delayed phenylephrine absorption, but not the total amount absorbed.

Comparison of hydrodynamically closed isotachophoresis-capillary zone electrophoresis with hydrodynamically open capillary zone electrophoresis hyphenated with tandem mass spectrometry in drug analysis: pheniramine, its metabolite and phenylephrine in human urine.

The advanced two dimensional isotachophoresis (ITP)-capillary zone electrophoresis (CZE) hyphenated with tandem mass spectrometry (MS/MS, here triple quadrupole, QqQ) was developed in this work to demonstrate analytical potentialities of this approach in the analysis of drugs in multicomponent ionic matrices. Pheniramine (PHM), phenylephrine (PHE), paracetamol (PCM) and their potential metabolic products were taken for the analysis by the ITP-CZE-ESI-QqQ technique working in hydrodynamically closed CE separation system and then a comparison with the conventional (hydrodynamically open) CZE-ESI-QqQ technique was made. The ITP-CZE-ESI-QqQ method was favorable in terms of obtainable selectivity (due to highly effective heart-cut analysis), concentration limits of detection (LOD at pgmL(-1) levels due to enhanced sample load capacity and ITP preconcentration), sample handling (on-line sample pretreatment, i.e. clean-up, preconcentration, preseparation), and, by that, possibilities for future automation and miniaturization. On the other hand, this experimental arrangement, in contrast to the CZE-ESI-QqQ arrangement supported by an electroosmotic flow, is principally limited to the analysis of uniformly (i.e. positively or negatively) charged analytes in one run without any possibilities to analyze neutral compounds (here, PCM and neutral or acidic metabolites of the drugs had to be excluded from the analysis). Hence, these general characteristics should be considered when choosing a proper analytical CE-MS approach for a given biomedical application. Here, the analytical potential of the ITP-CZE-ESI-QqQ method was demonstrated showing the real time profiles of excreted targeted drugs and metabolite (PHM, PHE, M-PHM) in human urine after the administration of one dose of Theraflu(®) to the volunteers.

Multidrug analysis of pharmaceutical and urine matrices by on-line coupled capillary electrophoresis and triple quadrupole mass spectrometry.

The present work illustrates potentialities of CE hyphenated with MS/MS for the simultaneous determination and identification of a mixture of simultaneously acting drugs in pharmaceutical and biological matrices. Here, the hyphenation was provided by ESI interface, while the MS/MS technique was based on the triple quadrupole configuration. Three drugs, namely pheniramine, phenylephrine, and paracetamol were determined and identified with high reliability due to their characterization in three different dimensions, i.e. electrophoresis and MS/MS, that prevented practically any interference. Appropriately selected transitions of the analytes (parent ion-quantifier product ion-qualifier product ion) provided their selective determination at maximum S/N. The proposed CE-MS/MS method was validated (LOD/LOQ, linearity, precision, recovery, accuracy) and applied for (i) the multidrug composition pharmaceuticals, namely Theraflu®, and (ii) human urine taken after per-oral administration of the same pharmaceutical preparation. The method was applied also for the investigation of potential weak associates of the drugs and monitoring of predicted (bio)degradation products of the drugs. Successful validation and application of the proposed method suggest its routine use in highly effective and reliable advanced drug control and biomedical research.

Immunoassay cross-reactivity of phenylephrine and methamphetamine.

Phenylephrine, an α(1) -adrenergic agonist, and methamphetamine, a prescription drug and substance of abuse, have similar chemical structures and thus have the potential to cross-react in qualitative screening tools such as a urine drug screening (UDS) performed by immunoassay. This cross-reactivity may yield a false-positive result that may affect the provision of care in certain patient populations and clinical situations. We describe a 36-year-old woman with confirmed brain death after a short hospital stay who had an initial UDS that was negative for methamphetamine. The patient was assessed for potential organ donation, which included obtaining a follow-up UDS. A urine sample was obtained after being hospitalized for 36 hours, which tested positive for methamphetamine, with no suspected ingestion of the target substance. Confirmatory laboratory testing indicated that intravenous phenylephrine and its metabolites were the likely cause of the false-positive UDS. However, the patient was not deemed to be a suitable candidate for organ donation, but clear documentation of the reason for denial of organ donation was not available in the patient's medical record. To our knowledge, this is the first case published in the English-language literature that describes the clinical occurrence of apparent immunoassay cross-reactivity of methamphetamine and phenylephrine that resulted in a false-positive UDS for methamphetamine. In addition, this report describes the potential implications of this situation on clinical care, including organ donation acceptance. Toxicology screening in the emergency department and intensive care unit is a tool to assist in the diagnosis of medical conditions, but it may not always be reliable. Therefore, positive immunoassay results that may change the management of a patient's condition should be quickly verified with confirmatory testing to minimize unfavorable consequences.

Thromboxane mediation of the pressor response to infused angiotensin II.

UNLABELLED: The role of thromboxane A2(Tx) in mediating the pressor response to angiotensin II (AII) was studied in anesthetized rats. Intravenous AII (500 ng/kg/min) increased mean arterial pressure (MAP) by 35 +/- 3 mm Hg and increased the excretion of prostaglandin PGE2, the metabolites of prostacyclin (6kPGF1 alpha) and Tx (TxB2) (P less than .05). A similar pressor infusion of the alpha 1-adrenoreceptor agonist phenylephrine (PE) increased the excretion of PGE2 and 6kPGF1 alpha but not TxB2. The increases in MAP and prostaglandin excretion produced by AII were reversed by the AII-receptor antagonist saralasin (10 micrograms/kg/min) while those produced by PE were reversed by the alpha-adrenoreceptor antagonist phenoxybenzamine (250 micrograms/kg). The Tx receptor antagonist, SQ-29,548 (8 mg/kg) attenuated (P less than .0001) the AII-induced rise in MAP (13 +/- 1 mm Hg) but did not modify the pressor response to PE. The Tx synthetase inhibitor, UK-38,485 (50 mg/kg/d) given for 3 days, reduced basal TxB2 excretion by 75% and also attenuated (P less than .001) the AII-induced rise in MAP (11 +/- 2 mm Hg). However, when given 40 min before the AII infusion, UK-38,485 did not attenuate the pressor response. In separate groups of rats, the log dose-response curve for bolus intravenous injection of AII was shifted to the right by SQ-29,548 while that for PE was unaffected. IN CONCLUSION: 1) AII releases Tx; 2) Tx release is not secondary to hypertension; and 3) Tx can mediate up to two-thirds of the short-term pressor response to high-dose AII infusion.

Drug interference with measurement of metanephrines in urine.

The influence of 35 commonly used drugs on measurement of metanephrines in urine was evaluated. Two concentrations of drugs were chosen for study based on usual doses and the percent of dose excreted unchanged in the urine. At "medium" drug concentrations, only phenylephrine falsely elevated metanephrine levels, whereas at a 10-fold higher drug concentration, guanethidine, hydrocortisone, imipramine, isoetharine, levodopa, phenobarbital, and phenylephrine caused positive interference. Propranolol and theophylline caused a negative interference at the two concentrations studied. The significance of these results is discussed.