Blood donor exposome and impact of common drugs on red blood cell metabolism.

Computational models based on recent maps of the RBC proteome suggest that mature erythrocytes may harbor targets for common drugs. This prediction is relevant to RBC storage in the blood bank, in which the impact of small molecule drugs or other xenometabolites deriving from dietary, iatrogenic, or environmental exposures ("exposome") may alter erythrocyte energy and redox metabolism and, in so doing, affect red cell storage quality and posttransfusion efficacy. To test this prediction, here we provide a comprehensive characterization of the blood donor exposome, including the detection of common prescription and over-the-counter drugs in blood units donated by 250 healthy volunteers in the Recipient Epidemiology and Donor Evaluation Study III Red Blood Cell-Omics (REDS-III RBC-Omics) Study. Based on high-throughput drug screenings of 1366 FDA-approved drugs, we report that approximately 65% of the tested drugs had an impact on erythrocyte metabolism. Machine learning models built using metabolites as predictors were able to accurately predict drugs for several drug classes/targets (bisphosphonates, anticholinergics, calcium channel blockers, adrenergics, proton pump inhibitors, antimetabolites, selective serotonin reuptake inhibitors, and mTOR), suggesting that these drugs have a direct, conserved, and substantial impact on erythrocyte metabolism. As a proof of principle, here we show that the antacid ranitidine - though rarely detected in the blood donor population - has a strong effect on RBC markers of storage quality in vitro. We thus show that supplementation of blood units stored in bags with ranitidine could - through mechanisms involving sphingosine 1-phosphate-dependent modulation of erythrocyte glycolysis and/or direct binding to hemoglobin - improve erythrocyte metabolism and storage quality.

Adverse Effects of Common Drugs: Children and Adolescents.

Drug use and harms are increasingly common among newborns, infants, children, and adolescents during ambulatory practice, emergency department, and in-hospital treatment, including treatment in pediatric intensive care units. The pharmacokinetic and pharmacodynamic parameters of drugs often are different for children compared with adults and must be considered before prescribing. Drug exposure and the potential for harms also should be considered for fetuses and breastfeeding infants. As with adult patients, a thorough drug and allergy history (including nonprescription drugs and herbal and dietary supplements) should be obtained and reviewed at each medical visit. Children and adolescents are increasingly at risk of drug harm/overdose through accidental or intentional ingestion of nonprescription and prescription drugs (eg, cough and cold preparations, candy-appearing vitamins, stimulants, narcotics). Parents and caregivers should receive training in the proper use, storage, and administration of all drugs. Prescribing clinicians should be vigilant in withholding unnecessary drugs, such as antibiotics for viral infections. When prescribing, clinicians should be aware of common drugs frequently associated with adverse reactions, including stimulants, antipsychotics, analgesics, asthma therapies, acne therapies, and tumor necrosis factor inhibitors. Scientifically based prescribing practices should be used and consultation with evidence-based resources and pharmacists sought as needed.

Comparative pharmacokinetic study of mangiferin after oral administration of pure mangiferin and US patented polyherbal formulation to rats.

The US patented polyherbal formulation for the prevention and management of type II diabetes and its vascular complications was used for the present study. The xanthone glycoside mangiferin is one of the major effector constituents in the Salacia species with potential anti-diabetic activity. The pharmacokinetic differences of mangiferin following oral administration of pure mangiferin and polyherbal formulation containing Salacia species were studied with approximately the same dose 30 mg/kg mangiferin and its distribution among the major tissue in Wistar rats. Plasma samples were collected at different time points (15, 30, 60, 120, 180, 240, 360, 480, 600, 1,440, 2,160, and 2880 min) and subsequently analyzed using a validated simple and rapid LC-MS method. Plasma concentration versus time profiles were explored by non-compartmental analysis. Mangiferin plasma exposure was significantly increased when administered from formulation compared to the standard mangiferin. Mangiferin resided significantly longer in the body (last mean residence time (MRTlast)) when given in the form of the formulation (3.65 h). Cmax values of formulation (44.16 µg/mL) administration were elevated when compared to equivalent dose of the pure mangiferin (15.23 µg/mL). Tissue distribution study of mangiferin from polyherbal formulation was also studied. In conclusion, the exposure of mangiferin is enhanced after formulation and administration and could result in superior efficacy of polyherbal formulation when compared to an equivalent dose of mangiferin. The results indicate that the reason which delays the elimination of mangiferin and enhances its bioavailability might the interactions of the some other constituents present in the polyherbal formulation. Distribution study results indicate that mangiferin was extensively bound to the various tissues like the small intestine, heart, kidney, spleen, and liver except brain tissue.

The sensitivity of metabolomics versus classical regulatory toxicology from a NOAEL perspective.

The identification of the no observed adverse effect level (NOAEL) is the key regulatory outcome of toxicity studies. With the introduction of "omics" technologies into toxicological research, the question arises as to how sensitive these technologies are relative to classical regulatory toxicity parameters. BASF SE and metanomics developed the in vivo metabolome database MetaMap®Tox containing metabolome data for more than 500 reference compounds. For several years metabolome analysis has been routinely performed in regulatory toxicity studies (REACH mandated testing or new compound development), mostly in the context of 28 day studies in rats (OECD 407 guideline). For those chemicals for which a toxicological NOAEL level was obtained at either high or mid-dose level, we evaluated the associated metabolome to investigate the sensitivity of metabolomics versus classical toxicology with respect to the NOAEL. For the definition of a metabolomics NOAEL the ECETOC criteria (ECETOC, 2007) were used. In this context we evaluated 104 cases. Comparable sensitivity was noted in 75% of the cases, increased sensitivity of metabolomics in 8%, and decreased sensitivity in 18% of the cases. In conclusion, these data suggest that metabolomics profiling has a similar sensitivity to the classical toxicological study (e.g. OECD 407) design.

Medications and breast-feeding: Current concepts.

OBJECTIVES: To describe the various factors that come into play when a breast-feeding mother is taking medications, including use of prescription drugs, over-the-counter medications, recreational drugs, galactogogues, and herbal remedies and to provide a framework used for counseling breast-feeding women. SETTING: Community and hospital pharmacy and health care settings. PRACTICE DESCRIPTION: Consultative services provided to breast-feeding mothers who had been prescribed or were using medications. MAIN OUTCOME MEASURES: Use of pharmacokinetic factors, maternal and child factors, a list of questions to ask breast-feeding mothers, and a stepwise approach to counsel breast-feeding mothers on the compatibility of using medications while breast-feeding. RESULTS: By positive intervention of pharmacists and health care providers, up to 1 million breast-feeding mothers, who must use medications, can continue to breast-feed while taking medications. CONCLUSION: Objectively weighing the benefits of drugs and breast-feeding versus the risks of drugs and not breast-feeding, in most cases, allows for pharmacists to give current and practical advice to mothers and other health professionals who counsel mothers.

Are one or two dangerous? Methyl salicylate exposure in toddlers.

Serious toxicity can result from exposure to small amounts of methyl salicylate. Methyl salicylate is widely available as a component in many over-the-counter brands of creams, ointments, lotions, liniments and medicated oils intended for topical application to relieve musculoskeletal aches and pains. Among the most potent forms of methyl salicylate is oil of wintergreen (98% methyl salicylate). Other products with varying concentrations of methyl salicylate are ubiquitous throughout many parts of the world, including a number of products marketed as Asian herbal remedies. The toxic potential of all of these formulations is often underestimated by health care providers and the general public. A comprehensive review of the existing medical literature on methyl salicylate poisoning was performed, and data compiled over the past two decades by the American Association of Poison Control Centers (AAPCC) was examined. Methyl salicylate continues to be a relatively common source of pediatric exposures. Persistent reports of life-threatening and fatal toxicity were found. In children less than 6 years of age, a teaspoon (5 mL) or less of oil of wintergreen has been implicated in several well-documented deaths. More needs to be done to educate both health care providers and the general public regarding the dangers of these widely available formulations.

Medication and nutrient administration considerations after bariatric surgery.

PURPOSE: Medication and nutrient administration considerations after bariatric surgery are discussed. SUMMARY: Bariatric surgery is categorized by surgical technique (i.e., restrictive procedure or a combination of restrictive and malabsorptive procedures). Roux-en-Y gastric bypass is the most frequently performed bariatric surgery in the United States. Patients who have undergone this surgery are at risk for nutrient deficiencies. Several factors, such as pH and absorption sites, should be considered when providing these patients with appropriate supplementation. Drug solubility and surface area for absorption are also affected by gastric bypass procedures. By bypassing major portions of the small intestine, Roux-en-Y procedures drastically reduce the surface area for absorption. These changes may warrant manipulation in drug route or dose to ensure adequate delivery. Drugs with long absorptive phases that remain in the intestine for extended periods are likely to exhibit decreased bioavailability in these patients. The reduced size of the stomach after surgery can place patients at risk for adverse events associated with some medications. Medications implicated in such adverse events include nonsteroidal antiinflammatory drugs, salicylates, and oral bisphosphonates. Drugs that are rapidly and primarily absorbed in the stomach or duodenum are likely to exhibit decreased absorption in patients who have had combination restrictive-malabsorptive procedures. Because reduced drug absorption may result in decreased efficacy rather than toxicity, increased patient monitoring for therapeutic effects can help detect potential absorption problems. CONCLUSION: Selection of appropriate nutrient salts can improve nutrient replacement in patients who have undergone bariatric surgery. Changes in dosage forms based on drug characteristics can improve bioavailability.

New OTC drugs and devices 2003: a selective review.

OBJECTIVES: To present current information about trends development and marketing of over-the-counter (OTC) medications and dietary supplement products and describe new products, delivery systems, home monitoring devices, and home accessories in these markets that are likely generating questions from or posing potential problems for patients. DATA SOURCES: Recently published clinical and pharmaceutical industry literature. STUDY SELECTION: By the authors. DATA EXTRACTION: By the authors. DATA SYNTHESIS: Last year witnessed the first effort of the Food and Drug Administration (FDA) to remove a dietary supplement from the U.S. market. Ephedra, because of its imminent danger when used for weight reduction and athletic enhancement, was the target of FDA action. FDA has issued a final rule implementing this ban, which prohibits the sale of dietary supplements containing ephedrine alkaloids (e.g., ephedra). Two newer diet-aid products are being actively promoted with little or no safety and effectiveness data. Thus, pharmacist's vigilance is important along with sensible advice on how to lose weight safely and effectively. Further, two independent organizations have created certification programs for dietary supplements that ensure product purity, active ingredient strength, and compliance with good manufacturing practices. In addition, through recent changes in federal legislation, consumers are now able to obtain reimbursement for their nonprescription purchases through flexible spending accounts. Information is presented in this article about selected products in these OTC, home care, and dietary supplement categories: heartburn (proton pump inhibitors), allergy (second-generation antihistamines), constipation (laxatives), diabetes mellitus (blood glucose monitoring systems), home testing (fertility monitoring), nicotine addiction (smoking cessation products), otic disorders (ear syringes), contraceptives and sexual aids (condoms and lubricants), and dermatology (wart removal). CONCLUSION: Patients continue to increase their reliance on self-care. To assist them, pharmacists must remain up-to-date on trends and have an understanding of the nuances of consumers' behavior and thinking in relation to OTC products and their use.

Acute psychosis following ingestion of 'Rapture'.

OBJECTIVES: To describe a brief psychotic episode associated with ingestion of a dietary supplement containing piperazine. METHODS: A case report was undertaken. RESULTS: A 20-year-old man developed a brief psychotic episode associated with persecutory delusional beliefs and auditory and visual hallucinations, leading him to commit the offence of arson. This episode occurred 12 h following the ingestion of 'Rapture' in addition to small quantities of cannabis and nitrous oxide, in a young man with no prior psychiatric history. This episode resolved with the use of benzodiazepines and 6 months later he has had no recurrence of psychiatric symptoms. CONCLUSIONS: Given the reported mechanism of action of the 'herbal high' dietary supplements, it would seem possible that they may be able to precipitate a psychotic episode in vulnerable individuals. With the increasing use of these substances, it is important for clinicians to be alert to this possibility.

Adverse neuropsychiatric reactions to herbal and over-the-counter "antidepressants".

BACKGROUND: Many unregulated over-the-counter agents for the treatment of depression are now available to patients and consumers. The potential for adverse neuropsychiatric effects with these agents has not been systematically studied in most cases. DATA SOURCES: The author performed a MEDLINE search on a variety of herbal and nonherbal over-the-counter agents said to be useful in the treatment of depression. The Physicians' Desk Reference for Herbal Medicines was also consulted. DATA SYNTHESIS: Although many of the herbal agents said to have benefits in depression appear to be safe, serious neuropsychiatric side effects and interactions have been reported for several over-the-counter "antidepressants." There is reason to suspect underreporting of those adverse events. Moreover, there is very little evidence from systematic studies regarding the potential for drug-drug or herb-drug interactions with these over-the-counter agents. Vitamins and amino acids touted for the treatment of depression are also not without risk. CONCLUSION: Although some over-the-counter remedies for depression are probably safe and effective for as-yet unidentified subgroups of depressed individuals, more research is required before these agents can be recommended for routine use. Stricter U.S. Food and Drug Administration oversight of these agents is indicated.

Clinically significant pharmacokinetic interactions between dietary caffeine and medications.

Caffeine from dietary sources (mainly coffee, tea and soft drinks) is the most frequently and widely consumed CNS stimulant in the world today. Because of its enormous popularity, the consumption of caffeine is generally thought to be safe and long term caffeine intake may be disregarded as a medical problem. However, it is clear that this compound has many of the features usually associated with a drug of abuse. Furthermore, physicians should be aware of the possible contribution of dietary caffeine to the presenting signs and symptoms of patients. The toxic effects of caffeine are extensions of their pharmacological effects. The most serious caffeine-related CNS effects include seizures and delirium. Other symptoms affecting the cardiovascular system range from moderate increases in heart rate to more severe cardiac arrhythmia. Although tolerance develops to many of the pharmacological effects of caffeine, tolerance may be overwhelmed by the nonlinear accumulation of caffeine when its metabolism becomes saturated. This might occur with high levels of consumption or as the result of a pharmacokinetic interaction between caffeine and over-the-counter or prescription medications. The polycyclic aromatic hydrocarbon-inducible cytochrome P450 (CYP) 1A2 participates in the metabolism of caffeine as well as of a number of clinically important drugs. A number of drugs, including certain selective serotonin reuptake inhibitors (particularly fluvoxamine), antiarrhythmics (mexiletine), antipsychotics (clozapine), psoralens, idrocilamide and phenylpropanolamine, bronchodilators (furafylline and theophylline) and quinolones (enoxacin), have been reported to be potent inhibitors of this isoenzyme. This has important clinical implications, since drugs that are metabolised by, or bind to, the same CYP enzyme have a high potential for pharmacokinetic interactions due to inhibition of drug metabolism. Thus, pharmacokinetic interactions at the CYP1A2 enzyme level may cause toxic effects during concomitant administration of caffeine and certain drugs used for cardiovascular, CNS (an excessive dietary intake of caffeine has also been observed in psychiatric patients), gastrointestinal, infectious, respiratory and skin disorders. Unless a lack of interaction has already been demonstrated for the potentially interacting drug, dietary caffeine intake should be considered when planning, or assessing response to, drug therapy. Some of the reported interactions of caffeine, irrespective of clinical relevance, might inadvertently cause athletes to exceed the urinary caffeine concentration limit set by sports authorities at 12 mg/L. Finally, caffeine is a useful and reliable probe drug for the assessment of CYP1A2 activity, which is of considerable interest for metabolic studies in human populations.