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.

Pharmacokinetic linearity of naproxen and efficacy of naproxen sodium at various doses
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OBJECTIVE: Naproxen sodium (NAPSO) is commonly used in a variety of pain conditions. There are several strengths of NAPSO available over the counter (OTC). Most published data are based on single or multiple doses using 220 mg, hence there is a need to assess the analgesic efficacy of other strengths of NAPSO used in the OTC setting. MATERIALS AND METHODS: We reviewed published and unpublished studies of naproxen (NAP) and NAPSO to establish the pharmacokinetic relationship between dosage, plasma concentration, and efficacy, and to compare the analgesic efficacy of NAPSO 220, 440, and 550 mg or NAP 500 mg versus placebo and active comparators. RESULTS: Increasing OTC doses of NAP are associated with linear pharmacokinetics, i.e., plasma levels of NAP increase proportionately with dosage. Accordingly, the therapeutic efficacy of higher doses of NAP or NAPSO is greater than lower doses. All OTC doses of NAP and NAPSO are significantly more effective than placebo. Higher strengths are as effective or more effective than lower strengths, and at least comparable to other active treatments. CONCLUSION: The pharmacokinetic linearity associated with NAP means that data on efficacy for the lower OTC doses of NAPSO can be extrapolated to the higher OTC doses. Thus, it is given that NAPSO 275 and 550 mg will be at least as effective as or superior to the lower doses of 220 and 440 mg.

Particle Size Distribution Analysis of OTC Aerosol or Powder Drug Products With Potential for Inadvertent Inhalation Exposure to Consumers.

The potential for inadvertent inhalation of over-the-counter (OTC) aerosol/powder drug products for topical application requires understanding of the characteristic size distributions of the airborne particles or droplets generated when these products are used as per the directions on the product label. Particle/droplet size is an important factor in determining the depth of particle penetration into the respiratory system after inhalation. Because particles penetrating beyond the larynx into the lung may lead to adverse respiratory effects, OTC aerosol or powder drug product particle size distribution is important to characterize. In this study, laser diffraction was used to analyze the particle size distribution of 32 currently marketed OTC drug products as emitted after actuation or air dispersion from their final package. Among the products surveyed were sunscreens, antiperspirants, topical analgesics, skin protectants, and acne products. The results may be useful to the U.S. Food and Drug Administration in its mission to protect as well as promote public health.

Effects of medicines used to treat gastrointestinal diseases on the pharmacokinetics of coadministered drugs: a PEARRL Review.

OBJECTIVES: Drugs used to treat gastrointestinal diseases (GI drugs) are widely used either as prescription or over-the-counter (OTC) medications and belong to both the 10 most prescribed and 10 most sold OTC medications worldwide. The objective of this review article is to discuss the most frequent interactions between GI and other drugs, including identification of the mechanisms behind these interactions, where possible. KEY FINDINGS: Current clinical practice shows that in many cases, these drugs are administered concomitantly with other drug products. Due to their metabolic properties and mechanisms of action, the drugs used to treat gastrointestinal diseases can change the pharmacokinetics of some coadministered drugs. In certain cases, these interactions can lead to failure of treatment or to the occurrence of serious adverse events. The mechanism of interaction depends highly on drug properties and differs among therapeutic categories. Understanding these interactions is essential to providing recommendations for optimal drug therapy. SUMMARY: Interactions with GI drugs are numerous and can be highly significant clinically in some cases. While alterations in bioavailability due to changes in solubility, dissolution rate, GI transit and metabolic interactions can be (for the most part) easily identified, interactions that are mediated through other mechanisms, such as permeability or microbiota, are less well-understood. Future work should focus on characterising these aspects.

Assessing the bioequivalence of over-the-counter esomeprazole banded capsules and multiple-unit pellet system tablets
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OBJECTIVE: To demonstrate bioequivalence between two esomeprazole formulations under fasted and fed conditions. MATERIALS: Esomeprazole 20 mg multiunit pellet system (test; MUPS) tablets and over-the-counter esomeprazole 20 mg banded capsules (reference). MATERIALS AND METHODS: This open-label, randomized, 6-period crossover study assigned healthy males and females to receive single doses of each study drug under fasted or fed conditions. The primary pharmacokinetic endpoints were esomeprazole area under the concentration-time curve from time zero to infinity (AUCinf) and maximum observed concentration (Cmax). For endpoints with high within-subject standard deviations of the reference product (Swr ≥ 0.294), a reference scaled average bioequivalence (RSAB) approach was used. For endpoints not highly variable (Swr < 0.294), an unscaled approach was used. In the RSAB, bioequivalence was defined as the 95% criteria bound (CB) ≤ 0 and geometric mean ratios (GMRs) within 0.80, 1.25. For the unscaled approach, bioequivalence was defined as 90% confidence intervals (CIs) of the GMR being within 80%, 125%. RESULTS: 60 subjects were randomized, and 46 subjects (76.7%) completed all study periods. For esomeprazole AUCinf, the variability of the reference product was low (Swr = 0.202), so the unscaled approach was used. The GMR (90% CI) was 0.948 (0.890 - 1.010), indicating bioequivalence. For the comparison of esomeprazole Cmax, the variability of the reference product was high (Swr = 0.304), so the RSAB approach was used. The GMR (95% CB) was 1.009 (-0.050), indicating bioequivalence. CONCLUSION: Esomeprazole 20 mg MUPS tablets and banded capsules were found to be bioequivalent based on the AUCinf and Cmax in the fasted state.
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Differing disintegration and dissolution rates, pharmacokinetic profiles and gastrointestinal tolerability of over the counter ibuprofen formulations.

OBJECTIVES: Formulations of over the counter (OTC) NSAIDs differ substantially, but information is lacking on whether this alters their gastrointestinal profiles. To assess disintegration and dissolution rates and pharmacokinetics of four preparations of OTC ibuprofen and relate these with spontaneously reported gastrointestinal adverse events. METHODS: Disintegration and dissolution rates of ibuprofen tablets as (a) acid, (b) sodium salt, (c) lysine salt, and (d) as a liquid gelatine capsule were assessed. Pharmacokinetic data gastrointestinal and spontaneously reported adverse events arising from global sales were obtained from files from Reckitt Benckiser. KEY FINDINGS: Disintegration at low pH was progressively shorter for the preparations from a-to-d with formation of correspondingly smaller ibuprofen crystals, while dissolution was consistently poor. Dissolution at a neutral pH was least rapid for the liquid gelatine capsule. Pharmacokinetic data showed a shorter tmax and a higher Cmax for preparations b-d as compared with ibuprofen acid. Spontaneously reported abdominal symptoms were rare with the liquid gelatine preparation. CONCLUSIONS: The formulations of OTC ibuprofen differ in their disintegration and dissolution properties, pharmacokinetic profiles and apparent gastrointestinal tolerability. Spontaneously reported abdominal symptoms were five times lower with the liquid gelatine capsule as compared with ibuprofen acid despite a 30% increase in Cmax .

Clinical management of medications in pregnancy and lactation.

Prescription and over-the-counter medication use during pregnancy and lactation is exceedingly common. There are many available resources to gather information and guide patient counseling. These include primary literature, online resources, professional society recommendations, and drug labels. One must consider both disease and drug characteristics when making decisions on medication use during pregnancy and lactation. Providers can then use this information to balance the risks of fetal or neonatal exposure against the potential benefits of maternal treatment and the risks of untreated disease.

Over-the-counter medications: Risk and safety in pregnancy.

Over-the-counter (OTC) medications are among the most commonly used products in pregnancy. Similar to prescription medications, for many products there is a lack of adequate data on safety of use in pregnancy. Assumptions of safety for these products based on long experience and OTC status, in the absence of data, may be ill founded. Examples of four OTC products used to treat common conditions in pregnancy are described. Potential links to adverse short- and long-term infant outcomes for these products are reviewed, and the strengths and limitations of data to support these. Research to detect or rule out these risks is essential.

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.

The role of the pharmacist in the selection and use of over-the-counter proton-pump inhibitors.

BACKGROUND: Heartburn and other symptoms of gastro-oesophageal reflux occur in ~30% of survey respondents in multiple countries worldwide. Heartburn and acid regurgitation are common complaints in the pharmacy, where patients frequently seek relief through medication and advice. The growing number of proton-pump inhibitors available in the over-the-counter setting provides an efficacious choice to patients experiencing frequent heartburn. Pharmacists can assist patients in their treatment decisions whilst inquiring about alarm symptoms that should prompt a physician referral. Aim of the review Provide pharmacists with a review of current clinical research and expert guidelines on use of over-the-counter proton-pump inhibitors. METHODS: This narrative review was conducted to identify publications relevant to the following themes: overview of available treatments for frequent episodes of heartburn/acid regurgitation; treatment algorithms providing guidance on when to use over-the-counter proton-pump inhibitors; and the role of the pharmacist in the use of over-the-counter proton-pump inhibitors. RESULTS: Frequent symptoms of acid reflux, such as heartburn and acid regurgitation, can interfere substantially with daily life activities. Proton-pump inhibitors are the most efficacious treatment for frequent reflux symptoms and are recommended as an appropriate initial treatment in uncomplicated cases. Proton-pump inhibitors have varying pharmacokinetics and pharmacodynamics across the class; 20 mg esomeprazole has higher bioavailability and exposure than over-the-counter omeprazole, for example. However, differences in clinical efficacy for symptom relief have not been demonstrated. The safety and tolerability of proton-pump inhibitors have been well established in clinical trial and post-marketing settings, and use of a short regimen is associated with a very low likelihood of missing a more serious condition. Pharmacists can assist patients with accurate self-diagnosis by asking short, simple questions to characterize the nature, severity, and frequency of symptoms. Additionally, pharmacists can inquire about alarm symptoms that should prompt referral to a physician. Pharmacists should inform those patients for whom over-the-counter proton-pump inhibitors are appropriate on their proper use. CONCLUSION: Over-the-counter proton-pump inhibitors have a valuable role in the treatment of frequent heartburn. Pharmacists have the opportunity to guide patients through selection of the best treatment option for their symptoms.

Dermatitis toxica faciei after boric acid.

An adverse toxic reaction to the topical application of a 2% boric acid solution is described in a 2-year-old girl. Topical boric acid is licensed for use in children above the age of 10 in the Czech Republic. However, it can be bought over the counter and it is very often used in younger children. Due to its fast absorption and slow elimination, there is a high risk of systemic side effects. On the other hand, topical side effects are not reported in the present literature.

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.

A clinician's guide to statin drug-drug interactions.

The statins are widely used worldwide to reduce risk for cardiovascular events in both the primary and secondary prevention settings. Although generally quite safe, the statins can be associated with a variety of serious side adverse effects, including myalgia, myopathy, and changes in plasma enzymes of hepatic origin. Although rare, the most serious of these is rhabdomyolysis. Several drugs can interfere with the metabolism and disposal of the statins, thereby increasing risk for adverse events. It is important that clinicians treating patients with statins be aware of the potential for drug-drug interactions between each statin and specific other drugs and take measures to prevent them. The prediction of potential drug-drug interactions derives from basic pharmacokinetic principles. Certain drug interactions are predicted by measuring the effect of interacting drugs on blood plasma concentrations of the statin. Individual patient variations resulting in part from polymorphisms in the metabolizing enzymes confound some of these predictions. Based on these known effects, a new classification for predicting statin drug interactions is proposed. This report discusses likely prescription and nonprescription interactions as well as potential alternatives for special populations.

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.

Acetaminophen/diphenhydramine overdose in profound hypothermia.

BACKGROUND: There are few reports of acetaminophen overdose in hypothermic patients and even fewer reports describing profound hypothermia. The kinetics, risk of hepatotoxicity, and the possible dose adjustments to N-acetylcysteine (NAC) therapy are not known in this setting. CASE REPORT: A 37-year-old female was found unconscious outside in December and was brought by ambulance to a tertiary care Emergency Department (ED) following a presumed overdose of acetaminophen and diphenhydramine. She later confirmed the ingestion and reported the ingestion had occurred approximately 18 hours prior to being found. On arrival, she was profoundly hypothermic, with a core rectal temperature of 17°C. Her initial serum acetaminophen concentration was 232 mcg/mL 19 hours post ingestion of a reported dose of approximately 50 grams of acetaminophen and 2.5 grams of diphenhydramine. Active rewarming was started immediately and IV NAC was initiated using the standard treatment protocol. The patient did not develop serious signs of hepatic injury or NAC toxicity. The patient's AST and ALT peaked 12 hours after admission at 84 IU/L (ref 10-37 U/L) and 104 IU/L (ref 12-78 U/L), respectively. Her INR peaked 2 hours after admission at 1.46 (ref < 1.2). DISCUSSION: Despite the significant ingestion of acetaminophen, delayed presentation, prolonged period of decreased responsiveness, and profound hypothermia, the patient did not develop any signs/symptoms of liver injury. NAC was administered in a standard dose during her rewarming period without apparent toxicity. The patient's absorption and/or metabolism of acetaminophen were likely slowed by her hypothermia and possibly by the anticholinergic coingestant. Initiation of IV NAC at a standard dose was apparently safe and effective in preventing hepatotoxicity as the patient was rewarmed. CONCLUSIONS: Profound hypothermia may be protective of hepatic injury in acetaminophen overdose. Delayed absorption from the coingestant, diphenhydramine, may also have played a role. IV NAC was given in a standard dose without apparent toxicity in the setting of profound hypothermia. Lastly, IV NAC, in standard dosing, appeared to be effective in preventing hepatotoxicity during rewarming in a patient with a potentially hepatotoxic concentration of acetaminophen with a coingestion of the anticholinergic agent, diphenhydramine.

Prodrugs of nonsteroidal anti-inflammatory drugs (NSAIDs), more than meets the eye: a critical review.

The design and the synthesis of prodrugs for nonsteroidal anti-inflammatory drugs (NSAIDs) have been given much attention by medicinal chemists, especially in the last decade. As a therapeutic group, NSAIDs are among the most widely used prescribed and over the counter (OTC) medications. The rich literature about potential NSAID prodrugs clearly shows a shift from alkyl, aryalkyl or aryl esters with the sole role of masking the carboxylic acid group, to more elaborate conjugates that contain carefully chosen groups to serve specific purposes, such as enhancement of water solubility and dissolution, nitric oxide release, hydrogen sulfide release, antioxidant activity, anticholinergic and acetylcholinesterase inhibitory (AChEI) activity and site-specific targeting and delivery. This review will focus on NSAID prodrugs that have been designed or were, later, found to possess intrinsic pharmacological activity as an intact chemical entity. Such intrinsic activity might augment the anti-inflammatory activity of the NSAID, reduce its side effects or transform the potential therapeutic use from classical anti-inflammatory action to something else. Reports discussed in this review will be those of NO-NSAIDs, anticholinergic and AChEI-NSAIDs, Phospho-NSAIDs and some miscellaneous agents. In most cases, this review will cover literature dealing with these NSAID prodrugs from the year 2006 and later. Older literature will be used when necessary, e.g., to explain the chemical and biological mechanisms of action.