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 MATERIALS AND METHODS: We reviewed published and unpublished studies of naproxen (NAP) and NAPSO to establish the pharmacokinetic relationship between dosage, plasma concentration, and efficacy, and to compare the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.

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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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.

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.

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.

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.

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.

Basic pharmacology of non-opioid analgesics.

Non-opioid analgesics, such as aspirin, non-steroidal anti-inflammatory drugs and paracetamol, are widely used in the treatment of pain, pyrexia and inflammation. Each has therapeutic advantages and potential disadvantages. This article discusses the indications, cautions and contraindications, adverse effects and interactions of these agents.

Bioequivalence study of low-dose diclofenac potassium tablet formulations.

BACKGROUND AND AIM: Diclofenac is a nonsteroidal antiinflammatory drug with potent analgesic and anti-inflammatory properties. An immediate-release formulation containing a low dose of 12.5 mg diclofenac-potassium (-K) is marketed as over the counter (OTC) medication in most European countries. An immediate-release formulation containing 25 mg diclofenac-K has now also been approved for OTC use. This study assessed the bioequivalence of two immediate-release diclofenac formulations when administered at the same dose. SUBJECTS AND METHODS: A randomized, crossover, open-label study was conducted in 29 healthy volunteers to assess the bioequivalence of single 25 mg dose of diclofenac-K in two formulations: 2 x 12.5 mg as film-coated tablets and 1 x 25 mg as sugar-coated tablet. Blood samples for pharmacokinetic analyses were obtained over 10 hours post administration. RESULTS: Plasma time courses of diclofenac were similar for the tested formulations. Mean AUC yen was 798 +/- 281 ng x h/ml (mean +/- SD) for the film-coated and 776 +/- 249 ng x h/ml for the sugar-coated formulation, respectively. The 2-sided 90% confidence interval for the mean test/reference ratio of AUCinfinity (95.5 - 107.5) fell within the predetermined equivalence range of 80 - 125%. Both formulations were rapidly absorbed; median time to maximal plasma concentration was 35 min in each group. Adverse events (peripheral erythema on the hand, headache, hypoesthesia) reported during the study were of mild severity and were considered as unlikely to be drug-related. CONCLUSION: The two diclofenac-K immediate release formulations were pharmacokinetically similar. It can be concluded that the new sugar-coated tablet formulation is equivalent to the available film-coated tablet formulation with respect to the extent of diclofenac absorption.

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.

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.

Pharmacokinetic comparison of the potential over-the-counter statins simvastatin, lovastatin, fluvastatin and pravastatin.

HMG-CoA reductase inhibitors (statins) dose-dependently lower both the level of low-density lipoprotein cholesterol and risk of cardiovascular disease. In 2004, the UK approved a low-dose over-the-counter (OTC) simvastatin, but the US has rejected applications for non-prescription preparations of statins. The pharmacokinetics and interaction potentials of the possible OTC candidate statins simvastatin, lovastatin, fluvastatin and pravastatin are clearly different. Simvastatin and lovastatin are mainly metabolized by cytochrome P450 (CYP) 3A, fluvastatin is metabolized by CYP2C9, and pravastatin is excreted largely unchanged. Several cell membrane transporters can influence the disposition of statins, e.g. the organic anion transporting polypeptide (OATP) 1B1 enhances their hepatic uptake. The c.521T>C (p.Val174Ala) genetic polymorphism of SLCO1B1 (encoding OATP1B1) considerably increases the plasma concentrations of simvastatin acid and moderately increases those of pravastatin but seems to have no significant effect on fluvastatin. Strong inhibitors of CYP3A (itraconazole, ritonavir) greatly (up to 20-fold) increase plasma concentrations of simvastatin, lovastatin and their active acid forms, thus enhancing the risk of myotoxicity. Weak or moderately potent CYP3A inhibitors such as verapamil, diltiazem and grapefruit juice can be used cautiously with low doses of simvastatin or lovastatin, but their concomitant use needs medical supervision. Potent inducers of CYP3A can greatly decrease plasma concentrations of simvastatin and simvastatin acid, and probably those of lovastatin and lovastatin acid. Although fluvastatin is metabolized by CYP2C9, its concentrations are changed less than 2-fold by inhibitors or inducers of CYP2C9. Pravastatin plasma concentrations are not significantly affected by any CYP inhibition and only slightly affected by inducers. Ciclosporin inhibits CYP3A, P-glycoprotein and OATP1B1. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. Ciclosporin and gemfibrozil increase plasma concentrations of statins and the risk of their myotoxicity, but fluvastatin seems to carry a smaller risk than other statins. Inhibitors of OATP1B1 may decrease the benefit-risk ratio of simvastatin, lovastatin and pravastatin by interfering with their (active acid forms) entry into hepatocytes. Understanding the differences in the pharmacokinetics and interaction potential of various statins helps in their selection for possible non-prescription status. On the pharmacokinetic basis, fluvastatin and pravastatin can be better choices than simvastatin or lovastatin for an OTC statin.

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 .

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.

Over-the-counter progesterone cream produces significant drug exposure compared to a food and drug administration-approved oral progesterone product.

Progesterone products are available in prescription form as well as over-the-counter (OTC) topical preparations sold for "cosmetic" uses. In a randomized study design, the authors compared the drug exposure from an OTC progesterone cream to a Food and Drug Administration-approved oral preparation at the labeled daily doses recommended for each product. Twelve healthy postmenopausal women received 200-mg oral progesterone capsules once daily for 12 days or progesterone cream 40 mg twice daily for 12 days. At steady state (day 12 of each phase), whole-blood samples were collected over 24 hours (oral progesterone) or 12 hours (topical progesterone) and assayed for total progesterone concentration. No significant differences were found in dose-normalized 24-hour progesterone exposure comparing the cream to oral capsules (median AUC(0-24) 12.5 ng x h/mL vs 10.5 ng x h/mL, respectively; P = .81). In light of the potential risks associated with long-term progesterone use, the authors question whether topical progesterone products should be available OTC.