RÉSUMÉ
Inflammation is a culprit in many conditions affecting millions of people worldwide. A plethora of studies has revealed that inflammation and inflammatory mediators such as cytokines and chemokines are associated with altered expression and activity of various proteins such as those involved in drug metabolism, specifically cytochrome P450 enzymes (CYPs). Emphasis of most available reports is on the inflammation-induced downregulation of CYPs, subsequently an increase in their substrate concentrations, and the link between the condition and the inflammatory mediators such as interleukin-6 and tumor necrosis factor alpha. However, reports also suggest that inflammation influences expression and/or activity of other proteins such as those involved in the drug-receptor interaction. These multifaced involvements render the clinical consequence of the inflammation unexpected. Such changes are shown in many inflammatory conditions including rheumatoid arthritis, Crohn's disease, acute respiratory illnesses as well as natural processes such as aging, among others. For example, some commonly used cardiovascular drugs lose their efficacy when patients get afflicted with inflammatory conditions such as rheumatoid arthritis and Crohn's disease. Interestingly, this is despite increased concentration subsequent to reduced clearance. The observation is attributed to a simultaneous reduction in the expression of target receptor proteins such as the calcium and potassium channel and ß-adrenergic receptor as well as the metabolic enzymes. This narrative review summarizes the current understanding and clinical implications of the inflammatory effects on both CYPs and drug-receptor target proteins.
Sujet(s)
Polyarthrite rhumatoïde , Maladie de Crohn , Humains , Inflammation/traitement médicamenteux , Cytokines , Polyarthrite rhumatoïde/traitement médicamenteux , Cytochrome P-450 enzyme system , Médiateurs de l'inflammationRÉSUMÉ
PURPOSE: Between January 2020 and December 2021, Health Canada provided a Summary Basis of Decision (SBD) for each of 110 products approved, including 29 oncology products and 21 non-oncology orphan drugs. This review sought to gain insight into how Real Word Evidence (RWE) impacts regulatory decision making. METHODS: SBDs for oncology drugs and non-oncology orphan drugs were reviewed for evidence of use of the RWE or historical data to support regulatory decisions. This information was compared with both FDA and EMA reviews. RESULTS: For the 29 Health Canada-approved oncology products, 11 were approved with Notice of Compliance with Conditions (NOCc) status. Two NOCc approvals received extensive RWE reviews, while two other approvals briefly mentioned the use of RWE/historical data. Of the 12 NOC approvals, one received RWE reviews. FDA also approved all 29 drugs, 14 of which received extensive comments on RWE and/or historical data and 8 of which mentioned RWE or historical data. EMA approved 25 of the 29 products and provided extensive comments on 10. Four products received a mention of RWE review. The percentages of submissions with RWE/historical reviews conducted by Health Canada, FDA and EMA were 24.1, 75.9 and 56.0 respectively. Of the 21 non-oncology orphan drugs, Health Canada provided priority review status to 11, with extensive RWE comments in 5 and the mention of RWE in 2 of the regular approvals. Two approvals that used third-party data were not included in the comparison. FDA approved 19, and provided extensive RWE assessment on 5 and mentioned use of historical data in 8. EMA approved 17 and provided extensive RWE and historical comments in 7 and mentioned historical data in 4. The percentages of submissions with RWE/historical reviews by Health Canada, FDA and EMA were 36.8, 68.4 and 64.7 respectively. CONCLUSIONS: Use of Real World Data is common among FDA/EMA reviews and Health Canada used RWE in recent NOCc and orphan drug approvals.
Sujet(s)
Prise de décision , Agrément de médicaments , CanadaRÉSUMÉ
COVID-19 infection is associated with systemic inflammation, and sometimes hyperinflammatory responses with cytokine storm. This plays a major role in COVID-19 severity and poor disease prognosis, even death. Higher levels of inflammatory hallmarks including C-reactive protein, ferritin, D-dimers, and cytokines such as interleukin (IL) -6, IL-10 and tumor necrosis factor- α (TNF-α) have been reported. Many anti-viral drugs have been tried, but none were proven fully effective. Supportive care and management of the complications that are caused mainly by inflammation might be the key to greater survival rates and shorter hospitalization (e.g., the use of remdesivir, lopinavir, ritonavir, umifenovir (arbidol), oseltamivir, ganciclovir, favipiravir, darunavir, hydroxychloroquine, chloroquine, colchicine, azithromycin, anakinra, canakinumab, tocilizumab, siltuximab, sarilumab, Type 1 interferon, interferon ß-1a, interferon α- 2b, baricitinib, ruxolitinib, fedratinib, methylprednisolone and dexamethasone). However, the efficacy of these treatments still needs well-planned clinical trials. In such trials, careful attention must be paid to the duration of the treatment, the onset of beneficial effects, and the severity of the disease, otherwise, the outcomes may still remain inconclusive. Herein, we present a review of the current drugs, which are being used in the management of the disease and their anti-inflammatory properties. We also investigated if these drugs directly interact with Angiotensin-Converting Enzyme (ACE 2), which is a crucial component of the virus entry to the cells.
Sujet(s)
Anti-inflammatoires/administration et posologie , Infections à coronavirus/traitement médicamenteux , Inflammation/traitement médicamenteux , Pneumopathie virale/traitement médicamenteux , Angiotensin-converting enzyme 2 , Anti-inflammatoires/pharmacologie , Antiviraux/administration et posologie , Antiviraux/pharmacologie , COVID-19 , Infections à coronavirus/virologie , Humains , Inflammation/virologie , Pandémies , Peptidyl-Dipeptidase A/métabolisme , Pneumopathie virale/virologie , Système rénine-angiotensine/effets des médicaments et des substances chimiques , Traitements médicamenteux de la COVID-19RÉSUMÉ
In this study, we tested whether the extent of drug presence in the heart contributes to the elevated cardiovascular risk of nonsteroidal anti-inflammatory drugs (NSAIDs). A fluorescently tagged nanoformulation of an NSAID with high cardiovascular (CV) risk (diclofenac) was developed as diclofenac ethyl ester (DFEE) encapsulated in traceable (cyanine-5.5-labeled) polymeric micelles (DFEE-TM) based on methoxypoly(ethylene oxide)-block-poly(ε-caprolactone)(PEO-b-PCL) (MW, 5000:3500 g/mol). Diclofenac pharmacokinetics and tissue distribution, as well as ex vivo near-infrared images of organs and whole bodies, were compared between healthy rats and rats with adjuvant arthritis (AA) following the administration of a single intravenous (iv) dose of DFEE-TM. Moreover, the biodistribution and antiarthritic activity of DFEE-TM were compared with those of free diclofenac (once-daily intraperitoneal, ip, 10 mg/kg for 7 days). The concentration ratios of cytochrome-P450-mediated cardiotoxic (20-hydroxyeicosatetraenoic acid) over cardioprotective (epoxyeicosatrienoic acids) metabolites of arachidonic acid (ArA) in the heart, kidneys, and plasma were measured as markers of cardiotoxicity. The nanocarrier was found in the joints of AA, but not in those of healthy rats. Both free diclofenac and DFEE-TM comparably controlled AA. Diclofenac delivery via PEO-b-PCL micelles reduced the accumulation of diclofenac in the heart of AA rats. Despite similar antiarthritic activity, the polymeric micellar formulation showed a reduction in the ratio of cardiotoxic-over-cardioprotective eicosanoids of ArA in the heart and plasma of AA rats. The results showed the positive effect of diclofenac prodrug nanodelivery in changing the normal biodistribution of diclofenac away from the heart, leading to lowered diclofenac-induced biomarkers of cardiotoxicity in the heart and plasma of AA rats.
Sujet(s)
Acide arachidonique/métabolisme , Arthrite expérimentale/traitement médicamenteux , Arthrite expérimentale/métabolisme , Cytochrome P-450 enzyme system/métabolisme , Diclofenac/effets indésirables , Diclofenac/pharmacologie , Coeur/effets des médicaments et des substances chimiques , Animaux , Anti-inflammatoires non stéroïdiens/effets indésirables , Anti-inflammatoires non stéroïdiens/pharmacologie , Caproates/composition chimique , Vecteurs de médicaments/composition chimique , Acide hydroxyeïcosatétraénoïque/composition chimique , Lactones/composition chimique , Mâle , Micelles , Nanoparticules/composition chimique , Polyesters/composition chimique , Polymères/composition chimique , Rats , Rat Sprague-Dawley , Distribution tissulaireRÉSUMÉ
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain and inflammatory conditions such as arthritis. However, both arthritis and many NSAIDs increase cardiovascular (CV) risks. The dose-dependency of the elevated CV risks of NSAIDs has not been well-studied. We tested the hypothesis that low but still effective doses of these drugs are void of CV side effects. As the model drug, we chose diclofenac because of its known high CV toxicity, as markers of CV risks, we assessed concentrations of cytochrome P450-mediated metabolites of arachidonic acid (ArA), and we used adjuvant arthritis as an experimental model of arthritis. Following 7 daily doses (2.5-15 mg/kg), the effective dosage range of diclofenac was identified (> 5 mg/kg/day). While 7 consecutive days of low therapeutic doses did not alter the CYP-mediated ArA metabolism, the highest dose of 15 mg/kg/day caused imbalances in ArA metabolic profiles toward cardiotoxicity by increasing the ratio of cardiotoxic 20-hydroxyeicosatetraenoic acid over cardioprotective epoxyeicosatrienoic acids. This is suggestive of dose-dependency of NSAID cardiotoxicity, and that low therapeutic doses may be void of CV side effects. Human studies are needed to examine the safety of low but effective doses of NSAIDs.
Sujet(s)
Anti-inflammatoires non stéroïdiens/administration et posologie , Anti-inflammatoires non stéroïdiens/effets indésirables , Arthrite expérimentale/traitement médicamenteux , Maladies cardiovasculaires/induit chimiquement , Animaux , Acide arachidonique/métabolisme , Arthrite expérimentale/métabolisme , Diclofenac/administration et posologie , Diclofenac/effets indésirables , Acide hydroxyeïcosatétraénoïque/métabolisme , Mâle , Rats , Rat Sprague-Dawley , Facteurs de risqueRÉSUMÉ
The nonsteroidal anti-inflammatory drugs elevate cardiovascular risk, perhaps, due to their accumulation in the heart and kidneys. We designed nanodelivery systems for cardiotoxic diclofenac to reduce its presence in these organs. Diclofenac ethyl ester (DFEE) was encapsulated in traceable micelles based on poly(ethylene oxide)-b-poly(ε-caprolactone) (DFEE-PCL-TM) or poly(ethylene oxide)-b-poly(α-benzyl carboxylate-ε-caprolactone) (DFEE-PBCL-TM). Diclofenac pharmacokinetics and tissue distribution were studied after intravenous (iv) and intraperitoneal administration of the nanoformulations and compared with those after iv doses of free diclofenac (n = 3-6/group). The average diameters for DFEE-PBCL-TM and DFEE-PCL-TM were 37.2 ± 0.06 and 45.1 ± 0.06 nm, respectively. Drug concentration dropped below the assay sensitivity after free drug administration in 6 h, but persisted for 24 h following DFEE-PBCL-TM (2.3 ± 1.4 µg/mL) and DFEE-PCL-TM (1.9 ± 0.6 µg/mL) iv administration. The diclofenac heart:blood and kidney:blood ratios were 5- to 12-fold lower with the nanoformulations than with free diclofenac. Near-infrared fluorescence measurements in tissues suggested exposure patterns to nanocarriers parallel with those achieved for delivered diclofenac by nanoformulations. Administration of DFEE-PCL-TM by iv or intraperitoneal injection, resulted in comparable pharmacokinetics and 6 h postdose near-infrared fluorescence in the heart, kidneys, liver, and spleen. When compared to each other, DFEE-PBCL-TM showed significantly lower diclofenac levels in the heart compared to DFEE-PCL-TM (0.3 ± 0.03 vs. 0.5 ± 0.1 µg/g). Developed nanoformulations of diclofenac prolonged diclofenac circulation and reduced its presence in the heart and kidneys, strongly suggesting cardiac-safe delivery vehicles for diclofenac.
Sujet(s)
Anti-inflammatoires non stéroïdiens/pharmacocinétique , Diclofenac/pharmacocinétique , Vecteurs de médicaments/composition chimique , Lactones/composition chimique , Micelles , Polyéthylène glycols/composition chimique , Animaux , Anti-inflammatoires non stéroïdiens/administration et posologie , Diclofenac/administration et posologie , Systèmes de délivrance de médicaments , Estérification , Mâle , Rats , Rat Sprague-DawleyRÉSUMÉ
Dabigatran is widely used for stroke prevention in atrial fibrillation. Dabigatran is no longer patent-protected in Canada and 2 generic formulations were recently approved by Health Canada. Branded dabigatran uses a complex formulation to maintain the acidic microenvironment required for maximal absorption. Consequently, food does not influence its bioavailability and the efficacy and safety of dabigatran are similar with or without concomitant intake of proton pump inhibitors (PPIs). Unfortunately, current bioequivalence criteria do not mandate testing of the generic formulations with food or with concomitant intake of PPIs; thus, the only data available for the approved generic products are in fasted, healthy volunteers. Without confirmation that the bioavailability of the generic dabigatran products is maintained in the presence of food or with coadministration of PPIs, it is uncertain whether they will afford patients the same protection from stroke as the branded product. Clinicians and patients must be made aware of this limitation to make informed prescribing decisions. The rules for establishing bioequivalence have not kept pace with the increasing complexity of pharmaceutical products; we urge regulators to update the regulatory process to ensure the therapeutic equivalence of generic products.
Sujet(s)
Fibrillation auriculaire/traitement médicamenteux , Biodisponibilité , Agrément de médicaments , Médicaments génériques , Accident vasculaire cérébral/prévention et contrôle , Équivalence thérapeutique , Antithrombiniques/pharmacocinétique , Antithrombiniques/usage thérapeutique , Fibrillation auriculaire/complications , Canada , Dabigatran/pharmacocinétique , Dabigatran/usage thérapeutique , Interactions médicamenteuses , Médicaments génériques/pharmacocinétique , Médicaments génériques/usage thérapeutique , Humains , Évaluation des besoins , Accident vasculaire cérébral/étiologieRÉSUMÉ
PURPOSE: Concomitant use of some non-Aspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) reduces the extent of platelet aggregation of Aspirin (acetylsalicylic acid). This is while many observational studies and clinical trials suggest that Aspirin reduces cardiovascular (CV) risk attributed to the use of NANSAIDs. Thus, the therapeutic outcome of the interaction needs to be assessed. METHODS: We searched various databases up to October 2017 for molecular interaction studies between the drugs and long-term clinical outcomes based on randomized clinical trials and epidemiological observations that reported the effect estimates of CV risks (OR, RR or HR; 95% CI) of the interacting drugs alone or in combinations. Comparisons were made between outcomes after Aspirin alone, NANSAIDs alone and Aspirin with naproxen, ibuprofen, celecoxib, meloxicam, diclofenac or rofecoxib. RESULTS: In total, 32 eligible studies (20 molecular interactions studies and 12 observational trials) were found. Conflicting in vitro/in vivo/ex vivo platelet aggregation data were found for ibuprofen, naproxen and celecoxib. Nevertheless, for naproxen, the interaction at the aggregation level did not amount to a loss of cardioprotective effects of Aspirin. Similarly, for ibuprofen, the results overwhelmingly suggest no negative clinical CV outcomes following the combination therapy. Meloxicam and rofecoxib neither interacted with Aspirin at the level of platelet aggregation nor altered clinical outcomes. The clinical outcomes data for celecoxib and diclofenac are in conflict. CONCLUSION: Aspirin appears to maintain its cardioprotective effect in the presence of naproxen, ibuprofen, meloxicam and rofecoxib. The limited available data suggest that the effect of interaction at the platelet aggregation level may dissipate shortly, or the reduced platelet aggregation yielded by the interaction may be sufficient for cardioprotection; i.e., no need for near complete aggregation. In addition, cardioprotective effect of Aspirin, despite reduced platelet aggregation caused by NANSAIDs, may be through its involvement in other mechanisms such as the renin-angiotensin system and/or metabolism of arachidonic acid to biologically active compounds mediated by cytochrome P450. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Sujet(s)
Anti-inflammatoires non stéroïdiens/pharmacologie , Acide acétylsalicylique/pharmacologie , Maladies cardiovasculaires/traitement médicamenteux , Agrégation plaquettaire/effets des médicaments et des substances chimiques , Anti-inflammatoires non stéroïdiens/administration et posologie , Acide acétylsalicylique/administration et posologie , Humains , Résultat thérapeutiqueRÉSUMÉ
Inflammatory conditions increase cardiovascular (CV) risk. Some nonsteroidal anti-inflammatory drugs (NSAIDs) that are used to treat pain and inflammation are also associated with CV complications. Inflammation, but not NSAIDs, disrupts the balance of vasodilator and vasoconstrictor components of the renin-angiotensin system within the heart. Herein, we report the effect of both inflammation and NSAIDs (rofecoxib, celecoxib, and meloxicam) on the physiologically active cytochrome P450 metabolites of arachidonic acid (ArA) in the rat with adjuvant arthritis. After oral administration of 7 daily therapeutically equivalent doses of NSAIDs or vehicle, the anti-inflammatory response, as well as the ArA metabolites and drug concentrations in plasma, heart and kidneys were assessed. Inflammation in the form of adjuvant arthritis caused a significant tissue-dependent imbalance of ArA metabolites by elevating the ratio of cardiotoxic 20-hydroxyeicosatetraenoic acid over cardioprotective epoxyeicosatrienoic acids in the heart, and reducing the ratio in the kidney. The observed imbalance was augmented by cardiotoxic rofecoxib but not by other examined NSAIDs with known milder cardiotoxicity. The cardio-renal toxicity of NSAIDs with known severe CV side effects may be due to altered cytochrome P450-mediated ArA acid metabolism. The ArA metabolism profile may be a marker of NSAIDs safety and toxicity.
Sujet(s)
Anti-inflammatoires non stéroïdiens/pharmacologie , Acide arachidonique/métabolisme , Cytochrome P-450 enzyme system/métabolisme , Inflammation/traitement médicamenteux , Inflammation/métabolisme , Animaux , Arthrite expérimentale/traitement médicamenteux , Arthrite expérimentale/métabolisme , Célécoxib/pharmacologie , Coeur/effets des médicaments et des substances chimiques , Acide hydroxyeïcosatétraénoïque/pharmacologie , Rein/effets des médicaments et des substances chimiques , Rein/métabolisme , Lactones/pharmacologie , Mâle , Méloxicam , Rats , Rat Sprague-Dawley , Sulfones/pharmacologie , Thiazines/pharmacologie , Thiazoles/pharmacologieRÉSUMÉ
A co-morbidity of inflammatory conditions is increased cardio-renal risks. Additionally, nonsteroidal anti-inflammatory drugs (NSAIDs) which are used to treat pain and inflammation are also associated with increase in such risks. We hypothesized that inflammation and NSAIDs impose the cardio-renal risk through the activation of the renin-angiotensin-system (RAS), a regulating pathway of the renal and cardiovascular homeostasis. We investigated the effect of adjuvant arthritis and NSAIDs on the RAS. Western blotting and ELISA were used to measure the RAS components. Inflammation caused significant imbalances in the cardiac and renal angiotensin converting enzymes, their biologically active angiotensin peptides (AngII and Ang1-7) and the target proteins involved in the peptide-receptor binding (AngII type 1 and type 2, and Ang1-7 receptor, Mas) toward cardio-renal toxicity. However, 7 days treatment of arthritic animals with NSAIDs (rofecoxib, meloxicam, celecoxib and flurbiprofen) restored the constitutive balances, perhaps due to their anti-inflammatory properties. Inflammation exerts its cardio-renal effects by causing imbalance in the RAS. NSAIDs through their anti-inflammatory effect restore this imbalance. Thus, mechanisms other than imbalances in the RAS may be involved in the NSAIDs cardiotoxicity.
RÉSUMÉ
OBJECTIVE: To review the potential drug interactions between low-dose methotrexate (LD-MTX) and nonsteroidal anti-inflammatory drugs (NSAIDs), penicillins, and proton-pump inhibitors (PPIs) given the disparity between interactions reported for high-dose and low-dose MTX to help guide clinicians. DATA SOURCES: A literature search was performed in MEDLINE (1946 to September 2016), EMBASE (1974 to September 2016), and International Pharmaceutical Abstracts (1970 to January 2015) to identify reports describing potential drug interactions between LD-MTX and NSAIDS, penicillins, or PPIs. Reference lists of included articles were reviewed to find additional eligible articles. STUDY SELECTION AND DATA EXTRACTION: All English-language observational, randomized, and pharmacokinetic (PK) studies assessing LD-MTX interactions in humans were analyzed to determine clinical relevance in making recommendations to clinicians. Clinical case reports were assigned a Drug Interaction Probability Scale score. DATA SYNTHESIS: A total of 32 articles were included (28 with NSAIDs, 3 with penicillins, and 2 with PPIs [1 including both PPI and NSAID]). Although there are some PK data to describe increased LD-MTX concentrations when NSAIDs are used concomitantly, the clinical relevance remains unclear. Based on the limited data on LD-MTX with penicillins and PPIs, no clinically meaningful interaction was identified. CONCLUSION: Given the available evidence, the clinical importance of the interaction between LD-MTX and NSAIDs, penicillins, and PPIs cannot be substantiated. Health care providers should assess the benefit and risk of LD-MTX regardless of concomitant drug use, including factors known to predispose patients to MTX toxicity, and continue to monitor clinical and laboratory parameters per guideline recommendations.
Sujet(s)
Anti-inflammatoires non stéroïdiens/effets indésirables , Méthotrexate/effets indésirables , Pénicillines/effets indésirables , Inhibiteurs de la pompe à protons/effets indésirables , Anti-inflammatoires non stéroïdiens/administration et posologie , Anti-inflammatoires non stéroïdiens/pharmacocinétique , Anti-inflammatoires non stéroïdiens/usage thérapeutique , Relation dose-effet des médicaments , Interactions médicamenteuses , Humains , Méthotrexate/administration et posologie , Méthotrexate/pharmacocinétique , Méthotrexate/usage thérapeutique , Pénicillines/administration et posologie , Pénicillines/pharmacocinétique , Pénicillines/usage thérapeutique , Inhibiteurs de la pompe à protons/administration et posologie , Inhibiteurs de la pompe à protons/pharmacocinétique , Inhibiteurs de la pompe à protons/usage thérapeutiqueRÉSUMÉ
PURPOSE: Ibuprofen liquigel has been believed to provide faster analgesic effect. However, comparative studies evaluating the efficacy of liquigel versus regular tablets are not available. Hence, we carried out a systematic review and a meta-analysis to compare the onset of action and efficacy of over-the-counter doses of ibuprofen liquigel (IBULG) vs ibuprofen tablets (IBUT). Methods. Published clinical trials of IBULG and IBUT were identified through a systematic search of various data bases up to October, 2015. RESULTS: In total 18 eligible studies on IBUT and 4 on IBULG were found. There was no significant difference in the median time to the first perceptible pain relief or the proportion of patients with more than 50% pain relief between the two products. However, IBULG yielded significantly greater odd ratios in meaningful pain relief at 60, 90 and 120 min, but not at 30 min, as compared with IBUT. Conclusion. The available evidence, although not overwhelming, suggest a faster onset of analgesia for liquigel as compared with tablets. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
Sujet(s)
Ibuprofène/administration et posologie , Ibuprofène/composition chimique , Douleur/traitement médicamenteux , Gels , Humains , Ibuprofène/usage thérapeutique , ComprimésRÉSUMÉ
PURPOSE: Studies have shown altered pharmacokinetic patterns (PK) in patient suffering from acute pain. Thus, we aimed to simulate pharmacokinetics of meloxicam and ibuprofen in pain and pain-free states using a physiological based software program to identify the underlining mechanistic changes for the observed differences. METHOD: Published in vivo data of meloxicam and ibuprofen were used for the simulations. Two drug formulations were studied: a fast dissolving (FD) and regular release (RR) tablet formulation. The oral bioavailability was compared between these formulations in vagally suppressed rats (gastric dysfunction) and a control group. For ibuprofen additional human data of a control and post dental surgery group were used. All simulations were performed using GastroPlus™. The in vivo drug release and PK of all formulations were estimated for both drugs using the software's immediate release (IR) or gastric release (GR) models. RESULT: For meloxicam, the IR model predicted the in vivo absorption in the control group after administration of the FD and RR formulations. When gastric dysfunction was induced, the IR model did not predict absorption while the GR model did for both formulations, FD and RR. For ibuprofen, the predictions were also very close for both formulations, using the IR model for the control group and the GR model for the vagally suppressed condition in rats and humans. CONCLUSIONS: Gastric control of the drug release in pain/disease state was identified as the major factor causing the observed differences in the pharmacokinetics. Computer simulations of disease states can be employed to optimize drug release from dosage forms to overcome the reported shortfalls in the drug absorption.
Sujet(s)
Simulation numérique , Modèles animaux de maladie humaine , Ibuprofène/pharmacocinétique , Thiazines/pharmacocinétique , Thiazoles/pharmacocinétique , Animaux , Humains , Méloxicam , Rats , ComprimésRÉSUMÉ
The carboxylic acid group (-COOH) present in classical NSAIDs is partly responsible for the gastric toxicity associated with the administration of these drugs. This concept has been extensively proven using NSAID prodrugs. However, the screening of NSAIDs with no carboxylic acid at all has been neglected. The goal of this work was to determine if new NSAID derivatives devoid of acidic moieties would retain the anti-inflammatory activity of the parent compound, without causing gastric toxicity. To test this concept, we replaced the carboxylic acid group in ibuprofen, flurbiprofen, and naproxen with three ammonium moieties. We tested the resulting water-soluble NSAID derivatives for anti-inflammatory and ulcerogenic activity in vitro and in vivo. In this regard, we observed that all non-acidic NSAIDs exerted a potent anti-inflammatory activity, suggesting that the acid group in commercial 2-phenylpropionic acid NSAIDs not be an essential requirement for anti-inflammatory activity. These data provide complementary evidence supporting the discontinuation of ulcerogenic acidic NSAIDs.
Sujet(s)
Anti-inflammatoires non stéroïdiens/pharmacologie , Anti-inflammatoires/pharmacologie , Acides carboxyliques/composition chimique , Anti-inflammatoires/composition chimique , Spectroscopie par résonance magnétique du carbone-13 , Simulation de docking moléculaire , Spectroscopie par résonance magnétique du proton , Spectrométrie de masse ESIRÉSUMÉ
BACKGROUND: Both omeprazole and its S enantiomer (esomeprazole) have been available and used to treat symptoms of gastroesophageal reflux disease (GERD) and conditions associated with excessive stomach acid secretion for more than a decade. Controversy exists over improved efficacy of S enantiomer (esomeprazole) over parent racemate (omeprazole). However, a comparison of the clinical outcomes of these products may reveal the rationale for switching from the racemate to single enantiomer. Since enantiomers of omeprazole are equipotent, we compared the outcomes of equal doses of each product to see if both actually differ in their efficacy's or the reported superiority of S enantiomer is just a dose effect. METHODS: A web search was carried out for randomized controlled trials with head-to-head comparisons of omeprazole and S-omeprazole. The data were abstracted and after calculating the odd ratios (OR) for the outcomes reported in each study, the combined overall odd ratios (OR') were estimated. The random effect inverse variance method with omeprazole as the reference (OR" = 1) was used. RESULTS: Out of 1171 studies, 14 were deemed eligible. There was no significant difference in the therapeutic success between omeprazole and S-omeprazole as a part of triple therapy for the treatment of H. pylori in both intention-to-treat (OR', 1.06; CI, 0.83, 1.36; p = 0.63) as well as per-protocol analysis (OR', 1.07; CI, 0.84, 1.36; p = 0.57). For the treatment of gastro-oesophageal reflux disease, S-omeprazole was significantly but marginally superior to the racemate (OR', 1.18; CI, 1.01, 1.38; p = 0.04). The two products were equipotent in all metrics used to assess intragastric pH except for the % patients maintaining a 24 h gastric pH above 4 (1.57; CI, 1.04, 2.381; p = 0.03). CONCLUSION: The therapeutic benefit of chiral switch of omeprazole is questionable considering the substantially greater economic burden involved.
Sujet(s)
Ésoméprazole/usage thérapeutique , Oméprazole/usage thérapeutique , Inhibiteurs de la pompe à protons/usage thérapeutique , Reflux gastro-oesophagien/traitement médicamenteux , Infections à Helicobacter/traitement médicamenteux , Humains , Inhibiteurs de la pompe à protons/composition chimique , Essais contrôlés randomisés comme sujet , StéréoisomérieRÉSUMÉ
The Canadian Society for Pharmaceutical Sciences organized a workshop on the current state of sciences of subsequent entry biologics (SEBs, biosimilars) on December 10th 2014 in the Health Canada location in Ottawa, ON. The day-long workshop provided an opportunity to discuss recent regulatory developments and a wide range of scientific issues related to SEBs. Following a discussion on the differences between the Canadian guidance and those of other countries, a series of presentations were made that focused on the regulatory requirements with regard to the product quality, methodology, non-clinical and clinical data. In addition, issues of extrapolation from one indication to another, interchangeability and reimbursement were articulated. It was also highlighted that both the patients and caregivers need to be better informed regarding the safety and efficacy of articulated SEBs.
Sujet(s)
Produits pharmaceutiques biosimilaires , Produits pharmaceutiques biosimilaires/effets indésirables , Produits pharmaceutiques biosimilaires/pharmacologie , Produits pharmaceutiques biosimilaires/normes , Canada , HumainsRÉSUMÉ
The aim of this study was to synthesize a peptide prodrug of glucosamine (GlcN) with increased gut permeability through the gut peptide transporter 1 (PepT1). Glycine-Valine ester derivative of GlcN (GVG) was synthesised using solid phase synthesis followed by characterization and evaluation of its physicochemical and intestinal stability. In addition, GVG was evaluated for its ability to be biotransformed to GlcN in the liver homogenate. In vitro absorption of the new prodrug through everted rat gut was also assessed. GVG demonstrated significant and meaningful increased gut permeability as compared with GlcN. It showed favorable stability in the gut and a quick cleavage to GlcN after exposure to the liver homogenate. In conclusion, a novel prodrug of glucosamine with superior gut permeability compared to GlcN was developed and successfully tested in vitro.
Sujet(s)
Glucosamine/composition chimique , Glucosamine/métabolisme , Muqueuse intestinale/métabolisme , Peptides/composition chimique , Peptides/métabolisme , Promédicaments/composition chimique , Promédicaments/métabolisme , Animaux , Transport biologique/physiologie , Biotransformation/physiologie , Esters/composition chimique , Glycine/composition chimique , Absorption intestinale/physiologie , Foie/métabolisme , Mâle , Transporteur-1 de peptides , Perméabilité , Rats , Rat Sprague-Dawley , Symporteurs/métabolisme , Valine/composition chimiqueRÉSUMÉ
Synthetic analogues of the peptide hormone calcitonin have been used in medicine as biologic drug therapies for decades, to treat pathological conditions of excessive bone turnover, such as osteoporosis, where more bones are removed than replaced during bone remodeling. Osteoporosis and other chronic skeletal diseases, including inflammatory arthritis, exact a substantial and growing toll on aging populations worldwide however they respond poor to synthetic biologic drug therapy, due in part to the rapid half-life of elimination, which for calcitonin is 43 minutes. To address those shortcomings, we have developed and synthesized bone-targeting variants of calcitonin as a targeted drug delivery strategy, by conjugation to bisphosphonate drug bone-seeking functional groups in highly specific reaction conditions. To evaluate their in vivo efficacy, bisphosphonate-mediated bone targeting with PEGylated (polyethylene glycol conjugated) and non-PEGylated salmon calcitonin analogues were synthesized and dose escalation was performed in female rats developing Osteoporosis. The bone-targeting calcitonin analogues were also tested in a separate cohort of male rats developing adjuvant-induced arthritis. Ovariectomized female rats developing Osteoporosis were administered daily sub-cutaneous injection of analogues equivalent to 5, 10 and 20 IU/kg of calcitonin for 3 months. Adjuvant arthritis was developed in male rats by administering Mycobacterium butyricum through tail base injection. Daily sub-cutaneous injection of analogues equivalent to 20 IU/kg of calcitonin was administered and the rats were measured for visible signs of inflammation to a 21 day endpoint. In both studies, the effect of drug intervention upon bone volume and bone mineral density (BMD) was assessed by measuring the trabecular bone volume percentage and BMD at the proximal tibial metaphysis using in vivo micro-computed tomography. With dose escalation studies, only bone targeting analogue dosed groups showed a trend towards increased BMD and bone volume at 4, 8 and 12 weeks. Significant preservation of bone volume and BMD as evidenced by nonsignificant (P<0.05) loss of bone volume and BMD at the end of 3 month study endpoint was seen in animals dosed with 20 IU/kg of calcitonin compounds. Similarly, in case of adjuvant-induced arthritis rats, there was a significant increase (P<0.05) in bone volume and BMD in calcitonin-bisphosphonate and calcitonin-PEG-bisphosphonate treated groups at 21 days compared to the baseline values. Improved efficacy in terms of preserving bone volume and BMD in Osteoporosis, and in rats developing adjuvant-induced arthritis, by these analogues suggests their potential as new drug candidates for further evaluation to determine their usefulness in bone diseases characterized by excessive bone resorption.
Sujet(s)
Arthrite expérimentale/traitement médicamenteux , Agents de maintien de la densité osseuse/administration et posologie , Calcitonine/administration et posologie , Diphosphonates/administration et posologie , Ostéoporose post-ménopausique/traitement médicamenteux , Animaux , Articulation talocrurale/imagerie diagnostique , Articulation talocrurale/effets des médicaments et des substances chimiques , Articulation talocrurale/physiopathologie , Arthrite expérimentale/imagerie diagnostique , Arthrite expérimentale/microbiologie , Arthrite expérimentale/physiopathologie , Densité osseuse/effets des médicaments et des substances chimiques , Agents de maintien de la densité osseuse/composition chimique , Remodelage osseux/effets des médicaments et des substances chimiques , Calcitonine/composition chimique , Chimie pharmaceutique , Diphosphonates/composition chimique , Vecteurs de médicaments , Femelle , Humains , Injections sous-cutanées , Mâle , Mycobacterium , Ostéoporose post-ménopausique/imagerie diagnostique , Ostéoporose post-ménopausique/étiologie , Ostéoporose post-ménopausique/physiopathologie , Ovariectomie , Polyéthylène glycols/composition chimique , Rat Sprague-Dawley , Technologie pharmaceutique/méthodes , Tibia/imagerie diagnostique , Tibia/effets des médicaments et des substances chimiques , Tibia/physiopathologie , Facteurs temps , Microtomographie aux rayons XRÉSUMÉ
Eicosanoids are biologically active lipid-derived oxidative metabolites of arachidonic acid. We, herein, present an improved sensitive, selective and robust high performance liquid chromatography (HPLC)-fluorescence assay for simultaneous quantification of eicosanoids in human plasma and rat tissues. Aliquots of 200 µL of plasma or 30 mg of heart or kidney tissues were spiked with 16-hydroxydecanoic acid as internal standard, and extracted with anhydrous acetonitrile using solid phase cartridges. The eluted samples were dried, reconstituted in anhydrous acetonitrile and labeled with 2-(2,3-naphthalimino)ethyl-trifluoromethanesulphonate in the presence of saturated potassium fluoride solution in anhydrous acetonitrile and N,N-diiospropylethylamine as catalyst. The derivatized eicosanoids were extracted with anhydrous acetonitrile using solid phase cartridges. Chromatographic separation was achieved on a C18 reversed phase column using gradient mobile phase of 0.05% of formic acid:acetonitrile:water at 0.8 mL/min flow rate. The analytes were detected at excitation and emission wavelength of 260 and 396 nm, respectively. The assay was linear (r(2)≥ 0.98) in the concentration range of 0.01-2.5 µg/mL. The intra-day and inter-day coefficients variation was less than 19.8%. Using this assay, we were able to quantify arachidonic acid metabolites simultaneously in human and rat biological samples.