PEG-b-PPS diblock copolymer aggregates for hydrophobic drug solubilization and release: cyclosporin A as an example

Micelles formed from amphiphilic block copolymers have been explored in recent years as carriers for hydrophobic drugs. In an aqueous environment, the hydrophobic blocks form the core of the micelle, which can host lipophilic drugs, while the hydrophilic blocks form the corona or outer shell and stabilize the interface between the hydrophobic core and the external medium. In the present work, mesophase behavior and drug encapsulation were explored in the AB block copolymeric amphiphile composed of poly(ethylene glycol) (PEG) as a hydrophile and poly(propylene sulfide) PPS as a hydrophobe, using the immunosuppressive drug cyclosporin A (CsA) as an example of a highly hydrophobic drug. Block copolymers with a degree of polymerization of 44 on the PEG and of 10, 20 and 40 on the PPS respectively (abbreviated as PEG44-b-PPS10, PEG44-b-PPS20, PEG44-b-PPS40) were synthesized and characterized. Drug-loaded polymeric micelles were obtained by the cosolvent displacement method as well as the remarkably simple method of dispersing the warm polymer melt, with drug dissolved therein, in warm water. Effective drug solubility up to 2 mg/mL in aqueous media was facilitated by the PEG- b-PPS micelles, with loading levels up to 19% w/w being achieved. Release was burst-free and sustained over periods of 9-12 days. These micelles demonstrate interesting solubilization characteristics, due to the low glass transition temperature, highly hydrophobic nature, and good solvent properties of the PPS block

Effects of thyromimetic drugs on aldosterone-dependent sodium transport in the toad bladder.

Aldosterone increases transepithelial Na+ transport in the urinary bladder of Bufo marinus. The response is characterized by 3 distinct phases: 1) a lag period of about 60 min, ii) an initial phase (early response) of about 2 hr during which Na+ transport increases rapidly and transepithelial electrical resistance falls, and iii) a late phase (late response) of about 4 to 6 hr during which Na+ transport still increases significantly but with very little change in resistance. Triiodothyronine (T3, 6 nM) added either 2 or 18 hr before aldosterone selectively antagonizes the late response. T3 per se (up to 6 nM) has no effect on base-line Na+ transport. The antagonist activity of T3 is only apparent after a latent period of about 6 to 8 hr. It is not rapidly reversible after a 4-hr washout of the hormone. The effects appear to be selective for thyromimetic drugs since reverse T3 (rT3) is inactive and isopropyldiiodothyronine (isoT2) is more active than T3. The relative activity of these analogs corresponds to their relative affinity for T3 nuclear binding sites which we have previously described. Our data suggest that T3 might control the expression of aldosterone by regulating gene expression, e.g. by the induction of specific proteins, which in turn will inhibit the late mineralocorticoid response, without interaction with the early response.

Efficacy and Safety of Canakinumab Vs Triamcinolone Acetonide in Patients with Gouty Arthritis Unable to Use Nonsteroidal Anti-Inflammatory Drugs and Colchicine, and On Stable Urate Lowering Therapy (ULT) or Unable to Use ULT

Background/Purpose: The primary treatment goals for gouty arthritis (GA) are rapid relief of pain and inflammation during acute attacks, and long-term hyperuricemia management. A post-hoc analysis of 2 pivotal trials was performed to assess efficacy and safety of canakinumab (CAN), a fully human monoclonal anti-IL-1_ antibody, vs triamcinolone acetonide (TA) in GA patients unable to use NSAIDs and colchicine, and who were on stable urate lowering therapy (ULT) or unable to use ULT. Methods: In these 12-week, randomized, multicenter, double-blind, double-dummy, active-controlled studies (_-RELIEVED and _-RELIEVED II), patients had to have frequent attacks (_3 attacks in previous year) meeting preliminary GA ACR 1977 criteria, and were unresponsive, intolerant, or contraindicated to NSAIDs and/or colchicine, and if on ULT, ULT was stable. Patients were randomized during an acute attack to single dose CAN 150 mg s.c. or TA 40 mg i.m. and were redosed "on demand" for each new attack. Patients completing the core studies were enrolled into blinded 12-week extension studies to further investigate on-demand use of CAN vs TA for new attacks. The subpopulation selected for this post-hoc analysis was (a) unable to use NSAIDs and colchicine due to contraindication, intolerance or lack of efficacy for these drugs, and (b) currently on ULT, or contraindication or previous failure of ULT, as determined by investigators. Subpopulation comprised 101 patients (51 CAN; 50 TA) out of 454 total. Results: Several co-morbidities, including hypertension (56%), obesity (56%), diabetes (18%), and ischemic heart disease (13%) were reported in 90% of this subpopulation. Pain intensity (VAS 100 mm scale) was comparable between CAN and TA treatment groups at baseline (least-square [LS] mean 74.6 and 74.4 mm, respectively). A significantly lower pain score was reported with CAN vs TA at 72 hours post dose (1st co-primary endpoint on baseline flare; LS mean, 23.5 vs 33.6 mm; difference _10.2 mm; 95% CI, _19.9, _0.4; P_0.0208 [1-sided]). CAN significantly reduced risk for their first new attacks by 61% vs TA (HR 0.39; 95% CI, 0.17-0.91, P_0.0151 [1-sided]) for the first 12 weeks (2nd co-primary endpoint), and by 61% vs TA (HR 0.39; 95% CI, 0.19-0.79, P_0.0047 [1-sided]) over 24 weeks. Serum urate levels increased for CAN vs TA with mean change from baseline reaching a maximum of _0.7 _ 2.0 vs _0.1 _ 1.8 mg/dL at 8 weeks, and _0.3 _ 2.0 vs _0.2 _ 1.4 mg/dL at end of study (all had GA attack at baseline). Adverse Events (AEs) were reported in 33 (66%) CAN and 24 (47.1%) TA patients. Infections and infestations were the most common AEs, reported in 10 (20%) and 5 (10%) patients treated with CAN and TA respectively. Incidence of SAEs was comparable between CAN (gastritis, gastroenteritis, chronic renal failure) and TA (aortic valve incompetence, cardiomyopathy, aortic stenosis, diarrohea, nausea, vomiting, bicuspid aortic valve) groups (2 [4.0%] vs 2 [3.9%]). Conclusion: CAN provided superior pain relief and reduced risk of new attack in highly-comorbid GA patients unable to use NSAIDs and colchicine, and who were currently on stable ULT or unable to use ULT. The safety profile in this post-hoc subpopulation was consistent with the overall _-RELIEVED and _-RELIEVED II population.

In vitro compatibility of remifentanil hydrochloride and sufentanil citrate with selected drugs

: Objectives Physicochemical incompatibilities between intravenous drugs are a recurrent problem in intensive care units. The present study was aimed at investigating the physical compatibility of remifentanil and sufentanil with other drugs (insulin, midazolam, propofol, potassium chloride, magnesium sulfate, furosemide, heparin, monobasic potassium phosphate) that are frequently administered together intravenously. In addition, the physicochemical compatibility of three common associations of drugs was evaluated in glass tube tests and during dynamic simulated Y site administrations (remifentanil-insulin-midazolam; remifentanil-insulin-propofol; sufentanil-insulin-midazolam). Methods Physical compatibility was verified by visual inspection of the various mixtures (two, three or four drugs) in glass tubes and by pH determination of the mixtures collected during simulated Y site administrations. Solutions were considered as compatible in the absence of any visual change in the solution and of any significant variation in pH value. In addition, chemical stability was checked during in vitro dynamic simulations. The solutions were prepared in 50 ml syringes, placed on syringe pumps and connected to a Swan-Ganz catheter; the liquid collected at the tip was assayed by high performance liquid chromatography. Results In the visual examinations, only the associations of remifentanil and furosemide were incompatible. The three assayed associations were compatible in the tested proportion range over 24 h. Conclusions Remifentanil was physically compatible with the tested drugs, except for furosemide (Lasix; Sanofi-Aventis, 250 mg/25 ml) and physicochemically compatible with insulin and midazolam and insulin and propofol. Sufentanil was physically compatible with all tested drugs and physicochemically compatible with insulin and midazolam

Simultaneous determination of antidementia drugs in human plasma: Procedure transfer from HPLC-MS to UPLC-MS/MS.

A previously developed high performance liquid chromatography mass spectrometry (HPLC-MS) procedure for the simultaneous determination of antidementia drugs, including donepezil, galantamine, memantine, rivastigmine and its metabolite NAP 226-90, was transferred to an ultra performance liquid chromatography system coupled to a tandem mass spectrometer (UPLC-MS/MS). The drugs and their internal standards ([(2)H(7)]-donepezil, [(13)C,(2)H(3)]-galantamine, [(13)C(2),(2)H(6)]-memantine, [(2)H(6)]-rivastigmine) were extracted from 250μL human plasma by protein precipitation with acetonitrile. Chromatographic separation was achieved on a reverse phase column (BEH C18 2.1mm×50mm; 1.7μm) with a gradient elution of an ammonium acetate buffer at pH 9.3 and acetonitrile at a flow rate of 0.4mL/min and an overall run time of 4.5min. The analytes were detected on a tandem quadrupole mass spectrometer operated in positive electrospray ionization mode, and quantification was performed using multiple reaction monitoring. The method was validated according to the recommendations of international guidelines over a calibration range of 1-300ng/mL for donepezil, galantamine and memantine, and 0.2-50ng/mL for rivastimgine and NAP 226-90. The trueness (86-108%), repeatability (0.8-8.3%), intermediate precision (2.3-10.9%) and selectivity of the method were found to be satisfactory. Matrix effects variability was inferior to 15% for the analytes and inferior to 5% after correction by internal standards. A method comparison was performed with patients' samples showing similar results between the HPLC-MS and UPLC-MS/MS procedures. Thus, this validated UPLC-MS/MS method allows to reduce the required amount of plasma, to use a simplified sample preparation, and to obtain a higher sensitivity and specificity with a much shortened run-time.

Non steroidal anti-inflammatory drugs and COX-2 inhibitors as anti-cancer therapeutics: hypes, hopes and reality.

Non-steroidal anti-inflammatory drugs (NSAIDs) and specific inhibitors of cyclooxygenase (COX)-2, are therapeutic groups widely used for the treatment of pain, inflammation and fever. There is growing experimental and clinical evidence indicating NSAIDs and COX-2 inhibitors also have anti-cancer activity. Epidemiological studies have shown that regular use of Aspirin and other NSAIDs reduces the risk of developing cancer, in particular of the colon. Molecular pathology studies have revealed that COX-2 is expressed by cancer cells and cells of the tumor stroma during tumor progression and in response to chemotherapy or radiotherapy. Experimental studies have demonstrated that COX-2 over expression promotes tumorigenesis, and that NSAIDs and COX-2 inhibitors suppress tumorigenesis and tumor progression. Clinical trials have shown that NSAIDs and COX-2 inhibitors suppress colon polyp formation and malignant progression in patients with familial adenomatous polyposis (FAP) syndrome. Recent advances in the understanding of the cellular and molecular mechanisms of the anti-cancer effects of NSAIDs and COX-2 inhibitors have demonstrated that these drugs target both tumor cells and the tumor vasculature. The therapeutic benefits of COX-2 inhibitors in the treatment of human cancer in combination with chemotherapy or radiotherapy are currently being tested in clinical trials. In this article we will review recent advances in the understanding of the anti-tumor mechanisms of these drugs and discuss their potential application in clinical oncology.

Simultaneous determination of antidementia drugs by HPLC-MS: validation data of the method and plasma level determinations in 300 patients

Aims: A rapid and simple HPLC-MS method was developed for the simultaneousdetermination of antidementia drugs, including donepezil, galantamine, rivastigmineand its major metabolite NAP 226 - 90, and memantine, for TherapeuticDrug Monitoring (TDM). In the elderly population treated with antidementiadrugs, the presence of several comorbidities, drug interactions resulting frompolypharmacy, and variations in drug metabolism and elimination, are possiblefactors leading to the observed high interindividual variability in plasma levels.Although evidence for the benefit of TDM for antidementia drugs still remains tobe demonstrated, an individually adapted dosage through TDM might contributeto minimize the risk of adverse reactions and to increase the probability of efficienttherapeutic response. Methods: A solid-phase extraction procedure with amixed-mode cation exchange sorbent was used to isolate the drugs from 0.5 mL ofplasma. The compounds were analyzed on a reverse-phase column with a gradientelution consisting of an ammonium acetate buffer at pH 9.3 and acetonitrile anddetected by mass spectrometry in the single ion monitoring mode. Isotope-labeledinternal standards were used for quantification where possible. The validatedmethod was used to measure the plasma levels of antidementia drugs in 300patients treated with these drugs. Results: The method was validated accordingto international standards of validation, including the assessment of the trueness(-8 - 11 %), the imprecision (repeatability: 1-5%, intermediate imprecision:2 - 9 %), selectivity and matrix effects variability (less than 6 %). Furthermore,short and long-term stability of the analytes in plasma was ascertained. Themethod proved to be robust in the calibrated ranges of 1 - 300 ng/mL for rivastigmineand memantine and 2 - 300 mg/mL for donepezil, galantamine and NAP226 - 90. We recently published a full description of the method (1). We found ahigh interindividual variability in plasma levels of these drugs in a study populationof 300 patients. The plasma level measurements, with some preliminaryclinical and pharmacogenetic results, will be presented. Conclusion: A simpleLC-MS method was developed for plasma level determination of antidementiadrugs which was successfully used in a clinical study with 300 patients.

First nationwide study on driving under the influence of drugs in Switzerland.

In Switzerland, a two-tier system based on impairment by any psychoactive substances which affect the capacity to drive safely and zero tolerance for certain illicit drugs came into force on 1 January 2005. According to the new legislation, the offender is sanctioned if Delta(9)-tetrahydrocannabinol THC is >or=1.5ng/ml or amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyethylamphetamine (MDEA), cocaine, free morphine are >or=15ng/ml in whole blood (confidence interval+/-30%). For all other psychoactive substances, impairment must be proven in applying the so-called "three pillars expertise". At the same time the legal blood alcohol concentration (BAC) limit for driving was lowered from 0.80 to 0.50g/kg. The purpose of this study was to analyze the prevalence of drugs in the first year after the introduction of the revision of the Swiss Traffic Law in the population of drivers suspected of driving under the influence of drugs (DUID). A database was developed to collect the data from all DUID cases submitted by the police or the Justice to the eight Swiss authorized laboratories between January and December 2005. Data collected were anonymous and included the age, gender, date and time of the event, the type of vehicle, the circumstances, the sampling time and the results of all the performed toxicological analyses. The focus was explicitly on DUID; cases of drivers who were suspected to be under the influence of ethanol only were not considered. The final study population included 4794 DUID offenders (4243 males, 543 females). The mean age of all drivers was 31+/-12 years (range 14-92 years). One or more psychoactive drugs were detected in 89% of all analyzed blood samples. In 11% (N=530) of the samples, neither alcohol nor drugs were present. The most frequently encountered drugs in whole blood were cannabinoids (48% of total number of cases), ethanol (35%), cocaine (25%), opiates (10%), amphetamines (7%), benzodiazepines (6%) and methadone (5%). Other medicinal drugs such as antidepressants and benzodiazepine-like were detected less frequently. Poly-drug use was prevalent but it may be underestimated because the laboratories do not always analyze all drugs in a blood sample. This first Swiss study points out that DUID is a serious problem on the roads in Switzerland. Further investigations will show if this situation has changed in the following years.

Drogues récréatives: le plaisir des complications [Recreational drugs: the complication's pleasure?].

Steadily increasing since 1990, the use of psychoactive substances was expanded to new designer drugs (bath salts, spice) with so original still unknown pharmacological effects. At the beginning, the pleasure, first feeling, turns sometimes, in acute medical emergency and then, in some cases, in chronic diseases. Side expected or not desired effects, seen in emergency departments could be necrotizing gangrene among consumers Krokodil or dystonic reactions in consumers of Spice. Moreover, adulterants could increase the dangerosity of the substances. Searching a toxidrome helps to find the incrimining substance.

The influence of drugs used in cardiac anaesthesia and critical care on multiple electrode aggregometry: an in-vitro volunteer study.

BACKGROUND: Multiple electrode aggregometry (MEA) is a point-of-care test evaluating platelet function and the efficacy of platelet inhibitors. In MEA, electrical impedance of whole blood is measured after addition of a platelet activator. Reduced impedance implies platelet dysfunction or the presence of platelet inhibitors. MEA plays an increasingly important role in the management of perioperative platelet dysfunction. In vitro, midazolam, propofol, lidocaine and magnesium have known antiplatelet effects and these may interfere with MEA interpretation. OBJECTIVE: To evaluate the extent to which MEA is modified in the presence of these drugs. DESIGN: An in-vitro study using blood collected from healthy volunteers. SETTING: Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, 2010 to 2011. PATIENTS: Twenty healthy volunteers. INTERVENTION: Measurement of baseline MEA was using four activators: arachidonic acid, ADP, TRAP-6 and collagen. The study drugs were then added in three increasing, clinically relevant concentrations. MAIN OUTCOME MEASURE: MEA was compared with baseline for each study drug. RESULTS: Midazolam, propofol and lidocaine showed no effect on MEA at any concentration. Magnesium at 2.5 mmol l had a significant effect on the ADP and TRAP tests (31 ± 13 and 96 ± 39 AU, versus 73 ± 21 and 133 ± 28 AU at baseline, respectively), and a less pronounced effect at 1 mmol l on the ADP test (39 ± 0 AU). CONCLUSION: Midazolam, propofol and lidocaine do not interfere with MEA measurement. In patients treated with high to normal doses of magnesium, MEA results for ADP and TRAP-tests should be interpreted with caution. TRIAL REGISTRATION: Clinicaltrials.gov (no. NCT01454427).

Génériques des médicaments antiépileptiques [Generics of antiepileptic drugs]

Generic substitution of antiepileptic drugs (EAD) have limited use because epilepsy is a chronic disease, seizure recurrence has an important impact of the quality of life and the potential risk of accidents. EADs have a narrow therapeutic window, non negligible side effects and complex interactions. Bioavailability of generic EADs, tested in healthy men during a limited period of time must be within the 90% IC, in which means that serum levels can range from 80% to 125% of the original drug. A slight drop in serum level could increase the risk of seizure recurrence, as indicated by several publications. Although no formal studies regarding cost effectiveness and the rate of seizure recurrence is available yet, the prevailing consensus recommends not to replace an original antiepileptic drug by a generic, due to the harmful risk of seizure recurrence.

Observational study on the consumption of recreational drugs and alcohol by Swiss travelers.

BACKGROUND: Studies carried out on specific travelers' groups such as students describe an increase in the consumption of alcohol and drugs during travel and vacation time. The present study investigates the risk behaviors (alcohol and drugs) in a general adult population in Switzerland travelling abroad who visited a travel clinic before departure. METHODS: This retrospective study was conducted in a travel clinic between January 2006 and December 2008. 14,496 patients came to the clinic for a pre-travel consultation. 3,537 of them answered a questionnaire about their life habits in Switzerland and during their last trip. The only exclusion criterion was an age inferior to 18 years old.The consumption habits of drugs and at-risk alcohol intake (8 standard drinks (SD) per week for women and 15 SD for men) was analyzed according to gender, sex, destination and profession. Predictors of adopting a risky behavior between habits in Switzerland and during their previous trip were also analyzed. RESULTS: 7% (229/3477) of participants declared having at-risk alcohol consumption in Switzerland and 14% (473/3275 [95% CI 13-16]) during their trip. 9% (332/3527) of the participants used drugs in Switzerland and 5% (178/3481) during their trip. Risk factors for at-risk alcohol consumption during a trip were: at-risk alcohol consumption in Switzerland (OR 31[95% CI 21-45]), smoking (1.7 [95% CI 1-2]), use of drugs in Switzerland (OR 2.2 [95% CI 2-3]), leisure travel (OR 1.6 [95% CI 1-2]) and managerial professions (OR 1.8 [95% CI 1-3]). Risk factors for the use of drugs during a trip were: alcohol consumption in Switzerland (OR 2.1 [95% CI 1-4]), smoking (OR 1.9 [95% CI 1-3]), and use of drugs in Switzerland (OR 29.7 [95% CI 19-45]). CONCLUSIONS: At-risk alcohol consumption and, to a lesser extent, use of drugs, affect a large number of travelers which expose them to health problems during a trip. Exploring the alcohol and drugs consumption patterns of people visiting a travel clinic should be part of the pre-travel routine consultation and would allow to identifying people who would benefit most from a specific prevention.

Malaria importée: des médicaments toujours plus efficaces et plus sûrs [Imported malaria: safer and more efficacious drugs?].

In response to the spread of parasite resistance to old antimalarial drugs, the large-scale implementation of artemisinine-based combinations has allowed to improving patient survival and reducing parasite transmission. Even though decreased susceptibility of parasites to artemisinine has been observed in South-East Asia, this phenomenon has no practical implications for travelers with uncomplicated malaria. The combination of artemether-lumefantrine is still very effective and safe, be it for P. falciparum or vivax. Intravenous administration of artesunate has allowed to significantly reducing case fatality rate of severe malaria patients when compared to quinine treatment in endemic areas. Artesunate is also recommended in travelers, but with close monitoring, especially for hematological parameters, in order to confirm its superiority.