Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.

OBJECTIVE: We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. METHODS: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. CONCLUSION: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.

Comparison of two oral probiotic preparations in a randomized crossover trial highlights a potentially beneficial effect of Lactobacillus paracasei NCC2461 in patients with allergic rhinitis.

BACKGROUND: There is promising but conflicting evidence to recommend the addition of probiotics to foods for prevention and treatment of allergy. Based on previous studies with fermented milk containing Lactobacillus paracasei NCC2461, we aimed to compare the effect of a powder form of the latter probiotic with the effect of a blend of Lactobacillus acidophilus ATCC SD5221 and Bifidobacterium lactis ATCC SD5219 in patients with allergic rhinitis. METHODS: A double-blind, randomized, cross-over study, involving 31 adults with allergic rhinitis to grass pollen, was performed outside the grass pollen season (registration number: NCT01233154). Subjects received each product for 4-weeks in two phases separated by a wash-out period of 6 to 8 weeks. A nasal provocation test was performed before and after each 4-week product intake period, and outcome parameters (objective and subjective clinical symptoms; immune parameters) were measured during and/or 24 hours after the test. RESULTS: Out of the 31 subject enrolled, 28 completed the study. While no effect was observed on nasal congestion (primary outcome), treatment with NCC2461 significantly decreased nasal pruritus (determined by VAS), and leukocytes in nasal fluid samples, enhanced IL-5, IL-13 and IL-10 production by peripheral blood mononuclear cells in an allergen specific manner and tended to decrease IL-5 secretion in nasal fluid, in contrast to treatment with the blend of L. acidophilus and B. lactis. CONCLUSIONS: Despite short-term consumption, NCC2461 was able to reduce subjective nasal pruritus while not affecting nasal congestion in adults suffering from grass pollen allergic rhinitis. The associated decrease in nasal fluid leukocytes and IL-5 secretion, and the enhanced IL-10 secretion in an allergen specific manner may partly explain the decrease in nasal pruritus. However, somewhat unexpected systemic immune changes were also noted. These data support the study of NCC2461 consumption in a seasonal clinical trial to further demonstrate its potentially beneficial effect.

Acute supra-therapeutic oral terbutaline administration has no ergogenic effect in non-asthmatic athletes.

This study aimed to investigate the effects on a possible improvement in aerobic and anaerobic performance of oral terbutaline (TER) at a supra-therapeutic dose in 7 healthy competitive male athletes. On day 1, ventilatory threshold, maximum oxygen uptake [Formula: see text] and corresponding power output were measured and used to determine the exercise load on days 2 and 3. On days 2 and 3, 8 mg of TER or placebo were orally administered in a double-blind process to athletes who rested for 3 h, and then performed a battery of tests including a force-velocity exercise test, running sprint and a maximal endurance cycling test at Δ50 % (50 % between VT and [Formula: see text]). Lactatemia, anaerobic parameters and endurance performance ([Formula: see text] and time until exhaustion) were raised during the corresponding tests. We found that TER administration did not improve any of the parameters of aerobic performance (p > 0.05). In addition, no change in [Formula: see text] kinetic parameters was found with TER compared to placebo (p > 0.05). Moreover, no enhancement of the force-velocity relationship was observed during sprint exercises after TER intake (p > 0.05) and, on the contrary, maximal strength decreased significantly after TER intake (p < 0.05) but maximal power remained unchanged (p > 0.05). In conclusion, oral acute administration of TER at a supra-therapeutic dose seems to be without any relevant ergogenic effect on anaerobic and aerobic performances in healthy athletes. However, all participants experienced adverse side effects such as tremors.

Adhésion thérapeutique en oncologie : persistance, qualité d'exécution et satisfaction des patients sous traitement oral et MEMS®

Introduction: en oncologie apparaissent sur le marché depuis quelques années de nouveaux traitements en formulation orale facilitant l'administration et améliorant la qualité de vie du patient mais augmentant le risque de non adhésion et d'erreurs de posologie. L'observation par MEMS® (Medication Event Monitoring System) permet le suivi et l'encadrement du traitement oral et par le biais d'entretiens semi structurés menés par le pharmacien, ouvre la discussion sur les problèmes révélés par cette prise en charge. Méthode: étude non randomisée prospective uni centrique regroupant 50 patients inclus dans 3 groupes de traitements oncologiques oraux courants (capecitabine, letrozole/exemestane, imatinib/sunitinib) bénéficiant d'un suivi oncologique classique et équipés d'un MEMS® pour un an maximum. La persistance et la qualité d'exécution sont les deux paramètres mesurés grâce aux données récoltées électroniquement. Les entretiens sont dédiés à la prévention de la non adhésion et à la gestion des effets secondaires médicamenteux. La satisfaction est évaluée par un questionnaire à la fin du suivi. Résultats: à ce jour 38 patients ont été inclus dans l'étude. Les données complètes sont disponibles pour les 19 premiers patients dont 10 sous capecitabine et 9 sous letrozole/exemestane. Dans ce collectif l'âge médian est de 66 ans avec une majorité de femmes (11:8). La persistance à 10 jours est de 85% et la qualité d'exécution de 99%. Les toxicités observées supérieures à grade 1 sont 1 syndrome mains-pieds (G3) et 1 syndrome coronarien aigu (G3). Le questionnaire de fin de suivi relève une satisfaction de 85% des patients pour les entretiens proposés (57% utiles, 28% très utiles, 15% inutiles) et le succès quant à l'intégration du MEMS® dans leur quotidien (57% très facile, 43% facile). Conclusion: la persistance et la qualité d'exécution observées dans notre collectif sont excellentes. La satisfaction retrouvée auprès des patients reflète le besoin d'un soutien complémentaire face à la complexité de la maladie oncologique. La gestion pluridisciplinaire profite tant aux patients qu'au binôme médecin-pharmacien par l'amélioration de la communication globale entre les divers acteurs et par l'identification précoce des risques de non adhésion. La poursuite de cette étude et l'analyse des futures données permettra de mesurer le réel impact de notre intervention et de justifier le bénéfice pour des patients sous traitement similaire.

Hospitalized women experiencing an episode of excessive oral anticoagulation had a higher bleeding risk than men.

OBJECTIVE: Overanticoagulated medical inpatients may be particularly prone to bleeding complications. Among medical inpatients with excessive oral anticoagulation (AC), we sought to identify patient and treatment factors associated with bleeding. METHODS: We prospectively identified consecutive patients receiving oral AC admitted to the medical ward of a university hospital (February-July 2006) who had at least one international normalized ratio (INR) value >3.0 during the hospital stay. We recorded patient characteristics, AC-related factors, and concomitant treatments (e.g., platelet inhibitors) that increase the bleeding risk. The outcome was overall bleeding, defined as the occurrence of major or minor bleeding during the hospital stay. We used logistic regression to explore patient and treatment factors associated with bleeding. RESULTS: Overall, 145 inpatients with excessive oral AC comprised our study sample. Atrial fibrillation (59%) and venous thromboembolism (28%) were the most common indications for AC. Twelve patients (8.3%) experienced a bleeding event. Of these, 8 had major bleeding. Women had a somewhat higher risk of major bleeding than men (12.5% vs 4.1%, p = 0.08). Multivariable analysis demonstrated that female gender was independently associated with bleeding (odds ratio [OR] 4.3, 95% confidence interval [95% C1] 1.1-17.8). Age, history of major bleeding, value of the index INR, and concomitant treatment with platelet inhibitors were not independent predictors of bleeding. CONCLUSIONS: We found that hospitalized women experiencing an episode of excessive oral AC have a 4-fold increased risk of bleeding compared with men. Whether overanticoagulated women require more aggressive measures of AC reversal must be examined in further studies.

Different PTH response to oral peptone load and oral calcium load in patients with normocalcemic primary hyperparathyroidism, primary hyperparathyroidism, and healthy subjects.

BACKGROUND: Normocalcemic primary hyperparathyroidism (PHPT-N) is a condition that may have similar long-term implications to primary hyperparathyroidism (PHPT); however, differential diagnosis and treatment for parathyroid disorders are not clearly defined. We investigated the effect of an oral peptone and an oral calcium load on calcium-regulating hormones in PHPT-N compared with PHPT and healthy controls to provide a new potential diagnostic tool. DESIGN: Case-control study. METHODS: We evaluated serum gastrin, PTH, ionized calcium, and phosphate responses to oral calcium (1 g) and peptone (10 g) load in 22 PHPT and 20 PHPT-N patients matched for PTH serum values. Moreover, 30 healthy subjects were enrolled as controls. In 12 patients for each group, we also performed the oral peptone test adding aluminum hydroxide (AH) to suppress phosphate absorption. RESULTS: In PHPT patients, PTH increased significantly 30 min after the oral peptone load, while no significant increase was found in PHPT-N and controls. After oral calcium load, PTH remained stable in PHPT while it decreased dramatically in PHPT-N patients, and ionized calcium increased significantly in each of the three groups. Peptones plus AH induced a blunted PTH increase in the three groups. CONCLUSIONS: Considering the marked difference in PTH response elicited by peptones in PHPT compared with PHPT-N, we suggest that the oral peptone test could be added to the diagnostic evaluation of PHPT patients. In case of absent response to peptones, patients should have their serum calcium levels assessed twice a year in accordance with recent guidelines.

Oral pregabalin as an add-on treatment for status epilepticus.

Oral antiepileptic drugs (AEDs) represent possible add-on options in refractory status epilepticus (SE). In this setting, pregabalin (PGB) has not been reported before. Over the last 42 months, we identified 11 SE episodes (10 patients) treated with PGB in our hospital. Its use was prompted by the favorable pharmacokinetic profile, devoid of drug-drug interactions. The patients mostly had refractory, partial SE. Only two patients were managed in the intensive care unit (ICU). We found a definite electroclinical response in 5 of 11, already evident 24 h after PGB introduction, and a possible response (concomitantly with other AEDs) in 3 of 11 of the episodes; 3/11 did not respond. The treatment was well tolerated. Partial SE appeared to better respond than generalized convulsive SE. PGB appears to be an interesting option as add-on treatment in refractory partial SE.

Can one or two high doses of oral vitamin D3 correct insufficiency in a non-supplemented rheumatologic population?

We evaluated the effectiveness of supplementation with high dose of oral vitamin D3 to correct vitamin D insufficiency. We have shown that one or two oral bolus of 300,000 IU of vitamin D3 can correct vitamin D insufficiency in 50% of patients and that the patients who benefited more from supplementation were those with the lowest baseline levels. INTRODUCTION: Adherence with daily oral supplements of vitamin D3 is suboptimal. We evaluated the effectiveness of a single high dose of oral vitamin D3 (300,000 IU) to correct vitamin D insufficiency in a rheumatologic population. METHODS: Over 1 month, 292 patients had levels of 25-OH vitamin D determined. Results were classified as: deficiency <10 ng/ml, insufficiency ≥10 to 30 ng/ml, and normal ≥30 ng/ml. We added a category using the IOM recommended cut-off of 20 ng/ml. Patients with deficient or normal levels were excluded, as well as patients already supplemented with vitamin D3. Selected patients (141) with vitamin D insufficiency (18.5 ng/ml (10.2-29.1) received a prescription for 300,000 IU of oral vitamin D3 and were asked to return after 3 (M3) and 6 months (M6). Patients still insufficient at M3 received a second prescription for 300,000 IU of oral vitamin D3. Relation between changes in 25-OH vitamin D between M3 and M0 and baseline values were assessed. RESULTS: Patients (124) had a blood test at M3. Two (2%) had deficiency (8.1 ng/ml (7.5-8.7)) and 50 (40%) normal results (36.7 ng/ml (30.5-5.5)). Seventy-two (58%) were insufficient (23.6 ng/ml (13.8-29.8)) and received a second prescription for 300,000 IU of oral vitamin D3. Of the 50/124 patients who had normal results at M3 and did not receive a second prescription, 36 (72%) had a test at M6. Seventeen (47%) had normal results (34.8 ng/ml (30.3-42.8)) and 19 (53%) were insufficient (25.6 ng/ml (15.2-29.9)). Of the 72/124 patients who receive a second prescription, 54 (75%) had a test at M6. Twenty-eight (52%) had insufficiency (23.2 ng/ml (12.8-28.7)) and 26 (48%) had normal results (33.8 ng/ml (30.0-43.7)). At M3, 84% patients achieved a 25-OH vitamin D level >20 ng/ml. The lowest the baseline value, the highest the change after 3 months (negative relation with a correlation coefficient r = -0.3, p = 0.0007). CONCLUSIONS: We have shown that one or two oral bolus of 300,000 IU of vitamin D3 can correct vitamin D insufficiency in 50% of patients.

Prevalence of patients' difficulties in swallowing solid oral dosage forms

Introduction Swallowing difficulties, or dysphagia, can occur in anyage group, although it is most common among elderly people. It canaffect patients' ability to take solid oral dosage forms, thus compromisingmedication adherence. Although literature is poor, availabledata show that prevalence in the general population ranges from 25 to60%. Prevalence in community pharmacies needs to be explored.Materials & Methods Community pharmacies were recruited from arandom selection in three Swiss states: Basel-Stadt (BS), Basel-Landschaft (BL) and Lausanne (LA). Patients' ability to swallowsolid oral medications was enquired with a semi-structured interview;the interviewer spent 4 h in each included pharmacy. Each consecutivepatient (18 years and older) entering the pharmacy with aprescription for at least 3 different solid oral forms was enrolled.Study was approved by the Lausanne ethics committee.Results Sixty pharmacies took part in the study (20 in BS, 10 in BL,30 in LA) between March and May 2010. Patient inclusion rate was77.8% (410/527). Prevalence of swallowing disorders was 22.4% (92/410). Patients with swallowing disorders were older (mean age: 67.5± 16 years vs. 63.0 ± 14 years, range 19-96; p = 0.03) and moreoften women (69.6% vs. 59.1%; Chi2 = 3.3, p = 0.04) than patientswithout swallowing disorders. They had on average 4.6 ± 2.7 drugswith a mean number of 5.5 ± 3.3 tablets or capsules to take daily,which didn't differ from the number of drugs taken by patientswithout swallowing difficulties (4.9 ± 2.5 drugs and 5.9 ± 3.5 tablets;n.s.). The difficulty was mainly related to the big size (63%) orthe quality of pill coating (rough, sticky, 14%). Twenty-one patients(37.5%) stated that their swallowing disorders resulted in nonadherence, rated as rarely (12 patients), sometimes (6 patients), veryoften (1 patient) or always (2 patients). According to patients, nopharmacist and only 2 physicians enquired about patients' swallowingissue.Discussion & Conclusion Swallowing difficulties are frequent amongpatients in community pharmacies in Switzerland with an estimatedprevalence of 22%. The problem resulted in non adherence or partialadherence in at least 35% of these patients. However, pharmacists andphysicians did not routinely inquire about the disorder. Guidelinesshould be developed for promoting systematic approaches of patientsin community pharmacies.

Oral and intravenous methadone use: some clinical and pharmacokinetic aspects.

A sample of 15 patients participating in an injectable methadone trial and of 15 patients in an oral methadone maintenance treatment, who admitted injecting part or all of their methadone take-home doses, were compared to 20 patients in maintenance treatment who use methadone exclusively by mouth. The present study confirms the poorer general health, the higher levels of emotional, psychological or psychiatric problems, the higher use of illicit drugs, and the higher number of problems related to employment and support associated with the use of the intravenous mode of administration of methadone. As expected, due to the shunt of metabolism in the gut wall and of the liver first-pass effect, higher concentration to dose ratios of (R)-methadone, which is the active enantiomer, were measured in the intravenous group (23% increase). This difference reached an almost statistically significant value (P = 0.054). This raises the question whether the effect of a higher methadone dose could be unconsciously sought by some of the intravenous methadone users.

Assessment of driving capability through the use of clinical and psychomotor tests in relation to blood cannabinoids levels following oral administration of 20 mg dronabinol or of a cannabis decoction made with 20 or 60 mg Delta9-THC.

Delta(9)-Tetrahydrocannabinol (THC) is frequently found in the blood of drivers suspected of driving under the influence of cannabis or involved in traffic crashes. The present study used a double-blind crossover design to compare the effects of medium (16.5 mg THC) and high doses (45.7 mg THC) of hemp milk decoctions or of a medium dose of dronabinol (20 mg synthetic THC, Marinol on several skills required for safe driving. Forensic interpretation of cannabinoids blood concentrations were attempted using the models proposed by Daldrup (cannabis influencing factor or CIF) and Huestis and coworkers. First, the time concentration-profiles of THC, 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) (active metabolite of THC), and 11-nor-9-carboxy-Delta(9)-tetrahydrocannabinol (THCCOOH) in whole blood were determined by gas chromatography-mass spectrometry-negative ion chemical ionization. Compared to smoking studies, relatively low concentrations were measured in blood. The highest mean THC concentration (8.4 ng/mL) was achieved 1 h after ingestion of the strongest decoction. Mean maximum 11-OH-THC level (12.3 ng/mL) slightly exceeded that of THC. THCCOOH reached its highest mean concentration (66.2 ng/mL) 2.5-5.5 h after intake. Individual blood levels showed considerable intersubject variability. The willingness to drive was influenced by the importance of the requested task. Under significant cannabinoids influence, the participants refused to drive when they were asked whether they would agree to accomplish several unimportant tasks, (e.g., driving a friend to a party). Most of the participants reported a significant feeling of intoxication and did not appreciate the effects, notably those felt after drinking the strongest decoction. Road sign and tracking testing revealed obvious and statistically significant differences between placebo and treatments. A marked impairment was detected after ingestion of the strongest decoction. A CIF value, which relies on the molar ratio of main active to inactive cannabinoids, greater than 10 was found to correlate with a strong feeling of intoxication. It also matched with a significant decrease in the willingness to drive, and it matched also with a significant impairment in tracking performances. The mathematic model II proposed by Huestis et al. (1992) provided at best a rough estimate of the time of oral administration with 27% of actual values being out of range of the 95% confidence interval. The sum of THC and 11-OH-THC blood concentrations provided a better estimate of impairment than THC alone. This controlled clinical study points out the negative influence on fitness to drive after medium or high dose oral THC or dronabinol.

Risk of falls and major bleeds in patients on oral anticoagulation therapy.

BACKGROUND: The risk of falls is the most commonly cited reason for not providing oral anticoagulation, although the risk of bleeding associated with falls on oral anticoagulants is still debated. We aimed to evaluate whether patients on oral anticoagulation with high falls risk have an increased risk of major bleeding. METHODS: We prospectively studied consecutive adult medical patients who were discharged on oral anticoagulants. The outcome was the time to a first major bleed within a 12-month follow-up period adjusted for age, sex, alcohol abuse, number of drugs, concomitant treatment with antiplatelet agents, and history of stroke or transient ischemic attack. RESULTS: Among the 515 enrolled patients, 35 patients had a first major bleed during follow-up (incidence rate: 7.5 per 100 patient-years). Overall, 308 patients (59.8%) were at high risk of falls, and these patients had a nonsignificantly higher crude incidence rate of major bleeding than patients at low risk of falls (8.0 vs 6.8 per 100 patient-years, P=.64). In multivariate analysis, a high falls risk was not statistically significantly associated with the risk of a major bleed (hazard ratio 1.09; 95% confidence interval, 0.54-2.21). Overall, only 3 major bleeds occurred directly after a fall (incidence rate: 0.6 per 100 patient-years). CONCLUSIONS: In this prospective cohort, patients on oral anticoagulants at high risk of falls did not have a significantly increased risk of major bleeds. These findings suggest that being at risk of falls is not a valid reason to avoid oral anticoagulants in medical patients.

Bioavailability of repeated oral administration of MDL 100,240, a dual inhibitor of angiotensin-converting enzyme and neutral endopeptidase in healthy volunteers.

BACKGROUND: MDL 100,240 (pyrido[2,1-a] [2]benzazepine-4-carboxylic acid,7-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-1,2,3,4,6,7,8, 12b-octahydro-6-oxo, [4S-[4alpha,7alpha(R(*)),12bbeta]]-) is a molecule possessing an inhibiting ability on both angiotensin converting enzyme (ACE) and neutral endopeptidase, the enzyme responsible for atrial natriuretic peptide (ANP) degradation. Such a dual mechanism of action presents a potential clinical interest for the treatment of hypertension and congestive heart failure. OBJECTIVES: To evaluate the bioavailability of MDL 100,240 and its accumulation over repeated oral administration, using ACE inhibition as a surrogate for plasma drug level and determining its profile after oral and i.v. administration. METHODS: First, in an open, one-period, single-dose study, the ACE inhibition profile was characterised following a 12.5 mg MDL 100,240 i.v. infusion. Second, in a three-group, parallel, randomised, double-blind study, each group of four subjects received q.d., over 8 days, 2.5, 10 or 20 mg of MDL 100,240 orally. The ACE inhibition profile was determined on day 1 and day 8. Trough plasma ACE was measured on days 2, 3 and 4. The recovery of ACE activity was monitored up to 72 h after the last dose of MDL 100,240. RESULTS: ACE inhibition profile was similar on day 1 and day 8, and trough inhibition remained unchanged after the 8 days of treatment with 10 mg or 20 mg. Following repeated 2.5-mg ingestion, trough inhibition increased from 33% to 44% after the eighth dose. The oral bioavailability of MDL 100,240 was estimated at 85%, not statistically different from 100%. The accumulation ratio at steady state was estimated at 112%. Expressing the accumulation ratio in terms of half-life, a t(1/2) of 0.31 days or 7. 5 h was estimated. CONCLUSION: MDL 100,240 (oral solution) has a good bioavailability, as estimated by ACE inhibition, and no drug accumulation seems to occur over 8 days with the 10-mg and 20-mg doses, but a slight rise in the trough level is observed with the 2. 5-mg dose.