Antonio Portolés

Effect of adverse drug reactions on length of stay in surgical intensive care units.

ObjectiveTo determine the frequency of adverse drug reactions in surgical intensive care units and evaluate their effect on the length of stay. DesignProspective cohort study. Between May 1997 and December 1999, while the patients were staying in the surgical intensive care unit, data were gathered regarding suspected adverse drug reactions and on different variables related to the length of stay. SettingSurgical intensive care units of our hospital. PatientsA total of 401 patients hospitalized in the surgical intensive care unit. Main ResultsIn 37 of the 401 patients seen (9.2%; 95% confidence interval, 6.6–12.5), 39 different adverse drug reactions were detected. The adverse drug reactions were most frequently caused by the following drugs: morphine hydrochloride (n = 13), meperidine hydrochloride (n = 9), and metamizole (n = 7). Five adverse drug reactions were severe, the suspected medication had to be discontinued in 14 cases, and new drugs were necessary to manage the adverse drug reaction in 28 cases. The crude estimation of the effect of adverse drug reactions performed on the length of stay with a bivariant regression model indicated that each adverse drug reaction was related to an increase of 3.39 days (95% confidence interval, 1.47–5.31) in the length of stay. This estimation was reduced to 2.31 days (95% confidence interval, 0.64–3.99) when considering other variables that might cause confusion for analysis, although it is still important. ConclusionsAdverse drug reactions are a significant clinical and economic problem in surgical intensive care units.

Physical dependence to morphine diminishes the interferon response in mice

Morphine pellet implantation in mice was demonstrated to diminish resistance to encephalomyocarditis virus infections. The variations in the response to three different interferon (IFN) inducers--Newcastle disease virus, Escherichia coli lipopolysaccharide and a tilorone analogue--were evaluated. A close relationship between morphine dependence and IFN response was detected. A clear inhibition in IFN induction appeared as a concomitant phenomenon with the syndrome of morphine dependence. In the response intensity, the mice strain tested was more important than the total drug dose in the pellet. This effect of morphine on IFN responses presented a characteristic age-related pattern and, perhaps, may also be influenced by the H-2 murine phenotype.

A new high-absorption-rate Paracetamol 500-mg formulation: A comparative bioavailability study in healthy volunteers

BACKGROUND Paracetamol is often the analgesic or antipyretic of choice, especially for patients for whom salicylates or other nonsteroidal anti-inflammatory drugs are contraindicated. OBJECTIVE The aim of this study was to compare the absorption rate of a new tablet formulation of paracetamol (500 mg) with a reference formulation of paracetamol at the same dose. METHODS This was a single-center, Phase I, open-label, randomized, 2-period, crossover, single-dose, comparative bioavailability clinical trial. During both study periods, healthy volunteers were given a single oral dose of a more hydrophilic test formulation of paracetamol, or a reference formulation. Fifteen plasma samples were obtained to determine paracetamol concentrations and to calculate kinetic parameters. RESULTS The study participants comprised 24 healthy volunteers (12 men, 12 women; mean [SD] age, 22.8 [1.5] years). The pharmacokinetic parameters calculated for the test versus the reference formulation were as follows: median time to maximum concentration (Tmax), 0.42 versus 0.75 hour; mean (SD) maximum plasma drug concentration (Cmax), 9.85 (2.40) μg/mL versus 8.33 (2.22) μg/mL; and mean (SD) area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞), 30.16 (8.87) μg·h/mL versus 28.49 (8.57) μg · h/mL. The 90% CIs of the ratios were as follows: base e logarithm (Ln)-transformed Cmax, 105.08% to 137.59%; Ln-AUC0-∞, 102.02% to 110.43%; and the difference in Tmax, -0.375 to -0.085 hours. CONCLUSIONS The speed of release and absorption was statistically significantly higher with the test formulation compared with the reference one (evaluated using Tmax, Cmax, and Cmax/AUC parameters). This speed is especially important for a rapid analgesic or antipyretic effect.

Bioequivalence study of two formulations of enalapril, at a single oral dose of 20 mg (tablets): A randomized, two-way, open-label, crossover study in healthy volunteers.

BACKGROUND Enalapril maleate is the monoethyl ester prodrug of enalapril- at, an angiotensin-converting enzyme inhibitor indicated in the management of essential and renovascular hypertension, and in the treatment of congestive heart failure and in asymptomatic patients with left ventricular dysfunction and an ejection fraction of ≥35%. Enalapril has little pharmacologic activity until hydrolyzed in vivo to enalaprilat. OBJECTIVE The aim of the present study was to compare the bioavailability and tolerability of 2 commercial brands (test and reference formulations) of enalapril tablets (20 mg), described as the rate and extent of absorption of the active moiety, to assess their bioequivalence. METHODS This single-dose, randomized, 2-way, open-label, crossover study in healthy volunteers aged 18 to 40 years was conducted at the Clinical Pharmacology Study Unit, Hospital Clínico San Carlos (Madrid, Spain). Subjects were randomized to receive (under fasting conditions) either the test or reference formulation of enalapril (20-mg tablet) at study period 1 and the opposite formulation at study period 2. Study periods were separated by a washout period of at least 7 days. During each study period, 15 plasma extractions were made to determine enalapril and enalaprilat plasma concentrations and to calculate the pharmacokinetic (PK) properties (maximal plasma drug concentration [Cmax], time to Cmax [Tmax], area under the plasma concentration-time curve [AUC] to the last measurable concentration [AUCt], AUC from time 0 to infinity [AUC0-∞], mean residence time, and elimination half-life [tl2]) of both. Physical examination, subject interview, laboratory analyses, electrocardiogram, and blood pressure (BP) were used to assess tolerability. RESULTS Twenty-four subjects were included in the study (12 men, 12 women; mean [SD] age, 22.8 [2.2] years [range, 19-30 years]). Of these, 1 subject (4.2%) withdrew from the study for personal reasons; thus, PK and statistical analyses included results from 23 subjects. No statistically significant sequence or period effect was found. Tmax was not statistically different between the 2 formulations, and the 90% CI calculated for Tmax for the difference of the medians was within the predefined range. The 90% CIs of the logarithmically transformed concentration-derived parameters (Cmax AUCt, and AUC0-∞) also were within the predefined range; thus, the 2 formulations are considered bioequivalent. For both formulations, systolic and diastolic BPs showed significant reductions compared with baseline values (P < 0.05). Seven adverse effects were recorded, all of them transient and none of severe intensity. CONCLUSIONS In this study of 2 commercial brands (test and reference formulations) of enalapril in healthy subjects, designed and conducted under Good Clinical Practice guidelines, a similar rate and extent of absorption for both formulations were found to be bioequivalent. Both formulations produced a significant decrease in BP values and were generally well tolerated.

Comparative Single-Dose Bioavailability Study of Two Oral Formulations of Ibuprofen in Healthy Volunteers

AbstractObjective: To compare the bioavailability of equivalent doses of two oral formulations of ibuprofen: ibuprofen lysinate 1025mg (powder for oral suspension) and ibuprofen free acid 600mg (effervescent granules). Design and Setting: Nonblind, comparative, two-way, crossover, randomised design carried out in a phase I study unit. Participants: 24 healthy volunteers (10 males, 14 females) with mean age 23.42 years, mean bodyweight 65.38kg, mean height 170.75cm and mean body mass index 22.31 kg/m2. Interventions: During each study period, a single oral dose of one of the formulations was administered, and 15 plasma samples were obtained to determine ibuprofen concentrations and calculate kinetic parameters. Results: The kinetic parameters [ibuprofen lysinate vs ibuprofen free acid (mean ±SD)] were: area under the concentration-time curve from zero to infinity (AUC0-∞) 181.64 ± 64.84 vs 176.99 ± 62.35 mg·h/L; maximum plasma concentration (Cmax) 62.03 ± 9.66 vs 51.39 ± 12.84 mg/L; time to reach Cmax (tmax) [median] 0.54 vs 1.75h. The 90% confidence intervals (CIs) of the ratios of logarithmically transformed values were 98.05 to 107.79% for AUC0-∞ and 112.87 to 137.07% for Cmax; the 90% CI of the difference in tmax was −1.5 to −1.0h. Conclusions: The extent of ibuprofen absorption is the same with both formulations. The speed of release/absorption is greater with the lysinate formulation. This is of particular significance for achieving a rapid analgesic or antipyretic effect.

Truncated area under the urinary excretion rate curve in the evaluation of alendronate bioequivalence after a single dose in healthy volunteers.

This study was designed to evaluate the bioequivalence of two formulations of alendronate (CAS 121268-17-5) 70 mg (test formulation, alendronate 70 mg tablets, vs. the reference formulation) in 80 healthy volunteers under fasting conditions. The trial followed an open, randomized, crossover design with a washout period of 28 days. Urine samples were collected up to 48 h post-dose, and the concentrations of alendronate were determined by HPLC. The mean Ae(0-48) was (mean +/- SD) 152.15 +/- 136.09 microg for the reference formulation and 150.37 +/- 126.20 microg for the test formulation, while the mean Rmax was 53.33 +/- 41.53 microg/h and 55.85 +/- 49.57 microg/h, respectively. No significant differences in pharmacokinetic parameters between the two formulations were found. The 90% confidence interval for the ratios of Ae(0-48) and Rmax of alendronate were within the acceptance range for bioequivalence trials. The results of the present study suggest that the test formulation is bioequivalent to the reference formulation. The analyses of truncated AURC to shorter times showed similar values, which were within the range of bioequivalence.

Pharmacokinetic Study of a New Ibuprofen 600mg plus Codeine 30mg Combination versus Ibuprofen or Codeine Alone in Single Oral Doses in Healthy Volunteers

AbstractObjective: To compare the bioavailability parameter values of ibuprofen 600mg or codeine 30mg when administered in a new combined solid oral formulation versus each agent administered alone. Design: Non-blind, comparative, crossover, three-way (ibuprofen, codeine, ibuprofen plus codeine) randomised clinical trial. Setting: Phase 1 study unit. Subjects: 24 healthy volunteers of both genders (12 males and 12 females) with the following average characteristics: age 22.6 years; bodyweight 63.2kg; height 171cm; body mass index 21.47 kg/m2. Interventions: During each study period, a single oral dose of one of the formulations was administered, and 13 plasma samples were obtained to determine drug concentrations and calculate pharamcokinetic parameter values. Results: The pharmacokinetic parameter values [mean ± standard deviation, except median for time to maximum plasma concentration (tmax)] calculated for each drug and formulation were as follows: For ibuprofen (combined with codeine) versus ibuprofen alone: area under the concentration-time curve from time zero to infinity (AUC0-∞), 202.06 ± 43.62 vs 204.19 ± 52.79 mg·h/L; maximum plasma concentration (Cmax), 64.93 ± 11.91 vs 57.01 ± 15.47 mg/L; tmax, 1.00 vs 1.50h. The 90% confidence intervals (CI90) of the ratios (%) of logarithmically transformed values were: AUC0-∞ 95.88 to 104.22; Cmax 104.75 to 129.63; the CI90 (Wilcoxon test) of the median difference in tmax was −0.80 to −0.13h. For codeine (combined with ibuprofen) versus codeine alone: AUC0-∞ 417.82 ±115.55 vs 354.36 ±114.43 μg·h/L; Cmax115.12 ± 38.85 vs 89.05 ± 27.09 μg/L; tmax 1.00 vs 1.00h. The CI90 of the ratios (%) of logarithmically transformed values were: AUC0-∞ 111.84 to 126.18; Cmax 116.66 to 139.57; the CI90 (Wilcoxon test) of the median difference in tmax was −0.25 to 0.17h. Conclusions: The rate and extent of ibuprofen release/absorption from both formulations are within bioequivalence limits. The extent of absorption of codeine is slightly greater from the combination form, with a similar rate of release/absorption. The slight differences found are attributable to the galenic formulations. These results confirm the good bioavailability of ibuprofen and codeine from the new formulation, and exclude any impairment of absorption when the drugs are formulated in combination.

Adverse Drug Reactions in a Cardiology Department

SummaryAdverse drug reactions (ADRs) pose an important problem in most healthcare areas. However, their importance in cardiology services has not previously been clearly quantified. Between 1985 and 1993, we performed a prospective observational study to evaluate the importance of ADRs in patients admitted to a cardiology department. Of the 1023 patients studied, 11 (1.1%) had an adverse reaction at the time of hospitalisation and 132 (12.9%) had at least one ADR while hospitalised. Ten of 11 ADRs at the time of hospitalisation were the reason for hospitalisation. A total of 178 (2.6% of the 6801 prescriptions) adverse reactions were detected during hospitalisation. The most frequently encountered adverse reactions were nonspecific gastrointestinal problems (n = 34) and headache (n = 33). Digoxin was the drug most frequently implicated in patients hospitalised because of ADRs. Nitrates, calcium antagonists, β-adrenoceptor antagonists and digitalis compounds were the drug classes most frequently associated with ADRs during hospitalisation. The length of hospital stay was almost 5 days longer in patients who developed ADRs during hospitalisation than in those who did not. ADR patients consumed 2.5 more drugs than non-ADR patients. Thus, ADRs during, or leading to, hospitalisation in patients in cardiology departments are associated with important health and economic consequences.

Modification of Albumin Use Pattern After an Educational Intervention

AbstractObjective: To determine whether an educational programme could reduce the inappropriate use of albumin. Study design and setting: A hospital albumin working group (San Carlos Clinical Hospital, Madrid, Spain) developed local guidelines for albumin prescribing. After the guidelines were disseminated, all albumin prescriptions were analysed according to these guidelines. Physicians who prescribed albumin for indications other than those in the guidelines were selected for a personalised face-to-face educational programme with a clinical pharmacologists. Adherence to the guidelines was then evaluated compared with an observational period with success being measured in terms of quality of prescribing and economic consequences. The effects of the intervention were assessed again during the intervention (7 months) and after the intervention (in the first 5-month period and in the subsequent year). Main outcomes measures and results: In the observational period, consumption was centralised in medical services and nearly 76% of prescriptions for albumin were inappropriate. During the intervention, the percentage of inappropriate albumin prescribing decreased to 38.8%. Albumin consumption decreased from 444 vials/month during the observational period to 249 vials/month during the intervention, and although the average monthly consumption increased slightly during the 17 months following the intervention, it was similar to that immediately after the intervention.Differences in albumin consumption and quality improvement between the observational period and during the intervention were statistically significant (p < 0.00001). These results led to cost savings of nearly 30% during the intervention and in the follow-up period. Conclusions: This educational programme improved the quality of albumin prescribing and controlled local expenses related to albumin use in a general hospital.

Use of Intravenous Omeprazole in a University Hospital

Objective: To evaluate the characteristics of using intravenous omeprazole in a university hospital. Method: A prospective follow-up of all patients (n = 108) treated with intravenous omeprazole in our hospital was done from October 1994 through May 1995. Based on requests sent to the pharmacy service, patients receiving this drug were located and their charts were reviewed. The patients were visited daily throughout the duration of their treatment to evaluate any change in dosage, addition of new drugs to the regimen, and the final date of treatment. Results: Only 52% of the patients received omeprazole for indications in which its usefulness is clearly demonstrated. The dosages used frequently exceeded those recommended by the pharmaceutical manufacturer and in the literature. In fact, more than 50% of the patients were treated with dosages over 40 mg/d. It would have been possible to administer omeprazole orally instead of intravenously in 17% of the patients. Twenty-three percent of the patients were treated simultaneously with omeprazole and histamine2-antagonists. Conclusions: The use of intravenous omeprazole in our hospital is not optimal; thus, it seems that a strategy to improve this situation should be designed.