Prolongación del tiempo QT
Eventos adversos de medicamentos
|Dolor de cabeza|
Variantes ✨Para la evaluación computacionalmente intensiva de las variantes, elija la suscripción estándar paga.
Explicaciones de las sustancias para pacientes.
No existen advertencias adicionales para la combinación de teofilina y loratadina. Consulte también la información especializada pertinente.
Los cambios informados en la exposición corresponden a los cambios en la curva de concentración plasmática-tiempo [ AUC ]. No esperamos ningún cambio en la exposición a teofilina, cuando se combina con loratadina (100%). No esperamos ningún cambio en la exposición a loratadina, cuando se combina con teofilina (100%).
Los parámetros farmacocinéticos de la población media se utilizan como punto de partida para calcular los cambios individuales en la exposición debidos a las interacciones.
La teofilina tiene una alta biodisponibilidad oral [ F ] del 100 %, por lo que el nivel plasmático máximo [Cmax] tiende a cambiar poco durante una interacción. La vida media terminal [ t12 ] es de 7 horas y se alcanzan niveles plasmáticos constantes [ Css ] después de aproximadamente 28 horas. La unión a proteínas [ Pb ] es relativamente débil al 100 % y el volumen de distribución [ Vd ] se encuentra en el rango medio a 36 litros, Dado que la sustancia tiene una tasa de extracción hepática baja de 0,9, el desplazamiento de la unión a proteínas [Pb] en el contexto de una interacción puede conducir a una mayor exposición. El metabolismo tiene lugar a través de CYP1A2, CYP2D6, CYP2E1 y CYP3A4, entre otros.
La loratadina tiene una baja biodisponibilidad oral [ F ] del 100 %, por lo que el nivel plasmático máximo [Cmax] tiende a cambiar fuertemente con una interacción. La unión a proteínas [ Pb ] es 100 % fuerte. El metabolismo tiene lugar a través de CYP2D6 y CYP3A4, entre otros y el transporte activo tiene lugar especialmente a través de PGP.
|Efectos serotoninérgicos a||0||Ø||Ø|
Clasificación: Según nuestro conocimiento, ni la teofilina ni la loratadina aumentan la actividad serotoninérgica.
|Kiesel & Durán b||2||+||+|
Recomendación: Como precaución, se debe prestar atención a los síntomas anticolinérgicos, especialmente después de aumentar la dosis y en dosis en el rango terapéutico superior.
Clasificación: La Teofilina y loratadina solo tienen un efecto leve sobre el sistema anticolinérgico. El riesgo de síndrome anticolinérgico con este medicamento es relativamente bajo si la dosis se encuentra en el rango habitual.
Prolongación del tiempo QT
No conocemos ningún potencial de prolongación del intervalo QT de la teofilina y loratadina.
Efectos adversos generales
|Efectos secundarios||∑ frecuencia||teo||lor|
|Dolor de cabeza||12.9 %||+||12.0|
|Reacciones alérgicas de la piel||1.0 %||+||n.a.|
|Aumento de la frecuencia de la micción||1.0 %||+||n.a.|
Hemorragia intracraneal: teofilina
Fibrilación auricular: teofilina
Síndrome de Stevens-Johnson: teofilina
Reacción anafiláctica: teofilina
Con base en sus respuestas e información científica, evaluamos el riesgo individual de efectos secundarios adversos. Estas recomendaciones están destinadas a asesorar a los profesionales y no sustituyen la consulta con un médico. En la versión de prueba restringida (alfa), el riesgo de todas las sustancias aún no se ha evaluado de manera concluyente.
Abstract: This histological and immunohistochemical study of 6 food handlers affected by immediate contact dermatitis due to foods shows that apparently normal skin of patients with this condition presents several histological and immunohistochemical abnormalities. Skin biopsies of normal hand skin showed focal parakeratosis and moderately dense dermal infiltrates. Immunohistochemistry showed an increased number of Langerhans cells in the epidermis and in the superficial dermis and a mononuclear dermal infiltrate consisting of peripheral T lymphocytes with a CD4/CD8 ratio of 5-6/1. Biopsies of the immediate vesicular reactions induced by foods showed spongiotic vesicles within the epidermis and a moderate to dense mononuclear dermal perivascular infiltrate. The immunohistochemical features were similar to those described in apparently normal skin. The mechanism of this immediate vesicular reaction requires further research. The rapid appearance of the lesions (after 20-30 min) probably excludes an immunological cell-mediated pathogenesis. A non-immunological mechanism due to direct liberation of mediators by foods is more readily conceivable than an immediate immunological type of contact reaction.
Abstract: To investigate a possible interaction between norfloxacin and theophylline, eight healthy nonsmoking volunteers (mean age 27 +/- 5.3 years) were administered aminophylline, 5 mg/kg, before and after a 6-day course of norfloxacin, 400 mg every 12 hours, and changes in pharmacokinetic parameters were measured and compared. Norfloxacin induced significant decreases in theophylline clearance (14.9%; p less than 0.01) and the terminal phase slope (13.3%; p less than 0.02) and increased the AUC (16.6%; p less than 0.01). The apparent volume of distribution at steady state was unchanged. The greatest norfloxacin-induced individual change in theophylline clearance was a reduction of 28.6%. Given these findings, we advise that, for patients who are treated with theophylline and are subsequently treated with norfloxacin, adjustment of the theophylline dosage may be necessary in some patients to minimize the risk of theophylline toxicity.
Abstract: In 42 subjects with chronic obstructive lung disease receiving chronic oral theophylline therapy, the venous whole blood theophylline concentration was closely related to the total plasma theophylline concentrations (r = 0.976, p less than 0.001). The blood/plasma concentration ratio was 0.85 +/- 0.13 and was not related to the haematocrit or the free fraction of theophylline in plasma. The red blood cell theophylline concentration was closely related and numerically similar to the free plasma concentration. This indicates that the free plasma concentration is the most important determinant of red blood cell concentration, and that binding of drug by red blood cells or active uptake into erythrocytes is unlikely to occur. Whole blood concentration can be used to predict plasma theophylline concentration in subjects with obstructive lung disease in situations where preparation of plasma is inconvenient. The therapeutic range for whole blood concentration is approximately 8.5-17 mg/L.
Abstract: The effect of erythromycin base on theophylline kinetics was studied in eight informed, nonsmoking, adult males who received a 15-min infusion of theophylline (aminophylline) 5 mg/kg, prior to (control) and after (experimental) a 7-day course of 1 gm daily erythromycin base (E-Mycin). Each subject acted as his own control. Multiple serum samples were collected for 24 hr after each dose and were analyzed for theophylline by high-pressure liquid chromatography. The mean +/- SD pharmacokinetic parameters for each phase of study were as follows: apparent volume of distribution (L/kg) 0.45 +/- 0.05 (control), 0.41 +/- 0.05 (experimental); clearance (ml . min/kg) 0.83 +/- 0.17 (control), 0.60 +/- 0.11 (experimental); elimination half-life (hr) 6.65 +/- 1.88 (control), 8.10 +/- 1.58 (experimental). Erythromycin significantly affected the elimination half-life and clearance of theophylline (p less than 0.05). The apparent volume of distribution was unaffected (p greater than 0.05). Therefore patients being administered theophylline appear to be at added risk for the development of toxicity when erythromycin is added to the therapeutic regimen.
Abstract: OBJECTIVE: To evaluate the effects of coadministration of loratadine and erythromycin on the pharmacokinetics and electrocardiographic repolarization (QTc) pharmacodynamics of loratadine and its metabolite descarboethoxyloratadine in healthy volunteers. METHODS: Twenty-four healthy volunteers were studied in a prospective, double-blind crossover design while confined in a Clinical Research Center. The primary pharmacodynamic end point of the study was the difference between baseline and day 10 mean QTc intervals obtained from surface electrocardiograms. Plasma concentrations of loratadine, descarboethoxyloratadine, and erythromycin were measured on treatment day 10 for pharmacokinetic analysis. Subjects received in random sequence the following three treatments for 10 consecutive days during three separate study periods: 10 mg loratadine every morning plus 500 mg erythromycin stearate every 8 hours, or 10 mg loratadine every morning plus placebo every 8 hours, or placebo every morning plus 500 mg erythromycin stearate. RESULTS: Concomitant administration of loratadine and erythromycin was associated with increased plasma concentrations of loratadine (40% increase in area under the plasma concentration-time curve [AUC]) and descarboethoxyloratadine (46% increase in AUC) compared with loratadine alone. Analysis of variance showed no difference between the treatment groups in effect on QTc intervals compared with baseline, and no significant change from baseline was observed. No clinically relevant changes in the safety profile of loratadine were observed, and there were no reports of sedation nor syncope. CONCLUSION: Although concomitant administration of loratadine and erythromycin was associated with increased plasma concentrations of loratadine and descarboethoxyloratadine, no clinically relevant changes in the safety profile of loratadine were observed. In this study, 10 mg loratadine administered orally for 10 consecutive days was well tolerated when coadministered with therapeutic doses of erythromycin stearate.
Abstract: The effects of famotidine (80 mg per day), cimetidine (1600 mg per day), and placebo on theophylline pharmacokinetic parameters in chronic obstructive pulmonary disease (COPD) patients were compared. This was an open-label, randomized, three-period cross-over study, in which each subject first underwent a seven-day theophylline washout period, and thereafter received three single intravenous doses of theophylline (5 mg/kg infused over 30 minutes) during the study. Each of the experimental treatments was administered orally every 12 hours for a total of 9.5 days (19 doses). Theophylline was infused after the 17th dose of each treatment. Fourteen serial blood samples were collected before the start of each infusion, and for 30 hours after the end of each infusion. Plasma samples were assayed for theophylline, pharmacokinetic parameters were estimated, and treatment effects on each parameter were compared. Fourteen COPD patients completed all three periods of the investigation. Famotidine treatment had virtually no effect on any of theophylline's pharmacokinetic parameters. In contrast, cimetidine treatment significantly altered every pharmacokinetic parameter of theophylline as follows: Cimetidine decreased theophylline geometric mean CL from 2.74 L/h to 2.07 L/h (P < .001), and prolonged theophylline harmonic mean half-life from 6.6 to 9.6 hours (P < .001) and mean residence time from 10.8 to 15.0 hours (P < .001). Cimetidine treatment slightly increased theophylline volume of distribution by approximately 10%, and that change also was statistically significant (P = .032). The authors conclude that the treatment effects of cimetidine on theophylline pharmacokinetic parameters were in accord with those reported by others, and that famotidine treatment had no effect on any of theophylline's pharmacokinetic parameters in COPD patients.
Abstract: Rifampin and rifabutin induce the metabolism of many drugs, which may result in subtherapeutic concentrations and failure of therapy. However, differences between rifabutin and rifampin in potency of induction, and the specific enzymes which are altered, are not clear. This study, involving 12 adult male volunteers, compared the effects of 14-day courses of rifampin and rifabutin on clearance of theophylline, a substrate for the hepatic microsomal enzyme CYP1A2. Subjects were given oral theophylline solution (5 mg/kg of body weight) on day 1 and then randomized to receive daily rifampin (300 mg) or rifabutin (300 mg) on days 3 to 16. Theophylline was readministered as described above on day 15. The first treatment sequence was followed by a 2-week washout period; subjects then received the alternative treatment. Theophylline concentrations were determined for 46 h after each dose, and pharmacokinetic parameters were determined. One subject developed flu-like symptoms while taking rifabutin and withdrew voluntarily. Results from the remaining 11 subjects are reported. Compared with the baseline, the mean area under the concentration-time curve (AUC) (+/- standard deviation) for theophylline declined significantly following rifampin treatment (from 140 +/- 37 to 100 +/- 24 micrograms . h/ml, P <0.001); there was no significant change following rifabutin treatment (136 +/- 48 to 128 +/- 45 micrograms.h/ml). Baseline theophylline AUCs before each treatment phase were not different. A comparison of equal doses of rifampin and rifabutin administered to healthy volunteers for 2 weeks indicates that induction of CYP1A2, as measured by theophylline clearance, is significantly less following rifabutin treatment than it is following rifampin treatment. However, the relative induction potency for other metabolic enzymes remains to be investigated.
Abstract: Twelve healthy volunteers were enrolled in an open-label, randomized, crossover study. Subjects received single doses of theophylline (5 mg/kg) with and without multiple-dose terbinafine, and 11 blood samples were collected over 24 h. The study phases were separated by a 4-week washout period. Theophylline serum data were modeled via noncompartmental analysis. When the control phase (i.e., no terbinafine) was compared to the treatment phase (terbinafine), theophylline exposure (the area under the serum concentration-time curve from time zero to infinity) increased by 16% (P = 0.03), oral clearance decreased by 14% (P = 0.04), and half-life increased by 24% (P = 0.002). No significant changes in other theophylline pharmacokinetic parameters were evident.
Abstract: AIMS: To evaluate whether ketoconazole or cimetidine alter the pharmacokinetics of loratadine, or its major metabolite, desloratadine (DCL), or alter the effects of loratadine or DCL on electrocardiographic repolarization in healthy adult volunteers. METHODS: Two randomized, evaluator-blind, multiple-dose, three-way crossover drug interaction studies were performed. In each study, subjects received three 10 day treatments in random sequence, separated by a 14 day washout period. The treatments were loratadine alone, cimetidine or ketoconazole alone, or loratadine plus cimetidine or ketoconazole. The primary study endpoint was the difference in mean QTc intervals from baseline to day 10. In addition, plasma concentrations of loratadine, DCL, and ketoconazole or cimetidine were obtained on day 10. RESULTS: Concomitant administration of loratadine and ketoconazole significantly increased the loratadine plasma concentrations (307%; 90% CI 205-428%) and DCL concentrations (73%; 62-85%) compared with administration of loratadine alone. Concomitant administration of loratadine and cimetidine significantly increased the loratadine plasma concentrations (103% increase; 70-142%) but not DCL concentrations (6% increase; 1-11%) compared with administration of loratadine alone. Cimetidine or ketoconazole plasma concentrations were unaffected by coadministration with loratadine. Despite increased concentrations of loratadine and DCL, there were no statistically significant differences for the primary electrocardiographic repolarization parameter (QTc) among any of the treatment groups. No other clinically relevant changes in the safety profile of loratadine were observed as assessed by electrocardiographic parameters (mean (90% CI) QTc changes: loratadine vs loratadine + ketoconazole = 3.6 ms (-2.2, 9.4); loratadine vs loratadine + cimetidine = 3.2 ms (-1.6, 7.9)), clinical laboratory tests, vital signs, and adverse events. CONCLUSIONS: Loratadine 10 mg daily was devoid of any effects on electrocardiographic parameters when coadministered for 10 days with therapeutic doses of ketoconazole or cimetidine in healthy volunteers. It is concluded that, although there was a significant pharmacokinetic drug interaction between ketoconazole or cimetidine and loratadine, this effect was not accompanied by a change in the QTc interval in healthy adult volunteers.
Abstract: This study investigated the effects of the concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6. In period 1, a single dose of 3.5 mg/kg theophylline was administered orally. In period 2, a single dose of 1.0 microg/kg/min toborinone was infused over 6 hours. In period 3, 3.5 mg/kg theophylline was coadministered with 1.0 microg/kg/min toborinone. Serial blood and pooled urine samples were collected before and after toborinone administration for the quantification of toborinone and its metabolites in plasma and urine. Serial blood samples were collected before and after theophylline administration for the quantification of theophylline and its metabolites in plasma. No significant differences were observed in toborinone pharmacokinetics between poor and extensive metabolizers via CYP2D6. Toborinone coadministration with theophylline did not result in a substantive effect on the disposition of theophylline and vice versa.
Abstract: OBJECTIVE: To examine the potential effect of daidzein on CYP1A2 activity and on the pharmacokinetics of theophylline by inhibiting its metabolism. METHODS: The experiment was conducted in a single-blind, placebo-controlled, parallel study. The caffeine metabolic ratio (CMR) used as an indicator of CYP1A2 function was completed at baseline and after daidzein or placebo co-administration. A single dose of 100 mg theophylline was taken by all 20 volunteers on day 3. Thereafter, volunteers were allocated for one of two regimens. One group received 200 mg daidzein twice daily for 10 days. The other group received placebo. On day 12, the test group received 200 mg daidzein with 100 mg theophylline; the parallel group received 100 mg theophylline with placebo. RESULTS: The baseline value of CMR between test group and control group did not show a difference (P=0.215). The percentage decrease in CMR ranged from -50% to 20%, with an average value of -19.8+/-19.7%. The percentage decrease in test group was statistically significant (P=0.009), and no significant changes were shown in the control group (t=0.12, P=0.914). By comparing the pharmacokinetic parameters of theophylline before and after daily treatment with daidzein, the effect of daidzein on the metabolism of theophylline was evident. Comparing the kinetics parameters of theophylline of day 1 (without co-medication) with those of day 12 (10-day daidzein), the AUC(0-48), AUC(0- infinity ), C(max) and t(1/2) were significantly increased by 33.57+/-21.75% (CI, 1.21-1.46, P< 0.05), 33.77+/-21.45% (CI, 1.20-1.46, P<0.05), 23.54+/-16.93% (CI, 1.23-1.52, P< 0.05) and 41.39+/-45.92% (t=-3.19, P=0.011), respectively. The pharmacokinetic parameters of theophylline within the placebo group showed no statistically significant difference (P >0.05). CONCLUSIONS: Daidzein, a principal isoflavone in soybean, in higher doses may inhibit CYP1A2 activity in vivo, and physicians should be aware of potential drug-food interactions.
Abstract: Loratadine is known to be a substrate for both CYP3A4 and CYP2D6 based on a previous in vitro study. In view of the large interindividual variability in loratadine pharmacokinetics and the greater genetically determined variability of CYP2D6 activity than of CYP3A4 in vivo, we hypothesized that CYP2D6 polymorphisms may contribute to the pharmacokinetic variability of loratadine. The purpose of this study was to evaluate the effect of CYP2D6 genotype (specifically the CYP2D6*10 allele) on the pharmacokinetics of loratadine in Chinese subjects. Three groups of healthy male Chinese subjects were enrolled: group I, homozygous CYP2D6*1 (*1/*1, n=4); group II, heterozygous CYP2D6*10 (*1/*10 or *2/*10, n=6); and group III, homozygous CYP2D6*10 (*10/*10, n=7) carriers. Each subject received a single oral dose of 20 mg of loratadine under fasting conditions. Multiple blood samples were collected over 48 h, and the plasma concentrations of loratadine and its metabolite desloratadine were determined by high-performance liquid chromatography. In comparing homozygous CYP2D6*10 (group III) to heterozygous CYP2D6*10 (group II) to homozygous CYP2D6*1 (group I) subjects, loratadine oral clearance values were 7.17+/- 2.54 versus 11.06+/-1.70 versus 14.59+/-2.43 l/h/kg, respectively [one-way analysis of variance (ANOVA), p<0.01], and the corresponding metabolic ratios [area under the plasma concentration-time curve (AUC)(desloratadine)/AUC(loratadine)] were 1.55+/-0.73 versus 2.47+/- 0.46 versus 3.32+/- 0.49, respectively (one-way ANOVA, p<0.05), indicating a gene-dose effect. The results demonstrated that CYP2D6 polymorphism prevalent in the Chinese population significantly affected loratadine pharmacokinetics.
Abstract: BACKGROUND AND OBJECTIVES: In vivo inhibition of cytochrome P450 (CYP) 1A2 by fluvoxamine causes a reduction in the clearance of the high-extraction drug lidocaine, which decreases in proportion to the degree of liver dysfunction. The objectives of this study were (1) to evaluate the effect of liver cirrhosis on the inhibition by fluvoxamine of the metabolic disposition of theophylline, a CYP1A2 substrate with a low-extraction ratio, to assess whether decreased sensitivity to CYP1A2 inhibition in liver disease is a general characteristic of CYP1A2 substrates, regardless of their pharmacokinetic properties, and (2) to investigate the mechanism(s) underlying the effect of liver dysfunction on CYP1A2 inhibition. METHODS: The study was carried out in 10 healthy volunteers and 20 patients with cirrhosis, 10 with mild liver dysfunction (Child class A) and 10 with severe liver dysfunction (Child class C), according to a randomized, double-blind, 2-phase, crossover design. In one phase all participants received placebo for 7 days; in the other phase they received one 50-mg fluvoxamine dose for 2 days and two 50-mg fluvoxamine doses, 12 hours apart, in the next 5 days. On day 6, 4 mg/kg of theophylline was administered orally 1 hour after the morning fluvoxamine dose. Concentrations of theophylline and its metabolites, 3-methylxanthine, 1-methyluric acid, and 1,3-dimethyluric acid, were then measured in plasma and urine up to 48 hours. RESULTS: Fluvoxamine-induced inhibition of theophylline clearance decreased from 62% in healthy subjects to 52% and 12% in patients with mild cirrhosis and those with severe cirrhosis, respectively. CYP1A2-mediated formations of 3-methylxanthine and 1-methyluric acid were almost totally inhibited in control subjects, whereas they were only reduced by one third in patients with Child class C cirrhosis. Inhibition of 1,3-dimethyluric acid formation, which is catalyzed by CYP1A2 and CYP2E1, progressively decreased from 58% in healthy subjects to 43% and 7% in patients with mild cirrhosis and those with severe cirrhosis, respectively. CONCLUSIONS: The effect of liver dysfunction on the inhibition of CYP1A2-mediated drug elimination is a general phenomenon, independent of the pharmacokinetic characteristics of the CYP1A2 substrate. Therefore, for any drug metabolized by CYP1A2, the clinical consequences of enzyme inhibition are expected to become less and less important as liver function worsens. Two mechanisms, as follows in order of importance, are responsible for the effect of liver dysfunction: (1) decreased sensitivity to fluvoxamine of CYP1A2-mediated biotransformations in the cirrhotic liver, probably resulting from reduced uptake of the inhibitory drug, and (2) reduced hepatic expression of CYP1A2, which makes its contribution to overall drug elimination less important.
Abstract: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
Abstract: OBJECTIVES: To examine the longitudinal relationship between cumulative exposure to anticholinergic medications and memory and executive function in older men. DESIGN: Prospective cohort study. SETTING: A Department of Veterans Affairs primary care clinic. PARTICIPANTS: Five hundred forty-four community-dwelling men aged 65 and older with diagnosed hypertension. MEASUREMENTS: The outcomes were measured using the Hopkins Verbal Recall Test (HVRT) for short-term memory and the instrumental activity of daily living (IADL) scale for executive function at baseline and during follow-up. Anticholinergic medication use was ascertained using participants' primary care visit records and quantified as total anticholinergic burden using a clinician-rated anticholinergic score. RESULTS: Cumulative exposure to anticholinergic medications over the preceding 12 months was associated with poorer performance on the HVRT and IADLs. On average, a 1-unit increase in the total anticholinergic burden per 3 months was associated with a 0.32-point (95% confidence interval (CI)= 0.05-0.58) and 0.10-point (95% CI=0.04-0.17) decrease in the HVRT and IADLs, respectively, independent of other potential risk factors for cognitive impairment, including age, education, cognitive and physical function, comorbidities, and severity of hypertension. The association was attenuated but remained statistically significant with memory (0.29, 95% CI=0.01-0.56) and executive function (0.08, 95% CI=0.02-0.15) after further adjustment for concomitant non-anticholinergic medications. CONCLUSION: Cumulative anticholinergic exposure across multiple medications over 1 year may negatively affect verbal memory and executive function in older men. Prescription of drugs with anticholinergic effects in older persons deserves continued attention to avoid deleterious adverse effects.
Abstract: BACKGROUND: Methadone plasma concentrations are decreased by nelfinavir. Methadone clearance and the drug interactions have been attributed to CYP3A4, but actual mechanisms of methadone clearance and the nelfinavir interaction are unknown. We assessed nelfinavir effects on methadone pharmacokinetics and pharmacodynamics, intestinal and hepatic CYP3A4/5 activity, and intestinal P-glycoprotein transport activity. CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively. METHODS: Twelve healthy HIV-negative volunteers underwent a sequential crossover. On three consecutive days they received oral alfentanil plus fexofenadine, intravenous alfentanil, and intravenous plus oral methadone. This was repeated after nelfinavir. Plasma and urine analytes were measured by mass spectrometry. Opioid effects were measured by pupil diameter change (miosis). RESULTS: Nelfinavir decreased intravenous and oral methadone plasma concentrations 40-50%. Systemic clearance, hepatic clearance, and hepatic extraction all increased 1.6- and 2-fold, respectively, for R- and S-methadone; apparent oral clearance increased 1.7- and 1.9-fold. Nelfinavir stereoselectively increased (S>R) methadone metabolism and metabolite formation clearance, and methadone renal clearance. Methadone bioavailability and P-glycoprotein activity were minimally affected. Nelfinavir decreased alfentanil systemic and apparent oral clearances 50 and 76%, respectively. Nelfinavir appeared to shift the methadone plasma concentration-effect (miosis) curve leftward and upward. CONCLUSIONS: Nelfinavir induced methadone clearance by increasing renal clearance, and more so by stereoselectively increasing hepatic metabolism, extraction and clearance. Induction occurred despite 50% inhibition of hepatic CYP3A4/5 activity and more than 75% inhibition of first-pass CYP3A4/5 activity, suggesting little or no role for CYP3A in clinical methadone disposition. Nelfinavir may alter methadone pharmacodynamics, increasing clinical effects.
Abstract: The present study demonstrated that in addition to CYP3A4 and CYP2D6, the metabolism of loratadine is also catalyzed by CYP1A1, CYP2C19, and to a lesser extent by CYP1A2, CYP2B6, CYP2C8, CYP2C9 and CYP3A5. The biotransformation of loratadine was associated with the formation of desloratadine (DL) and further hydroxylation of both DL and the parent drug (loratadine). Based on the inhibition and correlation studies contribution of CYP2C19 in the formation of the major circulating metabolite DL seems to be minor. Reported clinical results suggest that the steady state mean (%CV) plasma Cmax and AUC(24hr) of loratadine were 4.73 ng/ml (119%) and 24.1 ng.hr/ml (157%), respectively, after dosing with 10 mg loratadine tablets for 10 days. High inter-subject variability in loratadine steady-state data is probably due to the phenotypical characteristics of CYP2D6, CYP2C19, and CYP3A4. The relative abundance of CYP3A4 in the human liver exceeds that of CYP2C19 and CYP2D6 and therefore the contribution of CYP3A4 in the metabolism of loratadine should be major (approximately 70%).
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.