Verlängerung der QT-Zeit
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Eklärungen für Patienten zu den Wirkstoffen
Monitorisieren: Citalopram und Triazolam
Verstärkte ZNS-DepressionseffekteMechanismus: Beide Substanzen wirken ZNS-depressiv.
Effekt: Mögliche gegenseitige Verstärkung der zentral dämpfenden Effekte wie Sedation, verminderte Vigilanz und erhöhtes Risiko einer Atemdepression.
Massnahmen: Achten auf verstärkte zentraldämpfende Symptome, ggf. Dosisreduktion.
|Citalopram||1 [0.55,5.07] 1,2||1|
Die genannten Expositionsveränderungen beziehen sich jeweils auf Veränderungen der Plasmakonzentrations-Zeit-Kurve [ AUC ]. Für Triazolam erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Citalopram (100%) erfolgt. Für Citalopram erwarten wir keine Veränderung der Exposition, wenn eine Kombination mit Triazolam (100%) erfolgt. Die AUC liegt dabei je nach CYP2D6, CYP2C19
Für die Berechnung der individuellen Expositionsveränderungen durch die Wechselwirkungen werden als Ausgangsbasis die pharmakokinetischen Parameter der durchschnittlichen Population verwendet.
Triazolam hat eine mittlere orale Bioverfügbarkeit [ F ] von 50%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell verändern. Die terminale Halbwertszeit [ t12 ] ist mit 2.8 Stunden eher kurz und konstante Plasmaspiegel [ Css ] werden schnell erreicht. Die Proteinbindung [ Pb ] ist mit 89% mässig stark und das Verteilungsvolumen [ Vd ] liegt mit 38 Liter im mittleren Bereich, da die Substanz eine tiefe hepatische Extraktionsrate von 0.24 besitzt, kann eine Verdrängung aus der Proteinbindung [Pb] im Rahmen einer Interaktion die Exposition erhöhen. Die Metabolisierung findet vor allem über CYP3A4 statt.
Citalopram hat eine mittlere orale Bioverfügbarkeit [ F ] von 80%, weshalb die maximalen Plasmaspiegel [ Cmax ] sich bei einer Interaktion tendentiell verändern. Die terminale Halbwertszeit [ t12 ] ist mit 35 Stunden eher lang und konstante Plasmaspiegel [ Css ] werden erst nach mehr als 140 Stunden erreicht. Die Proteinbindung [ Pb ] ist mit 80% mässig stark und das Verteilungsvolumen [ Vd ] ist mit 980 Liter sehr gross, da die Substanz eine tiefe hepatische Extraktionsrate von 0.19 besitzt, kann eine Verdrängung aus der Proteinbindung [Pb] im Rahmen einer Interaktion die Exposition erhöhen. Die Metabolisierung findet unter anderem über CYP2C19, CYP2D6 und CYP3A4 statt und der aktive Transport erfolgt insbesondere über PGP.
|Serotonerge Effekte a||2||Ø||++|
Empfehlung: Insbesondere nach einer Dosiserhöhung und bei Dosierungen im oberen therapeutischen Bereich sollte vorsichtshalber auf Symptome einer serotonergen Überstimulation geachtet werden.
Bewertung: Citalopram moduliert das serotonerge System in moderatem Ausmass. Das Risiko für ein serotonerges Syndrom ist bei dieser Medikation eher als gering einzustufen, wenn die Dosierung sich im üblichen Bereich befindet. Gemäss unseren Erkenntnissen erhöht Triazolam nicht die serotonerge Aktivität.
|Kiesel & Durán b||2||+||+|
Empfehlung: Insbesondere nach einer Dosiserhöhung und bei Dosierungen im oberen therapeutischen Bereich sollte vorsichtshalber auf anticholinerge Symptome geachtet werden.
Bewertung: Triazolam und Citalopram beeinflussen das anticholinerge System nur mild. Das Risiko für ein anticholinerge Syndrom ist bei dieser Medikation eher als gering einzustufen, wenn die Dosierung sich im üblichen Bereich befindet.
Verlängerung der QT-Zeit
Bewertung: Citalopram kann potentiell ventrikuläre Arrhythmien vom Typ Torsades de pointes auslösen. Für Triazolam ist uns kein QT-Zeit verlängerndes Potential bekannt.
Durchfall (8%): Citalopram
Verlust von Appetit: Citalopram
Agitation (6.5%): Citalopram
Nervosität (5.2%): Triazolam
Suizidalität: Citalopram, Triazolam
Abnorme Ejakulation (6.1%): Citalopram
Erektile Dysfunktion: Citalopram
Müdigkeit (5%): Citalopram
Verlängerte Blutungszeit: Citalopram
Anaphylaktische Reaktion: Triazolam
Basierend auf Ihren
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: This study was designed to evaluate the relative and absolute bioavailability of triazolam, 0.25 mg, after the administration of the marketed oral tablet and a sublingual prototype wafer; an intravenous dose was used as a reference. Twelve men were evaluated in a three-way crossover study; study days were separated by 1 week. A single dose was administered to each subject at approximately 8 a.m.; serial blood samples were obtained for the determination of triazolam concentration. The fraction absorbed relative to intravenous was 20% higher in the sublingual than in the oral treatment (p = 0.0128); the difference between treatments was greatest in the first 2 hours as indicated by the area under the curve from 0 to 2 hours (p < 0.05). The extraction ratio ranged from 0.05 to 0.25, and the predicted availability after oral administration was 86% with a range of 75 to 95%. In contrast, the observed mean absolute availability was 44% (oral) and 53% (sublingual). A potential explanation for this discrepancy between predicted and observed bioavailability is that after oral administration, a fraction of triazolam may be metabolized by cytochrome P450IIIA4 in the gut wall, with a separate fraction subject to first-pass metabolism in the liver. Although this study was not designed to identify sites of triazolam metabolism, the proposed explanation is consistent with the occurrence of P450IIIA4 in the stomach, small intestine, and liver. Doses administered sublingually avoid first-pass metabolism, producing earlier and higher peak concentrations than do doses administered orally.
Abstract: No Abstract available
Abstract: The ability of fluoxetine, norfluoxetine, sertraline and desmethyl sertraline to inhibit the CYP3A subfamily of cytochromes P450 was examined in vitro, using the formation of 1'-hydroxy midazolam as a probe for CYP3A catalytic activity. The inhibition observed with these four compounds was modeled using competitive, noncompetitive, uncompetitive and mixed competitive/noncompetitive relationships by nonlinear regression analysis. The best fit model of the inhibition of CYP3A-mediated 1'-hydroxy midazolam formation by all four compounds examined was determined to be mixed inhibition. The calculated Ki values were 65.7 +/- 12.0 microM for fluoxetine, 19.1 +/- 1.9 microM for norfluoxetine, 64.4 +/- 11.6 microM for sertraline and 48.1 +/- 11.6 microM for desmethyl sertraline. Steady-state plasma levels of fluoxetine and norfluoxetine can approach a concentration of 1 microM (approximately 350 ng/ml of plasma). Assuming an inhibitor concentration of 1 microM and a concentration of the substrate substantially below its Km (at least 10-fold lower), the results reported predict that fluoxetine and norfluoxetine together would inhibit CYP3A catalytic activity by less than 7% (less than 0.7% if the unbound plasma concentration of fluoxetine is considered). By using the same assumptions and concentrations for sertraline and desmethyl sertraline, these agents together would be predicted to inhibit the metabolic clearance of a coadministered CYP3A metabolized drug by less than 4%. The observations reported here suggest that fluoxetine and sertraline would have little effect on CYP3A-mediated clearance of coadministered drugs.
Abstract: OBJECTIVE: To compare the pharmacokinetics of the antidepressant citalopram and its metabolites demethylcitalopram and didemethylcitalopram in subjects with moderate renal insufficiency and subjects with hepatic cirrhosis with that in healthy subjects. METHODS: Pharmacokinetic parameters from three individual, open-label, phase I trials were derived following single oral or intravenous citalopram dose (40 mg) to healthy subjects and a single oral dose (20 mg) to patients. Serum and urine concentrations of citalopram and metabolites were determined using a validated HPLC method. RESULTS: The absolute bioavailability of citalopram tablets in healthy subjects was 80%. The renal clearance was a minor component (<20%) of the total elimination of citalopram. Serum Cmax and t(max) for citalopram were essentially unaffected by the occurrence of renal or hepatic disease. In comparison with healthy subjects, renal impairment was associated with a significant reduction in the renal elimination of citalopram and its two metabolites and a slight prolongation of serum citalopram t1/2 (49.5 h vs 36.8 h in healthy subjects). Cirrhosis resulted in significant decrease in citalopram CLoral (0.21 vs 0.331 x h(-1) x kg(-1) in healthy subjects) and increase in Vz x f(-1) with an approximately twofold increase in t1/2 (83.4 h vs 36.8 h in healthy subjects). Indices of renal (creatinine or 51Cr-EDTA clearances) and hepatic (galactose elimination capacity or Child-Pugh score) function were poor predictors of the changes in the pharmacokinetics of citalopram and its metabolites in these populations. CONCLUSION: No reduction of citalopram dosage is warranted in patients with moderately impaired renal function. However, that may not apply for patients with severe renal failure. In patients with impaired hepatic function, prescription of a lower dosage of citalopram may be appropriate.
Abstract: BACKGROUND: Kinetic and dynamic consequences of metabolic inhibition were evaluated in a study of the interaction of ketoconazole, a P4503A inhibitor, with alprazolam and triazolam, two 3A substrate drugs with different kinetic profiles. METHODS: In a double-blind, 5-way crossover study, healthy volunteers received (A) ketoconazole placebo plus 1.0 mg alprazolam orally, (B) 200 mg ketoconazole twice a day plus 1.0 mg alprazolam, (C) ketoconazole placebo plus 0.25 mg triazolam orally, (D) 200 mg ketoconazole twice a day plus 0.25 mg triazolam, and (E) 200 mg ketoconazole twice a day plus benzodiazepine placebo. Plasma concentrations and pharmacodynamic parameters were measured after each dose. RESULTS: For trial B versus trial A, alprazolam clearance was reduced (27 versus 86 mL/min; P < .002) and apparent elimination half-life (t1/2) prolonged (59 versus 15 hours; P < .03), whereas peak plasma concentration (Cmax) was only slightly increased (16.1 versus 14.7 ng/mL). The 8-hour pharmacodynamic effect areas for electroencephalographic (EEG) beta activity were increased by a factor of 1.35, and those for digit-symbol substitution test (DSST) decrement were increased by 2.29 for trial B versus trial A. For trial D versus trial C, triazolam clearance was reduced (40 versus 444 mL/min; P < .002), t1/2 was prolonged (18.3 versus 3.0 hours; P < .01), and Cmax was increased (2.6 versus 5.4 ng/mL; P < .001). The 8-hour effect area for EEG was increased by a factor of 2.51, and that for DSST decrement was increased by 4.33. Observed in vivo clearance decrements due to ketoconazole were consistent with those anticipated on the basis of an in vitro model, together with in vivo plasma concentrations of ketoconazole. CONCLUSION: For triazolam, an intermediate-extraction compound, impaired clearance by ketoconazole has more profound clinical consequences than those for alprazolam, a low extraction compound.
Abstract: Thirteen subjects (seven men, six women) completed a placebo-controlled, randomized, double-blind, crossover study to determine whether an interaction occurs between clonazepam and sertraline. Ten days of once-daily doses of either clonazepam 1 mg and placebo (CZ + PL) or clonazepam 1 mg and sertraline 100 mg (CZ + SR) were administered; there was an 11-day washout period. Sertraline did not significantly affect the pharmacokinetics of clonazepam (p > 0.13). Clonazepam apparent oral clearance, volume of distribution, and half-life were 3.9 +/- 0.2 L/hr, 233 +/-11 L, and 40.5 +/- 0.3 hours, respectively. The kinetics of the inactive metabolite 7-aminoclonazepam were marginally affected by sertraline, with a 21% decrease in the elimination half-life (p = 0.03) relative to CZ + PL and no significant difference between treatments in area under the curve or metabolite ratio. Card sorting (CS), digit-symbol substitution test (DSST), nurse-rated sedation scale (NRSS), and self-rated sedation scores were assessed four times daily on days -1 (PL + PL), 1, 4, 7, and 10. There were no differences between treatments in area under the effect curve or maximum observed effect for CS, DSST, or NRSS. Maximum impairment on all assessment days was low, with a less than 10% change from the drug-free values for CS and DSST. Despite higher clonazepam concentrations, predose (time 0) psychomotor and sedation scores did not differ among days -1, 1, 4, 7, and 10 or between treatments. These results in healthy volunteers indicate that sertraline does not affect the pharmacokinetics or pharmacodynamics of clonazepam.
Abstract: BACKGROUND: The viral protease inhibitor ritonavir has the capacity to inhibit and induce the activity of cytochrome P450-3A (CYP3A) isoforms, leading to drug interactions that may influence the efficacy and toxicity of other antiretroviral therapies, as well as pharmacologic treatments of coincident or complicating diseases. METHODS: The inhibitory effect of ritonavir on the biotransformation of the hypnotic agents triazolam and zolpidem was tested in vitro using human liver microsomes. In a double-blind clinical study, volunteer study subjects received 0.125 mg triazolam or 5.0 mg zolpidem concurrent with low-dose ritonavir (four doses of 200 mg), or with placebo. RESULTS: Ritonavir was a potent in vitro inhibitor of triazolam hydroxylation but was less potent as an inhibitor of zolpidem hydroxylation. In the clinical study, ritonavir reduced triazolam clearance to < 4% of control values (p < .005), prolonged elimination half-life (41 versus 3 hours; p < .005), and magnified benzodiazepine agonist effects such as sedation and performance impairment. In contrast, ritonavir reduced zolpidem clearance to 78% of control values (p < .08), and slightly prolonged elimination half-life (2.4 versus 2.0 hours; NS). Benzodiazepine agonist effects of zolpidem were not altered by ritonavir. CONCLUSION: Short-term low-dose administration of ritonavir produces a large and significant impairment of triazolam clearance and enhancement of clinical effects. In contrast, ritonavir produced small and clinically unimportant reductions in zolpidem clearance. The findings are consistent with the complete dependence of triazolam clearance on CYP3A activity, compared with the partial dependence of zolpidem clearance on CYP3A.
Abstract: OBJECTIVE: To study the effects of severe renal failure and haemodialysis on the pharmacokinetics of citalopram. METHODS: Four patients with renal failure undergoing haemodialysis and eight healthy controls were given a single dose of citalopram. The concentrations of citalopram and its metabolites desmethylcitalopram and didesmethylcitalopram were measured in serum and urine. On a different day, the four patients undergoing haemodialysis were given another single dose of citalopram, and the drug concentrations were measured in serum from the artery leading to the dialyser and in the dialysate. In addition, one anuric patient treated with citalopram on a regular basis was included in the study. RESULTS: There were no significant differences between the two groups in any of the pharmacokinetic parameters with the exception of the renal clearance of citalopram, which was significantly lower in the renal failure group than in the control group (1.70 ml/min versus 66.2 ml/min, P<0.001). Oral clearance of citalopram was almost identical in the two groups (452 ml/min versus 456 ml/min). The process of haemodialysis cleared about 1% of the dose as citalopram and 1% as desmethylcitalopram only. CONCLUSION: Severe renal failure does not affect the pharmacokinetics of citalopram and modification of the usual citalopram dose does thus not seem to be necessary. The contribution of haemodialysis to the total elimination of citalopram is negligible.
Abstract: An antidepressant for use in the patient receiving concomitant drug treatment, over-the-counter medications, or herbal products should lack cytochrome P-450 (CYP) 3A4 inductive or inhibitory activity to provide the least likelihood of a drug-drug interaction. This study addresses the potential of 4 diverse antidepressants (venlafaxine, nefazodone, sertraline, and fluoxetine) to inhibit or induce CYP3A4. In a 4-way crossover design, 16 subjects received clinically relevant doses of venlafaxine, nefazodone, or sertraline for 8 days or fluoxetine for 11 days. Treatments were separated by a 7- to 14-day washout period and fluoxetine was always the last antidepressant taken. CYP3A4 activity was evaluated for each subject at baseline and following each antidepressant using the erythromycin breath test (EBT) and by the pharmacokinetics of alprazolam (ALPZ) after 2-mg dose of oral ALPZ. Compared to baseline, venlafaxine, sertraline, and fluoxetine caused no apparent inhibition or induction of erythromycin metabolism (P > 0.05). For nefazodone, a statistically significant inhibition was observed (P < 0.0005). Nefazodone was also the only antidepressant that caused a significant change in ALPZ disposition, decreasing its area under the concentration-versus-time curve (AUC; P < 0.01), and increasing its elimination half-life (16.4 vs. 12.3 hours; P < 0.05) compared with values at baseline. No significant differences were found in the pharmacokinetics of ALPZ with any of the other antidepressants tested. These results demonstrate in vivo that, unlike nefazodone, venlafaxine, sertraline, and fluoxetine do not possess significant metabolic inductive or inhibitory effects on CYP3A4.
Abstract: The purpose of this study was to develop a quantitative structure-activity relationship (QSAR) for the prediction of the apparent volume of distribution (Vd) in man for a heterogeneous series of drugs. The relationship of many computed, and some experimental, structural descriptors with Vd, and the Vd corrected for protein binding (unbound Vd), was investigated. Models were constructed using stepwise regression analysis for all the 70 drugs in the dataset, as well as for acidic drugs and basic drugs separately. The predictive power of the models was assessed using half the chemicals as a test set, and revealed that the models for Vd yielded lower prediction errors than those constructed for the unbound Vd (mean fold error of 2.01 for Vd compared with 2.28 for unbound Vd). Moreover, the separation of the compounds into acids and bases did not reduce the prediction error significantly.
Abstract: This investigation aimed to provide evidence on the lack of pharmacokinetic interaction of paroxetine (20 mg/d) and alprazolam (1 mg/d) in combined therapy. In addition, the central effects of both drugs when administered alone and in combination were assessed to rule out any relevant synergistic depressant central effect. Twenty-five healthy young adult volunteers participated in a double-blind, double-dummy, placebo-controlled, repeated dose (15 days), 4-period crossover study. Each subject received each of 4 treatment sequences (ie, paroxetine-alprazolam placebo, alprazolam-paroxetine placebo, paroxetine-alprazolam, and paroxetine placebo-alprazolam placebo) in randomized order. The ratios for area under the curve within a dosing interval and maximum plasma concentration of the paroxetine plus alprazolam sequence to single agent paroxetine were 1.07 (90% confidence interval = 0.99 to 1.16) and 1.05 (90% confidence interval = 0.97 to 1.13), respectively, with no statistically significant differences between the 2 treatments. Similarly, for alprazolam, ratios for the combined to the single treatment sequence were 0.99 (90% confidence interval = 0.93 to 1.05) and 1.00 (90% confidence interval = 0.94 to 1.07) for area under the curve within a dosing interval and maximum plasma concentration, respectively, showing no evidence for interaction. Comparative pharmacodynamics on the combination was assessed using 6 Psychomotor Performance Tests and 5 Visual Analogue Scales focused on mood variables. Alprazolam and paroxetine plus alprazolam induced similar and significant performance impairment and sedation after both single and repeated dose administration, being less evident on day 15. After dosing, paroxetine plus alprazolam showed a lower recovery pattern than alprazolam alone, especially on day 15. No treatment sequence showed cumulative effects after repeated dose administration. Psychomotor Performance Tests and Visual Analogue Scales data suggested lack of pharmacodynamic interactions. Accordingly, study results showed no evidence for pharmacologic interactions between paroxetine and alprazolam at steady state. The most commonly reported adverse event was drowsiness, with a higher incidence under both single and combined alprazolam treatments.
Abstract: BACKGROUND: Previous studies have not demonstrated good correlations between various presumed phenotypic measures of in vivo cytochrome P450 (CYP) 3A activity. However, in reality, few have used appropriate and validated in vivo probes that consider the complexities of CYP3A. Accordingly, the disposition of 3 closely related benzodiazepines with extensive and similar CYP3A-mediated metabolism characteristics but different pharmacokinetics was investigated, and correlations between the drugs were examined. METHODS: The single-dose oral clearances of alprazolam, midazolam, and triazolam and the systemic clearances of the latter 2 drugs were separately determined in 21 healthy subjects (10 men) according to a randomized experimental design with a minimum 1-week period between the individual studies. An erythromycin breath test was also performed. RESULTS: After intravenous administration, systemic clearance varied 3-fold compared with a 6-fold range in clearance after an oral dose for all 3 drugs. However, mean values differed markedly between the drugs, with the systemic clearance of midazolam being almost double that of triazolam (383 +/- 73 mL/min versus 222 +/- 54 mL/min). Oral clearances were even more dissimilar: alprazolam, 75 +/- 36 mL/min; triazolam, 360 +/- 195 mL/min; and midazolam, 533 +/- 759 mL/min. Estimates of CYP3A-mediated extraction by the intestine and liver indicated approximately equal contributions by both organs but larger values for midazolam than for triazolam, and these differences accounted for the differences in oral bioavailability, 30% +/- 13% versus 55% +/- 20%, respectively. Statistically significant ( P = .001 to .004) correlations between the 3 drugs' oral clearances ranged from 0.60 to 0.68 ( r s value), whereas the correlation for the systemic clearances of midazolam and triazolam was 0.66 ( P = .001). No statistically significant relationships were observed between any of the clearance parameters and the erythromycin breath test. CONCLUSION: Despite alprazolam, midazolam, and triazolam having markedly different pharmacokinetic characteristics, statistically significant correlations were present between the oral and systemic clearances of the 3 drugs, consistent with a major involvement of CYP3A in their metabolism and elimination. However, the magnitude of the coefficients of determination ( r s ) was such to suggest that an in vivo probe approach, even with the use of valid phenotypic trait values, will be unable to accurately and reliably predict the pharmacokinetic behavior of another CYP3A substrate, as determined by the enzyme's constitutive activity.
Abstract: The objective of this study was to examine urinary excretion profiles of two major triazolam metabolites, alpha-hydroxytriazolam (alpha-OHTRZ) and 4-hydroxytriazolam (4-OHTRZ) in humans. Urine samples were collected from three healthy male volunteers who had been previously administered single 0.25- and 0.5-mg doses of triazolam 24 h and 48 h, respectively, before sample collection. After enzymatic hydrolysis and extraction, each sample was analyzed by liquid chromatography-mass spectrometry. alpha-OHTRZ was rapidly excreted, with the maximum concentrations appearing in the first or second sample collected after ingestion, with the majority of the drug being excreted within 12 h. Meanwhile, 4-OHTRZ was excreted more slowly than alpha-OHTRZ. The alpha-OHTRZ/4-OHTRZ ratios were initially greater than 19.7, then decreased rapidly, reaching a nearly constant value for times in excess of 12 h.
Abstract: Anticholinergic Drug Scale (ADS) scores were previously associated with serum anticholinergic activity (SAA) in a pilot study. To replicate these results, the association between ADS scores and SAA was determined using simple linear regression in subjects from a study of delirium in 201 long-term care facility residents who were not included in the pilot study. Simple and multiple linear regression models were then used to determine whether the ADS could be modified to more effectively predict SAA in all 297 subjects. In the replication analysis, ADS scores were significantly associated with SAA (R2 = .0947, P < .0001). In the modification analysis, each model significantly predicted SAA, including ADS scores (R2 = .0741, P < .0001). The modifications examined did not appear useful in optimizing the ADS. This study replicated findings on the association of the ADS with SAA. Future work will determine whether the ADS is clinically useful for preventing anticholinergic adverse effects.
Abstract: The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug-free serum was added to medication and atropine standard-curve samples. For medications that showed detectable AA, average steady-state peak plasma and serum concentrations (C(max)) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L-hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above-average C(max) values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.
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: Cognitive decline is common in Parkinson's disease (PD). Although some of the aetiological factors are known, it is not yet known whether drugs with anticholinergic activity (AA) contribute to this cognitive decline. Such knowledge would provide opportunities to prevent acceleration of cognitive decline in PD. OBJECTIVE: To study whether the use of agents with anticholinergic properties is an independent risk factor for cognitive decline in patients with PD. METHODS: A community-based cohort of patients with PD (n=235) were included and assessed at baseline. They were reassessed 4 and 8 years later. Cognition was assessed using the Mini-Mental State Examination (MMSE). A detailed assessment of the AA of all drugs prescribed was made, and AA was classified according to a standardised scale. Relationships between cognitive decline and AA load and duration of treatment were assessed using bivariate and multivariate statistical analyses. RESULTS: More than 40% used drugs with AA at baseline. During the 8-year follow-up, the cognitive decline was higher in those who had been taking AA drugs (median decline on MMSE 6.5 points) compared with those who had not taken such drugs (median decline 1 point; p=0.025). In linear regression analyses adjusting for age, baseline cognition and depression, significant associations with decline on MMSE were found for total AA load (standardised beta=0.229, p=0.04) as well as the duration of using AA drugs (standardised beta 0.231, p=0.032). CONCLUSION: Our findings suggest that there is an association between anticholinergic drug use and cognitive decline in PD. This may provide an important opportunity for clinicians to avoid increasing progression of cognitive decline by avoiding drugs with AA. Increased awareness by clinicians is required about the classes of drugs that have anticholinergic properties.
Abstract: No Abstract available
Abstract: We comprehensively reviewed published literature to determine whether it supported the link between corrected QT (QTc) interval prolongation and torsade de pointes (TdP) for the 11 second-generation antipsychotics and seven second-generation antidepressants commonly implicated in these complications. Using PubMed and EMBASE, we identified four thorough QT studies (one each for iloperidone, ziprasidone, citalopram, and escitalopram), 40 studies specifically designed to assess QTc interval prolongation or TdP, 58 publications based on data from efficacy and safety trials, 18 toxicology studies, and 102 case reports. Thorough QT studies, QTc prolongation-specific studies, and studies based on efficacy and safety trials did not link drug-associated QTc interval prolongation with TdP. They only showed that the drugs reviewed caused varying degrees of QTc interval prolongation, and even that information was not clear and consistent enough to stratify individual drugs for this risk. The few toxicology studies provided valuable information but their findings are pertinent only to situations of drug overdose. Case reports were most informative about the drug-QTc interval prolongation-TdP link. At least one additional well established risk factor for QTc prolongation was present in 92.2 % of case reports. Of the 28 cases of TdP, six (21.4 %) experienced it with QTc interval <500 ms; 75 % of TdP cases occurred at therapeutic doses. There is little evidence that drug-associated QTc interval prolongation by itself is sufficient to predict TdP. Future research needs to improve its precision and broaden its scope to better understand the factors that facilitate or attenuate progression of drug-associated QTc interval prolongation to TdP.
Abstract: This study aimed to demonstrate the added value of integrating prior in vitro data and knowledge-rich physiologically based pharmacokinetic (PBPK) models with pharmacodynamics (PDs) models. Four distinct applications that were developed and tested are presented here. PBPK models were developed for metoprolol using different CYP2D6 genotypes based on in vitro data. Application of the models for prediction of phenotypic differences in the pharmacokinetics (PKs) and PD compared favorably with clinical data, demonstrating that these differences can be predicted prior to the availability of such data from clinical trials. In the second case, PK and PD data for an immediate release formulation of nifedipine together with in vitro dissolution data for a controlled release (CR) formulation were used to predict the PK and PD of the CR. This approach can be useful to pharmaceutical scientists during formulation development. The operational model of agonism was used in the third application to describe the hypnotic effects of triazolam, and this was successfully extrapolated to zolpidem by changing only the drug related parameters from in vitro experiments. This PBPK modeling approach can be useful to developmental scientists who which to compare several drug candidates in the same therapeutic class. Finally, differences in QTc prolongation due to quinidine in Caucasian and Korean females were successfully predicted by the model using free heart concentrations as an input to the PD models. This PBPK linked PD model was used to demonstrate a higher sensitivity to free heart concentrations of quinidine in Caucasian females, thereby providing a mechanistic understanding of a clinical observation. In general, permutations of certain conditions which potentially change PK and hence PD may not be amenable to the conduct of clinical studies but linking PBPK with PD provides an alternative method of investigating the potential impact of PK changes on PD.
Abstract: OBJECTIVES: The aim of this systematic review is to identify case reports of citalopram use resulting in QTc prolongation, torsades de pointes, or both, in the medical literature. METHODS: A literature search was conducted of PubMed, MEDLINE, EMBASE, Scopus, and PsycINFO databases for case reports published in any language that reported the relationship between citalopram use and the development of QTc prolongation or torsades de pointes or both. In addition, bibliographic databases of published articles were searched for additional cases. RESULTS: A total of 18 case reports of citalopram use resulting in QTc prolongation were identified. Of these, 10 cases were also associated with the development of torsades de pointes. A total of 14 cases occurred in women and 4 in men. There were 7 cases involving an overdose with citalopram. Of the 18 cases, 12 occurred in individuals who were aged <60 years and 6 were in individuals aged >60 years. In 8 of the 18 cases, the individuals were taking a dose between 20 and 60mg of citalopram in a day. Hypertension was the most common comorbid medical condition, as seen in 5 of the cases. CONCLUSIONS: QTc prolongation or torsades de pointes are infrequently reported adverse effects associated with citalopram use.
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.
Abstract: INTRODUCTION: Citalopram is a selective serotonin reuptake inhibitor used for treatment of depression. Metabolism is primarily through CYP3A4 and CYP2C19; activity of the latter can vary depending on genetics. Although rare after single agent exposure, large citalopram ingestions can lead to serotonin syndrome. We report a case of citalopram overdose in an intermediate CYP2C19 metabolizer complicated by severe serotonin syndrome. CASE DETAILS: A 25-year-old female presented after intentional citalopram overdose with seizures, tachycardia, persistent neuromuscular findings, and severe hyperthermia requiring aggressive sedation and cooling. Protracted symptoms required critical care services throughout a 14 day hospital stay despite traditional treatment of serotonin syndrome. Pharmacogenomic studies revealed intermediate CYP2C19 metabolism which reduces citalopram inactivation and may cause increased levels and toxicity. DISCUSSION: In the majority of serotonin syndrome cases, symptoms resolve rapidly after treatment initiation and discontinuation of the offending agents. Severe cases are typically associated with ingestion of multiple serotonergic agents. Our patient had severe toxicity after single agent ingestion. Pharmacogenetic testing identified abnormal CYP2C19 activity and previous cases have associated enzyme dysfunction and citalopram toxicity. CONCLUSION: Citalopram overdose may be associated with severe serotonin syndrome and further investigation is warranted to understand the impact of enzyme genotype on toxicity.