Avvisi di avvertenza
Estensione di tempo QT
Effetti avversi del farmaco
|Mal di testa|
Varianti ✨Per la valutazione computazionalmente intensiva delle varianti, scegli l'abbonamento standard a pagamento.
Aree di applicazione
Spiegazioni per i pazienti
Avvisi di avvertenza
La somministrazione di ciprofloxacina e teofillina deve essere evitata.
Aumento delle concentrazioni di teofillina - diminuzione della soglia convulsivaMeccanismo: la ciprofloxacina inibisce il CYP1A2 e quindi anche il metabolismo della teofillina. Entrambe le sostanze possono anche portare a un aumento delle convulsioni.
Effetto: le concentrazioni di teofillina sono aumentate di circa il 30% in combinazione con ciprofloxacina. La combinazione di chinoloni con teofillina può anche portare a una soglia convulsiva abbassata.
Misure: la combinazione di teofillina e ciprofloxacina dovrebbe essere evitata. Ofloxacina o levofloxacina sarebbero più adatte, poiché con queste sostanze sono state osservate solo minime variazioni nella clearance della teofillina. Se è necessaria la combinazione, monitorare i segni di aumento della tossicità da teofillina e aumento dell'attività convulsiva. La concentrazione di teofillina deve essere controllata e la dose aggiustata per il singolo paziente, se necessario. Secondo le istruzioni del produttore, la dose di teofillina deve essere ridotta a un massimo del 60% quando co-somministrata con ciprofloxacina.
|Citalopram||1.01 [0.55,5.22] 1,2||1.01||1|
I cambiamenti nell'esposizione menzionati si riferiscono ai cambiamenti nella curva concentrazione plasmatica-tempo [AUC]. L'esposizione alla teofillina aumenta al 188%, se combinato con ciprofloxacina (168%) e citalopram (107%). Questo può portare a un aumento degli effetti collaterali. L'esposizione alla citalopram aumenta al 101%, se combinato con ciprofloxacina (101%) e teofillina (100%). L'AUC è compresa tra 55% e 522% a seconda del
I parametri farmacocinetici della popolazione media sono utilizzati come punto di partenza per il calcolo delle singole variazioni di esposizione dovute alle interazioni.
La ciprofloxacina ha una biodisponibilità orale media [ F ] del 70%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare con un'interazione. L'emivita terminale [ t12 ] è piuttosto breve a 3.5 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti rapidamente. Il legame proteico [ Pb ] è molto debole al 30%. Circa il 55.0% di una dose somministrata viene escreta immodificata attraverso i reni e questa proporzione è raramente modificata dalle interazioni. Il metabolismo avviene principalmente tramite CYP1A2 e il trasporto attivo avviene in parte tramite BCRP, OATP1A2 e PGP.
La citalopram ha una biodisponibilità orale media [ F ] del 80%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare con un'interazione. L'emivita terminale [ t12 ] è piuttosto lunga a 35 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti solo dopo più di 140 ore. Il legame proteico [ Pb ] è moderatamente forte al 80% e il volume di distribuzione [ Vd ] è molto grande a 980 litri, Poiché la sostanza ha una bassa velocità di estrazione epatica di 0,9, lo spostamento dal legame proteico [Pb] nel contesto di un'interazione può aumentare l'esposizione. Il metabolismo avviene tramite CYP2C19, CYP2D6 e CYP3A4, tra gli altri e il trasporto attivo avviene in particolare tramite PGP.
La teofillina ha un'elevata biodisponibilità orale [ F ] del 85%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare poco durante un'interazione. L'emivita terminale [ t12 ] è di 7 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti dopo circa 28 ore. Il legame proteico [ Pb ] è piuttosto debole al 40% e il volume di distribuzione [ Vd ] è di 36 litri nell'intervallo medio, Poiché la sostanza ha una bassa velocità di estrazione epatica di 0,9, lo spostamento dal legame proteico [Pb] nel contesto di un'interazione può aumentare l'esposizione. Il metabolismo avviene tramite CYP1A2, CYP2D6, CYP2E1 e CYP3A4, tra gli altri.
|Effetti serotoninergici a||2||Ø||++||Ø|
Raccomandazione: Come misura precauzionale, devono essere presi in considerazione i sintomi della sovrastimolazione serotoninergica, specialmente dopo aver aumentato la dose e alle dosi nell'intervallo terapeutico superiore.
Valutazione: La citalopram modula il sistema serotoninergico in misura moderata. Il rischio di una sindrome serotoninergica può essere classificato basso con questo farmaco se il dosaggio rientra nell'intervallo abituale. Secondo le nostre conoscenze, né la ciprofloxacina né la teofillina aumentano l'attività serotoninergica.
|Kiesel & Durán b||2||Ø||+||+|
Raccomandazione: A scopo precauzionale, occorre prestare attenzione ai sintomi anticolinergici, soprattutto dopo aver aumentato la dose ea dosi nel range terapeutico superiore.
Valutazione: La citalopram e la teofillina hanno solo un lieve effetto sul sistema anticolinergico. Il rischio di sindrome anticolinergica con questo farmaco è piuttosto basso se il dosaggio è nel range usuale. Secondo i nostri risultati, la ciprofloxacina non aumenta l'attività anticolinergica.
Estensione di tempo QT
Valutazione: In combinazione, ciprofloxacina e citalopram possono potenzialmente innescare aritmie ventricolari di tipo torsione di punta. Non conosciamo alcun potenziale di prolungamento dell'intervallo QT per la teofillina.
Effetti collaterali generali
|Effetti collaterali||∑ frequenza||cip||cit||teo|
|Mal di testa||21.3 %||3.0||18.0||+|
Diarrea (8.9%): ciprofloxacina, citalopram
Diarrea da Clostridium difficile: ciprofloxacina
Emorragia gastrointestinale: ciprofloxacina
Perdita di appetito: citalopram
Agitazione (6.5%): citalopram
Irritabilità (5%): ciprofloxacina
Suicida: ciprofloxacina, citalopram
Eiaculazione anormale (6.1%): citalopram
Disfunzione erettile: citalopram
Disturbo dell'orgasmo: citalopram
Rinofaringite (5%): ciprofloxacina
Secrezione nasale (3%): ciprofloxacina
Fatica (5%): citalopram
Eruzione cutanea (1.8%): ciprofloxacina
Necrolisi epidermica tossica: ciprofloxacina
Sindrome di Stevens Johnson: ciprofloxacina, teofillina
Infarto miocardico: ciprofloxacina
Fibrillazione atriale: teofillina
Insufficienza epatica: ciprofloxacina
Reazione di ipersensibilità: ciprofloxacina
Reazioni allergiche della pelle: teofillina
Reazione anafilattica: teofillina
Perdita di peso: citalopram
Cistite emorragica: ciprofloxacina
Insufficienza renale: ciprofloxacina
Nefrite tubulointerstiziale: ciprofloxacina
Aumento della frequenza della minzione: teofillina
Convulsioni: ciprofloxacina, teofillina
Incidente cerebrovascolare: citalopram
Disturbo dell'attenzione: ciprofloxacina
Sindrome di Guillain-Barré: ciprofloxacina
Compromissione della memoria: ciprofloxacina
Neuropatia periferica: ciprofloxacina
Pseudotumor cerebri: ciprofloxacina
Aumento della pressione intracranica: ciprofloxacina
Emorragia intracranica: teofillina
Anemia aplastica: ciprofloxacina
Anemia emolitica: ciprofloxacina
Tempo di sanguinamento prolungato: citalopram
Miastenia grave: ciprofloxacina
Rottura del tendine: ciprofloxacina
Aneurisma aortico: ciprofloxacina
Sulla base delle vostre
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: A number of quinolone antibiotics have been found to reduce the hepatic clearance of coadministered drugs such as theophylline. Enoxacin appears to be the most potent inhibitor, consistently decreasing theophylline clearance by more than 50%, while a single study suggests a similar degree of inhibition with pipemidic acid. Ciprofloxacin and pefloxacin reduce theophylline clearance to a smaller extent (approximately 20 to 30%). However, with ciprofloxacin, larger changes and theophylline toxicity have been reported in some subjects. Norfloxacin, ofloxacin and nalidixic acid appear to have minimal effects on theophylline clearance. Enoxacin and ciprofloxacin have also been found to reduce the clearance of caffeine, while ofloxacin has no effect. Few other substrates have been studied. Enoxacin decreases the clearance of R-warfarin with no effect on S-warfarin. In addition, enoxacin has been reported to reduce the clearance of antipyrine, with no effect on chlorpropamide, glibenclamide (glyburide) or phenytoin. The mechanism of these interactions is largely unexplored. It has been suggested that inhibition may be related to the production of 4-oxoquinolone metabolites; however, this hypothesis has not been confirmed. No unique structural feature has been identified to date which explains differences between these compounds in their propensity to affect drug metabolism. Further studies are needed to evaluate the effects of these drugs on other substrates not yet examined and to assess whether or not inhibition is dose related. Clinically, caution is advised when using a quinolone, particularly enoxacin, pipemidic acid, ciprofloxacin or pefloxacin, in combination with theophylline. Close monitoring of theophylline concentrations is recommended in any patient receiving these drugs. The clinical significance of inhibited metabolism of other substrates remains unclear at present. Until further data are available, clinicians should be aware of the possibility of reduced drug clearance resulting in adverse effects whenever the fluoroquinolones are coadministered with drugs that depend on hepatic metabolism for their elimination.
Abstract: The effect of a multiple-dose regimen of oral ciprofloxacin (750 mg every 12 h for 11 doses) on the clearance and steady-state concentrations of theophylline in trough (predose) serum was evaluated in nine healthy male subjects, each serving as his own control. Theophylline was taken as a sustained release tablet per os in a dose of 200 mg every 12 h for 19 doses. Theophylline concentrations in serum were measured immediately before each theophylline dose. Ciprofloxacin was administered on study day 4 through the first dose of study day 8. Theophylline concentrations in serum were also measured on study days 3, 6, 8, and 10 at the following times after the first dose of each day: 0, 0.25, 0.50, 1, 2, 4, 6, 8, 10, and 12 h. Steady-state theophylline concentrations in trough serum were significantly higher during ciprofloxacin treatment (day 8) than before (day 3) or after (day 10) ciprofloxacin administration (P less than 0.01). Likewise, theophylline clearance was significantly slower (P less than 0.01) during ciprofloxacin treatment (day 8) than before it (day 3) or after it (day 10). The magnitude of ciprofloxacin-induced changes was approximately 30%. These results suggest that a multidose regimen of ciprofloxacin significantly slows the clearance of theophylline and elevates theophylline concentrations in serum.
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: The effect of pipemidic acid and five new synthetic antibacterial agents--norfloxacin, enoxacin, ofloxacin, ciprofloxacin, and pefloxacin--on the serum level of theophylline was studied in healthy male adult volunteers after concomitant oral administration of these agents with a slow release preparation of theophylline. The results indicated that enoxacin, ciprofloxacin, and pipemidic acid might decrease the clearance of theophylline in the liver, and the attention should be paid in clinical use when enoxacin or pipemidic acid is coadministered with theophylline.
Abstract: Pharmacokinetic parameters of the bronchodilator theophylline were assessed in eight patients with chronic obstructive lung disease when administered alone and when comedicated with ciprofloxacin 500 mg twice daily, ofloxacin 400 mg twice daily, or pefloxacin 400 mg twice daily. Compared to the control period, in which only theophylline was administered, the total body clearance of theophylline decreased significantly during ciprofloxacin (30.4%) and pefloxacin (29.4%) coadministration, whereas no change of the renal clearance of theophylline occurred. Ofloxacin did not influence the pharmacokinetic parameters of theophylline. From these observations it is concluded that ciprofloxacin and pefloxacin reduce the metabolic clearance of theophylline.
Abstract: Enoxacin decreases the metabolic clearance of the bronchodilator theophylline not only in severely ill patients, but also in patients with stable chronic obstructive airways disease. In this comparative study, significantly increased plasma theophylline concentrations were measured during co-administration of enoxacin (110.9%) and, to a lesser degree, also during co-administration of pefloxacin (19.6%) and ciprofloxacin (22.8%). Total body clearance of theophylline was significantly decreased by enoxacin (63.6%), ciprofloxacin (30.4%) and pefloxacin (29.4%). The pharmacokinetic parameters of theophylline did not change during co-administration of ofloxacin and nalidixic acid. There is growing evidence that the observed interaction is caused not by the parent drugs, but by the 4-oxo metabolite of enoxacin, pefloxacin and ciprofloxacin.
Abstract: During a clinical trial of orally administered ciprofloxacin in respiratory tract infections, changes in serum theophylline levels were evaluated in 33 hospitalized patients who also required theophylline therapy. Patients received intravenous theophylline in standard titrated doses and 750 mg of oral ciprofloxacin twice daily. Serum theophylline levels in all patients were measured before and during ciprofloxacin therapy. The mean serum pretreatment theophylline level was 7.8 +/- 4.6 micrograms/ml; during ciprofloxacin therapy, the level increased to 14.6 +/- 7.4 micrograms/ml. Twenty of the 33 (61 percent) patients evaluated had increases in serum theophylline levels by a mean value of 10.5 micrograms/ml. In 30 percent of patients who experienced increases, theophylline concentrations were in the toxic range. This occurred more frequently in elderly patients with chronic obstructive pulmonary disease. In light of the frequency and potential severity of this interaction, careful monitoring of serum theophylline levels in patients receiving theophylline and ciprofloxacin is recommended.
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: 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: No Abstract available
Abstract: Five adults completed this four-way randomized crossover study to compare the effects of oral treatment with ciprofloxacin, clarithromycin, and a combination of the two drugs on theophylline pharmacokinetics. The area under the concentration-time curve for theophylline during combination therapy was not different from that for ciprofloxacin alone. Beta error may explain this finding, but any real effect from combination treatment appears to be clinically unimportant.
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: The pharmacokinetics of intravenous ciprofloxacin and its metabolites were characterized in 42 subjects with various degrees of renal function (group 1, Clcr (mL/min/1.73 m2) > 90, n = 10; group 2, Clcr 61-90, n = 11; group 3, Clcr 31-60, n = 11; group 4, Clcr < or = 30, n = 10). The dosage regimens were-groups 1 and 2: 400 mg i.v. at 8 hourly intervals; group 3: 400 mg i.v. at 12 hourly intervals and group 4: 300 mg i.v. at 12 hourly intervals. Subjects received a single dose on days 1 and 5 and multiple doses on days 2-4. Multiple plasma and urine samples were collected on days 1 and 5 for the analysis of ciprofloxacin and its metabolites (M1, M2 and M3). Plasma concentrations (Cmax and AUC) of ciprofloxacin and its M1 and M2 metabolites were significantly increased in subjects with reduced Clcr values (Clcr < 60 mL/min/1.73 m2) compared with normal subjects (Clcr > 90 mL/min/1.73 m2). A positive correlation was observed between ciprofloxacin clearance (Cl) and Clcr with a slope of 0.29 (r2 = 0.78) and between renal clearance (Clr) and Clcr with a slope of 0.19 (r2 = 0.84). For patients with severe infections a dosage regimen of 400 mg iv 8 hourly is appropriate in patients with Clcr > 60 mL/min/1.73 m2. In patients with Clcr values of 31-60 mL/min/1.73 m2 a dosage regimen of 400 mg 12 hourly provides similar plasma concentrations to those observed for subjects with Clcr 61-90 mL/min/1.73 m2 receiving 400 mg 8 hourly. Based on modeling of the plasma concentrations in subjects with Clcr < or = 30 ml/min/1.73 m2, a dosage regimen of 400 mg every 24 h will provide plasma concentrations similar to those observed in subjects with Clcr between 61-90 mL/min/1.73 m2 given 400 mg every 8 h.
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: 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: 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: STUDY OBJECTIVE: To compare the rates of torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin administration. DESIGN: Retrospective database analysis. INTERVENTION: Evaluation of reported rates of torsades de pointes in patients who received these quinolones between January 1, 1996, and May 2, 2001. MEASUREMENTS AND MAIN RESULTS: In the United States, 25 cases of torsades de pointes associated with these quinolones (ciprofloxacin 2, ofloxacin 2, levofloxacin 13, gatifloxacin 8, moxifloxacin 0) were identified. Ciprofloxacin was associated with a significantly lower rate of torsades de pointes (0.3 cases/10 million prescriptions, 95% confidence interval [CI] 0.0-1.1) than levofloxacin (5.4/10 million, 95% CI 2.9-9.3, p<0.001) or gatifloxacin (27/10 million, 95% CI 12-53, p<0.001 for comparison with ciprofloxacin or levofloxacin). When the analysis was limited to the first 16 months after initial U.S. approval of the agent, the rates for levofloxacin (16/10 million) and gatifloxacin (27/10 million) were similar (p>0.5). CONCLUSION: Levofloxacin should be administered with caution in patients with risk factors for QT prolongation. Gatifloxacin should be avoided in the same patient population, and the recommended dosage of 400 mg/day should not be exceeded.
Abstract: Ciprofloxacin has been widely used for treating infections and has been found to have very low cardiovascular side effects. QTc prolongation with the use of ciprofloxacin is yet to be reported in literature. A case report highlighting QTc prolongation by use of ciprofloxacin is being presented.
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: 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: The new respiratory fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and on the horizon, garenoxacin) offer many improved qualities over older agents such as ciprofloxacin. These include retaining excellent activity against Gram-negative bacilli, with improved Gram-positive activity (including Streptococcus pneumoniae and Staphylococcus aureus). In addition, gatifloxacin, moxifloxacin and garenoxacin all demonstrate increased anaerobic activity (including activity against Bacteroides fragilis). The new fluoroquinolones possess greater bioavailability and longer serum half-lives compared with ciprofloxacin. The new fluoroquinolones allow for once-daily administration, which may improve patient adherence. The high bioavailability allows for rapid step down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve quality of life of patients. Clinical trials involving the treatment of community-acquired respiratory infections (acute exacerbations of chronic bronchitis, acute sinusitis, and community-acquired pneumonia) demonstrate high bacterial eradication rates and clinical cure rates. In the treatment of community-acquired respiratory tract infections, the various new fluoroquinolones appear to be comparable to each other, but may be more effective than macrolide or cephalosporin-based regimens. However, additional data are required before it can be emphatically stated that the new fluoroquinolones as a class are responsible for better outcomes than comparators in community-acquired respiratory infections. Gemifloxacin (except for higher rates of hypersensitivity), levofloxacin, and moxifloxacin have relatively mild adverse effects that are more or less comparable to ciprofloxacin. In our opinion, gatifloxacin should not be used, due to glucose alterations which may be serious. Although all new fluoroquinolones react with metal ion-containing drugs (antacids), other drug interactions are relatively mild compared with ciprofloxacin. The new fluoroquinolones gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin have much to offer in terms of bacterial eradication, including activity against resistant respiratory pathogens such as penicillin-resistant, macrolide-resistant, and multidrug-resistant S. pneumoniae. However, ciprofloxacin-resistant organisms, including ciprofloxacin-resistant S. pneumoniae, are becoming more prevalent, thus prudent use must be exercised when prescribing these valuable agents.
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: 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: 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: PURPOSE: Ciprofloxacin can inhibit the cytochrome P450-mediated metabolism of theophylline, but the clinical relevance of this drug interaction is uncertain. We studied the risk of theophylline toxicity associated with the co-prescription of ciprofloxacin and theophylline. METHODS: This was a population-based, nested case-control study of a cohort of Ontario residents aged 66 years of age or older treated with theophylline between April 1, 1992 and March 31, 2009. Within this group, case patients were those hospitalized with theophylline toxicity. For each case, 50 age- and sex-matched control patients were identified from the same cohort. The odds ratio (OR) for the association between hospitalization for theophylline toxicity and receipt of ciprofloxacin in the 14 days preceding hospitalization was determined. RESULTS: Among the 77,251 elderly patients receiving therapy with theophylline, 180 eligible case patients hospitalized for theophylline toxicity and 9000 matched controls were identified. Following multivariable adjustment, a nearly twofold increase in the risk of theophylline toxicity following the receipt of ciprofloxacin was observed [adjusted OR 1.86, 95% confidence interval (CI) 1.18-2.93]. In contrast, there was no increased risk of theophylline toxicity within a group of patients receiving neutral comparator antibiotics (levofloxacin, trimethoprim-sulfamethoxazole or cefuroxime) (adjusted OR 0.78; 95% CI 0.38-1.62). CONCLUSION: Treatment with ciprofloxacin is associated with a significant increase in the risk of theophylline toxicity. When clinically appropriate, alternate antibiotics should be considered for elderly patients receiving theophylline.
Abstract: Fluoroquinolone antimicrobial drugs are absorbed efficiently after oral administration despite of their hydrophilic nature, implying an involvement of carrier-mediated transport in their membrane transport process. It has been that several fluoroquinolones are substrates of organic anion transporter polypeptides OATP1A2 expressed in human intestine derived Caco-2 cells. In the present study, to clarify the involvement of OATP in intestinal absorption of ciprofloxacin, the contribution of Oatp1a5, which is expressed at the apical membranes of rat enterocytes, to intestinal absorption of ciprofloxacin was investigated in rats. The intestinal membrane permeability of ciprofloxacin was measured by in situ and the vascular perfused closed loop methods. The disappeared and absorbed amount of ciprofloxacin from the intestinal lumen were increased markedly in the presence of 7,8-benzoflavone, a breast cancer resistance protein inhibitor, and ivermectin, a P-glycoprotein inhibitor, while it was decreased significantly in the presence of these inhibitors in combination with naringin, an Oatp1a5 inhibitor. Furthermore, the Oatp1a5-mediated uptake of ciprofloxacin was saturable with a K(m) value of 140 µm, and naringin inhibited the uptake with an IC(50) value of 18 µm by Xenopus oocytes expressing Oatp1a5. Naringin reduced the permeation of ciprofloxacin from the mucosal-to-serosal side, with an IC(50) value of 7.5 µm by the Ussing-type chamber method. The estimated IC(50) values were comparable to that of Oatp1a5. These data suggest that Oatp1a5 is partially responsible for the intestinal absorption of ciprofloxacin. In conclusion, the intestinal absorption of ciprofloxacin could be affected by influx transporters such as Oatp1a5 as well as the efflux transporters such as P-gp and Bcrp.
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: 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: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
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.