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Estensione di tempo QT
Effetti avversi del farmaco
Varianti ✨Per la valutazione computazionalmente intensiva delle varianti, scegli l'abbonamento standard a pagamento.
Aree di applicazione
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La somministrazione di eritromicina e alprazolam deve essere evitata.
Concentrazioni elevate di alprazolam - sedazione aumentata / prolungataMeccanismo: il metabolismo di alprazolam avviene in larga misura attraverso il sistema CYP epatico, in particolare tramite CYP3A4. L'eritromicina è un moderato inibitore di questo isoenzima, quindi l'inibizione della degradazione dell'alprazolam potrebbe portare ad un aumento della concentrazione di benzodiazepine.
Effetto: concentrazioni aumentate di benzodiazepine possono portare ad un aumento significativo della sedazione e ad un prolungamento dell'effetto sedativo.
Misure: la combinazione è da evitare. Se la terapia con benzodiazepine è indicata per l'ansiolisi, deve essere selezionata una benzodiazepina dall'eritromicina, il cui metabolismo è mediato in modo meno forte dal CYP3A4 (ad es. Lorazepam o oxazepam). Se la combinazione è inevitabile, deve essere effettuato un attento monitoraggio per i segni di aumento della sedazione. Deve essere considerata una riduzione della dose di alprazolam.
I cambiamenti nell'esposizione menzionati si riferiscono ai cambiamenti nella curva concentrazione plasmatica-tempo [AUC]. L'esposizione alla alprazolam aumenta al 155%, se combinato con eritromicina (155%). Questo può portare a un aumento degli effetti collaterali. Non ci aspettiamo alcun cambiamento nell'esposizione alla eritromicina, se combinato con alprazolam (100%).
I parametri farmacocinetici della popolazione media sono utilizzati come punto di partenza per il calcolo delle singole variazioni di esposizione dovute alle interazioni.
La eritromicina ha una bassa biodisponibilità orale [ F ] del 24%, motivo per cui il livello plasmatico massimo [Cmax] tende a cambiare fortemente con un'interazione. L'emivita terminale [ t12 ] è piuttosto breve a 2.3 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti rapidamente. Il legame proteico [ Pb ] è moderatamente forte al 73% e il volume di distribuzione [ Vd ] è di 56 litri, ecco perché, con una velocità di estrazione epatica media di 0,9, sono rilevanti sia il flusso sanguigno epatico [Q] che una variazione del legame proteico [Pb]. Il metabolismo avviene principalmente tramite CYP3A4 e il trasporto attivo avviene in parte tramite MRP2 e PGP.
La alprazolam ha un'elevata biodisponibilità orale [ F ] del 88%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare poco durante un'interazione. L'emivita terminale [ t12 ] è di 11.7 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti dopo circa 46.8 ore. Il legame proteico [ Pb ] è moderatamente forte al 70.2% e il volume di distribuzione [ Vd ] è di 50 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 principalmente tramite CYP3A4.
|Effetti serotoninergici a||0||Ø||Ø|
Valutazione: Secondo le nostre conoscenze, né la eritromicina né la alprazolam aumentano l'attività serotoninergica.
|Kiesel & Durán b||0||Ø||Ø|
Valutazione: Secondo i nostri risultati, né la eritromicina né la alprazolam aumentano l'attività anticolinergica.
Estensione di tempo QT
Valutazione: La eritromicina può scatenare aritmie ventricolari de torsionali potenzialmente torsionali. Non conosciamo alcun potenziale di prolungamento dell'intervallo QT per la alprazolam.
Effetti collaterali generali
|Effetti collaterali||∑ frequenza||eri||alp|
|Problema di coordinamento||24.8 %||n.a.||24.8|
|Compromissione della memoria||24.3 %||n.a.||24.3|
|Aumento dell'appetito||19.9 %||n.a.||19.9|
|Aumento di peso||14.9 %||n.a.||14.9|
Xerostomia (12.4%): alprazolam
Dolore addominale: eritromicina
Perdita di appetito: eritromicina
Diarrea da Clostridium difficile: eritromicina
Depressione (11.7%): alprazolam
Effetto rimbalzo: alprazolam
Riduzione della libido (10.2%): alprazolam
Confusione (6%): alprazolam
Perdita dell'udito: eritromicina
Aritmia ventricolare: eritromicina
Sindrome di Stevens Johnson: eritromicina, alprazolam
Necrolisi epidermica tossica: eritromicina
Epatite colestatica: eritromicina
Insufficienza epatica: eritromicina, alprazolam
Reazioni allergiche della pelle: eritromicina
Nefrite tubulointerstiziale: eritromicina
Sulla base delle vostre
Abstract: No Abstract available
Abstract: Alprazolam is a short-acting triazolobenzodiazepine with anxiolytic and antidepressant properties. It has a half-life of 10-15 hours after multiple oral doses. Approximately 20% of an oral dose is excreted unchanged in the urine. The major urinary metabolites are alpha-OH alprazolam glucuronide and 3-HMB benzophenone glucuronide. The objective of this study was to characterize the reactivity of alprazolam and three metabolites in the Abbott ADx and TDx urinary benzodiazepine assays compared with the EMIT d.a.u. benzodiazepine assay. Alprazolam (at 300 ng/mL) gave an equivalent response as the 300 ng/mL low control (nordiazepam). alpha-OH alprazolam gave an equivalent response to this control between 300-500 ng/mL and 4-OH alprazolam between 500-1000 ng/mL. The 3-HMB benzophenone was not positive even at 10,000 ng/mL. The ADx screening assay was positive in 26 of 31 urine specimens collected from alprazolam-treated patients. All 31 of these specimens were confirmed positive for alpha-OH alprazolam by GC/MS after enzymatic hydrolysis and formation of a TMS derivative. For the TDx, 27 of 31 specimens were positive for benzodiazepines and all 31 were confirmed by GC/MS. All 5 of the negative ADx specimens and 4 of 5 TDx specimens contained 150-400 ng/mL of alpha-OH alprazolam. In conclusion, both the ADx and TDx urine benzodiazepine assays are acceptable screening assays for alprazolam use when the alpha-OH alprazolam concentration is greater than 400 ng/mL.
Abstract: No Abstract available
Abstract: No Abstract available
Abstract: Alprazolam, a triazolobenzodiazepine, is the first of this new class of benzodiazepine drugs to be marketed in the United States and Canada. It achieves peak serum levels in 0.7 to 2.1 hours and has a serum half-life of 12 to 15 hours. When given in the recommended daily dosage of 0.5 to 4.0 mg, it is as effective as diazepam and chlordiazepoxide as an anxiolytic agent. Its currently approved indication is for the treatment of anxiety disorders and symptoms of anxiety, including anxiety associated with depression. Although currently not approved for the treatment of depressive disorders, studies published to date have demonstrated that alprazolam compares favorably with standard tricyclic antidepressants. Also undergoing investigation is the potential role of alprazolam in the treatment of panic disorders. Alprazolam has been used in elderly patients with beneficial results and a low frequency of adverse reactions. Its primary side effect, drowsiness, is less than that produced by diazepam at comparable doses. Data on toxicity, tolerance, and withdrawal profile are limited, but alprazolam seems to be at least comparable to other benzodiazepines. Drug interaction data are also limited, and care should be exercised when prescribing alprazolam for patients taking other psychotropic drugs because of potential additive depressant effects.
Abstract: Six fasting male subjects (20-32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam were as follows: volume of distribution (Vd) 0.72 and 0.84 l/kg; elimination half-life (t1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in Vd, t1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.
Abstract: Erythromycin is a widely used antibiotic in today's armamentarium of antibiotics. Although erythromycin induced ventricular tachyarrhythmia is rare, this potentially life-threatening reaction should be kept in mind. The relative rarity of 'torsades de pointes' arrhythmia suggests that other predisposing factors contribute to the acquired long QT syndrome. Since more and more macrolide products have been approved by the Food and Drug Administration for use in the United States, the potential problem with 'torsades de pointes' may exist with each of the macrolide antibiotic. Until the exact mechanisms of the arrhythmia are worked out, close monitoring of rhythms and QT intervals of high risk patients who require erythromycin is certainly advisable. Only a heightened awareness among the physicians and medical personnel can the adverse outcome be minimized.
Abstract: To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 +/- 0.08 (mean +/- SD) hours and for the capsule was 2.92 +/- 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 +/- 7% and for the duodenal solution 43 +/- 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 +/- 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.
Abstract: OBJECTIVE: To assess the possible involvement of CYP3A4 in the metabolism of alprazolam in vivo. METHOD: Twelve healthy male volunteers were randomly allocated to one of the two different treatment sequences, placebo-erythromycin or erythromycin-placebo, with an at least 6-week washout period between the two trial phases. Each volunteer received 400 mg erythromycin or matched placebo given orally three times a day for 10 days and an oral dose (0.8 mg) of alprazolam on the posttreatment day 8. Plasma concentration of alprazolam was measured up to 48 hours after the administration, and psychomotor function was assessed at each time of blood samplings with use of the Digit Symbol Substitution Test, visual analog scale, and Udvalg for kliniske undersøgelser side effect rating scale. RESULTS: Erythromycin significantly (p < 0.001) increased the area under the plasma concentration-time curves (200 +/- 43 versus 322 +/- 49 ng . hr/ml from 0 to 48 hours and 229 +/- 52 versus 566 +/- 161 ng . hr/ml from 0 hour to infinity), decreased the apparent oral clearance (1.02 +/- 0.31 versus 0.41 +/- 0.12 ml/min/kg), and prolonged the elimination half-life (16.0 +/- 4.5 versus 40.3 +/- 14.4 hours) of alprazolam. However, any psychomotor function variables did not differ significantly between the erythromycin and placebo trial phases. CONCLUSION: This study suggests that erythromycin, an inhibitor of CYP3A4, inhibits the metabolism of alprazolam, providing an in vivo evidence for the involvement of CYP3A4 in its metabolism. However, the kinetic change of alprazolam by erythromycin does not result in the pharmacodynamic change of this triazolobenzodiazepine, at least after single dosing.
Abstract: Drug interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance. Pharmacokinetic interactions often occur as a result of a change in drug metabolism. Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes. The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition. Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein. Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice. Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfenadine, astemizole, cisapride or pimozide. Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ('statins') and CYP3A4 inhibitors. Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil. Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors. Ataxia can occur with carbamazepine, and ergotism with ergotamine, following the addition of a CYP3A4 inhibitor. Beneficial drug interactions can occur. Administration of a CYP3A4 inhibitor with cyclosporin may allow reduction of the dosage and cost of the immunosuppressant. Certain HIV protease inhibitors, e.g. saquinavir, have low oral bioavailability that can be profoundly increased by the addition of ritonavir. The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related. Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Less pronounced pharmacokinetic interactions may still be clinically important for drugs with a steep concentration-response relationship or narrow therapeutic index. In most cases, the extent of drug interaction varies markedly among individuals; this is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age. Interactions may occur under single dose conditions or only at steady state. The pharmacodynamic consequences may or may not closely follow pharmacokinetic changes. Drug interactions may be most apparent when patients are stabilised on the affected drug and the CYP3A4 inhibitor is then added to the regimen. Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction.
Abstract: OBJECTIVE: Our objective was to evaluate the effect of the CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of alprazolam in healthy volunteers. METHODS: Nineteen healthy male volunteers were divided into 3 groups on the basis of the genetic polymorphism of CYP3A5. The groups comprised subjects with CYP3A5*1/*1 (n=5), CYP3A5*1/*3 (n=7), or CYP3A5*3/*3 (n=7). After a single oral 1-mg dose of alprazolam, plasma concentrations of alprazolam were measured up to 72 hours, together with assessment of psychomotor function by use of the Digit Symbol Substitution Test, according to CYP3A5 genotype. RESULTS: The area under the plasma concentration-time curve for alprazolam was significantly greater in subjects with CYP3A5*3/*3 (830.5+/-160.4 ng . h/mL [mean+/-SD]) than in those with CYP3A5*1/*1 (599.9+/-141.0 ng . h/mL) (P=.030). The oral clearance of alprazolam was also significantly different between the CYP3A5*1/*1 group (3.5+/-0.8 L/h) and CYP3A5*3/*3 group (2.5+/-0.5 L/h) (P=.036). Although a trend was noted for the area under the Digit Symbol Substitution Test score change-time curve (area under the effect curve) to be greater in subjects with CYP3A5*3/*3 (177.2+/-84.6) than in those with CYP3A5*1/*1 (107.5+/-44), the difference did not reach statistical significance (P=.148). CONCLUSIONS: The CYP3A5*3 genotype affects the disposition of alprazolam and thus influences the plasma levels of alprazolam.
Abstract: Nonrenal clearance of drugs can be significantly lower in patients with end-stage renal disease (ESRD) than in those with normal renal function. Using erythromycin (ER) as a probe compound, we investigated whether this decrease in nonrenal clearance is due to reduced hepatic clearance (CL(H)) and/or gut metabolism. We also examined the potential effects of the uremic toxins 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate (Indox) on ER disposition. Route-randomized, two-way crossover pharmacokinetic studies of ER were conducted in 12 ESRD patients and 12 healthy controls after oral (250 mg) and intravenous (125 mg) dosing with ER. In patients with ESRD, CL(H) decreased 31% relative to baseline values (0.35 +/- 0.14 l/h/kg vs. 0.51 +/- 0.13 l/h/kg, P = 0.01), with no change in steady-state volume of distribution. With oral dosing, the bioavailability of ER increased 36% in patients with ESRD, and this increase was not related to changes in gut availability. As expected, plasma levels of CMPF and Indox were significantly higher in the patients than in the healthy controls. However, no correlation was observed between CL(H) of ER and the levels of uremic toxins.
Abstract: The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for cytochrome P450 (CYP) 3A4 activity. By means of a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Because these proteins are highly expressed on the biliary surface of hepatocytes, we hypothesized that impaired Abcc2 function may influence the rate of hepatobiliary excretion and thereby enhance erythromycin metabolism. Using Abcc2 knockout mice, we found that Abcc2 deficiency was associated with a significant increase in erythromycin metabolism, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked to an increase in erythromycin metabolism but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.
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.