Avvisi di avvertenza
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
Spiegazioni per i pazienti
Avvisi di avvertenza
Non abbiamo ulteriori avvertenze per la combinazione di cimetidina e praziquantel. Si prega di consultare anche le informazioni specialistiche pertinenti.
I cambiamenti nell'esposizione menzionati si riferiscono ai cambiamenti nella curva concentrazione plasmatica-tempo [AUC]. L'esposizione alla praziquantel aumenta al 200%, se combinato con cimetidina (200%). Questo può portare a un aumento degli effetti collaterali. Non ci aspettiamo alcun cambiamento nell'esposizione alla cimetidina, se combinato con praziquantel (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 cimetidina ha una biodisponibilità orale media [ F ] del 65%, motivo per cui i livelli plasmatici massimi [Cmax] tendono a cambiare con un'interazione. L'emivita terminale [ t12 ] è piuttosto breve a 1.6333333 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti rapidamente. Il legame proteico [ Pb ] è molto debole al 19% e il volume di distribuzione [ Vd ] è molto grande a 91 litri. Il metabolismo non avviene tramite i comuni citocromi e il trasporto attivo avviene in parte tramite BCRP e PGP.
La biodisponibilità della praziquantel non è nota. L'emivita terminale [ t12 ] è piuttosto breve a 1.15 ore e i livelli plasmatici costanti [ Css ] vengono raggiunti rapidamente. Il legame proteico [ Pb ] è moderatamente forte al 80%. Il metabolismo avviene tramite CYP1A2, CYP2C19 e CYP3A4, tra gli altri.
|Effetti serotoninergici a||0||Ø||Ø|
Valutazione: Secondo le nostre conoscenze, né la cimetidina né la praziquantel aumentano l'attività serotoninergica.
|Kiesel & Durán b||1||+||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 cimetidina ha 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 praziquantel non aumenta l'attività anticolinergica.
Estensione di tempo QT
Raccomandazione: Assicurati che i fattori di rischio influenzabili siano ridotti al minimo. Disturbi elettrolitici come bassi livelli di calcio, potassio e magnesio devono essere compensati. Deve essere utilizzata la dose minima efficace di cimetidina.
Valutazione: La cimetidina può potenzialmente prolungare il tempo dell'intervallo QT e in presenza di fattori di rischio, possono essere preferite le aritmie di tipo torsioni di punta. Non conosciamo alcun potenziale di prolungamento dell'intervallo QT per la praziquantel.
Effetti collaterali generali
|Effetti collaterali||∑ frequenza||cim||pra|
|Dolore addominale||37.0 %||n.a.||37.0|
|Reazione di ipersensibilità||0.0 %||n.a.||0.0|
Sulla base delle vostre
Abstract: A rational strategy for chemotherapy demands that dosage schedules be based on an adequate knowledge of clinical and biochemical pharmacology. Many anthelmintic drugs (e.g. suramin, diethylcarbamazine, hycanthone) were introduced before modern techniques for drug evaluation (controlled clinical trials) and before the development of specific and sensitive analytical methods for the assay of drugs and metabolites in biological fluids. Thus, many of the regimens used today for the treatment of parasitic diseases are largely empirically derived. By means of specific analytical methodology (high performance liquid chromatography, gas chromatography and mass-spectrometry) introduced in the 1960s, it is now possible to measure drugs and their metabolites with specificity and sensitivity. Much of this review deals with compounds which are active against the major systemic helminths, i.e., filariae (diethylcarbamazine, ivermectin and suramin) and schistosomes (niridazole, metrifonate, oxamniquine and praziquantel), but recent advances in the treatment of hydatid disease involving the benzimidazole carbamates albendazole and mebendazole are also discussed. Among the imidazole derivatives, mebendazole, a broad-spectrum anthelmintic, is poorly absorbed from the gastrointestinal tract after a therapeutic dose, but that fraction which is absorbed and escapes hepatic first-pass extraction is pharmacologically active against systemic helminths. Albendazole is more completely absorbed, but is almost undetectable in plasma due to its rapid conversion to an active sulphoxide metabolite. This compound may well become the drug of choice for the chemotherapy of echinococcosis. Levamisole, the 1-isomer of tetramisole, is rapidly and completely absorbed, but has not been widely used in systemic helminthiases because of severe side effects associated with prolonged dosage. Diethylcarbamazine is microfilaricidal against Onchocerca volvulus, but its use has been associated with major adverse effects resulting from its action on the microfilariae. These effects are related to the concentration of the drug in the plasma which, in turn, is influenced by urinary pH. The elimination half-life of diethylcarbamazine is prolonged and renal clearance reduced in alkaline urine. Under these conditions the microfilaricidal effect is enhanced, but the adverse reactions to treatment are more severe. Suramin is the only available antifilarial agent with macrofilaricidal activity. It has a long elimination half-life (36 to 54 days), and is highly (99.7%) bound to plasma protein which limits its removal from the blood.(ABSTRACT TRUNCATED AT 400 WORDS)
Abstract: Recently, the use of astemizole and terfenadine, both non-sedating H1-antihistamines, caused considerable concern. Several case reports suggested an association of both drugs with an increased risk of torsades de pointes, a special form of ventricular tachycardia. The increased risk of both H1-antihistamines was associated with exposure to supratherapeutic doses; for terfenadine the risk was also associated with concomitant exposure to the cytochrome P-450 inhibitors ketoconazole, erythromycin and cimetidine. To predict the size of the population that runs the risk of developing this potentially fatal adverse reaction in the Netherlands, the prevalence of prescribing supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was studied. Data were obtained from the PHARMO data base in 1990, a pharmacy-based record linkage system encompassing a catchment population of 300,000 individuals. The results of the study showed that the prescribing of supratherapeutic doses and the concomitant exposure to terfenadine and cytochrome P-450 inhibitors was low. Furthermore, the results of a sensitivity analysis showed that the risk of fatal torsades de pointes has to be as high as 1 in 10,000 to cause one death in the Netherlands in one year.
Abstract: Astemizole (Hismanal), an antihistamine agent, has been reported to be associated with ventricular arrhythmias. In this paper we present a case of QT prolongation and torsades de pointes (TdP) in a 77-year-old woman who had been taking astemizole (10 mg/day) for 6 months because of allergic skin disease. At the time of admission, the serum concentration of astemizole and its metabolites was markedly elevated at 15.85 ng/ml, approximately 3 times the normal level. The patient was also taking cimetidine, a known inhibitor of cytochrome P-450 enzymatic activity, and during her admission was diagnosed as having vasospastic angina. To the best of our knowledge, this is the first report of astemizole-induced QT prolongation and TdP in Japan.
Abstract: After a single oral dose of praziquantel with 250 ml of grapefruit juice, the area under the concentration-time curve and the maximum concentration in plasma of praziquantel (Cmax) were significantly increased (Cmax for water treatment, 637.71 +/- 128.5 ng/ml; and Cmax for grapefruit juice treatment, 1,037.65 +/- 305.7 ng/ml, P < 0.05). No statistically significant differences were found in the time to maximum concentration of drug in plasma or elimination half-life.
Abstract: BACKGROUND AND OBJECTIVE: Praziquantel is extensively metabolized by the hepatic cytochrome P450 (CYP) enzymes. The CYP3A isoforms are likely to be major enzymes responsible for praziquantel metabolism. Rifampin (INN, rifampicin), a potent enzyme inducer of CYP-mediated metabolism (especially CYP2C9, CYP2C19, and CYP3A4), is known to markedly decrease plasma concentrations and effects of a number coadministered drugs. The aim of this investigation was to study the possible pharmacokinetic interaction between rifampin and praziquantel. METHODS: An open, randomized, 2-phase crossover design was used in each study of single or multiple doses. In the single-dose study, 10 healthy Thai male volunteers ingested single doses of 40 mg/kg praziquantel alone (phase 1) or after pretreatment with 600 mg of oral rifampin once daily for 5 days (phase 2). In the multiple-dose study, all participants received multiple doses of 25 mg/kg praziquantel alone (phase 1) or after 5-day pretreatment with 600 mg of oral rifampin once daily (phase 2). Plasma concentrations of praziquantel in each phase were determined by the HPLC method. RESULTS: In the single-dose study, rifampin decreased plasma praziquantel concentrations to undetectable levels in 7 of 10 subjects, whereas praziquantel concentrations were reduced by rifampin to undetectable levels in 5 of 10 subjects in the multiple-dose study. In 3 subjects with measurable concentrations in the single-dose study, rifampin significantly decreased the mean maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from 0 to 24 hours [AUC(0-24)] of praziquantel by 81% (P <.05) and 85% (P <.01), respectively, whereas rifampin significantly decreased the mean C(max) and AUC(0-24) of praziquantel by 74% (P <.05) and 80% (P <.01), respectively, in 5 subjects with measurable concentrations in the multiple-dose study. The mean C(max) and AUC(0-24) of praziquantel in subjects whose praziquantel concentrations could not be detected in the single-dose study (7 subjects) after rifampin pretreatment were reduced by approximately 99% (P <.001) and 94% (P <.001), respectively, and in the multiple-dose study (5 subjects), they were reduced by 98% (P <.05) and 89% (P <.01), respectively. CONCLUSIONS: Rifampin greatly decreased plasma concentrations of single and multiple oral doses of praziquantel to levels lower than that of the minimum therapeutic concentration. Because praziquantel and rifampin are widely used in the treatment of liver flukes (Opisthorchis viverrini) and Mycobacterium tuberculosis, respectively, in Thailand and in some other countries in southeast Asia, the possibility of one drug influencing the pharmacokinetics of the other must be considered. Therefore simultaneous use of rifampin and praziquantel must be avoided in medical practice to optimize the therapeutic efficacy of praziquantel.
Abstract: Renal drug interactions can result from competitive inhibition between drugs that undergo extensive renal tubular secretion by transporters such as P-glycoprotein (P-gp). The purpose of this study was to evaluate the effect of itraconazole, a known P-gp inhibitor, on the renal tubular secretion of cimetidine in healthy volunteers who received intravenous cimetidine alone and following 3 days of oral itraconazole (400 mg/day) administration. Glomerular filtration rate (GFR) was measured continuously during each study visit using iothalamate clearance. Iothalamate, cimetidine, and itraconazole concentrations in plasma and urine were determined using high-performance liquid chromatography/ultraviolet (HPLC/UV) methods. Renal tubular secretion (CL(sec)) of cimetidine was calculated as the difference between renal clearance (CL(r)) and GFR (CL(ioth)) on days 1 and 5. Cimetidine pharmacokinetic estimates were obtained for total clearance (CL(T)), volume of distribution (Vd), elimination rate constant (K(el)), area under the plasma concentration-time curve (AUC(0-240 min)), and average plasma concentration (Cp(ave)) before and after itraconazole administration. Plasma itraconazole concentrations following oral dosing ranged from 0.41 to 0.92 microg/mL. The cimetidine AUC(0-240 min) increased by 25% (p < 0.01) following itraconazole administration. The GFR and Vd remained unchanged, but significant reductions in CL(T) (655 vs. 486 mL/min, p < 0.001) and CL(sec) (410 vs. 311 mL/min, p = 0.001) were observed. The increased systemic exposure of cimetidine during coadministration with itraconazole was likely due to inhibition of P-gp-mediated renal tubular secretion. Further evaluation of renal P-gp-modulating drugs such as itraconazole that may alter the renal excretion of coadministered drugs is warranted.
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: BACKGROUND: Adverse effects of anticholinergic medications may contribute to events such as falls, delirium, and cognitive impairment in older patients. To further assess this risk, we developed the Anticholinergic Risk Scale (ARS), a ranked categorical list of commonly prescribed medications with anticholinergic potential. The objective of this study was to determine if the ARS score could be used to predict the risk of anticholinergic adverse effects in a geriatric evaluation and management (GEM) cohort and in a primary care cohort. METHODS: Medical records of 132 GEM patients were reviewed retrospectively for medications included on the ARS and their resultant possible anticholinergic adverse effects. Prospectively, we enrolled 117 patients, 65 years or older, in primary care clinics; performed medication reconciliation; and asked about anticholinergic adverse effects. The relationship between the ARS score and the risk of anticholinergic adverse effects was assessed using Poisson regression analysis. RESULTS: Higher ARS scores were associated with increased risk of anticholinergic adverse effects in the GEM cohort (crude relative risk [RR], 1.5; 95% confidence interval [CI], 1.3-1.8) and in the primary care cohort (crude RR, 1.9; 95% CI, 1.5-2.4). After adjustment for age and the number of medications, higher ARS scores increased the risk of anticholinergic adverse effects in the GEM cohort (adjusted RR, 1.3; 95% CI, 1.1-1.6; c statistic, 0.74) and in the primary care cohort (adjusted RR, 1.9; 95% CI, 1.5-2.5; c statistic, 0.77). CONCLUSION: Higher ARS scores are associated with statistically significantly increased risk of anticholinergic adverse effects in older patients.
Abstract: BACKGROUND: Praziquantel (PZQ) is the treatment of choice for infections with the liver fluke Opisthorchis viverrini, a major health problem in Southeast Asia. However, pharmacokinetic (PK) studies investigating the disposition of PZQ enantiomers (R- and S-PZQ) and its main metabolite, R-trans-4-OH-PZQ, in diseased patients are lacking. The implementation of a dried blood spot (DBS) sampling technique would ease the performance of PK studies in remote areas without clinical facilities. The aim of the present study is to provide data on the disposition of PZQ enantiomers and R-trans-4-OH-PZQ in opisthorchiasis patients and to validate the use of DBS compared to plasma and blood sampling. METHODOLOGY/PRINCIPAL FINDINGS: PZQ was administered to nine O. viverrini-infected patients at 3 oral doses of 25 mg/kg in 4 h intervals. Plasma, blood and DBS were simultaneously collected at selected time points from 0 to 24 h post-treatment. PK parameters were determined using non-compartmental analysis. Drug concentrations and areas under the curve (AUC0-24h) measured in the 3 matrices were compared using Bland-Altman analysis. We observed plasma AUC0-24hs of 1.1, 9.0 and 188.7 μg/ml*h and half-lives of 1.1, 3.3 and 6.4 h for R-PZQ, S-PZQ and R-trans-4-OH, respectively. Maximal plasma concentrations (Cmax) of 0.2, 0.9 and 13.9 μg/ml for R-PZQ, S-PQZ and R-trans-4-OH peaked at 7 h for PZQ enantiomers and at 8.7 h for the metabolite. Individual drug concentration measurements and patient AUC0-24hs displayed ratios of blood or DBS versus plasma between 79-94% for R- and S-PZQ, and between 108-122% for R-trans-4-OH. CONCLUSIONS/SIGNIFICANCE: Pharmacodynamic (PD) in vitro studies on PZQ enantiomers and R-trans-4-OH-PZQ are necessary to be able to correlate PK parameters with efficacy. DBS appears to be a valid alternative to conventional venous sampling for PK studies in PZQ-treated patients.
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: AIM: The study sought to determine the effect of ketoconazole (KTZ) on the pharmacokinetics of praziquantel (PZQ) and on the formation of its major hydroxylated metabolites, cis- and trans-4-OH-PZQ, and X-OH-PZQ in healthy subjects. METHODS: Two treatments were evaluated by single-dose PK studies; the reference treatment was a 20 mg/kg dose of praziquantel given alone. The test treatment was a 20 mg/kg dose of praziquantel given in combination with 200 mg of ketoconazole. The study had a balanced and randomised cross-over design. Serial blood samples were collected between 0 and 12 h after each drug administration. PZQ, and cis- and trans-4-OH-PZQ and X-OH-PZQ concentrations in plasma were determined by LC-MS. A non-compartmental approach was used for pharmacokinetic analysis. Data were analysed using ANOVA and assessment of the 90% confidence interval of the geometric means of the log-transformed PK parameters obtained for each treatment. RESULTS: The pharmacokinetics of PZQ following the two treatments, PZQ alone and PZQ + KTZ, were not equivalent based on the assessment of the 90% CI of the geometric mean ratios of the AUC and C,(α = 0.05). The geometric mean ratios of the AUC and C,were found to be 176.8% and 227% respectively. The 90% CI of the AUC and C,were found to be 129.8%-239.8% and 151.4%-341.4% respectively. The AUC of PZQ was increased by 75% with KTZ co-administration (3516 vs 6172 ng h/ml) (p < 0.01). Meanwhile, the mean AUC of trans-4-OH-PZQ increased by 67% (61,749 ng h/ml vs 103,105 ng h/ml) (p < 0.01). X-OH-PZQ levels were reduced by about 57% (semi-quantified as 7311 ng h/ml vs 3109 ng h/ml by using trans-4-OH as standards) (p < 0.01) with KTZ co-administration. CONCLUSIONS: The relative bioavailability of praziquantel was increased by concomitant KTZ administration. KTZ preferentially inhibited the formation of X-OH-PZQ rather than 4-OH-PZQ, confirming in vitro data which implicates CYP3A4 in the formation of X-OH-PZQ rather than 4-OH-PZQ. The 4-hydroxylation of PZQ was shown to be the major metabolic pathway of PZQ, as evidenced by larger quantities of 4-OH-PZQ produced, thus explaining the modest albeit significant effect of ketoconazole on PZQ pharmacokinetics.