Coadministration Of Erythromycin Research Articles

The effect of erythromycin and clarithromycin versus azithromycin on serum valproate concentration

IntroductionUnlike azithromycin, erythromycin and clarithromycin strongly inhibit CYP450, which metabolizes valproic acid. The aim of this study was to evaluate the impact of macrolide administration on serum valproate trough levels. MethodsThis retrospective cohort study included hospitalized adult patients who concomitantly received valproate with a macrolide. Patients who received a carbapenem, those who do not have a baseline and/or post-levels, and those who received different doses of valproate were excluded. The change in serum valproate trough level from baseline to after the occurrence of co-administration (post-level) was compared in patients who received either erythromycin or clarithromycin versus those who received azithromycin. ResultsA total of thirteen patients were included in the comparison. The mean ± SD for change in serum valproate trough levels was significantly higher in the erythromycin/clarithromycin group than the azithromycin group (209.1 ± 105.9 µmol/L [equivalent to 30.1 ± 15.2 mg/L] vs. 12.7 ± 52.1 µmol/L [equivalent to 1.8 ± 7.5 mg/L]; P = 0.002). ConclusionThis study found a significantly higher increase in serum trough levels of valproate after co-administration of erythromycin/clarithromycin versus azithromycin. Clinicians should consider avoiding co-administration of erythromycin and clarithromycin with valproate if possible or close monitoring of valproate levels with dose reduction.

Metabolic interactions between flumatinib and the CYP3A4 inhibitors erythromycin, cyclosporine, and voriconazole.

Flumatinib, indicated for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia, is a structural analog of imatinib and has shown higher potency than imatinib as a BCR-ABL inhibitor. In this paper, the metabolic profile of flumatinib was studied. It was found that CYP3A4 and CYP2C8 were the main cytochrome P450 enzyme substyles catalyzing the metabolism of flumatinib, and CYP3A4 has a stronger metabolic ability for flumatinib than CYP2C8. Erythromycin, cyclosporine, and voriconazole can inhibit the metabolism of flumatinib in vitro. Accordingly, co-administration of erythromycin and cyclosporine with flumatinib increased the plasma concentration and the systemic exposure of flumatinib in rats, which indicated that lower doses should be considered in clinical practice.

Co-administration of Erythromycin and Leech Salivary Extract Alleviates Osteomyelitis in Rats Induced by Methicillin-Resistant Staphylococcus aureus.

Erythromycin (Ery) and leech saliva (LS) can inhibit Staphylococcus aureus growth in in vitro conditions. This study aimed to evaluate the activities and synergy between Ery and LS on chronic osteomyelitis in male Wistar rat's tibia induced by methicillin-resistant S. aureus (MRSA). Four weeks after osteomyelitis induction, rats were divided into four groups including no treatment (control), Ery monotherapy (orally), LS monotherapy, or Ery + LS twice daily for 2 weeks. Staphylococcus aureus growth, pathological signs and inflammatory cytokine tumour necrosis factor-alpha (TNF-α) levels were assessed. Rats tolerated all therapeutic strategies well during the experiment. The Ery treatment alone significantly decreased bacterial growth, pathological signs and TNF-α levels. Leech saliva alone reduced TNF-α level significantly, but did not produce a significant reduction in bacterial growth and pathological signs. Ery + LS treatment significantly decreased bacterial growth, considerably alleviated bone pathological signs and decreased TNF-α levels compared with other groups. Statistical analysis suggested that there was a stronger efficiency and synergistic action of Ery and LS when combined against MRSA-induced osteomyelitis in rats. The present study suggests that LS may have clinical utility to treat MRSA-induced osteomyelitis when combined with Ery or other therapeutics.

Coadministration of Erythromycin to Increase Tacrolimus Concentrations in Liver Transplant Recipients

BackgroundWe evaluated the effects of using erythromycin (ERY) in liver transplant recipients to improve the early postoperative control of tacrolimus (TAC) concentration. MethodsThis study adopts a retrospective medical record analysis method from January 2015 to December 2017. Assessment items include TAC daily dose (D), TAC whole blood trough level (Co), rejection episodes, and adverse effects. The magnitude of ERY inhibition on TAC metabolism was decided by analyzing dose-corrected trough concentration (Co/D). Oral 250 mg ERY every day to every other day was prescribed when patients needed to swallow more than 10 capsules of TAC per day, TAC trough levels rose too slowly, and/or acute rejection occurred. TAC trough levels were obtained daily. ERY was stopped when the TAC trough level was above 10 ng/mL or rejection episode relieved. ResultsA total of 8 liver transplant recipients was collected. Oral ERY was administered at 6 to 13 days after transplantation. The duration of ERY regimen was 2 to 7 days. The average initial and maximum Co/D was 0.6 ± 0.0 and 1.8 ± 1.0. After ERY was deleted, Co/D was back to the value without ERY at about 2 to 20 days. The magnitude of interaction between tacrolimus and erythromycin is 1.4- to 4.6-fold. The highest dose of TAC was 10 to 12 mg/d. There were no drug-related complications during this period. Acute rejection relapsed in 1 patient after we stopped ERY. ConclusionCoadministration of ERY and TAC is a strategic choice for liver transplant recipients whose TAC blood concentration was difficult in approaching therapeutic levels.

Elevated alpha1-acid glycoprotein in gastric cancer patients inhibits the anticancer effects of paclitaxel, effects restored by co-administration of erythromycin.

Paclitaxel (PTX) which easily elutes into ascites is widely used to treat gastric cancer patients with peritoneal carcinomatosis (PC), but clinical outcomes are suboptimal. Increased concentrations of α1-acid glycoprotein (AGP), an important drug-binding protein, have been reported in the plasma and ascites of cancer patients. This study sought to clarify whether AGP binds to PTX and alters its anticancer effects. AGP concentrations were measured in the serum and ascites of gastric cancer patients with PC and in the serum of healthy volunteers. The in vitro effects of AGP and AGP plus erythromycin (EM) on PTX were evaluated by MTT assays in the gastric cancer cell lines. We also measured AGP concentrations in the ascites of PC model mice and examined the effects of EM plus PTX on PC. The mean AGP concentrations in the serum and ascites of gastric cancer patients with PC were 1524 and 834 μg/mL, respectively, higher than the mean AGP concentration of 650 μg/mL observed in the sera of healthy volunteers. AGP > 400 μg/mL significantly suppressed the cell growth inhibitory effect of PTX in vitro, but the co-administration of EM restored it. Elevated AGP concentrations were observed in the ascites of PC model mice. Administration of PTX alone did not markedly diminish PC, whereas co-administration of PTX and EM significantly reduced PC (p = 0.011). AGP is an important regulatory factor modulating the anticancer activity of intraperitoneal PTX. The co-administration of PTX and EM may be effective in treating gastric cancer patients with PC.

Relevance of P-glycoprotein in stroke prevention with dabigatran, rivaroxaban, and apixaban.

The new oral anticoagulants (NOAC) dabigatran etexilate, rivaroxaban, and apixaban show similar efficacy for stroke prevention in patients with atrial fibrillation (AF) as the vitamin K antagonist warfarin. Absorption of NOACs is dependent on the intestinal P-glycoprotein (P-gp) system and P-gp activity is modulated by a variety of drugs and food components. The aim of this review is to give an overview of P-gp-associated drug-drug and drug-food interactions with NOACs in AF patients. A literature search was carried out by screening MEDLINE for the terms dabigatran, rivaroxaban, apixaban, P-glycoprotein, and atrial fibrillation from 1998 to 2013. Randomized clinical trials, longitudinal studies, case series, and case reports were included. Concomitant medication with proton pump inhibitors, amiodarone, clarithromycin, and verapamil increased bioavailability whereas rifampicin decreased the bioavailability of dabigatran. Coadministration of erythromycin, clarithromycin, fluconazole, ketoconazole, and ritonavir increased rivaroxaban plasma concentrations. No data were found on apixaban and P-gp-modulating drugs or on NOACs and food components modulating P-gp. The clinical relevance of interactions between NOACs and P-gp-modulating drugs or food components is largely unknown as bleeding complications under NOACs and P-gp-inhibiting drugs are mainly reported from patients with concomitant renal failure. There is an urgent need to investigate the role of P-gp-modulating substances as potential sources of drug-drug and drug-food interactions. A thorough analysis of the data accumulated in the three large NOAC trials regarding the role of P-gp-modulating drugs in bleeding and embolic events is desirable. Pharmacological studies should investigate the influence of P-gp-modulating drugs and food on NOAC plasma concentrations and coagulation parameters. When prescribing NOACs, patients should be informed about the potential interactions with drugs and herbal drugs. Patients who develop bleeding or embolic events under treatment with NOACs should be investigated for co-medications as well as for over-the-counter drugs and dietary habits. In post-marketing surveillance of NOACs, the association with drug or food intake with complications, bleeding, and embolic events should be registered.

Erythromycin, QTc interval prolongation, and torsade de pointes: Case reports, major risk factors and illness severity.

Erythromycin is a macrolide antibiotic that is widely used for various infections of the upper respiratory tract, skin, and soft tissue. Similar to other macrolides (clarithromycin, azithromycin), erythromycin has been linked to QTc interval prolongation and torsade de pointes (TdP) arrhythmia. We sought to identify factors that link to erythromycin-induced/associated QTc interval prolongation and TdP. In a critical evaluation of case reports, we found 29 cases: 22 women and 7 men (age range 18-95 years). With both oral and intravenous erythromycin administration, there was no significant relationship between dose and QTc interval duration in these cases. Notably, all patients had severe illness. Other risk factors included female sex, older age, presence of heart disease, concomitant administration of either other QTc prolonging drugs or agents that were substrates for or inhibitors of CYP3A4. Most patients had at least two risk factors. On the basis of case report evaluation, we believe that major risk factors for erythromycin-associated TdP are female sex, heart disease and old age, particularly against a background of severe illness. Coadministration of erythromycin with other drugs that inhibit or are metabolized by CYP3A4 or with QTc prolonging drugs should be avoided in this setting.

Allosteric effects of erythromycin pretreatment on thioridazine block of hERG potassium channels.

The prevalence of concurrent use of two or more drugs that block human ether-a-go-go-related gene product (hERG) K(+) channels is not uncommon, but is not well characterized. This study defined the effects of concurrent exposure of two hERG-blocking drugs on hERG current amplitude. Experiments were conducted to determine if concomitant exposure to two potent pore hERG blockers, thioridazine and terfenadine and a weak hERG blocker, erythromycin, would result in an additive, synergistic or inhibitory effect. hERG currents from stably transfected HEK cells were measured using the whole-cell variant of the patch-clamp method at physiological temperatures. Concentration-response relationships for thioridazine or terfenadine were obtained with cells pre-exposed to erythromycin. Pre-exposure of cells to erythromycin resulted in an approximately 14-22-fold rightward shift in the hERG concentration-response curve for thioridazine and terfenadine respectively. This reduction in affinity was not the result of a change in the voltage-dependent characteristics of the channel. Results suggest an external binding site for erythromycin. Pretreatment with erythromycin induced an approximately 14-22-fold reduction in hERG affinity for pore-binding drugs at concentrations of erythromycin, which by themselves only block hERG by 10% or less. These results suggest distinct, allosterically linked binding sites on opposite sides of the hERG channel. Occupancy of the external site by erythromycin reduces the affinity of the pore binding site. Furthermore, these results suggest that co-administration of erythromycin may provide some reduction in cardiac liability of potent hERG-blocking drugs.

Evaluation of the effects of rifampicin, ketoconazole and erythromycin on the steady-state pharmacokinetics of the components of a novel oral contraceptive containing estradiol valerate and dienogest in healthy postmenopausal women

BackgroundWe evaluated the effects of cytochrome P450 3A4 (CYP3A4) induction and inhibition on steady-state pharmacokinetics of the components of a novel oral contraceptive (OC) containing estradiol valerate (E2V) and dienogest (DNG). Study DesignCYP3A4 induction was assessed in an open-label, one-arm study. Sixteen healthy postmenopausal women received E2V 2 mg/DNG 3 mg (days 1–17) and concomitant rifampicin (600 mg, days 12–16). Ratios of the area under the serum concentration–time curve between 0 and 24 h [AUC(0–24 h)] and maximum serum concentration (Cmax) of E2 and DNG on days 17 and 11 (after and before rifampicin intervention) are presented. CYP3A4 inhibition was investigated in an open-label, parallel-group study in 24 healthy postmenopausal women receiving E2V 2 mg/DNG 3 mg (days 1–14) and concomitant ketoconazole (400 mg, n=12) or erythromycin (500 mg three times daily, n=12) on days 8–14. Mean ratios of AUC(0–24 h) and Cmax of E2 and DNG on days 7 and 14 are presented. ResultsConcomitant administration of rifampicin decreased systemic drug exposure and yielded geometric mean ratios for E2Cmax and AUC(0–24 h) of 75% and 56%, respectively. Corresponding mean ratios for DNG were 48% and 17%, respectively. Ketoconazole coadministration increased systemic drug exposure and yielded ratios of E2 of 165% and 157%, respectively, and ratios of DNG of 194% and 286%, respectively. Erythromycin coadministration also resulted in increased mean Cmax and AUC(0–24 h) of both E2 and DNG. Geometric mean ratios of Cmax and AUC(0–24 h) for E2 were 151% and 133%, respectively. Corresponding ratios for DNG were 133% and 162%, respectively. ConclusionsSignificant drug–drug interactions are apparent when CYP3A4 modulators are coadministered with the components of a novel OC containing E2V/DNG. Coadministration of CYP3A4 modulators should be avoided where possible, and another type of contraception should be used when coadministration of CYP3A4 inducers like rifampicin is unavoidable.

Estimation of P-glycoprotein-mediated efflux in the oral absorption of P-gp substrate drugs from simultaneous analysis of drug dissolution and permeation

The purpose of this study was to establish an in vitro system that evaluates the effects of P-glycoprotein (P-gp)-mediated efflux on the oral absorption of P-gp substrates. An in vitro system (dissolution/permeation system, D/P system) was developed that consisted of apical and basal chambers and a Caco-2 cell monolayer mounted between the chambers. Both sides of the monolayer were filled with physiological solution and were stirred at 200 rpm. The dissolution in the apical medium and permeation to the basal medium were monitored for 2 h after P-gp substrates were applied to the apical side of the system. When erythromycin existed in the apical medium, the permeations of fexofenadine and talinolol were significantly enhanced without change in their dissolution. The prediction of oral absorptions of fexofenadine and talinolol from in vitro data indicated that co-administration of erythromycin results in 2.1- and 1.9-fold higher oral absorptions, respectively. Moreover, the D/P system could estimate the effect of cremophor EL on the oral absorption of saquinavir. These estimations corresponded well to in vivo human observations. Our in vitro system is useful in assessment of the effect of P-gp-mediated efflux on in vivo oral absorption of P-gp substrates.

Evaluation of possible drug–drug interaction between gadoxetic acid and erythromycin as an inhibitor of organic anion transporting peptides (OATP)

To evaluate if erythromycin compromises liver-specific enhancement of gadoxetic acid; both compounds competing in organic anion transporting peptides (OATP) -mediated hepatocytic uptake. The study was approved by institutional review board. Twelve healthy subjects (nine men, three woman; mean age, 38.7 years) were examined twice by MR imaging with prior administration of NaCl solution (placebo) or 1000 mg of erythromycin following a randomized sequence. Gadoxetic acid (0.025 mmol/kg body weight) was administered 15 min after the end of infusions. Pre- and 20 min postcontrast two-dimensional gradient-recalled-echo sequences were acquired. Relative enhancements of liver parenchyma and ratio of means were calculated from signal intensity measurements. Plasma levels of gadoxetic acid and erythromycin were determined and given in geometric means and coefficients of variation (CV). Concentration of erythromycin directly after end of infusion was 13.9 mg/L (CV 14.9%). Gadolinium plasma concentrations 5 min after gadoxetic acid administration were 138.7 μmol/L (CV 20.4%) after erythromycin infusion and 129.6 μmol/L (CV 22.8%) after placebo. Mean relative enhancements of liver parenchyma were 88.1 (SD 24.9%) after erythromycin infusion and 92.6 (SD 17.9%) after placebo. Ratio of relative enhancements was 0.951 (95% confidence interval, 0.833; 1.061; statistically not significant). Coadministration of erythromycin has no effect on gadoxetic acid enhanced liver MR imaging.

Erythromycin, an inhibitor of mitoribosomal protein biosynthesis, alters the amphotericin B susceptibility of Candida albicans.

Exposure of the yeast Candida albicans to the macrolide antibiotic erythromycin (C(37)H(67)NO(13)) results in elevated tolerance to the polyene antifungal amphotericin B. Erythromycin displays no fungistatic activity against C. albicans but inhibits the synthesis of cytochromes, particularly cytochrome aa(3). Consequently there is a reduction in aerobic respiration by up to 90% when cells are exposed to 10 mg mL(-1) erythromycin. Cellular ergosterol levels are also severely reduced. Erythromycin inhibits protein biosynthesis in ribosomes (mitoribosomes) located within the mitochondrion of the yeast cell, which results in a disruption of cytochrome biosynthesis with an adverse effect on respiration. The synthesis of ergosterol is oxygen dependent and consequently ergosterol levels are depleted in erythromycin-treated C. albicans. Ergosterol is the target for amphotericin B and since there is less of this sterol in erythromycin-treated cells, there is an increase in tolerance of the antifungal agent. Our work indicates that co-administration of erythromycin and amphotericin B to control bacterial and fungal infections, respectively, may inadvertently lead to an elevation in the tolerance of C. albicans for this antifungal agent.

Interactions between Antiinfective Agents and Immunosuppressants

Interactions between Antiinfective Agents and Immunosuppressants

Effect of repeated dose of erythromycin on the pharmacokinetics of roflumilast and roflumilast N-oxide

To investigate the effects of steady state erythromycin on the pharmacokinetics of roflumilast and its pharmacodynamically active metabolite roflumilast N-oxide in healthy subjects. Both roflumilast and roflumilast N-oxide have similar intrinsic PDE4 inhibitory activity; the total PDE4 inhibition (tPDE4i) in humans is likely due to the combined effect of roflumilast and roflumilast N-oxide. Subjects (n = 16) received single oral roflumilast 500 microg once daily (Days 1 and 15), and repeated oral erythromycin 500 mg three times daily (Days 9 - 21). Percent ratios of Test/Reference (Reference: roflumilast alone; Test: roflumilast and steady-state erythromycin) were calculated for the geometric means and their 90% confidence intervals for systemic exposure (AUC), maximum concentration (Cmax) (roflumilast and roflumilast N-oxide), and apparent clearance of roflumilast. After co-administration of erythromycin and roflumilast, the mean AUC and Cmax of roflumilast increased by 70% and 40%, respectively. The mean apparent clearance of roflumilast decreased from 8.2 l/h (Reference) to 4.8 l/h (Test). Steady-state erythromycin did not alter the mean AUC of roflumilast N-oxide, however, the mean Cmax decreased by 34%. The AUCroflumilast N-oxide/AUCroflumilast ratio decreased from 10.6 (Reference) to 6.4 (Test). Co-administration of erythromycin and roflumilast did not influence the integrated total exposure to roflumilast and roflumilast N-oxide, i.e. mean tPDE4i. No clinically relevant adverse events were observed during the study. Co-administration of erythromycin (a moderate CYP3A4 inhibitor) and roflumilast does not require dose adjustment of roflumilast.

Simvastatin‐Associated Rhabdomyolysis After Coadministration of Macrolide Antibiotics in Two Patients

Two men, aged 83 and 78 years, who received stable therapy with simvastatin 80 mg/day were hospitalized 1-2 weeks after completion of short-term treatment with erythromycin and clarithromycin, respectively. Both patients were admitted with myalgia, muscle weakness, functional disability (inability to raise arms and legs), and serum creatine kinase levels more than 60 times the upper limit of normal (ULN). Substantial elevations in aspartate aminotransferase (> 30 times the ULN) and alanine aminotransferase (> 7 times the ULN) levels were also observed. Rhabdomyolysis was diagnosed in both patients. Both recovered, but the combined events resulted in almost 40 days of hospitalization, the cost of which is considerable. According to the Naranjo adverse drug reaction probability scale, the likelihood that the rhabdomyolysis was secondary to a simvastatin-macrolide interaction was probable. Four cases of rhabdomyolysis after therapy with combined simvastatin and clarithromycin have been reported previously, but this is apparently the first report of rhabdomyolysis after coadministration of erythromycin. The interacting mechanism likely was inhibited cytochrome P450 (CYP) 3A4 metabolism and possibly P-glycoprotein transport of simvastatin as well. Previous reports of simvastatin-clarithromycin-related events involved additional drugs that inhibited CYP3A4 and P-glycoprotein. However, this was not the situation with our two patients. To prevent future events, it is crucial that clinicians recognize the interaction risk associated with concurrent use of simvastatin and clarithromycin or erythromycin. The risk could be managed by temporary interruption of simvastatin treatment or administration of a noninteracting antimicrobial agent.

Effect of multiple-dose erythromycin on everolimus pharmacokinetics

We sought to quantify the influence of the CYP3A inhibitor erythromycin on the pharmacokinetics of everolimus, a CYP3A substrate. This was a two-period, single-sequence, crossover study in 16 healthy subjects. In period 1, subjects received the reference treatment of a single 2-mg dose of everolimus. In period 2, they received the test treatment of erythromycin 500 mg three times daily for a total of 9 days and a single 2-mg dose of everolimus coadministered on the fifth day of erythromycin therapy. The test/reference ratio and 90% confidence interval (CI) were derived for everolimus C (max) and AUC. During erythromycin coadministration, everolimus C (max) increased 2.0-fold (90% CI, 1.8-2.3) from 20+/-5 ng/ml to 40+/-10 ng/ml. Everolimus AUC increased 4.4-fold (90% CI, 3.5-5.4) from 116+/-37 ng h/ml to 524+/-225 ng h/ml. Everolimus half-life was prolonged by 39% from 32+/-6 h to 44+/-6 h. Erythromycin predose concentrations were not changed after single-dose administration of everolimus. Multiple-dose erythromycin increased single-dose everolimus blood levels by an average 4.4-fold (range, 2.0-12.6). During erythromycin treatment, a compensatory everolimus dose reduction should be made guided by everolimus therapeutic drug monitoring.

Prediction of the in vivo interaction between midazolam and macrolides based on in vitro studies using human liver microsomes.

Clinical studies have revealed that plasma concentrations of midazolam after oral administration are greatly increased by coadministration of erythromycin and clarithromycin, whereas azithromycin has little effect on midazolam concentrations. Several macrolide antibiotics are known to be mechanism-based inhibitors of CYP3A, a cytochrome P450 isoform responsible for midazolam hydroxylation. The aim of the present study was to quantitatively predict in vivo drug interactions in humans involving macrolide antibiotics with different inhibitory potencies based on in vitro studies. alpha- and 4-Hydroxylation of midazolam by human liver microsomes were evaluated as CYP3A-mediated metabolic reactions, and the effect of preincubation with macrolides was examined. The hydroxylation of midazolam was inhibited in a time- and concentration-dependent manner following preincubation with macrolides in the presence of NADPH, whereas almost no inhibition was observed without preincubation. The kinetic parameters for enzyme inactivation (K'app and kinact) involved in midazolam alpha-hydroxylation were 12.6 microM and 0.0240 min-1, respectively, for erythromycin, 41.4 microM and 0.0423 min-1, respectively, for clarithromycin, and 623 microM and 0.0158 min-1, respectively, for azithromycin. Similar results were obtained for the 4-hydroxylation pathway. These parameters and the reported pharmacokinetic parameters of midazolam and macrolides were then used to simulate in vivo interactions based on a physiological flow model. The area under the concentration-time curve (AUC) of midazolam after oral administration was predicted to increase 2.9- or 3.0-fold following pretreatment with erythromycin (500 mg t.i.d. for 5 or 6 days, respectively) and 2.1- or 2.5-fold by clarithromycin (250 mg b.i.d. for 5 days or 500 mg b.i.d. for 7 days, respectively), whereas azithromycin (500 mg o.d. for 3 days) was predicted to have little effect on midazolam AUC. These results agreed well with the reported in vivo observations.

Compound Cardiac Toxicity of Oral Erythromycin and Verapamil

OBJECTIVE:To report a case of complete atrioventricular (AV) block and QTc prolongation following coadministration of high-dose verapamil and erythromycin.CASE SUMMARY:A 79-year-old white woman was admitted to the hospital due to extreme fatigue and dizziness. On admission, heart rate was 40 beats/min and blood pressure was 80/40 mm Hg. An electrocardiogram showed complete atrioventricular (AV) block, escape rhythm of 50 beats/min, and QTc prolongation 583 msec. This event was attributed to concomitant treatment with verapamil 480 mg/d and erythromycin 2000 mg/d, which was prescribed one week before admission.DISCUSSION:This is the first case published describing complete AV block and prolongation of QTc following coadministration of erythromycin and verapamil. CYP3A4 is the main isoenzyme responsible for metabolism of erythromycin and verapamil. Both drugs are potent inhibitors of CYP3A4 and of P-glycoprotein; this may be the basis for the pharmacokinetic interaction between erythromycin and verapamil. In addition to being a woman, our patient had other risk factors for QT prolongation: slow baseline heart rate (probably induced by verapamil), left-ventricular hypertrophy, and possibly ischemic heart disease.CONCLUSIONS:This life-threatening arrhythmia was probably the result of a pharmacokinetic and/or pharmacodynamic interaction of high-dose verapamil and erythromycin.

Surgical Internet at a glance: healthcentral and drKoop

Surgical patients today are different from those of earlier centuries, or even earlier decades. They demand, and deserve, a right to informed consent about operations. In addition to one-on-one counseling by a surgeon, a patient often looks to other sources for information about diagnoses and operations. A current turning point to procure this knowledge is the world-wide-web. However, not all medical information presented on a web page is true, applicable, or even useful. At present there is no quality assurance system to verify facts presented on medical web pages. In a recent review of representation of common vascular surgical problems on the world-wide-web, Soot and colleagues found that 96 out of 150 websites (66%) had virtually no useful patientoriented information. Of the vascular web pages that had information considered relevant to patient education, 33% had areas that were classified by the authors as misleading or unconventional. Until problems of verifying accuracy and integrity of the online content are solved, it is up to health care professionals to guide patients to reliable resources. One such way is to produce a “selected links” section for patients who seek additional medical facts online. This link would represent web pages that a physician has previously visited and “approved.” Such a program was established at the Family Practice Department of Medical College of Wisconsin where patients were given access to web pages that had been reviewed and sanctioned by their doctors. Ninetyfour percent of participants found this group of web pages useful and 77% said that they would modify an unhealthy behavior because of information read on online. Patients usually refer to search engines or corporate web pages as starting points in their information quest. Two commercial web pages featuring well-known doctors are highlighted here: television and radio celebrity Dr. Dean Edell’s Health Central at http://www.healthcentral.com and former US Surgeon General Dr. C. Everett Koop’s self-titled http://www.drkoop.com. While both web pages are informative, interactive, and fun, make no mistake— they are commercial ventures. Each is heavily laden with advertising banners that, when clicked upon, whisk the viewer away from patient information sections to a different site with a distinct agenda. Unfortunately, the future of medical web pages appears to be a cyberspace hybrid of patient information pamphlet and television commercial. Banners aside, these pages contain a reasonable amount of data aimed at health care consumers. Both are searchable by topics. Test searches that included the phrase “colon cancer” returned 205 “matches” on healthcentral.com and 33 on drkoop.com. Each match is a link to a published article contained within the respective web page. The articles read like newspaper columns and are generally up-to-date and factual. Other search topics included carotid endarterectomy (15 matches on healthcentral.com, 2 matches on drkoop.com), melanoma (94,33), hernia (35,37), cholecystectomy (9,5), and skin graft (29,5). In addition to a search and find technique, both web pages contain helpful interactive applications. At drkoop. com, an interactive “drug-checker” can determine whether a patient’s medication will interact with other medication, or interact with a certain food. To do this, a patient types in the medication and the web page responds with interactions. A sample on erythromycin and cisapride returned: “Severe! Erythromycin may inhibit the metabolism of cisapride. Plasma cisapride concentrations may be increased. This interaction may lead to a prolongation of the QT interval and the occurrence of serious ventricular arrhythmias such as torsades de pointes. Interactions between similar drugs have been fatal. Coadministration of erythromycin and cisapride is contraindicated.” This simple online tool would probably be a welcome addition to most any doctor’s office. At healthcentral.com, the “cool tools” section contains interactive calculators designed to determine personal health profiles. By answering a series of questions, the visitor is issued personal feedback about a variety of medical topics, including drugs and alcohol, eye and vision, nutrition, stress, and others. A more comprehensive assessment can be obtained via a ten-minute profile in the “Know Your Health” section that consists of answering a number of questions. The profile will even predict life expectancy and advise the visitor what areas need improvement. As medical web pages increase, it becomes less feasible for an organization or committee to monitor and approve the content, especially true with dynamic web pages that frequently change content. It is up to health care professionals to stay abreast of web pages within their specialty and help refer inuiring patients to appropriate sites. The large corporate web pages, which number in the hundreds, are a good place to start.

Pharmacodynamic analysis of the electrocardiographic interaction between disopyramide and erythromycin in rats

Disopyramide (DP) is known to induce QT prolongation and Torsades de Pointes (TdP) when administered concomitantly with erythromycin (EM). To define and evaluate quantitatively the arrhyth‐mogenic risk of the concomitant administration of DP and EM, we investigated the influence of EM on the pharmacokinetics and pharmacodynamics of DP in rats. The time profiles of change in QT interval and plasma concentration of each drug were evaluated during and after constant intravenous infusion of DP (6.0 or 15.0 mg/kg/h), EM (4.0 or 8.0 mg/kg/h), and coadministration of DP and EM (DP 6.0 mg/kg/h plus EM 4.0 mg/kg/h). Each agent induced QT prolongation at plasma concentrations within the therapeutic range in humans. DP‐induced QT prolongation was proportional to its plasma concentration. In the case of EM, the Emax model with an “effect compartment” could explain the relationship between plasma EM concentrations and changes in QT interval. Although coadministration of EM with DP gave enhanced QT prolongation compared to dosing with DP alone, EM did not affect the pharmacokinetics of DP. In conclusion, it was shown that a pharmacodynamic interaction contributes to the electrocardiographic adverse reaction (i.e., QT prolongation) induced by coadmin‐istration of DP and EM in rats.