A drug-drug interaction (DDI) is a pharmacokinetic or pharmacological influence of 1 medication on another that differs from the known or anticipated effects of each agent alone.1 A DDI may result in a change in either drug efficacy or drug toxicity for 1 or both of the interacting medications.2 Pharmacokinetic DDIs result in altered absorption, distribution, metabolism, or excretion of a medication. A pharmacodynamic DDI occurs when 1 medication modifies the pharmacological effect of another in an additive, a synergistic, or an antagonistic fashion.It is estimated that ≈2.8% of hospital admissions occur as a direct result of DDIs. 3 However, the actual incidence of hospitalization secondary to clinically significant DDIs is likely to be highly underestimated because medication-related issues are more commonly reported as adverse drug reactions. Complex underlying disease states also may make recognizing a DDI more challenging, further contributing to a lower reported incidence. The overall clinical impact of a DDI can range from mild to life-threatening. Therefore, not all DDIs require a modification in therapy. The variability in the clinical significance of a DDI depends on both medication-specific and patient-specific factors. Medication-specific factors include the individual pharmacokinetic characteristics of each medication implicated in the DDI (eg, binding affinity, half-life [t 1/2 ]), dose of the medications, serum concentrations, timing and sequence of administration, and duration of therapy. Patient-specific factors include age, sex, lifestyle, genetic polymorphisms causing differences in enzyme expression or activity, and disease impairment affecting drug metabolism (eg, hepatic or renal impairment, cardiac failure) or predisposition to differences in efficacy or safety (eg, statin intolerance in patients with a history of myopathy). Clinically significant DDIs are usually preventable. To optimize patient safety, healthcare providers must have an understanding of the mechanisms, magnitude, and potential consequences of any given DDI. Interpreting this information will assist clinicians in the safe prescribing of medications and permits careful consideration of the benefits and risks of concomitant medications.Statins reduce morbidity and mortality in patients with known atherosclerotic cardiovascular disease (ASCVD) and in many primary prevention patients.4-9 Current guidelines recommend high-intensity statin therapy in all patients with ASCVD age ≤75 years and moderate-to high-intensity statin therapy in patients with ASCVD and age >75 years, diabetes mellitus, and familial hypercholesterolemia and in primary prevention patients with 10-year ASCVD risk ≥7.5%.10 Given the important role of statins in patients with ASCVD and those at high ASCVD risk, combination therapy with statins and other cardiovascular medications is highly likely, and potentially significant DDIs must be considered in patients treated with statins.Another important aspect of prescribing medications in combination is evalu...

In the present study we investigated cardiac hypertrophy and cardiac complications in mice subjected to hyperoxia. Results demonstrate that there is a significant increase in average heart weight to tibia length (22%) in mice subjected to hyperoxia treatment vs. normoxia. Functional assessment was performed in mice subjected to hyperoxic treatment, and results demonstrate impaired cardiac function with decreased cardiac output and heart rate. Staining of transverse cardiac sections clearly demonstrates an increase in the cross-sectional area from hyperoxic hearts compared with control hearts. Quantitative real-time RT-PCR and Western blot analysis indicated differential mRNA and protein expression levels between hyperoxia-treated and control left ventricles for ion channels including Kv4.2 (Ϫ2 Ϯ 0.08), Kv2.1 (2.54 Ϯ 0.48), and Scn5a (1.4 Ϯ 0.07); chaperone KChIP2 (Ϫ1.7 Ϯ 0.06); transcriptional factors such as GATA4 (Ϫ1.5 Ϯ 0.05), Irx5 (5.6 Ϯ 1.74), NFB1 (4.17 Ϯ 0.43); hypertrophy markers including MHC-6 (2.17 Ϯ 0.36) and MHC-7 (4.62 Ϯ 0.76); gap junction protein Gja1 (4.4 Ϯ 0.8); and microRNA processing enzyme Drosha (4.6 Ϯ 0.58). Taken together, the data presented here clearly indicate that hyperoxia induces left ventricular remodeling and hypertrophy and alters the expression of Kv4.2 and MHC6/7 in the heart. ion channel regulation; hyperoxia; heart; hypertrophy; potassium channel; redox PATIENTS in critical or intensive care units (ICU) with acute lung injury or cardiac disease are often administered 100% O 2 for treatment. Recent studies indicate that hyperoxia induces cardiac injury due to dysfunctional lung and compromised pulmonary functioning (37), even though the exact nature of this problem remains unknown. Here, we evaluated changes in expression of the ion channel and key transcriptional factors in the heart that occur with hyperoxia and likely play a role in cardiovascular remodeling.Potassium channels and their auxiliary subunits such as potassium channel interacting protein-2 (KChIP2) are abundantly expressed in the heart (5, 7, 35). It is established that the potassium channels Kv4.2 and Kv1.5 are responsive to oxygen changes (29, 39). In the present study, we investigate whether hyperoxia alters expression of the transcription factors Irx5 and Mef2c, which are implicated to play a direct role in regulating Kv4.2 expression (7,15,22). Cardiac-specific markers used to identify hypertrophy and transcriptional changes (9, 22) were also evaluated by assessing myosin heavy chain-6, and -7 (MHC6, MHC7), zinc finger transcription factor (GATA4), histone-lysine N-methyltransferase (Ezh2), and Six-1 expression levels with hyperoxia.Key inflammatory mediators such as TNF␣ and NFB are central regulators or master switches for many pathological processes (10,20,30). Recent evidence indicates that NFB regulates KChIP2, which in turn regulates Kv4.2 expression (26). Therefore we assessed the levels of Kv4.2, KChIP2, and NFB in the mouse heart subjected to hyperoxia. We hypothesized that hyperoxia induces cardi...

Objective. Chlamydia trachomatis and Chlamydophila (Chlamydia) pneumoniae are known triggers of reactive arthritis (ReA) and exist in a persistent metabolically active infection state in the synovium, suggesting that they may be susceptible to antimicrobial agents. The goal of this study was to investigate whether a 6-month course of combination antibiotics is an effective treatment for patients with chronic Chlamydiainduced ReA.Methods. This study was a 9-month, prospective, double-blind, triple-placebo trial assessing a 6-month course of combination antibiotics as a treatment for Chlamydia-induced ReA. Eligible patients had to be positive for C trachomatis or C pneumoniae by polymerase chain reaction (PCR). Groups received 1) doxycycline and rifampin plus placebo instead of azithromycin; 2) azithromycin and rifampin plus placebo instead of doxycycline; or 3) placebos instead of azithromycin, doxycycline, and rifampin. The primary end point was the number of patients who improved by 20% or more in at least 4 of 6 variables without worsening in any 1 variable in both combination antibiotic groups combined and in the placebo group at month 6 compared with baseline.Results. The primary end point was achieved in 17 of 27 patients (63%) receiving combination antibiotics and in 3 of 15 patients (20%) receiving placebo. Secondary efficacy end points showed similar results. Six of 27 patients (22%) randomized to combination antibiotics believed that their disease went into complete remission during the trial, whereas no patient in the placebo arm achieved remission. Significantly more patients in the active treatment group became negative for C trachomatis or C pneumoniae by PCR at month 6. Adverse events were mild, with no significant differences between the groups.Conclusion. These data suggest that a 6-month course of combination antibiotics is an effective treatment for chronic Chlamydia-induced ReA.

Herbal medicines are often used in combination with conventional drugs, and this may give rise to the potential of harmful herb-drug interactions. This paper updates our knowledge on clinical herb-drug interactions with an emphasis of the mechanistic and clinical consideration. In silico, in vitro, animal and human studies are often used to predict and/or identify drug interactions with herbal remedies. To date, a number of clinically important herb-drug interactions have been reported, but many of them are from case reports and limited clinical observations. Common herbal medicines that interact with drugs include St John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba), ginger (Zingiber officinale), ginseng (Panax ginseng), and garlic (Allium sativum). For example, St John's wort significantly reduced the area under the plasma concentration-time curve (AUC) and blood concentrations of cyclosporine, midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline. The common drugs that interact with herbal medicines include warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Herbal medicines may interact with drugs at the intestine, liver, kidneys, and targets of action. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). The underlying mechanisms for most reported herb-drug interactions are not fully understood, and pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. In particular, enzyme induction and inhibition may play an important role in the occurrence of some herbdrug interactions. Because herb-drug interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of herb-drug interactions has important implications.