Absence Of Drug Interactions Research Articles

Major Depression in Comorbidity with Substance use Disorders: Patients' Features and Clinical-Neurobiological Rationale of Antidepressant Treatments.

The frequent co-occurrence of major depressive disorder (MDD) and substance use disorders (SUDs) entails significant clinical challenges. Compared to patients with MDD alone, patients with MDD and SUD often show increased anhedonia, emotional blunting, and impaired cognitive function. These symptoms lead to an inability to control cravings, more substance use, increased relapse rates, and poor adherence to the treatment. This fosters a detrimental cycle leading to more severe depressive symptoms, functional impairment, and chronicity, culminating in heightened morbidity, mortality, and healthcare resource utilization. Data on antidepressant treatment of MDD-SUD patients are inconclusive and often conflicting because of a number of confounding factors in clinical trials or difficulty in dissecting the specific contributions of pharmacological versus psychological interventions in real-world studies. The patient's unique clinical features and specific SUD and MDD subtypes must be considered when choosing treatments. Ideally, drug treatment for MDD-SUD should act on both conditions and address core symptoms such as anhedonia, craving, and cognitive dysfunction while ensuring minimal emotional blunting, absence of drug interactions, and no addictive potential. This approach aims to address unmet needs and optimize the outcomes in a clinical population often underrepresented in treatment paradigms.

Physiologically based pharmacokinetic models for predicting lamotrigine exposure and dose optimization in pediatric patients receiving combination therapy with carbamazepine or valproic acid.

Lamotrigine (LTG) is an antiepileptic drug that has been used in pediatric epilepsy as a combination therapy or monotherapy after stabilization in recent years. However, there are significant drug-drug interactions (DDI) between LTG and combined drugs such as carbamazepine (CBZ) and valproic acid (VPA). It is particularly important to consider the risk of DDI in combination therapy for intractable epilepsy in pediatric patients. Therefore, it is necessary to adjust the dosage of LTG accordingly. The aim of this study was to establish and validate a pediatric physiologically based pharmacokinetic (PBPK) model for predicting LTG exposure. The model is designed to explore the potential for quantifying pharmacokinetic (PK) DDI of LTG when administered concurrently with CBZ or VPA in pediatric patients. Adult and pediatric PBPK models for LTG and VPA were developed using PK-Sim® software in combination with physiological information and drug-specific parameters, and a DDI model was developed in combination with the published CBZ model. The models were validated against available PK data. Predictive and observational results in adults, children, and the DDI model were in good agreement. The recommended doses of LTG for preschool children (2-6 years) and school-aged children (6-12 years) in the absence of drug interactions were 1.47 and 1.2 times higher than those for adults, respectively; 3.1 and 2.6 times higher than those for adults in combination with CBZ; and 0.67 and 0.57 times lower than those for adults in combination with VPA. In addition, plasma exposures in adolescents (12-18 years) were similar to those in adults at the same doses. We have successfully developed PBPK models and DDI models for LTG in adults and children, which provide a reference for rational drug use in the pediatric population.

Hybrid laser activated phycocyanin/capecitabine treatment of cancerous MCF7 cells.

Laser-induced fluorescence is recently used as an efficient technique in cancer diagnosis and non-invasive treatment. Here, the synergic therapeutical efficacies of the Capecitabine (CAP) chemodrug, photosensitive Phycocyanin (PC) and graphene oxide (GO) under laser irradiation were investigated. The therapeutical efficacies of diverse concentrations of CAP (0.001-10 mg/ml) and PC (0.5-10 mg/ml) alone and with laser irradiation on human breast adenocarcinoma (MCF-7) cells were examined. The interactional effects of 100 mW SHG Nd:YAG laser at 532nm and GaAs laser at 808 nm ranging power of 150 mW- 2.2W were considered. The contribution of graphene oxide (GO) in biocompatible concentrations of 2.5-20 ng/ml and thermal characteristics of laser exposure at 808 nm on GO + fluorophores have been studied. The effects of the bare and laser-excited CAP + PC on cell mortality have been obtained. Despite the laser irradiation could not hold up the cell proliferation in the absence of drug interaction considerably; however, the viability of the treated cells (by a combination of fluorophores) under laser exposure at 808 nm was significantly reduced. The laser at 532 nm excited the fluorescent PC in (CAP + PC) to trigger the photodynamic processes via oxygen generation. Through the in-vitro experiments of laser-induced fluorescence (LIF) spectroscopy of PC + CAP, the PC/CAP concentrations of the maximum fluorescence signal and spectral shifts have been characterized. The synergic effects of the laser exposures and (CAP + PC) treatment at different concentrations were confirmed. It has been shown here that the laser activation of (CAP + PC) can induce the mortality of the malignant cells by reducing the chemotherapeutic dose of CAP to avoid its non-desirable side effects and by approaching the minimally invasive treatment. Elevation of the laser intensity/exposure time could contribute to the therapeutic efficacy. Survival of the treated cells with a combination of GO and fluorophores could be reduced under laser exposure at 808 nm compared to the same combination therapy in the absence of GO. This survey could benefit the forthcoming clinical protocols based on laser spectroscopy for in-situ imaging/diagnosis/treatment of adenocarcinoma utilizing PC + CAP + GO.

Improving Tolerance and Compliance of New Targeted Therapies with Homeopathy: A Major Challenge in Oncology

The application of targeted therapies (TT) in oncology has prolonged survivals and even enabled complete remission of cancers previously considered incurable. With small therapeutic indices, the reduction in dosage or spacing out of the doses of TT due to side effects, represents a significant loss of treatment opportunity for the patients. In the absence of drug interaction and significant side effects, homeopathy used in supportive care improves the quality of life of patients, compliance with oncological treatments and consequently their survival. Based on the author’s clinical experience and published studies, a therapeutic regimen for systematic supportive care of TT is proposed in this study. The originality of the treatment lies in combining a symptomatic diluted and dynamised homeopathic medicine with the patient’s constitutional homeopathic medicine as well as the isotherapeutic agent used for targeted therapy in 7c (10-14). If needs be, the eponymous organotherapy of the organ most affected by the side effects can be added in 4c (10-8). This therapeutic regimen is well accepted and well tolerated. It has been prescribed to approximately 5,000 patients over 25 years including those patients who were given hormone therapy. Facilitating tolerance and acceptance of targeted therapies is very important in oncology in order to fully benefit from the TT efficacy. Homeopathy, organotherapy and isotherapy, by supporting the whole body and treating the major side effects, might improve observance and consequently therapeutic results. Clinical trials could be carried out following the designs and protocols presented in this article.

Thrombosis prevention and treatment in oncology patients employed in hazardous occupations

Relevance. Neoplasms tend to increase among the firemen and military personnel, according to their medical and statistical indicators. People with hazardous occupation are at high risk of malignancies. Thus, the issues of diagnostics, prophylaxis and treatment of oncology diseases and their thrombotic complications are of essential importance for this category of patients. Intention. To analyze the literature data on the role of hemostatic system disorders, possible ways of prophylaxis and treatment of thrombotic complications in case of oncology diseases. Results. Thrombotic complications affect negatively the antineoplastic therapy outcomes and become one of the leading death causes. The thrombosis in oncology patients 30-fold increases death risk due to the fatal thromboembolism and more aggressive neoplastic process. Hemostasis system disorders are caused both by neoplasms and their treatment. Low molecular weight heparin (LMWH) is considered a basis for thromboembolism prevention in oncology patients. LMWH decreases effectively the venous thromboses after surgery and during chemotherapy. Direct oral anticoagulants are promising medications for oral administration; they are indicated for patients with tumor-associated thromboses in case of a low bleed risk and absence of drug interactions with system chemotherapy.

Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants: A Systematic Review

Direct oral anticoagulants (DOACs) are the treatment of choice for most patients with atrial fibrillation and/or noncancer-associated venous thromboembolic disease. Although routine monitoring of these agents is not required, assessment of anticoagulant effect may be desirable in special situations. The objective of this review was to summarize systematically evidence regarding laboratory assessment of the anticoagulant effects of dabigatran, rivaroxaban, apixaban, and edoxaban. PubMed, Embase, and Web of Science were searched for studies reporting relationships between drug levels and coagulation assay results. We identified 109 eligible studies: 35 for dabigatran, 50 for rivaroxaban, 11 for apixaban, and 13 for edoxaban. The performance of standard anticoagulation tests varied across DOACs and reagents; most assays, showed insufficient correlation to provide a reliable assessment of DOAC effects. Dilute thrombin time (TT) assays demonstrated linear correlation (r2= 0.67-0.99) across a range of expected concentrations of dabigatran, as did ecarin-based assays. Calibrated anti-Xa assays demonstrated linear correlation (r2= 0.78-1.00) across a wide range of concentrations for rivaroxaban, apixaban, and edoxaban. An ideal test, offering both accuracy and precision for measurement of any DOAC is not widely available. We recommend a dilute TT or ecarin-based assay for assessment of the anticoagulant effect of dabigatran and anti-Xa assays with drug-specific calibrators for direct Xa inhibitors. In the absence of these tests, TT orAPTT is recommended over PT/INR for assessment of dabigatran, and PT/INR is recommended over APTT for detection of factor Xa inhibitors. Time since last dose, the presence or absence of druginteractions, and renal and hepatic function should impact clinical estimates of anticoagulant effectin a patient for whom laboratory test results are not available.

Absence of drug interaction between Hwang-Ryun-Hae-Dok-Tang and Phenolsulfonphthalein

Hwang-Ryun-Hae-Dok-Tang (HT; a standardized herbal formula consisting of extracts from Coptidis Rhizoma, Scutellariae Radix, Phellodendri Cortex, and Gardeniae Fructus) was reported to modulate a function of multidrug resistance associated protein 2 (Mrp2) in vitro. The aim of this study was to assess the in vivo pharmacokinetic interactions between HT and phenolsulfonphthalein (PSP), a typical model Mrp2 substrate eliminated via bile through Mrp2 in rats. Rats received intravenous PSP (0.8 mg/kg) followed by either a single oral dose of HT (0.42 g/kg) or multiple oral doses of HT (0.42 g/kg for 7 days). The effect of HT treatment was also investigated at a steady-state after intravenous PSP infusion. In contrast to previous in vitro results, in this study, we found that the HT-treated and control groups did not show any significant difference in the plasma PSP concentration and pharmacokinetic parameters, including area under the plasma concentration-time curve (AUC; control: 118 ± 19, single dose: 116 ± 40, and multiple dose: 137 ± 4, in mg/(min·mL)) and biliary clearance (control: 3.15 ± 0.69, single dose: 2.59 ± 1.11, and multiple dose: 2.53 ± 0.65, in mL/(min·kg)). However, cyclosporine A (5 mg/kg, an inhibitor of Mrp2) significantly decreased the AUC and biliary clearance of PSP. The steady-state plasma concentration and biliary clearance of PSP-were also similar between the groups. Taken together, our results suggest that HT may not be affected by Mrp2-mediated herb-drug interaction in vivo.

Long-term use of Levetiracetam in patients with severe childhood-onset epilepsy

Objective To assess the efficacy and tolerability of Levetiracetam (LEV) in children and adolescents with refractory epilepsy with a special interest in the long-term retention rate. Method One hundred and twenty-nine patients (83 male, 46 female; mean age 10.6 years/range: 6 months–39 years 9 months) were included in a prospective, open-label, add-on trial of LEV for up to 3 years. All patients had severe forms of epilepsy starting before the age of 10 often accompanied by mental retardation. Primary outcome measures were changes in seizure frequency after 6 months on the medication with LEV, with initial responders (>50% seizure reduction). Further objective was the retention rate of LEV therapy after 3 years defined as percentage of patients still taking LEV. Results Thirty-five patients (27.1%) were initial responders of which 5 became seizure free. The average maximum LEV dosage was 39.8 mg/kg/day (range: 6–70 mg/kg/day) with no difference responders vs. no responders. The retention rate for responders after 3 years was 22.5%. The rate of side effects was 39.8% in all patients, with the most frequent side effects being fatigue (12.5%), aggressiveness (7.8%) and gastrointestinal disorders (13.3%). Conclusions Our study in patients with refractory epilepsy suggests that our initial responders were very likely to be still taking LEV after 3 years. We therefore consider treatment with LEV in this special group of patients with refractory epilepsy a promising therapeutic option, because of its favourable tolerance profile, the option of fast titration and the absence of drug interactions.

Steady-State Pharmacokinetics of Micafungin and Voriconazole after Separate and Concomitant Dosing in Healthy Adults

We assessed the pharmacokinetics and interactions of steady-state micafungin (Mycamine) or placebo with steady-state voriconazole in 35 volunteers. The 90% confidence intervals around the least-squares mean ratios for micafungin pharmacokinetic parameters and placebo-corrected voriconazole pharmacokinetic parameters were within the 80%-to-125% limits, indicating an absence of drug interaction.

Management of Overactive Bladder and Urge Urinary Incontinence in the Elderly Patient

The symptoms of overactive bladder (OAB) and urge urinary incontinence may occur at any age but are particularly common among the elderly. These symptoms are associated with significant morbidity and often have a profound impact on patient quality of life. Urinary incontinence is an important contributor to the complications and economic cost of OAB for both community-dwelling and institutionalized elderly individuals. Many patients with OAB do not seek treatment because of embarrassment, fear of surgery, or the misperceptions that the problem is untreatable or is a normal and inevitable consequence of aging. Nonpharmacologic therapies improve bladder control by modifying lifestyle and behavior to prevent urine loss. This requires patient and caregiver motivation and can be time consuming. Improved results may be obtained by combining these strategies with pharmacotherapy or by means of pharmacotherapy alone. The most commonly used pharmacologic agents are the muscarinic receptor antagonists. These include oxybutynin, tolterodine, and three agents that have recently been approved for use in the United States: trospium, darifenacin, and solifenacin. In general, these therapies are well tolerated and safe; however, the selection of an optimal agent merits careful consideration. For elderly patients, important considerations include tolerability, absence of drug interactions, and the availability of a range of dosages to tailor treatment to individual patients. Primary care practitioners and geriatricians can have a key role in successful diagnosis and treatment of OAB. It is important for these physicians to realize that satisfactory outcomes may be achieved within the scope of a busy outpatient practice.

An open-label, crossover study of the pharmacokinetics of Insoluble Drug Delivery®-MicroParticle fenofibrate in combination with atorvastatin, simvastatin, and extended-release niacin in healthy volunteers

Background: Fenofibrate has been prescribed concomitantlywith other lipid-lowering agents as a treatment for dyslipidemia. However, combination therapy, particularly a statin-fibrate combination, may be associated with an increased risk of myopathy, although this risk appears to be less with fenofibrate than with other fibrates. Objective: The objective of this study was to determinethe effect of administering a single dose of atorvastatin, simvastatin, or extended-release (ER) niacin on the pharmacokinetics and safety of a single dose of fenofibrate Insoluble Drug Delivery®-MicroParticle (IDD-P). Methods: This was an open-label, single-center,randomized, 4-treatment, 4-period crossover study in healthy adult volunteers. Subjects were randomized to 1 of 4 treatment sequences, administered 1 week apart, that included all 4 of the following treatments: 1 IDD-P fenofibrate 160-mg tablet alone; 1 IDD-P fenofibrate 160-mg tablet plus 1 atorvastatin 10-mg tablet; 1 IDD-P fenofibrate 160-mg tablet plus 1 simvastatin 10-mg tablet; and 1 IDD-P fenofibrate 160-mg tablet plus 1 ER niacin 500-mg tablet. Blood samples for pharmacokinetic analysis were obtained immediately before and up to 72 hours after administration during each of the 4 treatment periods. If the 90% CI for the log-transformed parameter was between 0.80 and 1.25, and the 90% CI for the nontransformed parameter was between 0.80 and 1.20, then the absence of a clinically significant drug interaction was assumed. However, the absence of a drug interaction was not to be ruled out if one or more of the CIs exceeded the boundary, provided the CI included 1.00. Results: Twenty healthy subjects were enrolled.Sixteen (80%) of the subjects were male and 17 (85%) were black; mean (SD) age was 35 (9.3) years. The mean C max, AUC from the time of administration to the last quantifiable concentration (AUC 0−t), and AUC from the time of administration to infinity (AUC 0−∞) were 5%, 6%, and 2% lower, respectively, with IDD-P fenofibrate plus atorvastatin than with IDD-P fenofibrate alone; the mean C max, AUC 0−t, and AUC 0-∞ were 6% lower, and 10% and 9% higher, respectively, with IDD-P fenofibrate plus simvastatin than with IDD-P fenofibrate alone; and the mean C max, AUC 0−t, and AUC 0−∞ were 12%, 6%, and 5% lower, respectively, with IDD-P fenofibrate plus ER niacin than with IDD-P fenofibrate alone. The 90% CIs surrounding the mean ratios for AUC 0−∞ and AUC 0−∞ for all 3 comparisons were between 0.80 and 1.25, suggesting the absence of a drug interaction for these parameters. For C max, an absence of a drug interaction was observed between concomitantly administered IDD-P fenofibrate and both atorvastatin and simvastatin; absence of drug interaction was not found for IDD-P fenofibrate plus ER niacin. All treatments were well tolerated; headache was the most common adverse event (AE) (10%). One subject with creatinine kinase levels of 1300 IU/L (>6 times the upper limit of normal) at baseline experienced a seizure ≈12 to ≈13 hours after administration of IDD-P fenofibrate plus atorvastatin; this serious AE was deemed to be possibly related to study drug. Conclusions: Concomitant administration of a singledose of either atorvastatin or simvastatin had no significant effect on the pharmacokinetics of a single dose of IDD-P fenofibrate. A drug interaction between concomitantly administered single doses of IDD-P fenofibrate and ER niacin could not be ruled out.

Absence of Drug Interaction between Oral Moxifloxacin and Intramuscular Morphine Sulfate in Healthy Volunteers

Objective To determine the effects of intramuscular morphine sulfate on the pharmacokinetics of moxifloxacin.

Monotherapy or polytherapy for epilepsy?

Monotherapy has been promoted as the ideal in epilepsy treatment because of reduced side effects, absence of drug interactions, better compliance, lower cost and, in many cases, improved seizure control compared to polytherapy. The question of monotherapy vs. polytherapy has assumed increasing importance with the availability of multiple new antiepileptic drugs (AEDs), initially tested as add-on agents. The new drugs clobazam, lamotrigine, vigabatrin, gabapentin and topiramate, have also been shown to be effective as monotherapy. These data bring up the possibility of using them as first-line agents. However, a high percentage of patients with resistant epilepsy are treated with polytherapy, which probably benefits only a minority of them. The availability of multiple drugs with different mechanisms of action favours the possibility of "rational polytherapy", taking advantage of possible synergism, a yet unproven concept. This article reviews the theoretical advantages of monotherapy and monotherapy with traditional and newer AEDs.

Pantoprazole: a new and more specific proton pump inhibitor

Pantoprazole is the third proton pump inhibitor (PPI) to be launched for the treatment of acid-peptic diseases. Like other drugs in this class, pantoprazole causes long-lasting inhibition of acid secretion by inactivating the parietal cell H+/K+-ATPase. Compared with H2 antagonists, pantoprazole results in faster pain relief, more rapid ulcer healing, healing of resistant ulcers and far greater efficacy in oesophageal reflux disease. The three PPIs currently available display almost identical efficacy in the treatment of acid-peptic diseases and when included as part of Helicobacter pylori eradication regimes. However, pantoprazole shows improvements in selectivity and pharmacokinetic properties compared with omeprazole and lansoprazole. The bioavailability of pantoprazole is considerably higher than omeprazole, remains constant upon repeated dosing, and is unaffected by food. Significantly, pantoprazole does not influence hepatic cytochrome P450 activity and does not therefore interact with co-administered drugs. This is in contrast to omeprazole, which inhibits P450, and lansoprazole, which appears to weakly induce multiple metabolic pathways. Although pantoprazole is entering an antisecretory market dominated by omeprazole and ranitidine, it has a number of potential advantages. In this respect it is worth recalling that enhanced specificity and the absence of drug interactions were decisive factors in determining market share in the H2 antagonist era. Pantoprazole may therefore achieve significant market penetration, particularly at the expense of lansoprazole and the H2 blockers.

Important pharmacokinetic properties of antiepileptic drugs.

The choice of an antiepileptic drug (AED) is guided primarily by efficacy and safety criteria. However, the pharmacokinetic properties of an AED determine its ease of use, i.e., its ability to predictably produce and maintain optimal plasma concentrations. Desirable and clinically important pharmacokinetic properties of an AED include complete or constant bioavailability, slow enteral absorption or availability of a sustained-release formulation, availability of a parenteral formulation for acute treatment, rapid penetration into the brain, a single-compartment volume of distribution, low and nonsaturable protein binding, and linear elimination kinetics, with an elimination half-life of about 24 h. The absence of autoinduction of enzymatic biotransformation, active metabolites, and pharmacokinetic drug interactions is also important. In clinical practice, the most undesirable pharmacokinetic properties are lack of a parenteral formulation, short elimination half-life, nonlinear elimination kinetics, autoinduction of enzymatic biotransformation, and interaction with other drugs. No AED is presently marketed or under development that meets all of the desirable criteria. Some of the newer AEDs, although not "ideal" agents, have pharmacokinetic profiles that are not shared by their predecessors, including elimination exclusively by the kidney, absence of drug interactions, and dose-related bioavailability.

Absence of drug interaction between temafloxacin and low dose heparin.

An open 5-day study was conducted in 12 healthy male volunteers to determine the potential for drug interaction between low dose standard heparin and temafloxacin, a new fluorinated quinolone antibiotic. Heparin 5000IU was administered subcutaneously on the morning of the first and last study days and temafloxacin 600mg was administered twice daily for 4 days. The mean change in activated factor X (antifactor Xa) concentration relative to baseline 2h after coadministration was similar to that after heparin alone. Likewise, changes in activated partial prothrombin time, prothrombin time and thrombin time were similar after either heparin alone or concomitant temafloxacin administration, indicating the absence of interaction between temafloxacin and low dose standard heparin in healthy volunteers.

Absence of drug interaction between heparin and nitroglycerin. Randomized placebo-controlled crossover study

Absence of drug interaction between heparin and nitroglycerin. Randomized placebo-controlled crossover study