Undesirable Drug Interactions Research Articles

A road to bring Brij52 back to attention: Shear stress sensitive Brij52 niosomal carriers for targeted drug delivery to obstructed blood vessels

Thrombosis is a shared perpetrating event in the pathophysiology of several cardiovascular disorders such as ischemic stroke, venous thromboembolism, atherosclerosis, and myocardial infarction. Despite holding a wide range of ammunition in our arsenal to ameliorate such conditions, we are still facing with many stumbling blocks in the satisfactory pharmacotherapy of cardiovascular diseases among which the risk of hemorrhage and life threatening drug interactions can be highlighted. Our hypothesis focuses on mimicking the nature of platelet activation, to design a novel targeted delivery system based on the alterations of a physical parameter, the hemodynamic shear stress, to aim at the offending thrombi in an attempt to offer a noninvasive, rapid, and monitoring-free method that not only can prolong the circulation time of the cargo, but also deliver it locally and reduce both the undesirable adverse effects and drug interactions. Brij52 is our chosen candidate due to its unique non-spherical morphology after forming a niosomal vesicle. We surmised that thanks to its non-spherical shape, diverse shear rates may generate different shear stresses to its equators and axes which might result in the breakdown or at least distortion of niosomal structure under elevated shear stress. The vesicles have to be synthesized in the size of platelets or in the nano-sized scale. In order to prolong the time vesicles are circulating in the blood, PEGylation may help and to make such carriers highly selective to be only activated during pathophysiological clot formation, attachment of domain A1 von Willebrand factor can be of benefit to lead this proposed delivery system to the site of thrombus formation where shear rate exceeds those of 1000 s−1. There is now an emerging fast growing universal research on shear activated carriers, and the present theory is an endeavor to reach a successful treatment strategy to combat cardiovascular diseases based on the hypothesis that a non-spherical nano-carrier such as Brij 52 niosomal vesicle can be of paramount benefit to deliver current antithrombotic agents in a targeted and controlled manner in the presence of elevated shear stress of the obstructed blood vessels. With more radical advanced drug delivery systems being developed and new strategies being pursued, there will be more options in our arsenal to represent a promising avenue for achieving preventive, well-tolerated, and intelligent drug carriers to circumvent the drawbacks of antithrombotic pharmacotherapy.

Undesirable effects of polypharmacotherapy in patients with cancer-associated pain treated under palliative care

In patients with pain associated with cancer that is treated as part of palliative care, the most commonly used method is polypharmacotherapy. From the analysis of adverse reactions in this group of patients, it appears that the high incidence of adverse drug reactions occurring in this group of patients is due to the undesired drug interactions. Based on pharmacoepidemiological analysis of pharmacotherapy of 600 patients, 373 cases of adverse drug reactions were identified, with the consequence of adverse drug reactions. The paper presents an analysis of these interactions, identifying their sources and methods of prevention, and discussing their legal aspects.

Enhancement of lung gene delivery after aerosol: a new strategy using non-viral complexes with antibacterial properties.

The pathophysiology of obstructive pulmonary diseases, such as cystic fibrosis (CF), leads to the development of chronic infections in the respiratory tract. Thus, the symptomatic management of the disease requires, in particular, repetitive antibiotherapy. Besides these antibacterial treatments, certain pathologies, such as CF or chronic obstructive pulmonary disease (COPD), require the intake of many drugs. This simultaneous absorption may lead to undesirable drug interactions. For example, Orkambi® (lumacaftor/Ivacaftor, Vertex), a pharmacological drug employed to treat F508del patients, cannot be used with antibiotics such as rifampicin or rifabutin (rifamycin family) which are necessary to treat Mycobacteriaceae. As far as gene therapy is concerned, bacteria and/or biofilm in the airways present an additional barrier for gene transfer. Thus, aerosol administration of nanoparticles have to overcome many obstacles before allowing cellular penetration of therapeutic compounds. This review focusses on the development of aerosol formulations adapted to the respiratory tract and its multiple barriers. Then, formulations that are currently used in clinical applications are summarized depending on the active molecule delivered. Finally, we focus on new therapeutic approaches to reduce possible drug interactions by transferring the antibacterial activity to the nanocarrier while ensuring the transfection efficiency.

Old Friends With New Faces: Are Sodium Channel Blockers the Future of Adjunct Pain Medication Management?

Providers are being asked to decrease the emphasis and overutilization of long-term opioid therapy, but many are left without proper guidance on appropriate utilization of nonopioid therapies. Furthermore, therapeutic options are quite limited and many providers lack confidence in distinguishing available alternatives. When first-line therapy has failed in a patient, there is an apparent lack of knowledge on how to proceed with choosing subsequent therapy. To choose among alternative agents, an understanding of pharmacology, pharmacokinetics, and efficacy in targeting various pain conditions is necessary. This article focuses on the use of the carboxamide class of sodium channel blockers (carbamazepine, oxcarbazepine, eslicarbazepine) for adjunct pain medication management including research updates in pharmacology, pharmacokinetics, and current evidence for pain along with promising areas of research. It is an evidence update for clinical use of sodium channel blockers, clarifies misconceptions regarding their use, and highlights emerging research for improved pain targets that justifies additional study. We performed a complete review of the literature using the search terms, “oxcarbazepine,” “carbamazepine,” and “eslicarbazepine” in conjunction with “pharmacokinetics,” “adverse effects,” “pharmacology,” “voltage-gated sodium channel subtype,” “neuropathic pain,” “inflammatory pain,” “metabolism,” “epoxide metabolite formation,” “drug interactions,” “CYP450 interactions,” “pain phenotype,” and “chronic pain management.” Databases searched included PubMed and Google Scholar. Package inserts were used for drug structure illustration, adverse reactions, and bioavailability. Pharmacology and pharmacokinetic data were taken from randomized controlled trials evaluating this area as well as in vitro published results. For validity, only peer-reviewed literature was included. Evidence for sodium channel blockers in chronic pain management was limited. This review focuses on highlighting the data available for the use of sodium channel blockers for certain pain syndromes as well as underutilized potential. Emerging literature on sodium channel subtypes and their connection to neuropathic, inflammatory, and mechanical pain transmission is elucidated. The authors also scrutinize literature surrounding the pharmacokinetics of oxcarbazepine and eslicarbazepine to provide clearer guidance to the significance of any drug interactions and refute assumptions made on the basis of structural similarity to carbamazepine and its known undesirable drug interactions. Side effect profiles are outlined and compared, emphasizing the differences between agents. Sodium channel blocker doses used in certain pain syndromes are outlined with a call for further research to better understand their place in chronic pain management. Identification of sodium channel subtypes with links to specific pain conditions and the ability to target them hints at the potential for truly individualized therapy. Sodium channel inhibitors are underutilized on the basis of available evidence, and emerging research has identified this area as promising for additional clinical trials to better guide clinical practice. PerspectiveThis article provides a review of the pharmacology, evidence for pain management, and pharmacokinetics of oxcarbazepine, carbamazepine, and eslicarbazepine. There is a disparity in evidence using sodium channel blockers for pain and this article highlights the potential that is currently underutilized. The authors believe this will catalyze interest for further studies.

Prevalence and Associated Factors of Regular Nonsteroidal Anti-inflammatory Drugs used in a Rural Community, Thailand

BACKGROUND: In Thailand, 67.2% of the population widely uses analgesics including nonsteroidal anti-inflammatory drugs (NSAIDs), which may lead to serious side effects. However, the information of regular NSAIDs used in Thailand is still limited.METHODS: A mixed method cross-sectional study was conducted. Quantitative data were collected using questionnaires to determine the prevalence and factors associated with regular NSAID use. The qualitative study was conducted using group and in-depth interviews to determine the knowledge, attitudes and practices of NSAID users.RESULTS: Of 771 participants, the prevalence of NSAID use was 31.1 and regular NSAID use was 7.4. Age, pain at the hips or thighs and pain score were independent factors associated with regular NSAID use. The qualitative study indicated that the use of NSAIDs was influenced by drug effectiveness, sources of NSAIDs and consideration of benefits and risks of the drugs.CONCLUSION: This was the first report on the prevalence and associated factors of regular NSAID use in Thailand. In this community, nonprescribed NSAIDs might cause some serious side effects and undesirable drug interaction. Information on side effects of pain medications should be disseminated to the public including guidelines on how to use pain medications.

Effects of frequently used pharmaceutical excipients on the organic cation transporters 1–3 and peptide transporters 1/2 stably expressed in MDCKII cells

There is ample evidence that pharmaceutical excipients, which are supposed to be pharmacologically inactive, have an impact on drug metabolism and efflux transport. So far, little is known whether they also modulate uptake transporter proteins. We have recently shown that commonly used solubilizing agents exert significant effects on the function of organic anion uptake transporting polypeptides. Therefore, we investigated in this study the influence of frequently used pharmaceutical excipients on the transport activity of organic cation transporters OCT1, OCT2 and OCT3 and the peptide transporters PEPT1 and PEPT2.Inhibition of the OCTs and PEPTs by the excipients polyethylene glycol 400 (PEG), hydroxypropyl-β-cyclodextrin (HPCD), Solutol® HS15 (SOL), Cremophor® EL (CrEL), Tween® 20 (Tw20), Tween® 80 (Tw80), Kolliphor® P188 (P188) and Kolliphor® P407 (P407) was evaluated using stably transfected MDCKII cells with radio-labeled reference substrates and established inhibitors as controls. Intracellular accumulation of [3H]-1-methyl-4-phenylpyridinium (MPP+) for the OCTs and [3H]-glycyl-sarcosine (Gly-Sar) for the PEPTs was measured by liquid scintillation counting after cell lysis.Our studies revealed that PEG, HPCD, SOL, CrEL, Tw20 and Tw80 were potent inhibitors of OCT1-3 (e.g., Tw20 IC50 values<0.04%). Cellular uptake of Gly-Sar by PEPT1 and PEPT2 was strongly inhibited by both Tw20 and Tw80. SOL was also a strong inhibitor of PEPT1 and PEPT2 (e.g., SOL IC50 values<0.02%), while CrEL showed significantly inhibition of only PEPT2. The substantial inhibitory effects of certain solubilizing agents on OCTs and PEPTs should be considered if they are to be used in dosage forms for new chemical entities and registered drugs to avoid misinterpretation of pharmacokinetic data and undesired drug interactions.

The effect of antibacterial and non-antibacterial compounds alone or associated with antifugals upon fungi.

During the last 30 years the incidence of fungal infections has increased dramatically. While the antifungal therapeutic options available are somewhat reduced, most pathogenic microorganisms have an incredible capacity to mutate and acquire resistance. In addition, multiple drugs are often required concomitantly to manage clinically complex disorders. The combination of antibiotics or other compounds with antifungal drugs, simultaneously or sequentially, is commonly adopted in clinical practice, although without a full knowledge of the consequences. Thus, the role of combined therapy and the effect of antibiotics upon fungal growth promotion need to be critically evaluated and understood in order to avoid undesirable drug interactions. With this review we intend discuss the studies that report about antibiotics inhibiting fungal growth, as well as studies describing the synergistic effect of the combined therapy, i.e., associations between antibiotics or other compounds with antifungal drugs. Alternative therapeutic protocols for fungal disease could be designed, taking advantage of such drug combinations. Critical revision of previously published data is crucial in order to define future research strategies.

Topical issues of the efficiency and safety of using the first direct thrombin inhibitor in real clinical practice

A Regional Expert Council meeting was held in Moscow on August 21, 2015 to consider different aspects of the efficiency and safety of using the first direct thrombin inhibitor dabigatran etexilate in real clinical practice. The complex and debatable issues of prevention of systemic thromboembolic events in patients with non-valvular atrial fibrillation (AF) were the focus of attention. Five-year clinical use of dabigatran etexilate was noted to confirm its positive safety and efficacy profiles in real practice in more than 250,000 patients from nearly 100 countries of the world. The risk of ischemic stroke, intracerebral bleeding, and death was shown to be statistically significantly lower in the dabigatran group than in the warfarin group. The rate of major bleeding and myocardial infarction was comparable or even lower. An increased risk for bleeding was generally associated with undesirable drug interactions, polypragmasia, and underestimated kidney dysfunction. Renal function was recorded to decrease statistically less significantly in diabetic patients receiving dabigatran 150 mg twice daily than in those treated with warfarin. It was particularly emphasized that direct oral anticoagulants along with warfarin as fist-line agents might be used in patients with AF and acute coronary syndrome. It has been concluded that rich international experience with clinically used dabigatran provides support for a favorable benefit/risk ratio if all dosage guidelines are followed.

Diindolylmethane, a naturally occurring compound, induces CYP3A4 and MDR1 gene expression by activating human PXR

Activation of human pregnane X receptor (hPXR)-regulated expression of cytochrome P450 3A4 (CYP3A4) and multidrug resistance protein 1 (MDR1) plays an important role in mediating adverse drug interactions. Given the common use of natural products as part of adjunct human health behavior, there is a growing concern about natural products for their potential to induce undesired drug interactions through the activation of hPXR-regulated CYP3A4 and MDR1. Here, we studied whether 3,3′-diindolylmethane (DIM), a natural health supplement, could induce hPXR-mediated regulation of CYP3A4 and MDR1 in human hepatocytes and intestinal cells. DIM, at its physiologically relevant concentrations, not only induced hPXR transactivation of CYP3A4 promoter activity but also induced gene expression of CYP3A4 and MDR1. DIM decreased intracellular accumulation of MDR1 substrate rhodamine 123, suggesting that DIM induces the functional expression of MDR1. Pharmacologic inhibition or genetic knockdown of hPXR resulted in attenuation of DIM induced CYP3A4 and MDR1 gene expression, suggesting that DIM induces CYP3A4 and MDR1 in an hPXR-dependent manner. Together, these results support our conclusion that DIM induces hPXR-regulated CYP3A4 and MDR1 gene expression. The inductive effects of DIM on CYP3A4 and MDR1 expression caution the use of DIM in conjunction with other medications metabolized and transported via CYP3A4 and MDR1, respectively.

Inhibitory Effects of Spirulina platensis on Carcinogen-Activating Cytochrome P450 Isozymes and Potential for Drug Interactions

Spirulina platensis (SP) has been considered as potential food source of 21st century due to its remarkable nutrient profile and therapeutic benefits. However, the cytochrome P450 (CYP)-mediated drug/chemical interaction potential of SP has not yet been pursued. We investigated the effects of SP on the expressions and enzymatic activities of main CYP isozymes. After the rats were orally administered with SP daily for 5 consecutive weeks, there were significant downregulations in hepatic expression levels and inhibition in enzymatic activities of CYP1A2 and CYP2E1 compared to controls. In addition, a significant decrease was observed in CYP2C6-associated enzyme activity with no remarkable changes in messenger RNA (mRNA)/protein levels. The SP application resulted in significant increases in mRNA/protein levels of both CYP2B1 and CYP3A1 without a significant change in enzyme activities. These findings partly explain the chemopreventive properties of SP toward various organ toxicities, mutagenesis, and carcinogenesis; however, its coadministration with some CYP substrates may lead to undesirable drug interactions.

Self-Nanoemulsifying Drug Delivery System of Lutein: Physicochemical Properties and Effect on Bioavailability of Warfarin

Objective of present study was to prepare and characterize self-nanoemulsifying drug delivery system (SNEDDS) of lutein and to evaluate its effect on bioavailability of warfarin. The SNEDDS was prepared using an oil, a surfactant, and co-surfactants with optimal composition based on pseudo-ternary phase diagram. Effect of the SNEDDS on the bioavailability of warfarin was performed using Sprague Dawley rats. Lutein was successfully formulated as SNEDDS for immediate self-emulsification and dissolution by using combination of Peceol as oil, Labrasol as surfactant, and Transcutol-HP or Lutrol-E400 as co-surfactant. Almost complete dissolution was achieved after 15 min while lutein was not detectable from the lutein powder or intra-capsule content of a commercial formulation. SNEDDS formulation of lutein affected bioavailability of warfarin, showing about 10% increase in Cmax and AUC of the drug in rats while lutein as non-SNEDDS did not alter these parameters. Although exact mechanism is not yet elucidated, it appears that surfactant and co-surfactant used for SNEDDS formulation caused disturbance in the anatomy of small intestinal microvilli, leading to permeability change of the mucosal membrane. Based on this finding, it is suggested that drugs with narrow therapeutic range such as warfarin be administered with caution to avoid undesirable drug interaction due to large amount of surfactants contained in SNEDDS.

Oral treatment with etoposide in small cell lung cancer – dilemmas and solutions

BackgroundEtoposide is a chemotherapeutic agent, widely used for the treatment of various malignancies, including small cell lung cancer (SCLC), an aggressive disease with poor prognosis. Oral etoposide administration exhibits advantages for the quality of life of the patient as well as economic benefits. However, widespread use of oral etoposide is limited by incomplete and variable bioavailability. Variability in bioavailability was observed both within and between patients. This suggests that some patients may experience suboptimal tumor cytotoxicity, whereas other patients may be at risk for excess toxicity.ConclusionsThe article highlights dilemmas as well as solutions regarding oral treatment with etoposide by presenting and analyzing relevant literature data. Numerous studies have shown that bioavailability of etoposide is influenced by genetic, physiological and environmental factors. Several strategies were explored to improve bioavailability and to reduce pharmacokinetic variability of oral etoposide, including desired and undesired drug interactions (e.g. with ketoconazole), development of suitable drug delivery systems, use of more water-soluble prodrug of etoposide, and influence on gastric emptying. In addition to genotype-based dose administration, etoposide is suitable for pharmacokinetically guided dosing, which enables dose adjustments in individual patient.Further, it is established that oral and intravenous schedules of etoposide in SCLC patients do not result in significant differences in treatment outcome, while results of toxicity are inconclusive. To conclude, the main message of the article is that better prediction of the pharmacokinetics of oral etoposide may encourage its wider use in routine clinical practice.

A major constituent from Zanthoxylum nitidum, compound X, is a naturally occurring antagonist of the human and rat pregnane X receptor

Discrepancy expression and regulation of drug‐metabolizing enzymes (DMEs) is a common cause of adverse drug effects in some drugs with narrow therapeutic index (TI). A important cytochrome P450 3A4 (CYP3A4) is predominantly regulated by a nuclear receptor, pregnane X receptor (PXR). A pure compound isolated from Zanthoxylum nitidum, compound X, exhibits variety of biological functions, however the effect of compound X on the modulation of CYP3A4 is not well understood. In this study, the effects of compound X on the PXR‐CYP3A4 pathway, and the underlying mechanisms, were characterized. Compound X potently and dose‐dependently attenuated CYP3A4 induction by blocking the activation of nuclear receptors, especially PXR. Further mechanistic studies revealed that compound X inhibited PXR by interrupting the binding of steroid receptor cofactor‐1 (SRC‐1) and hepatocyte nuclear factor 4α (HNF4α). Our results may lead to the development of important new therapeutic and dietary approaches to reduce the frequency of undesirable drug interactions. Here, we established compound X as a novel and natural potent inhibitor of PXR and can be a useful tools for modulating DME expression and drug efficacies. Modification of CYP3A4 expression and activity by consumption of compound X could have important implications for drug safety.

Challenges and opportunities for hepatitis C drug development in HIV–hepatitis C virus-co-infected patients

The approval of the first direct-acting antivirals (DAAs) against the hepatitis C virus (HCV) has been eagerly expected for treating chronic hepatitis C in HIV individuals given that progression to cirrhosis and end-stage liver disease occurs faster in the co-infected population. The appropriate and judicious use of DAAs may provide cure to a large number of HIV-HCV patients. On the contrary, the widespread use of DAAs will occasionally be off-label or under unsatisfactory medical conditions, which may result in undesirable toxicities, drug interactions or selection of drug resistance in HCV. As a result of using first-generation DAAs in HIV-HCV-co-infected patients, a growing proportion of the remaining hepatitis C individuals will be those harboring non-HCV 1 genotypes or drug-resistant HCV variants. Over time, the largest reservoir of HCV genotype 1 patients will accumulate in resource-poor nations where access to hepatitis C therapy has been elusive and HIV treatment remains the primary health issue for the co-infected population.

Use of Medicines Among a Brazilian Elderly Sample: A Cross-sectional Study

The use of multiple medicines is very frequent among the elderly, allowing them to perceive more often adverse side effects from drugs and present undesirable drug interactions. This article presents a cross-sectional survey about the use of medicines among 300 elderly Brazilians, equally divided into institutionalized and community-dwelling groups. The average daily intake of medicines is 3.2 among institutionalized elderly, a higher ( p < 0.001) number when compared with community-dwelling elderly, who takes an average of 1.8 medicines daily. The most commonly used medications are antihypertensives (58.0%), diuretics (23.0%), nonsteroidal anti-inflammatory drugs (22.7%), supplements (21.7%), antidiabetics (16.3%), and antiulcerants (14.0%). Antiulcerants, diuretics, supplements, and central nervous system drugs are more frequently used by institutionalized than by community-dwelling elderly. In this Brazilian elderly sample, the most widely used medicines were antihypertensives, diuretics, and nonsteroidal anti-inflammatory drugs, and institutionalized used more medications than community-dwelling elderly.

P03-60 - Levetiracetam showed lower depression, insomnia and mood instability incidence than phenytoin after supratentorial tumour neurosurgery

BackgroundPhenytoin used to prevent seizures linked to brain cancer neurosurgery has shown many undesirable side effects and drug interactions with chemotherapy.AimTo evaluate the incidence of depression, insomnia, mood instability and early post surgery seizures, after Phenytoin (PHE) vs. Levetiracetam (LEV) monotherapy in patients with brain tumour subjected to a supratentorial brain tumour resection.MethodsA prospective study in patients with supratentorial cancer diagnosis subjected to neurosurgery of resection was done. Patients were consecutive randomized to be treated with PHE (n = 26) 15 ml/kg IV-bolus, 125 mg/8 h IV x48 h, 100 mg/8 h O x7 days or with LEV (n = 34) 500 mg/12 h IV x48 h, 500 mg/12 h O x 7 days. Clinical, histological, TAC, EEG, seizures and undesirable side effects were analyzed.Results and discussion60 patients (53% male, aged 52.5 ± 20 years) with glioblastoma multiform 45%, meningioma 43%, Ewing's sarcoma 6.7%, others 5.3% (size between 3–6 cm, in the right brain site-65.2%, in the frontal lobe-56.2%) were subjected to followed for a week after tumour resection. Undesirable side effects (USE) were (%LEV/%PHE): total (7.3%/31.5%), somnolence (0%/32.8%), headache (6.1%/22.3%), dizziness (0%/25.6%), difficulty with coordination (0%/23.5%), depression (6.2%/18.7%), lack of energy/strength (12.5%/33.8%), insomnia (11.3%/37.9%), mood instability (12.5%/22,6%), leukopenia (0%/16.9%) after surgery (p &lt; 0.05). None of the patients taking Levetiracetam vs. 4 of the patients taking Phenytoin (0% vs. 15.3%) had seizures after surgery (p &lt; 0.05).ConclusionLevetiracetam showed lower depression, insomnia, mood instability and seizures incidence than Phenytoin after supratentorial tumour neurosurgery.

Recent Advances in the Development of P-gp Inhibitors

During the last decades multidrug resistance (MDR) emerged as main problem in the anti-cancer therapy with cytostatically active agents. Classical as well as recently developed cytostatics develop the phenomenon of loosing activity in former drug-sensitive cells. Although MDR is a multifactorial process, the main obstacle is the expression of multidrug-efflux pumps that lowers the intracellular drug levels. P-glycoprotein (P-gp) is the longest identified efflux pump. As the attempt to overcome MDR by the use of inhibitors of the efflux pump activities turned out as most promising effect, the development of P-gp inhibitors has been a challenge for medicinal chemists. The article reviews the advances in P-gp inhibitor development by focussing on structure-activity relationships in the different compound classes to document improvements. The success has been the reduction of cytotoxic properties. The undesired activities could be much lowered in the case of compound classes that were derived from pharmacologically active drugs. Undesired drug interactions and limited in vivo activities are still a problem.

Safety and feasibility of switching from phenytoin to levetiracetam monotherapy for glioma-related seizure control following craniotomy: a randomized phase II pilot study

Seizures are common in patients with gliomas, and phenytoin (PHT) is frequently used to control tumor-related seizures. PHT, however, has many undesirable side effects (SEs) and drug interactions with glioma chemotherapy. Levetiracetam (LEV) is a newer antiepileptic drug (AED) with fewer SEs and essentially no drug interactions. We performed a pilot study testing the safety and feasibility of switching patients from PHT to LEV monotherapy for postoperative control of glioma-related seizures. Over a 13-month period, 29 patients were randomized in a 2:1 ratio to initiate LEV therapy within 24 h of surgery or to continue PHT therapy. 6 month follow-up data were available for 15 patients taking LEV and for 8 patients taking PHT. In the LEV group, 13 patients (87%) were seizure-free. In the PHT group, 6 patients (75%) were seizure-free. Reported SEs at 6 months was as follows (%LEV/%PHT group): dizziness (0/14), difficulty with coordination (0/29), depression (7/14) lack of energy or strength (20/43), insomnia (40/43), mood instability (7/0). The pilot data presented here suggest that it is safe to switch patients from PHT to LEV monotherapy following craniotomy for supratentorial glioma. A large-scale, double-blinded, randomized control trial of LEV versus PHT is required to determine seizure control equivalence and better assess differences in SEs.

Invasive fungal infections in lung transplantation: role of aerosolised amphotericin B

Immunocompromised patients, especially solid organ transplant (SOT) and hematopoietic stem cell transplant recipients, have a high morbidity and mortality rate as a result of invasive fungal infections (IFIs). Therefore, effective and correct prophylaxis of these IFIs continues to be an important issue in these patient populations. Fungal infections in the lung are most often due to Aspergillus spp., but other non- Aspergillus moulds such as Mucor spp. can also cause pulmonary infections. Lung transplant recipients have the highest incidence of invasive aspergillosis of all SOT patients. Prophylaxis should consider the risk factors affecting each group of patients. As the lung is the target organ of most fungal infections due to moulds, aerosolised antifungal prophylaxis has been potentially considered to be a safe and effective strategy. Administration of a nebulised antibiotic achieves high local concentration of the drug, avoiding undesirable systemic effects and drug interactions. The use of aerosolised amphotericin B (AmB) as prophylaxis or co-adjuvant treatment for pulmonary fungal infections has been reported in several groups of immunosuppressed patients. Lipid formulations of AmB penetrate the lung better and have a longer half-life than amphotericin B deoxycholate (ABD). Prophylaxis with aerosolised lipid-based AmB products has several advantages over ABD: it can be administered at much longer intervals and is equally effective and better tolerated. Although several studies have been published using aerosolised AmB both as deoxycholate and lipid formulations, available data remain inconclusive owing a lack of standardisation of administration procedures and doses.

CHARACTERIZATION OF HUMAN CYTOCHROME P450 ENZYMES INVOLVED IN THE METABOLISM OF THE PIPERIDINE-TYPE PHENOTHIAZINE NEUROLEPTIC THIORIDAZINE

The aim of the present study was to identify human cytochrome P450 enzymes (P450s) involved in mono-2-, di-2-, and 5-sulfoxidation, and N-demethylation of the piperidine-type phenothiazine neuroleptic thioridazine in the human liver. The experiments were performed in vitro using cDNA-expressed human P450s (Supersomes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4), liver microsomes from different donors, and P450-selective inhibitors. The results indicate that CYP1A2 and CYP3A4 are the main enzymes responsible for 5-sulfoxidation and N-demethylation (34-52%), whereas CYP2D6 is the basic enzyme that catalyzes mono-2- and di-2-sulfoxidation of thioridazine in human liver (49 and 64%, respectively). Besides CYP2D6, CYP3A4 contributes to a noticeable degree to thioridazine mono-2-sulfoxidation (22%). Therefore, the sulforidazine/mesoridazine ratio may be an additional and more specific marker than the mesoridazine/thioridazine ratio for assessing the activity of CYP2D6. In contrast to promazine and perazine, CYP2C19 insignificantly contributes to the N-demethylation of thioridazine. Considering serious side-effects of thioridazine and its 5-sulfoxide (cardiotoxicity), as well as strong dopaminergic D2 and noradrenergic alpha1 receptor-blocking properties of mono-2- and di-2-sulfoxides, the obtained results are of pharmacological and clinical importance, in particular, in a combined therapy. Knowledge of the catalysis of thioridazine metabolism helps to choose optimum conditions (a proper coadministered drug and dosage) to avoid undesirable drug interactions.