Concurrent Drug Administration Research Articles

Ultrasensitive response explains the benefit of combination chemotherapy despite drug antagonism.

Most aggressive lymphomas are treated with combination chemotherapy, commonly as multiple cycles of concurrent drug administration. Concurrent administration is in theory optimal when combination therapies have synergistic (more than additive) drug interactions. We investigated pharmacodynamic interactions in the standard 4-drug 'CHOP' regimen in Peripheral T-Cell Lymphoma (PTCL) cell lines and found that CHOP consistently exhibits antagonism and not synergy. We tested whether staggered treatment schedules could improve tumor cell kill by avoiding antagonism, using in vitro models of concurrent or staggered treatments. Surprisingly, we observed that tumor cell kill is maximized by concurrent drug administration despite antagonistic drug-drug interactions. We propose that an ultrasensitive dose response, as described in radiology by the linear-quadratic (LQ) model, can reconcile these seemingly contradictory experimental observations. The LQ model describes the relationship between cell survival and dose, and in radiology has identified scenarios favoring hypofractionated radiation - the administration of fewer large doses rather than multiple smaller doses. Specifically, hypofractionated treatment can be favored when cells require an accumulation of DNA damage, rather than a 'single hit', in order to die. By adapting the LQ model to combination chemotherapy and accounting for tumor heterogeneity, we find that tumor cell kill is maximized by concurrent administration of multiple drugs, even when chemotherapies have antagonistic interactions. Thus, our study identifies a new mechanism by which combination chemotherapy can be clinically beneficial that is not contingent on positive drug-drug interactions.

Alternating WEE1-PARP Blockade: High Potential.

Alternating treatment with the WEE1 inhibitor adavosertib and the PARP inhibitor olaparib helps control the growth of cancers with DNA repair defects with less toxicity than concurrent drug administration, according to data from a phase Ib trial presented at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

Mechanisms of opioid-induced respiratory depression.

Opioid-induced respiratory depression (OIRD), the primary cause of opioid-induced death, is the neural depression of respiratory drive which, together with a decreased level of consciousness and obstructive sleep apnea, cause ventilatory insufficiency. Variability of responses to opioids and individual differences in physiological and neurological states (e.g., anesthesia, sleep-disordered breathing, concurrent drug administration) add to the risk. Multiple sites can independently exert a depressive effect on breathing, making it unclear which sites are necessary for the induction of OIRD. The generatorof inspiratoryrhythm is the preBötzinger complex (preBötC) in the ventrolateral medulla. Other important brainstem respiratory centres includethe pontine Kölliker-Fuse and adjacent parabrachial nuclei (KF/PBN) in the dorsal lateral pons, and the dorsal respiratory group in the medulla. Deletion of μ opioid receptors from neurons showed that the preBötC and KF/PBN contribute to OIRD with the KF as a respiratory modulator and the preBötC as inspiratory rhythm generator. Glutamatergic neurons expressing NK-1R and somatostatin involved in the autonomic function of breathing, and modulatory signal pathways involvingGIRK and KCNQ potassium channels, remain poorly understood. Reversal of OIRD has relied heavily on naloxone which also reverses analgesia but mismatches between the half-lives of naloxone and opioids can make it difficult to clinically safely avoid OIRD. Maternal opioid use, which is rising, increases apneas and destabilizes neonatal breathing but opioid effects on maternal and neonatal respiratory circuits in neonatal abstinence syndrome (NAS) are not well understood. Methadone, administered to alleviate symptoms of NAS in humans, desensitizes rats to RD.

Influence of exposure to microbial ligands, immunosuppressive drugs and chronic kidney disease on endogenous immunomodulatory gene expression in feline adipose-derived mesenchymal stem cells.

Feline autologous mesenchymal stem cells (MSCs) show promise for immunomodulatory activity, but the functional impact of chronic kidney disease (CKD), concurrent immunosuppressive drug administration or infection is unknown. The study objectives compare endogenous cytokine gene expression (interleukin [IL]-6, IL-10, IL-12p40, IL-18 and transforming growth factor beta [TGF-β]) in adipose-derived MSCs (aMSCs) from cats with and without CKD, following in vitro exposure to microbial ligands and treatment with common immunosuppressive drugs. Previously obtained aMSCs, phenotype CD44+, CD90+, CD105+ and MHCII-, from cats with (n = 6) and without (n = 6) CKD were compared via real-time PCR (RT-PCR) for immunomodulatory gene expression. aMSCs were exposed in vitro to lipopolysaccharide (LPS), peptidoglycan or polyinosinic:polycytidylic acid (Poly I:C), simulating bacterial or viral exposure, respectively. aMSCs were also exposed to ciclosporin, dexamethasone or methotrexate. Gene expression was measured using RT-PCR, and Cq was utilized after each run to calculate the delta cycle threshold. aMSCs isolated from healthy and CKD cats showed no significant differences in gene expression in the five measured cytokines. No significant changes in measured gene expression after drug treatment or microbial ligand stimulation were observed between normal or CKD affected cats. Proinflammatory genes (IL-6, IL-12p40 and IL-18) showed altered expression in aMSCs from both groups when compared with the same cells in standard culture after exposure to methotrexate. Poly I:C altered IL-6 and TGF-β gene expression in aMSCs from both healthy and CKD cats when compared with the same cells in standard culture. The five genes tested showed no statistical differences between aMSCs from healthy or CKD cats. There was altered cytokine gene expression between the control and treatment groups of both healthy and CKD cats suggesting feline aMSCs have altered function with immunosuppressive treatment or microbial ligand exposure. Although the current clinical relevance of this pilot study comparing brief exposure to select agents in vitro in aMSCs from a small number of cats is unknown, the study highlights a need for continued investigation into the effects of disease and concurrent therapies on use of cell-based therapies in feline patients.

Current Perspectives On The Role Of The Ketogenic Diet In Epilepsy Management.

Drug-refractory epilepsy is a commonly prevalent pediatric neurological illness of global significance. Ketogenic diet (KD) is a time-tested therapeutic modality for refractory epilepsy, which has reemerged as a robust alternative to anti-epileptic pharmacotherapy. There is a growing body of evidence which supports the anti-seizure efficacy, safety profile and feasibility of KD use in childhood epilepsy. In addition, this modality has been recognized to reduce anti-epileptic exposure, improve cognition and behavioral profile of patients as well as improve the quality-of-life of care-givers. Current indications of KD include refractory epilepsy syndromes, selected metabolic disorders (such as pyruvate dehydrogenase deficiency) and a host of varied neurological entities. KD research has broadened the knowledge-base about its mechanisms of action. Four types of KD are in vogue currently with varying nutritional constitution, palatability, administration protocols and comparable efficacy. KD initiation and maintenance are the result of concerted effort of a team of pediatric neurologist/epileptologist, nutritionist and patient’s primary care-giver. Consensus is being formulated about various practical aspects of KD such as patient-selection, parental counseling, baseline work-up, dietary prescription, nutritional supplementation, concurrent anti-epileptic drug administration, follow-up and treatment-duration. Novel applications of KD include its use in neonatal epilepsy and super-refractory status epilepticus and tailor-made formulations such as cooking oil-based KD in predominantly rice-fed populations. Increasing body of clinical experience, improved nutritional designs and translational research are promoting KD as a major therapeutic modality. Currently, KD forms a core essence in the armamentarium against refractory epilepsy. In this review, we summarize the recent advances and current perspectives in the use of KD in refractory epilepsy.

Effects of a novel selenium substituted-sugar (1,4-anhydro-4-seleno-d-talitol, SeTal) on human coronary artery cell lines and mouse aortic rings

Chronic low-grade inflammation and oxidative damage are strongly associated with pathologies including cardiovascular disease. As a consequence, there is considerable interest in agents that mitigate damage. Selenium compounds can act as potent protective agents against oxidation due to the high reactivity and nucleophilicity of the selenium atom. 1,4-Anhydro-4-seleno-d-talitol (SeTal, a novel water-soluble selenium-based sugar) is a potent oxidant scavenger in vitro and in human plasma. Here we show that SeTal is highly stable in solutions that mimic biological fluids and the gastrointestinal tract, and is not rapidly degraded or metabolized unlike some other selenium-containing compounds. SeTal remains intact during extended storage, and it rapidly penetrates into, and effluxes from, primary human coronary artery endothelial and smooth muscle cells, but does not induce loss of metabolic activity, or modulate cell survival and growth rates at concentrations ≤2 mM. Steady-state intracellular concentrations can reach 2–10 μM. SeTal affords protection against H2O2- and HOCl-mediated oxidative damage, with this being independent of the concentration or activities of the selenium-dependent protective enzymes TrxR and GPx. Protection was observed with both concurrent drug and oxidant administration and also (to a lesser extent) with cellular pre-loading. SeTal also affords protection to isolated arterial segments, with the compound decreasing HOCl (50 μΜ) mediated effects on aortic ring relaxation, consistent with the preservation of NO bioavailability. The stability, bioavailability and protective actions of this compound, suggest that it is worthy of further investigation as a protective agent, particularly in the area of cardiovascular disease.

Efficacy of fluoxetine for canine behavioral disorders

The objectives of this retrospective descriptive study were to compare the efficacy of fluoxetine in conjunction with a behavior modification plan for the treatment of common canine behavioral disorders, and to compare the effects of other factors, including patient sex, fluoxetine dosage, and concurrent drug administration. Owners of all dogs prescribed fluoxetine through the Animal Behavior Clinic at the Cornell University Hospital for Animals in Ithaca, NY, between June 15th, 2012, and December 31st, 2016, were queried regarding their dogs’ behavior after prescription of fluoxetine. Behavioral diagnosis, fluoxetine dosage, concurrently administered psychoactive medications, sex, and response to fluoxetine for each dog were recorded. Of the 134 owners contacted, 93 responded. Eighty-eight dogs met inclusion criteria and were included in the study. Overall, 59% of owners reported that their dogs showed improvement, 32% reported no appreciable response, and 9% reported negative responses. Behavioral diagnoses were grouped into three categories: “Anxiety”, “Aggression”, and “Other” (which included compulsive/obsessive-compulsive behavior and self-mutilation). Most dogs in each category of diagnosis responded positively to treatment: 69% of dogs diagnosed with “Anxiety”, 55% of dogs diagnosed with “Aggression”, and 50% of dogs with a diagnosis of “Other”. A negative response to treatment was reported in 0% of dogs with a diagnosis of “Anxiety”, 13% of dogs diagnosed with “Aggression”, and 0% of dogs with a diagnosis of “Other”. More dogs prescribed fluoxetine at a daily dose of 0.5–0.99 mg/kg and 1.0–1.49 mg/kg responded positively to treatment (63% and 64%, respectively) than did dogs prescribed fluoxetine at 1.5–1.99 mg/kg daily (31%). Sixty-seven percent (N = 14/21) of dogs prescribed only trazodone in addition to fluoxetine and 63% (N = 5/8) of dogs prescribed only clonidine concurrently with fluoxetine responded positively to treatment, as compared with 59% (N = 23/39) of dogs prescribed fluoxetine as the sole agent. However, this difference was not significant. There was no significant effect of sex on treatment efficacy (Pearson chi square; [χ2 = 0.000; P = 0.999]). Sixty-eight percent (N = 19/28) of spayed females responded positively to treatment and 14% (N = 4/28) responded negatively, whereas 55% (N = 31/56) of castrated males responded positively and 9% (N = 5/56) responded negatively, a nonsignificant difference (Pearson chi square; (χ2 = 2.990; P = 0.224). Limitations of this study included its retrospective nature, number of owners who responded (N = 93; 66%) owner recall bias, and lack of control group (i.e., dogs with the same behavioral disorders that were not prescribed fluoxetine).

Concurrent intravenous drug administration to critically ill children: Evaluation of frequency and compatibility

PurposeTo evaluate the frequency of concurrent drug administration and drug-drug incompatibility of concurrently administered drugs in critically ill children based on available references. Materials and methodsWe retrospectively evaluated concurrent intravenous drug administration in children admitted to a single centre. Eligible patients included those admitted to the critical care unit for at least 6-hours in the ten-year period ending 30 July 2015 and received two or more IV drug administrations. Compatibilities were classified using local reference documents. ResultsThe 16,863 eligible patients were admitted to ICU for 2,212,326h and received 3,664,667 concurrent administrations. Concurrent infusions ran for 6,263,600h. There were 2,284,066 (62%) concurrent administrations; 334,144 (9%) were compatible, 293,856 (8%) were incompatible, 293,856 (8%) required pharmacist consultation, and 752,601 (21%) had ‘unknown’ compatibility. Individual patients received a median (IQR) of 33 (10−132) concurrent administrations, comprised of 7 (1−30) concurrent injections 1 (0–5) concurrent infusions and 13 (0–74) concurrently administered injections and infusions. ConclusionsConcurrent IV-drug administration is frequent in critically ill children. Known incompatible concurrent administration occurs, however the compatibilities of many drug-drug pairs were unknown - adding complexity to routine bedside management and identifying information gaps for future research.

A questionnaire study to bridge the gap in teaching and prescribing of analgesics by dentists

This study focus on the current trend of prescribing of non-steroidal anti-inflammatory drug at a tertiary care teaching dental hospital in Jaipur. After taking permission from the Institutional Ethical Committee, this questionnaire study was carried out with the final year and intern students at tertiary care centre. Our study revealed paracetamol (41.4%) as the commonly prescribed analgesics followed by ibuprofen (24.5%). More than 60% of the respondents had good knowledge of contraindications to the use of these analgesics. Respondent’s knowledge regarding drug-drug interactions was fair. More than 70% were aware of interactions of diuretics and non-steroidal anti-inflammatory drugs, while about 95% correctly recognized the interaction of these analgesics with corticosteroids. Our study highlights the importance of knowledge of concurrent drug administration by the dentists to prevent adverse drug events.

Adverse effects of rifampicin in dogs and serum alanine aminotransferase monitoring recommendations based on a retrospective study of 344 dogs

Rifampicin has been reported to have potent activity against Staphylococci, including meticillin-resistant Staphylococcus pseudintermedius. There is limited documented information regarding adverse effects and recommendations for serum biochemistry monitoring. The aims of this retrospective study were as follows: (i) to document the occurrence of adverse events in dogs receiving oral rifampicin; (ii) to determine the relationship between adverse events and the dosage/duration of therapy and concurrent medications; and (iii) to report findings associated with changes on serum alanine aminotransferase (ALT). Client-owned dogs. A retrospective review of 344 medical records was carried out. Serum ALT concentrations and adverse effects were recorded and analysed. Correlations between different time intervals (days 0-9, 10-18, 19-27, 28-36 and >36) and serum ALT elevation were compared. Dogs received 2.9-16 mg/kg/day of rifampicin. Adverse events occurred in 16.27% of dogs (56 of 344) and included vomiting (6.97%), anorexia (6.10%) and lethargy (3.77%). Adverse events were significantly more common in dogs concurrently treated with trimethoprim-sulfamethoxazole (P = 0.018), doxycycline (P = 0.044), levothyroxine sodium (P = 0.044), cephalosporins (P = 0.002) and nonsteroidal anti-inflammatories (P < 0.001). Twenty-five of 94 dogs (26.59%) had serum elevations of ALT. These increases were significantly associated with the duration of therapy during two time periods, 19-27 days (P = 0.04) and >36 days (P = 0.01). Significant adverse events were noted in association with concurrent drug administration and with serum ALT elevations. Pretreatment and weekly serum biochemistry monitoring is recommended to identify dogs at risk for hepatotoxicosis.

A retrospective study of antipsychotic drug switching in a pediatric population

BackgroundAntipsychotic drugs can be used to help treat a wide variety of psychiatric disorders. However, specific antipsychotic drugs for any particular patient may need to be changed for a number of different reasons, including a lack of therapeutic efficacy and / or intolerance to medication side-effects. Drug switching may occur through a limited number of established patterns. The nature of these changes is not well characterized in youth, despite their frequent occurrence.MethodsA retrospective analysis of antipsychotic drug switches was conducted on patients who had been admitted as inpatients to a tertiary care child and adolescent psychiatric institute. PharmaNet (a large, central administrative database) records of all medications prescribed in the 52 weeks prior to admission, and then between admission and discharge, were analyzed for switching patterns. Additional data regarding diagnoses were obtained from medical chart review.ResultsPatients represented a diagnostically heterogeneous population, and almost all antipsychotic drugs were administered off-label. In the one year prior to and during admission to the hospital, a total of 31 out of 139 patients switched antipsychotic drugs. The frequency of switching increased closer to the time of admission, and the proportional rate of switching was even higher during hospital stay. The most common switch was from risperidone to quetiapine. Our analysis identified three main patterns of drug switching, all occurring with similar frequency: titrated drug switches, abrupt drug switches and concurrent drug administration.ConclusionsThe present study indicates that antipsychotic drug switching in youth may be relatively common, particularly in the year prior to hospitalization. No specific manner of drug switching predominates. This study also demonstrates the feasibility of using large administrative databases to characterise switching patterns in youth.

Evaluation of a new analyser for rapid measurement of blood propofol concentration during cardiac surgery

We report laboratory and clinical evaluations of a blood propofol concentration analyser. Laboratory experiments used volunteer blood spiked with known propofol concentrations over the clinically relevant concentrations from 0.5 to 16 μg.ml(-1) to assess linearity and the influence of haematocrit and concurrent drug administration. Analyser concentrations demonstrated excellent linearity (R(2) = 0.999). Blood spiked with commonly used drugs showed no significant variation compared to unspiked controls. Propofol measurements were largely independent of haemoglobin concentration. A 6% decay in propofol concentration was observed at the highest prepared concentration. Clinical performance of the analyser was assessed using 80 arterial blood samples from 72 patients receiving propofol infusions during cardiac surgery. Samples were processed using the propofol analyser, and high performance liquid chromatography (HPLC) used as a gold-standard comparator. These data demonstrated excellent agreement between the propofol analyser and HPLC with a bias of 0.13 μg.ml(-1) and precision of -0.16 to 0.42 μg.ml(-1).

Inappropriate line use within the in-patient parenteral nutrition population: frequency & usage

IntroductionIn June 2010, the National Confidential Enquiry into Patient Outcome and Death published ‘A Mixed Bag: an enquiry into the care of in-patients receiving parenteral nutrition’ (PN). This study found...

Genome-wide transcription analysis of interaction between the human macrophage and Mycobacterium tuberculosis during concurrent drug administration by conventional and novel methods

AbstractTargeted drug delivery to alveolar macrophages harboring Mycobacterium tuberculosis (Mtb) holds promise of high efficacy against pulmonary tuberculosis (TB). It was investigated whether inhalable microparticles (MP) can rescue macrophages from ‘alternative’ activation induced by pathogenic Mtb in addition to achieving targeted drug delivery. A genome-wide transcription analysis (Affymetrix HG-U133 Plus 2.0 DNA microarray) of THP-1 cell line derived macrophages was undertaken after exposing them to infection with 10 MOI of MTB H37Rv at 0, 12 and 24 hours post infection. The Molecular markers of macrophage bactericidal activity were assayed in THP-1- and primary human peripheral blood mononuclear cell (PBMC)-derived macrophages, in the presence or absence of soluble anti-tuberculosis drugs, drug-containing MP and blank MP. About 1,500 genes were differentially upregulated and about 500 genes differentially downregulated in response to various modes of treatment. Variations were also observed in the kinetics of gene expression. Cluster analysis indicated activation of several pathways related to innate immune response (cytokines, chemokines, receptors and ligands), apoptosis, cytoskeleton and membrane remodeling, general metabolism and general housekeeping. Some of these results were validated at the functional level, by studying caspase activities, concentrations and time-courses of effector molecules , rates/extents of apoptosis and nitrite oxide induction. Production of cytokines and NO, apoptosis, and bacterial survival were studied as pharmacodynamic outcomes. Cytokine responses of THP-1 derived macrophages were estimated. MP reversed suppression of tumor necrosis factor (TNF) induced by infection, and transiently upregulated γ-interferon (IFN-γ). Drug-free MP surprisingly induced IFN-γ, but not TNF. Primary cells responded to MP, regardless of drug content, by upregulation of NO; but THP-1-derived cells did not respond to blank MP. About 19% of infected cells exposed to MP underwent apoptosis as compared to ~11% cells treated with soluble drugs or blank MP. Cell death induced by blank MP was caspase-independent. Only drug-containing MP induced apoptosis through caspase-8 and caspase-9. Bacterial survival after different treatments varied between individuals. In the best case, while untreated infection resulted in survival of 900±141 colony forming units (CFU), treatment with soluble drugs, drug-containing MP and blank MP respectively, reduced CFU counts to 8.5± 0.7, 3±1.4 and 102±138.6. The results suggest a role of the drug delivery system in macrophage activation as a component of therapeutic strategy against TB.

Genome-wide transcription analysis of interaction between the human macrophage and Mycobacterium tuberculosis during concurrent drug administration by conventional and novel methods

Genome-wide transcription analysis of interaction between the human macrophage and Mycobacterium tuberculosis during concurrent drug administration by conventional and novel methods

Concurrent Infusions.

Clarification of the appropriate use of the concurrent drug administration code.

Chemical Compatibility of Depacon® with Medications Frequently Administered by Intravenous Y-Site Delivery in Patients with Epilepsy or Head Trauma

Intravenous Y-site administration of more than one medication through the same in-line catheter is a common practice used in the management of acute seizures. The objective of this study was to determine the compatibility of valproate sodium (Depacon(®); 2 or 20 mg/mL) with 13 medications that are frequently administered to manage seizures or are given to patients with an acute head injury who are at risk for developing post-traumatic epilepsy. The study medications included atracurium, dexamethasone, diazepam, fosphenytoin, lorazepam, magnesium sulfate, mannitol, methyl-prednisolone, midazolam, pentobarbital, phenytoin, ranitidine, and thiopental. Equal volumes of valproate and each of the study drugs were admixed and immediately examined using several physiochemical criteria: Tyndall effect, color and pH change, gas evolution, and particle formation (HIAC/Royco liquid particle counter). Samples were also evaluated using HPLC analysis (C(18) column; methanol/tetrahydrofuran/ phosphate buffer; 44/1/55% v/v, at 1.5 mL/min; 50°C) with UV (190-400 nm) photodiode detection. The valproate peak (220 nm) was quantified by both peak area and height. Samples were analyzed within 5 minutes of admixture and were reassessed at 15 and 30 minutes. With the exception of diazepam, midazolam, and phenytoin, all of the remaining drugs were chemically compatible with valproate, both in 5% Dextrose Injection, USP(D5W) and in 0.9% Sodium Chloride Injection, USP (Normal Saline -NS). None of the compatible medications produced a significant pH change, discernible gas, particle formation, reduced valproate titer by HPLC analysis (coefficient of variability < 1.5%), or the temporal formation of unidentified UV absorbing (190-400 nm) peaks. Intravenous valproate is compatible with most agents employed in seizure management or used in patients at risk for seizures following head injury and is safe for concurrent Y-site drug administration.

Tube Feeding in Mechanically Ventilated Critically Ill Patients: A Prospective Clinical Audit

When and whether early enteral nutrition (EN) benefits critically ill patients is debatable. This prospective clinical audit aimed to evaluate the feasibility of an early EN protocol and to identify factors that may hinder EN delivery in critically ill patients. Thirty-six medical patients with severe respiratory failure under invasive ventilation and scheduled to receive early EN, with a length of ICU stay >72 hours, were included. As asserted by the Society of Critical Care Medicine, 8% of patients were priority 1, 72% priority 2, and 20% priority 3 for intensive therapeutic and vital support interventions. Overall, because of gastrointestinal complications, only 39% of the prescribed EN was administered; only 8 (22%) patients did tolerate EN within the first 48 hours after admission and did achieve their minimum nutritional requirements. The most frequent complication (78%) was high volume of gastric residuals followed by abdominal distention (61%), both associated with hemodynamic instability (HI). Gastrointestinal dysfunction was associated with high Acute Physiologic and Chronic Health Evaluation II score (p = .01), total calorie intake (p = .02), total carbohydrate intake (p = .02), HI (p = .03), malnutrition (p = .04), volume of IV saline (p = .04), and concurrent vasoactive drug administration (p = .05). This audit in extremely severe intensive care patients identified several factors that impair gastrointestinal function and preclude EN at any stage, namely early EN. Nutrition management must take into account concurrent therapies, given their potential interference with nutrition and organ function.

A double-lumen intrathecal catheter for studies of modulation of spinal opiate tolerance

Studies of spinal opioid tolerance frequently employ a spinal infusion model in which a single-lumen intrathecal (IT) catheter is connected to an osmotic mini pump. We have modified this model by developing a double-lumen catheter system that permits continuous delivery of the toleragen to the IT space and allows for examination of the effects of concurrent IT drug administration without interruption of the ongoing infusion. The catheter is constructed of two pieces of PE10 tubing fused to the lumens of a dual-lumen catheter (8 cm) with one PE10 tube used as an infusion line connected to an osmotic pump and the other for injection. The catheter is inserted through the cisterna magna. Most implanted rats (66 out of 73) showed full recovery of motor and sensory function without detectable neurological deficit. The profile of the tolerance development and the response to drug manipulation using the double-lumen catheter are similar to previous findings in the spinal infusion model which used a single-lumen catheter. Most importantly, we demonstrate that concurrent probe drug testing and/or concurrent drug treatment can be achieved without interruption of spinal infusion of morphine. Using the double-lumen catheter model expands the range of possibility for studies of spinal opiate tolerance and spinal drug delivery.

Xanthine oxidase inhibition by allopurinol affects the reliability of urinary caffeine metabolic ratios as markers for N-acetyltransferase 2 and CYP1A2 activities.

To evaluate the in vivo effect of xanthine oxidase (XO) inhibition by allopurinol on the determination of polymorphic N-acetyltransferase 2 (NAT2) and cytochrome P450 1A2 (CYP1A2) with urinary caffeine metabolic ratios. In an open, prospective study involving 21 healthy subjects (eight fast, 13 slow NAT2 acetylators) allopurinol (300 mg perday) was administered orally on trial days 1-8, followed by a wash-out period of 8 days. Urinary caffeine tests (200 mg caffeine p.o.) were performed repetitively. Urine was collected for 8 h and venous blood samples for the determination of allopurinol, oxypurinol and uric acid were drawn. The urinary caffeine metabolites 1-methyluric acid (1MU), 1-methylxanthine (1MX), 1,7-dimethyluric acid (17MU), 1,7-dimethylxanthine (17MX), 5-acetylamino-6-formylamino-3-methyluracil (AFMU), plasma allopurinol and oxypurinol were analysed using high-performance liquid chromatography (HPLC). During XO inhibition by allopurinol, the formation of 1MU from 1MX and therefore the XO ratio 1MU/1MX decreased to 15.9 (1.2)% [mean with (SEM)] of baseline values (P < 0.005). The NAT2 ratio AFMU/1MX decreased likewise to 56.7 (6.3)% (P < 0.005). AFMU/(AFMU + 1MX + 1MU), an alternative NAT2 ratio, remained constant, but the CYP1A2 ratio (AFMU + 1MX + 1MU)/17MU, used to express CYP1A2 activity, transiently increased to 167 (13)% (P < 0.005). The NAT2 phenotype did not influence CYP1A2 and XO ratios or plasma oxypurinol pharmacokinetics. Several caffeine metabolic ratios are commonly used to express the activities of NAT2, CYP1A2 and XO both in healthy volunteers and in polymedicated patients, although their reliability has not been evaluated thoroughly during concurrent drug administration. The findings of this study suggest that NAT2 phenotyping should be performed using the ratio AFMU/(AFMU + 1MX + 1MU) if an XO inhibitor may be present. It also shows that the determination of CYP1A2 activity with caffeine as a metabolic probe is considerably altered under these conditions. Thus, concomitant drug administration may impair the robustness of multiple pathways of the complex caffeine test. This points to the need for alternative probes, designed to assess only the activity of a single enzyme because, in contrast to healthy volunteers, in patients known or unknown drug interactions may often be present.