Effects of the excitatory amino acid transporter subtype 2 (EAAT-2) inducer ceftriaxone on different pain modalities in rat.

Glutamate is the major excitatory amino acid in the mammalian CNS and is involved in transmission of pain together with processes for cognition, memory and learning. In order to terminate glutamatergic neurotransmission and avoid excitotoxic damage, a balanced glutamate homeostasis is of critical importance. The level of glutamate in the synaptic cleft is regulated through the action of five subtypes of excitatory amino acid transporters (EAAT1-5). Ceftriaxone, a ß-lactam, induces EAAT-2 and has proven effect for the treatment of neuropathic pain. This pilot study investigated the effects of ceftriaxone upon acute and inflammatory pain and additionally, the analgesic effect of ceftriaxone after introduction of neuropathic pain. Methods Rats were tested before, during and after treatment of ceftriaxone for changes in response to both mechanical and thermal stimuli, using calibrated von Frey filaments and Hargreaves instrument, respectively. Inflammatory responses were investigated by assessing the response to intra-plantar injections of formalin; lastly, neuropathic pain was introduced using the spinal nerve ligation (SNL) model after which changes in both mechanical and thermal responses were again investigated. Results A significant increase in mechanical withdrawal threshold was observed following acute pain inducement in ceftriaxone treated rats. A marked increase in thermal withdrawal latency was also observed. In response to intra plantar administered formalin, ceftriaxone delayed the intensity of nocifensive behaviours. Applying the SNL model of neuropathic pain on naive rats created significant mechanical allodynia, but only a negligibly different response to thermal stimulation. After treatment with ceftriaxone the treated rats developed a hypoalgesic response to thermal stimulation, whilst the response to mechanical pain was insignificant. Conclusion In conclusion, ceftriaxone clearly interfered in the transmission of noxious signalling and proved in this study to have an effect upon acute thermal and mechanical pain thresholds as well as pathologic pain conditions. The present results are a piece in the large puzzle where administration route, dosage and pain models must be thoroughly investigated before a study can be planned for a proof of concept in different clinical pain states. Implications The current study demonstrates that ceftriaxone has a mitigating effect upon many pain modalities including acute and inflammatory, and that these modalities should be included in future studies characterising the anti-nociceptive effect of beta-lactams such as ceftriaxone. The fact that ß-lactams also has antibiotic properties implies that similar chemical structures could be identified with the positive effect upon expression levels of EAAT2, but lacking the antibiotic side effect.

Third-space fluid distribution of pemetrexed in non-small cell lung cancer patients.

AIM: Hydrophilic drugs particularly those with low plasma protein binding may accumulate in third-space fluid in the body. Cytotoxic drugs like methotrexate (MTX) cause damage in the tissue, and evacuation of the third-space fluid in pleura is strongly recommended before new dosing. Pemetrexed (PEM) is a multi-targeted antifolate similar to MTX approved for the treatment for malignant pleural mesothelioma and non-small cell lung cancer. Current recommendations for patients receiving treatment with PEM prescribe draining of the pleural fluid. This is based upon the recommendations for MTX and not directly to any specific findings relating to PEM. The recommendations are the same because PEM is an analogue of MTX; the molecular structures and pharmacokinetic parameters are similar. However, since draining the pleural fluid is painful and cancer patient are particularly susceptible to infection subsequently, it is relevant to examine the recommendations for PEM explicitly. METHOD: Eight patients treated with a 500 mg/m(2) PEM combined with platinum salt were examined. Plasma samples were first collected in relation to the start of PEM infusion. Thereafter, plasma and pleura samples were taken at various times after drug infusion from each patient; in two patients, sampling was done twice but on different occasions. The quantitative determination of PEM was performed with reversed-phase high-performance liquid chromatography, and sample preparation was performed using protein precipitation with perchloric acid. Pharmacokinetic analysis was performed using a non-compartment method as well a two-compartment model. RESULTS: The results were calculated from 10 samples taken from eight patients, where data from one patient point were excluded as the patient had impaired renal function, and three samples were reported as below limit of quantification. The plasma PEM pharmacokinetics calculated showed an elimination half-life (t ½ elimination) of 3.2 h and distribution half-life (t ½-distribution) of 6 min. Clearance (CL) was 5.1 L/h, central volume of distribution (V(central)) 23.2 L and peripheral volume distribution (V(peripheral)) 10.6 L, and the area under the curve was 186 µg h/mL. Using non-compartment methods, an elimination half-life of 3.1 h and an apparent CL of 3.2 L/h were measured, whereas an apparent steady-state volume became 14.2 L. The pleura concentrations were only half of simultaneous plasma concentrations, and elimination half-life was 3.15 h. CONCLUSION: Pemetrexed is not likely to accumulate in the pleural fluid, and evacuation of fluid might not be necessary. Further investigation is needed to recommend no drainage of the fluid, i.e., in patients with renal impairment.

Insights about health-related quality of life in cancer patients indicate demands for better pharmaceutical care.

OBJECTIVES: To highlight the health-related quality of life scale scores for Saudi patients with different types of cancer, to get understanding and foundation for improvements. To suggest suitable plans for quality of life improvement based on study outcome. The role of oncology pharmacy will be stressed. METHODS: A cross-sectional descriptive study was conducted at a tertiary regional hospital using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. Attendees were patients diagnosed with any type of cancer and eligible for active anticancer treatment and/or palliative care. RESULTS: Quality of life was evaluated for 87 participants. Most of patients were aged between 51 and 60 years; and 50% had active treatment with chemotherapy. Patients seemed to perform well with respect to average scores in both the symptoms and the functional health status scales. The mean score for the global quality of life scale was 47.2 ± 27.1, while the range of mean scores for the five function subscales was 59.0 ± 27.1 to 81.6 ± 13.8, indicating average level of general wellbeing with above average to high level of functional health status, while >50% of the patients met the operational criterion having less severe symptoms. Outpatients generally had somewhat higher scores as compared to hospitalized patients. CONCLUSION: The general quality of life seemed satisfactory, but there is still need to improve care. Based on results from other studies, oncology pharmacists' roles are essential to improve quality of life through treatment counseling, follow-up on drug support therapy, stress on patient's education through specific programs, review and update the local guidelines, and conduct more research.

Clinical pharmacist service in the acute ward.

BACKGROUND: The majority of hospitalised patients have drug-related problems. Clinical pharmacist services including medication history, medication reconciliation and medication review may reduce the number of drug-related problems. Acute and emergency hospital services have changed considerably during the past decade in Denmark, and the new fast-paced workflows pose new challenges for the provision of clinical pharmacist service. OBJECTIVE: To describe and evaluate a method for a clinical pharmacist service that is relevant and fit the workflow of the medical care in the acute ward. SETTING: Acute wards at three Danish hospitals. METHODS: The clinical pharmacist intervention comprised medication history, medication reconciliation, medication review, medical record entries and entry of prescription templates into the electronic medication module. Drug-related problems were categorised using The PCNE Classification V6.2. Inter-rater agreement analysis was used to validate the tool. Acceptance rates were measured as the physicians' approval of prescription templates and according to outcome in the PCNE classification. MAIN OUTCOME MEASURE: Acceptance rate of the clinical pharmacists' interventions through the described method and inter-rater agreement using the PCNE classification for drug-related problems. RESULTS: During 17 months, 188 patients were included in this study (average age 72 years and 55 % women). The clinical pharmacists found drug-related problems in 85 % of the patients. In the 1,724 prescriptions, 538 drug-related problems were identified. The overall acceptance rate by the physicians for the proposed interventions was 76 % (95 % CI 74-78 %). There was a substantial inter-rater agreement when using the PCNE classification system. CONCLUSION: The methods for a clinical pharmacist service in the acute ward in this study have been demonstrated to be relevant and timely. The method received a high acceptance rate, regardless of no need for oral communication, and a substantial inter-rater agreement when classifying the drug-related problems.

Population pharmacokinetics of cytarabine, etoposide, and daunorubicin in the treatment for acute myeloid leukemia.

PURPOSE: Interpatient variability in the pharmacokinetics (PK) of cytarabine, etoposide, and daunorubicin following body surface area-adjusted doses calls for studies that point to other covariates to explain this variability. The purpose of this study was to investigate such relationships and give insights into the PK of this combination treatment. METHODS: A prospective population PK study of twenty-three patients with acute myeloid leukemia was undertaken. Plasma concentrations of patients were determined by high-pressure liquid chromatography. PK models were developed with NONMEM; for daunorubicin, PK information from a prior study was utilized. RESULTS: Baseline white blood cell count (bWBC) influenced the PK for all drugs. A small, statistically insignificant improvement in model fit was achieved when a relationship between bWBC and daunorubicin central volume of distribution was included. The volume increased 1.9% for each increase in bWBC by 1 × 10(6) cells/mL. The clearances of etoposide and cytarabine were significantly increased and decreased, respectively, by increased bWBC. Tenfold changes in bWBC were needed for these relationships to have potential clinical relevance. A decrease in creatinine clearance of 60 mL/min resulted in a decrease in etoposide clearance of 32%. CONCLUSIONS: Population-based models characterized the PK for all three drugs. bWBC was a significant covariate for etoposide and cytarabine and showed a trend for daunorubicin. Linking the significant bWBC relationships and the relationship between kidney function and etoposide clearance to clinical end points would support dose individualization. Patients with above-normal creatinine clearances and high bWBC may receive sub-optimal treatment due to elevated etoposide clearances.

Hospital admission interviews are time-consuming with several interruptions.

INTRODUCTION: The admission interview is an important procedure to reduce medication errors. Studies indicate that physicians do not spend much time on the interview and that the major obstacles are lack of time and heavy workload. The aim of this study was to measure the time physicians spend on admission interviews and to describe factors that affect time consumption. MATERIAL AND METHODS: This time study was conducted at an acute medicine department. Physicians conducting admission interviews were observed, and time consumption was recorded. RESULTS: Fifty admission interviews were observed; they lasted an average of 45 (range 8-84) minutes. The effective time consumption was 32 (range 7-59) minutes. Fifteen (range 3-41) minutes were spent on actually interviewing and examining the patient and compiling the medication history. It took zero to five (mean 2.2) minutes to collect the medication history. The number of interruptions per interview was zero to nine (mean two); they were mostly caused by phone calls from physicians or nurses or by nurses asking for advice on problems with other patients. The mean duration of an interruption was 7.1 minutes. CONCLUSION: Physicians spend an average of 45 minutes on admission interviews and are interrupted up to nine times. Only a few minutes are spent on collecting the medication history. Though the quality of the interviews and the actual error rate were not assessed, the observed working conditions may imply a high potential for medication errors.

Multidisciplinary management of metastatic renal cell carcinoma in the era of targeted therapies.

The use of targeted agents to treat metastatic renal cell carcinoma (mRCC) has significantly extended progression-free and overall survival but raises issues relating to the long-term delivery of care and the sustained monitoring of efficacy and toxicities, certain of which have not previously been experienced. In this paper, an expert group of medical oncologists, urologists and oncology nurses and pharmacists review and make informal recommendations on the multidisciplinary management of mRCC in the light of progress made and problems that have arisen. Decentralisation of care, with a shift in emphasis from large to small hospitals and possibly to the community, may offer advantages of cost and convenience. However, the major responsibility for care should continue to lie with clinicians (either medical oncologists or urologists) with extensive experience in mRCC, assisted by specialist nurses, and working in centres with facilities adequate to monitor efficacy and manage toxicities. That said, the extended survival of patients emphasises the importance of compliance and the long-term prevention, detection and management of side effects. Much of this will take place in the community. There is therefore a need for multidisciplinary working to extend beyond specialist centres to include general practitioners, community nurses and pharmacists. Although this paper focuses on mRCC, many of the considerations discussed are also relevant to the management of more common solid tumours in the era of targeted therapy.

Pharmacy student driven detection of adverse drug reactions in the community pharmacy setting.

PURPOSE: Post-marketing safety studies of adverse drug reactions (ADRs) form an important part of pharmacovigilance. Countries having a formal pharmacovigilance system to a large extent rely on voluntary ADR reporting from health professionals through spontaneous report systems. The contribution of pharmacists in ADR reporting, although varies significantly among countries. Pharmacists in community pharmacies are in a unique position for detection of experienced ADRs by the drug users. The study reports from a study on community pharmacy internship students' proactive role in ADR detection through direct encountering and questioning with drug users. METHOD: Pharmacy students undertaking internship in a community pharmacy were approached. Thirteen students from nine community pharmacies participated in the project as data collectors. Prior to the study students attended an educational seminar focusing on ADR detection and reporting in general. Ibuprofen was chosen as the drug of study. Pharmacy students approached recurrent drug users purchasing the drug. Participating users were asked about experienced ADRs linked to ibuprofen use. Reported ADRs were collected and analysed. RESULTS: Hundred and twenty eight ibuprofen users participated in the study out of who thirty three reported forty five ADRs possibly linked to ibuprofen use. The reported ADRs followed earlier reported patterns of distribution with gastric pain showing up as the most commonly reported symptom followed by heartburn, nausea, diarrhoea and constipation. CONCLUSIONS: Through adequate training community pharmacy internship students get competencies and are capable of detecting and reporting ADRs through direct questions to drug users.

Neuropathic pain models in the development of analgesic drugs.

Introduction Animal disease models are predictive for signs seen in disease. They may rarely mimic all signs in a specific disease in humans with respect to etiology, cause or development. Several models have been developed for different pain states and the alteration of behavior has been interpreted as a response to external stimulus or expression of pain or discomfort. Considerable attention must be paid not to interpret other effects such as somnolence or motor impairment as a pain response and similarly not to misinterpret the response of analgesics. Neuropathic pain is caused by injury or disease of the somatosensory system. The clinical manifestations of neuropathic pain vary including both stimulus-evoked and non-stimulus evoked (spontaneous) symptoms. By pharmacological intervention, the threshold for allodynia and hyperalgesia in the various pain modalities can be modulated and measured in animals and humans. Animal models have been found most valuable in studies on neuropathic pain and its treatment. Aim of the study With these interpretation problems in mind, the present text aims to describe the most frequently used animal models of neuropathic pain induced by mechanical nerve injury. Methods The technical surgical performance of these models is described as well as pain behavior based on the authors own experience and from a literature survey. Results Nerve injury in the hind limb of rats and mice is frequently used in neuropathic pain models and the different types of lesion may afford difference in the spread and quality of the pain provoked. The most frequently used models are presented, with special focus on the spared nerve injury (SNI) and the spinal nerve ligation/transection (SNL/SNT) models, which are extensively used and validated in rats and mice. Measures of mechanical and thermal hypersensitivity with von Frey filaments and Hargreaves test, respectively, are described and shown in figures. Conclusions A number of animal models have been developed and described for neuropathic pain showing predictive value in parallel for both humans and animals. On the other hand, there are still large knowledge gaps in the pathophysiologic mechanisms for the development, maintenance and progression of the neuropathic pain syndrome Implications Better understanding of pathogenic mechanisms of neuropathic pain in animal models may support the search for new treatment paradigms in patients with complex neuropathic pain conditions.

Predictive validity of pharmacologic interventions in animal models of neuropathic pain.

Introduction The pathophysiologic and neurochemical characteristics of neuropathic pain must be considered in the search for new treatment targets. Breakthroughs in the understanding of the structural and biochemical changes in neuropathy have opened up possibilities to explore new treatment paradigms. However, long term sequels from the damage are still difficult to treat. Aim of the study To examine the validity of pharmacological treatments in humans and animals for neuropathic pain. Method An overview from the literature and own experiences of pharmacological treatments employed to interfere in pain behavior in different animal models was performed. Results The treatment principles tested in animal models of neuropathic pain may have predictive validity for treatment of human neuropathies. Opioids, neurotransmitter blockers, drugs interfering with the prostaglandin syntheses as well as voltage gated sodium channel blockers and calcium channel blockers are treatment principles having efficacy and similar potency in humans and in animals. Alternative targets have been identified and have shown promising results in the validated animal models. Modulators of the glutamate system with an increased expression of glutamate re-uptake transporters, inhibition of pain promoters as nitric oxide and prostaglandins need further exploration. Modulation of cytokines and neurotrophins in neuropathic pain implies new targets for study. Further, a combination of different analgesic treatments may as well improve management of neuropathic pain, changing the benefit/risk ratio. Implications Not surprisingly most pharmacologic principles that are tested in animal models of neuropathic pain are also found to be active in humans. Whereas many candidate drugs that were promising in animal models of neuropathic pain turned out not to be effective or too toxic in humans, animal models for neuropathic pain are still the best tools available to learn more about mechanisms of neuropathic pain. Better understanding of pathogenesis is the most hopeful approach to improve treatment of neuropathic pain.

Low dose of donepezil improves gabapentin analgesia in the rat spared nerve injury model of neuropathic pain: single and multiple dosing studies.

The use of cholinergic drugs, either alone or in combination with other drugs, has been suggested as an approach to improve treatment outcome for patients suffering from neuropathic pain. The present study was undertaken in the rat spared nerve injury model of neuropathic pain to evaluate the effect of the cholinesterase inhibitor donepezil when administered (1) alone and (2) as low-dose in combination with the first-line recommendation gabapentin. The co-administration studies were performed following single and multiple dosing. Single, parenteral dosing of donepezil (1, 1.5 and 3 mg/kg s.c.) produced a dose-dependent reversal of the neuropathic pain behaviour. Co-administration of a sub-effective dose of donepezil (0.5 mg/kg s.c.) and low doses of gabapentin (10 and 30 mg/kg s.c.) resulted in a three- to fourfold increase of the analgesic effect, in comparison with gabapentin administered alone. Following multiple, oral dosing, gabapentin (25 mg/kg p.o.) was administered once daily over 20 days. Addition of donepezil (1.5 mg/kg p.o.) from day 11 to day 20 resulted in improved analgesia during the period of combination therapy, in comparison with the gabapentin monotherapy period. Furthermore, the treatment effects were stable in both the mono- and the combination therapy period, indicating that tolerance development does not occur within the studied time frame. In conclusion, the results from this preclinical study support the use of donepezil as adjunctive to gabapentin to improve the therapeutic outcome in the management of neuropathic pain.

Simultaneous determination of cytosine arabinoside, daunorubicin and etoposide in human plasma.

A method for simultaneous bioanalysis of the three cytotoxic drugs cytosine arabinoside, daunorubicin and etoposide in human plasma was developed and validated. A HPLC method with ultra-violet and fluorescence detection, preceded by mixed-mode cation-exchange solid phase extraction sample preparation, was used for the quantification of the analytes. The assay was used for the simultaneous measurement of cytosine arabinoside, daunorubicin and etoposide with linearity in the ranges of 13-1500 ng/mL, 15-1000 ng/mL and 52.5-3500 ng/mL, respectively. The chromatographic run-time was 15.5 min. The overall precision (% relative standard deviation) was within 0.2-13.5% and the recovery ranged between 86.1% and 110.1% for the three drugs at all concentrations tested. Plasma samples were stable for at least two months when stored at -20 degrees C. The method was successfully applied to quantification of the three drugs in blood samples from patients undergoing induction treatment for acute myeloid leukaemia, thus demonstrating its suitability for clinical studies.

Co-administered gabapentin and venlafaxine in nerve injured rats: Effect on mechanical hypersensitivity, motor function and pharmacokinetics.

A high proportion of patients suffering from neuropathic pain do not receive satisfactory pain relief from their current treatment, due to incomplete efficacy and dose-limiting adverse effects. Hence, one strategy to improve treatment outcome is the use of a combination of analgesic drugs. The potential benefits of such approach include improved and prolonged duration of analgesic effect and fewer or milder adverse effects with lower doses of each drug. Gabapentin is recommended as a first-line drug in the treatment of neuropathic pain, and has recently been demonstrated to act on supraspinal structures to stimulate the descending noradrenergic pain inhibitory system. Hypothetically, the analgesic effect of gabapentin may be potentiated if combined with a drug that prolongs the action of noradrenaline. In this study, gabapentin was co-administered with the serotonin and noradrenaline reuptake inhibitor venlafaxine, and subsequently evaluated for its effect on mechanical hypersensitivity in the rat spared nerve injury model of neuropathic pain. In this model, two branches of the sciatic nerve (the tibial and common peroneal nerves) are ligated and cut, leaving the third branch (the sural nerve) intact to innervate the hind paw of the animal. Treatment-induced ataxia was tested in order to exclude biased effect measurements. Finally, the pharmacokinetics of gabapentin was investigated alone and in combination with venlafaxine to elucidate any alterations which may have consequences for the pharmacological effect and safety. The overall effect on nerve injury-induced hypersensitivity of co-administered gabapentin (60 mg/kg s.c.) and venlafaxine (60 mg/kg s.c.), measured as the area under the effect-time curve during the three hour time course of testing, was similar to the highest dose of gabapentin (200 mg/kg s.c.) tested in the study. However, this dose of gabapentin was associated with ataxia and severe somnolence, while the combination was not. Furthermore, when administered alone, an effect delay of approximately one hour was observed for gabapentin (60 mg/kg s.c.) with maximum effect occurring 1.5 to 2.5 h after dosing, while venlafaxine (60 mg/kg s.c.) was characterised by a rapid onset of action (within 30 min) which declined to baseline levels before the end of the three hour time of testing. The effect of co-administered drugs (both 60 mg/kg s.c.), in the doses used here, can be interpreted as additive with prolonged duration in comparison to each drug administered alone. An isobolographic study design, enable to accurately classify the combination effect into additive, antagonistic or synergistic, was not applied. The pharmacokinetics of gabapentin was not altered by co-administered venlafaxine, implying that a pharmacokinetic interaction does not occur. The effect of gabapentin on the pharmacokinetics of venlafaxine was not studied, since any alterations are unlikely to occur on the basis of the pharmacokinetic properties of gabapentin. In conclusion, the results from this preclinical study support the rationale for improved effect and less adverse effects through combination therapy with gabapentin and venlafaxine in the management of neuropathic pain.

Developmental pharmacokinetics of gentamicin in preterm and term neonates: population modelling of a prospective study.

BACKGROUND AND OBJECTIVE: Preterm and term newborn infants show wide interindividual variability (IIV) in pharmacokinetic parameters of gentamicin. More extensive knowledge and use of predictive covariates could lead to faster attainment of therapeutic concentrations and a reduced need for concentration monitoring. This study was performed to characterize the population pharmacokinetics of gentamicin in preterm and term neonates and to identify and quantify relationships between patient characteristics and IIV. A secondary aim was to evaluate cystatin C as a marker for gentamicin clearance in this patient population. METHODS: Data were collected in a prospective study performed in the Neonatal Intensive Care Unit at the University Children's Hospital, Uppsala, Sweden. Population pharmacokinetic modelling was performed using nonlinear mixed-effects modelling (NONMEM) software. Bodyweight was included as the primary covariate according to an allometric power model. Other evaluated covariates were age (postmenstrual age, gestational age [GA], postnatal age [PNA]), markers for renal function (serum creatinine, serum cystatin C) and concomitant medication with cefuroxime, vancomycin or indometacin. Covariate-parameter relationships were explored using a stepwise covariate model building procedure. The predictive performance of the developed model was evaluated using an independent external dataset for a similar patient population. RESULTS: Sixty-one newborn infants (GA range 23.3-42.1 weeks, PNA range 0-45 days) were enrolled in the study. In total, 894 serum gentamicin samples were included in the analysis. The concentration-time profile was described using a three-compartment model. Gentamicin clearance increased with the GA and PNA (included in a nonlinear fashion). The GA was also identified as having a significant influence on the central volume of distribution, with a preterm neonate having a larger central volume of distribution per kilogram of bodyweight than a term neonate. Cystatin C and creatinine were not correlated with gentamicin clearance in this study population. The external dataset was well predicted by the developed model. CONCLUSION: Bodyweight and age (GA and PNA) were found to be major factors contributing to IIV in gentamicin clearance in neonates. Based on these data, cystatin C and serum creatinine were not correlated with gentamicin clearance and therefore not likely to be predictive markers of renal function in this patient population. Based on predictions from the developed model, preterm neonates do not reach targeted peak and trough gentamicin concentrations after a standard dosage regimen of 4 mg/kg given once daily, suggesting a need for higher loading doses and prolonged dosing intervals in this patient population.