Per Hartvig Honoré

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

AbstractBackground 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.

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.

Neuropathic pain models in the development of analgesic drugs

Abstract 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

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.

The quality and quantity of patients' own drugs brought to hospital during admission

Objectives Patients’ own drugs (PODs) are the medicines that patients have obtained in the community setting and bring to hospital. Little is known about the frequency with which patients bring PODs when admitted to hospital and the quality of these drugs has not been well investigated. The purpose of this study was to evaluate the quantity and quality of the PODs brought to hospital during admission. Methods Clinical pharmacists in four wards at three different hospitals evaluated the quantity and quality of PODs. The quantity of PODs relates to the number of patients who brought one or more of their medicines to hospital and the total number of PODs. The quality of PODs was evaluated by assessing the appearance, container, labelling, identification of contents, storage conditions and expiration, and thereby the usability of the POD. Results From March 2010 to July 2011, 4600 drugs from 529 patients were assessed. In total, 59% of patients took PODs to hospital and 43% (n=1985) of drugs from patients’ medication histories were brought to the hospital. The majority of PODs were usable (58.6%, n=1164) but most were unnecessary (52.3%, n=1039) because substitution was possible. In total, 92.5% (n=1836) of all PODs were not used during admission, although 33.5% (n=615) of these added information to the patients’ medication history. Conclusions More than half of patients brought PODs to hospital which gave the advantage of providing medication history. The majority of PODs were suitable for use in hospital. Only 7.5% of all PODs were actually used because substitution to generic or equivalent drugs from the hospitals formulary was preferred.

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

Abstract 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.

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.

Predictive validity of pharmacologic interventions in animal models of neuropathic pain

Abstract 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.

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

Abstract 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 β-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 β-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.

Drug–drug combinations revisited

The use of fixed-dose combinations (FDCs) in the daily practice of pharmacotherapy is increasing after years in the shadows. The main reasons for this renewed popularity are the increasing number of drugs prescribed per patient and the complexity of current pharmacotherapy. A lack of efficacy of current monotherapies in many diseases together with advances in knowledge on pathophysiological disease mechanisms have also created a push towards development of new FDCs. For the regulatory authorities in Europe, however, it is unclear whether FDCs in general have a positive benefit–risk balance. Hence, more research is needed to show that use of FDCs improves treatment effectiveness through better compliance, adherence and quality of life for patients, which may lead to a positive pharmacoeconomical benefit for society. Evidence-based data are thus needed, especially for those patient groups requiring multiple drugs—for example, the elderly. In this context, hospital practice regarding FDCs is crucial, as the recommended pharmacotherapy at discharge of the patient serves as a role model for outpatient care, and therefore needs greater recognition. The benefit–risk balance and pharmacoeconomical consequences of FDCs should also be a subject for attention in the hospital pharmacy setting.