Therapeutic drug monitoring and pharmacogenetic tests as tools in pharmacovigilance.

Therapeutic drug monitoring (TDM) and pharmacogenetic tests play a major role in minimising adverse drug reactions and enhancing optimal therapeutic response. The response to medication varies greatly between individuals, according to genetic constitution, age, sex, co-morbidities, environmental factors including diet and lifestyle (e.g. smoking and alcohol intake), and drug-related factors such as pharmacokinetic or pharmacodynamic drug-drug interactions. Most adverse drug reactions are type A reactions, i.e. plasma-level dependent, and represent one of the major causes of hospitalisation, in some cases leading to death. However, they may be avoidable to some extent if pharmacokinetic and pharmacogenetic factors are taken into consideration. This article provides a review of the literature and describes how to apply and interpret TDM and certain pharmacogenetic tests and is illustrated by case reports. An algorithm on the use of TDM and pharmacogenetic tests to help characterise adverse drug reactions is also presented. Although, in the scientific community, differences in drug response are increasingly recognised, there is an urgent need to translate this knowledge into clinical recommendations. Databases on drug-drug interactions and the impact of pharmacogenetic polymorphisms and adverse drug reaction information systems will be helpful to guide clinicians in individualised treatment choices.

Intraarterial nimodipine for the treatment of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage: a preliminary study.

OBJECTIVE: Despite dramatic advances in all medical era, cerebral vasospasm is still the major complication in patients with subarachnoid hemorrhage (SAH). The purpose of this study was to assess the influence of intraarterial (IA) nimodipine in the treatment of symptomatic vasospasm and in preventing neurological disabilities. MATERIALS AND METHODS: We retrospectively reviewed 10 patients of SAH who received IA nimodipine in 15 procedures. The decision to perform angiography and endovascular treatment was based on the neurological examination, brain computed tomography (CT) and CT-angiography. The procedure reports, anesthesia records, neurological examination before and after the procedure, brain imaging and short- and long-term outcome were studied. RESULTS: The average dose of nimodipine was 2 mg. The median change in mean arterial pressure at 10 min was -10 mmHg. No significant change of heart rate was observed at 10 min. There was radiological improvement in 80% of the procedures. Neurological improvement was noted after eight out of 12 procedures when nimodipine was used as the sole treatment and after 10 out of 15, overall. Six patients clinically improved after the treatment and had good outcome. In one patient, an embolus caused fatal anterior and middle cerebral arteries infarction. There was no other neurological deficit or radiological abnormality due to the nimodipine treatment itself. CONCLUSION: Low-dose IA nimodipine is a valid adjunct for the endovascular treatment of cerebral vasospasm. Beneficial effects are achieved in some patients, prompting a prospective control study.

Is use of nifurtimox for the treatment of Chagas disease compatible with breast feeding? A population pharmacokinetics analysis.

Introduction Women with Chagas disease receiving treatment with nifurtimox are discouraged from breast feeding. Many patients who would receive treatment with nifurtimox live in extreme poverty, have limited access to resources such as clean water and baby formula and may not have safe alternatives to breast milk. Aim We aimed to estimate, using limited available pharmacokinetics data, potential infant exposure to nifurtimox through breast milk. Methods Original nifurtimox plasma concentrations were obtained from published studies. Pharmacokinetic parameters were estimated using non-linear mixed-effect modelling with NONMEM V.VI. A total of 1000 nifurtimox plasma-concentration profiles were simulated and used to calculate the amount of drug that an infant would be exposed to, if breast fed 150 ml/kg/day. Results Breast milk concentrations on the basis of peak plasma levels (1361 ng/ml) and milk-plasma ratio were estimated. We calculated infant nifurtimox exposure of a breastfed infant of a mother treated with this drug to be below 10% of the maternal weight-adjusted dose, even if milk-plasma ratio were overestimated. Simulation led to similar estimates. Discussion Risk for significant infant exposure to nifurtimox through breast milk seems small and below the level of exposure of infants with Chagas disease receiving nifurtimox treatment. This potential degree of exposure may not justify discontinuation of breast feeding.

Severe hypertension following accidental clonidine overdose during the refilling of an implanted intrathecal drug delivery system.

BACKGROUND:   Complications associated with intrathecal pumps may be linked to the surgical procedure, the implanted device, or the medication itself.¦CASE REPORTS:   Three patients treated chronically with intrathecal clonidine presented with clonidine overdose due to inadvertent extravasation during the refilling procedure. All patients experienced loss of consciousness and severe systemic hypertension that required aggressive parenteral treatment.¦DISCUSSION:   Clonidine is an alpha-2 agonist with a nearly 100% bioavailability after oral or rectal administration. With high plasma concentration secondary to massive systemic overdose, the specificity for the alpha-2 receptor is lost and an alpha-1 agonist activity predominates and causes marked hypertension. Management of clonidine overdose consists of supportive therapy guided by signs and symptoms.¦CONCLUSION:   Inadvertent injection into the subcutaneous pocket rather than the reservoir is rare but very dangerous as the drug cannot be retrieved and massive doses are involved. Signs and symptoms of systemic overdose with drugs commonly used in implanted drugs delivery system should be well known to ensure early diagnosis and treatment.

Photodynamic therapy for enhanced drug delivery to tumor

Photodynamic therapy (PDT) has been used as an adjunct to cytoreductive surgery in patients with malignant pleura mesothelioma (MPM). However, it was associated with substantial side effects and found to be only of modest clinical benefit. In contrast, Visudyne®-mediated low-dose PDT has been shown to selectively increase the concentration of macromolecular cytostatic compounds in various tumors grown subpleurally on rodent lungs. Consequently, it was thought that PDT-assisted enhanced tumor penetration for cytostatic agents might be better suited to achieve additional tumor control after cytoreductive surgery for mesothelioma. This effect seems to be mainly related to PDT-mediated modulations of tumor vessels which improve the distribution of circulating, systemically administered chemotherapeutic macromolecular agents. However, the mechanisms involved and the optimization of this effect for therapeutic implications remain to be solved. By using the dorsal skin fold chamber method we demonstrated that both angiogenesis and microcirculation of human mesothelioma xenografts can be continuously assessed in vivo by intravital microscopy. We described a new, simple, reproducible and reliable scoring system for the assessment of tumor angiogenesis and microcirculation in this model, thereby allowing the quantitative description of the neo-vascular network development while avoiding a complicated technical setup. This method can serve as a useful tool for the assessment of novel vessel-targeted therapies against MPM. We then applied this newly established model so as to elucidate the underlying mechanisms of PDT-induced extravasation of macromolecular compounds across the endothelial barrier in tumors and surrounding normal tissue. We found that low-dose PDT selectively enhanced the uptake of macromolecular compounds in human mesothelioma xenografts compared to surrounding normal tissue. Interestingly, this increase of effective permeability of tumor vasculature was not related to the inflammatory stimuli generated by PDT such as the mobilization of leucocytes and their adhesion and penetration of the injured vessel wall. We then used the model for optimizing the drug-light conditions of low- dose PDT in order to obtain maximal leakage of the macromolecular compounds in the tumor with minimal uptake in normal surrounding tissue and we were able to identify such a therapeutic window. With these optimized PDT treatment conditions, we assessed the therapeutic effect of this new treatment concept in vivo by measuring tumor growth rates on subcutaneously grown mesothelioma xenografts in nude mice after low-dose PDT of the tumors following systemically administered liposomal (macromolecular) cisplatin, a cytostatic compound commonly used in clinical practice. We were able to demonstrate that low-dose PDT with optimized drug-light conditions combined with systemic chemotherapy indeed resulted in a reduction in tumor growth compared to chemotherapy or PDT alone. In conclusion, our work demonstrates that low-dose PDT may selectively enhance the uptake of macromolecular cytostatic drugs in superficially growing tumors such as mesotheliomas and opens new perspectives for the treatment of these diseases. - Les effets cytotoxiques de la thérapie photodynamique (PDT) sur le mésothéliome pleural malin (MPM) n'ont pas apporté de bénéfice clinique significatif. Toutefois, une application innovante non cytotoxique de la PDT serait la bienvenue en supplément des chimiothérapies pour améliorer le contrôle local de la tumeur. Le prétraitement des néovaisseaux tumoraux par une PDT à bas régime, qui améliorerait la distribution d'une chimiothérapie administrée par voie systémique de façon concomitante, a attiré une attention particulière pour de futures applications cliniques. Toutefois, les mécanismes impliqués dans cet événement et les implications thérapeutiques de ces changements physiopathologiques restent non résolus. Dans cette thèse, nous avons observé en premier que l'angiogenèse et la microcirculation dans les xénogreffes de mésothéliomes humains peuvent être observées et analysées in vivo par microscopie intravitale. Le nouveau système de score appliqué pour l'évaluation de l'angiogenèse et de la microcirculation tumorale dans cette étude est une méthode simple, reproductible et fiable servant à décrire de manière quantitative le réseau néo-vasculaire en développement, tout en évitant d'utiliser une installation technique compliquée. Ce modèle sert de nouvel outil pour l'évaluation des thérapies anti-vasculaires dirigées contre le MPM. Le modèle animal nouvellement établi a alors été utilisé pour élucider les mécanismes sous-jacents de Γ extravasation d'agents macromoléculaires induite par PDT dans les vaisseaux tumoraux et normaux. Nous avons trouvé que la PDT à fable dose améliore la distribution ciblée de drogues macromoléculaires dans des greffes de mésothéliome humain, de manière sélective pour la tumeur. La perméabilité vasculaire tumorale n'est pas influencée par les stimuli inflammatoires générés par la PDT, ce qui joue un rôle important dans la sélectivité de notre photodynamic drug delivery. Ensuite, nous avons recherché la fenêtre thérapeutique optimale de la PDT pour obtenir une accumulation sélective du colorant macromoléculaire dans le tissu tumoral ainsi qu'une efficacité de la PDT combinée avec une chimiothérapie macromoléculaire sur la croissance tumorale. Nous avons démontré que la PDT à faible dose combinée avec une administration systémique de cisplatine liposomale mène à un ralentissement de la croissance tumorale dans notre modèle de mésothéliome malin humain. En conclusion, l'utilisation de la PDT comme prétraitement pour améliorer sélectivement la distribution d'agents thérapeutiques dans des tumeurs poussant superficiellement est prometteuse. Cette observation fourni une preuve du concept remarquable et garanti la suite des investigations, éventuellement ayant pour but de développer de nouveaux concepts de thérapie pour les patients atteints de mésothéliome. Une PDT intra cavitaire à faible dose après pleuro- pneumonectomie pourrait améliorer la pénétration des agents cytostatiques administrés de façon concomitante par voie systémique dans les îlots tumoraux résiduels, et ainsi améliorer le contrôle local.

Long-term treatment of hypertension in man by an orally active angiotensin-converting enzyme inhibitor.

1. Captopril or SQ 14 225, administered orally twice a day, reduced the blood pressure of hypertensive patients whatever their clinical diagnosis and even when their plasma renin activity was 'normal' or low. 2. Long-term administration of captopril, either alone or together with diuretics, provides a powerful new tool with which to treat ambulatory hypertensive patients. 3. The renin system may play an important role in maintaining blood pressure in a majority of hypertensive patients.

Knochenanabole Therapie mit Teriparatid [Bone anabolic treatment with Teriparatide].

The recombinant amino-terminal fragment of human parathyroid hormone (Teriparatide) is a bone anabolic agent which reduces fracture risk by increasing bone mass and improving bone microarchitecture. Teriparatide reduces vertebral fracture risk by 65 % and non-vertebral by 50 %. Its efficacy is higher as bisphosphonates to prevent corcicosteroid-induced osteoporosis. Teriparatide may also have a direct effect on bone pain. Teriparatide may be initiating immediately after an anticatabolic agent. However, it is not recommended to associate both treatments. At the end of teripatide treatment, an anticatabolic agent may be given. According to cost-effectiveness studies, Teriparatide should be considered as first line treatment for postmenopausal women and for men with severe osteoporosis.

Vectorisation intra-oculaire [Drug delivery to target the posterior segment of the eye].

Retinal diseases are nowadays the most common causes of vision threatening in developed countries. Therapeutic advances in this field are hindered by the difficulty to deliver drugs to the posterior segment of the eye. Due to anatomical barriers, the ocular biodisponibility of systemically administered drugs remains poor, and topical instillation is not adequate to achieve therapeutic concentrations of drugs in the back of the eye. Ocular drug delivery has thus become one of the main challenges of modern ophthalmology. A multidisciplinary research is being conducted worldwide including pharmacology, biomaterials, ophthalmology, pharmaceutics, and biology. New promising fields have been developed such as implantable or injectable slow release intravitreal devices and degradable polymers, dispersed polymeric systems for intraocular drug delivery, and transscleral delivery devices such as iontophoresis, osmotic pumps or intra-scleraly implantable materials. The first clinical applications emerging from this research are now taking place, opening new avenues for the treatment of retinal diseases.

Systèmes de délivrance des médicaments pour le segment antérieur: bases fondamentales et applications cliniques [Drug delivery systems to target the anterior segment of the eye: fundamental bases and clinical applications].

The development of new drug delivery systems to target the anterior segment of the eye may offer many advantages: to increase the biodisponibility of the drug, to allow the penetration of drug that cannot be formulated as solutions, to obtain constant and sustained drug release, to achieve higher local concentrations without systemic effects, to target more specifically one tissue or cell type, to reduce the frequency of instillation and therefore increase the observance and comfort of the patient while reducing side effects of frequent instillation. Several approaches are developed, aiming to increase the corneal contact time by modified formulation or reservoir systems, or by increasing the tissue permeability using iontophoresis. To date, no ocular drug delivery system is ideal for all purposes. To maximize treatment efficacy, careful evaluation of the specific pathological condition, the targeted Intraocular tissue and the location of the most severe pathology must be made before selecting the method of delivery most suitable for each individual patient.

Assessment of drug compliance in patients with high blood pressure resistant to antihypertensive therapy.

The persistence of high blood pressure under antihypertensive treatment (resistant hypertension) entails an increased cardiovascular risk. It occurs in three of ten treated hypertensive patients, and has several possible contributing factors, notably insufficient therapeutic adherence. There are a number of ways to evaluate whether patients take their medication as prescribed. These include interviewing the patient, pill counting, prescription follow-up, assay of drugs in blood or urine, and use of electronic pill dispensers. None is perfect. However, the essential is to discuss with the patient the importance of complying with the treatment as soon as it is prescribed for the first time, and not waiting for the appearance of resistant hypertension. The measurement of blood pressure outside the medical office and the monitoring of adherence may help to identify patients in whom hypertension is truly resistant and so to tailor the measures required to improve the control of blood pressure in the most appropriate manner.

Modifying effect of dual antiplatelet therapy on incidence of stent thrombosis according to implanted drug-eluting stent type.

AIM: To investigate the putative modifying effect of dual antiplatelet therapy (DAPT) use on the incidence of stent thrombosis at 3 years in patients randomized to Endeavor zotarolimus-eluting stent (E-ZES) or Cypher sirolimus-eluting stent (C-SES). METHODS AND RESULTS: Of 8709 patients in PROTECT, 4357 were randomized to E-ZES and 4352 to C-SES. Aspirin was to be given indefinitely, and clopidogrel/ticlopidine for ≥3 months or up to 12 months after implantation. Main outcome measures were definite or probable stent thrombosis at 3 years. Multivariable Cox regression analysis was applied, with stent type, DAPT, and their interaction as the main outcome determinants. Dual antiplatelet therapy adherence remained the same in the E-ZES and C-SES groups (79.6% at 1 year, 32.8% at 2 years, and 21.6% at 3 years). We observed a statistically significant (P = 0.0052) heterogeneity in treatment effect of stent type in relation to DAPT. In the absence of DAPT, stent thrombosis was lower with E-ZES  vs. C-SES (adjusted hazard ratio 0.38, 95% confidence interval 0.19, 0.75; P = 0.0056). In the presence of DAPT, no difference was found (1.18; 0.79, 1.77; P = 0.43). CONCLUSION: A strong interaction was observed between drug-eluting stent type and DAPT use, most likely prompted by the vascular healing response induced by the implanted DES system. These results suggest that the incidence of stent thrombosis in DES trials should not be evaluated independently of DAPT use, and the optimal duration of DAPT will likely depend upon stent type (Clinicaltrials.gov number NCT00476957).

Viral suppression rates in salvage treatment with raltegravir improved with the administration of genotypic partially active or inactive nucleoside/tide reverse transcriptase inhibitors.

BACKGROUND: Nucleoside reverse transcriptase inhibitors (NRTIs) are often administered in salvage therapy even if genotypic resistance tests (GRTs) indicate high-level resistance, but little is known about the benefit of these additional NRTIs. METHODS: The effect of <2 compared with 2 NRTIs on viral suppression (HIV-1 RNA < 50 copies/mL) at week 24 was studied in salvage patients receiving raltegravir. Intent-to-treat and per-protocol analyses were performed; last observation carried forward imputation was used to deal with missing information. Logistic regressions were weighted to create a pseudopopulation in which the probability of receiving <2 and 2 NRTIs was unrelated to baseline factors predicting treatment response. RESULTS: One-hundred thirty patients were included, of whom 58.5% (n = 76) received <2 NRTIs. NRTIs were often replaced by other drug classes. Patients with 2 NRTIs received less additional drug classes compared with patients with <2 NRTIs [median (IQR): 1 (1-2) compared with 2 (1-2), P Wilcoxon < 0.001]. The activity of non-NRTI treatment components was lower in the 2 NRTIs group compared with the <2 NRTIs group [median (IQR) genotypic sensitivity score: 2 (1.5-2.5) compared with 2.5 (2-3), P Wilcoxon < 0.001]. The administration of <2 NRTIs was associated with a worse viral suppression rate at week 24. The odds ratios were 0.34 (95% confidence interval: 0.13 to 0.89, P = 0.027) and 0.19 (95% confidence interval: 0.05 to 0.79, P = 0.023) when performing the last observation carried forward and the per-protocol approach, respectively. CONCLUSIONS: Our findings showed that partially active or inactive NRTIs contribute to treatment response, and thus the use of 2 NRTIs in salvage regimens that include raltegravir seems warranted.

Salmonella epidural abscess in sickle cell disease: failure of the nonsurgical treatment.

In patients suffering from sickle cell disease (SCD), bone is a preferred site of infection. We report the case of a five-year-and-eight-month-old black African boy with homozygous-SS disease who developed a cranial epidural abscess. This intracranial infectious complication originated from a Salmonella enteritidis osteitis of the frontal bone. Antibiotic treatment alone did not control the disease, so surgery was necessary to remove the necrotic bone and to evacuate the epidural pus. The numerous factors interfering with normal healing of a septic focus in sickle cell anemia, particularly in this previously undescribed intracranial complication, emphasize the need for a primary and early surgical treatment in similar situations.

Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment

Methadone is a 50:50 mixture of two enantiomers and (R)-methadone accounts for the majority of its opioid effect. The aim of this study was to determine whether a blood concentration of (R)-methadone can be associated with therapeutic response in addict patients in methadone maintenance treatment. Trough plasma concentrations of (R)-, (S)- and (R,S)-methadone were measured in 180 patients in maintenance treatment. Therapeutic response was defined by the absence of illicit opiate or cocaine in urine samples collected during a 2-month period prior to blood sampling. A large interindividual variability of (R)-methadone concentration-to-dose-to-weight ratios was found (mean, S.D., median, range: 112, 54, 100, 19-316 ng x kg/ml x mg). With regard to the consumption of illicit opiate (but not of cocaine), a therapeutic response was associated with (R)- (at 250 ng/ml) and (R,S)-methadone (at 400 ng/ml) but not with (S)-methadone concentrations. A higher specificity was calculated for (R)- than for (R,S)-methadone, as the number of non-responders above this threshold divided by the total number of non-responders was higher for (R,S)-methadone (19%) than for (R)-methadone (7%). The results support the use of therapeutic drug monitoring of (R)-methadone in cases of continued intake of illicit opiates. Due to the variability of methadone concentration-to-dose-to-weight ratios, theoretical doses of racemic methadone could be as small as 55 mg/day and as large as 921 mg/day to produce a plasma (R)-methadone concentration of 250 ng/ml in a 70-kg patient. This demonstrates the importance of individualizing methadone treatment.