Demographics, clinical characteristics, health resource utilization and cost of chronic thromboembolic pulmonary hypertension patients: retrospective results from six European countries.

BACKGROUND: Chronic Thromboembolic Pulmonary Hypertension (CTEPH) results from incomplete resolution of a pulmonary embolus, leading to pulmonary hypertension and progressive right heart failure and death. We aimed to describe the demographics, treatment patterns, health resource utilization and related costs of patients with CTEPH. METHODS: In specialized PH centres across six European countries, medical charts of CTEPH patients on PH medication were retrospectively extracted (chart review between 2006 and 2009). Resource utilization was valued using country-specific unit costs. Descriptive statistical analyses were performed. RESULTS: Twenty-one hospitals documented 119 consecutive CTEPH patients over an average of 25.4 months. Patients were inoperable (83.9%) or persistent after surgery (16.0%) with mean age 67.5 ± 12.3 years, 61% were female. The average 6-minute walking distance was 298 ± 120 meters, and NYHA class II/III/IV was 27/59/14%. At baseline, 59.7% patients received endothelin receptor antagonist, 34.4% phosphodiesterase-5 inhibitors, and 5.8% prostacyclin. Adding a second PH medication was the most common regimen change. CTEPH patients experienced 1.8 ± 2.2 hospitalizations per year accounting for 14.8 ± 26.1 days in hospital. Patients paid on average 2.8 office visits per year to their general practitioner and 1.3 visits to a specialist. Unadjusted annual mortality rate was 6.0%. Annual cost of PH specific medication was the predominant economic factor averaging € 36,768 per year. Costs for hospitalizations (€ 4,496) and concomitant medications (€ 2,510) were substantially lower. Other health care resource items only accounted for marginal additional costs. CONCLUSION: CTEPH patients are characterised by substantial morbidity and mortality. Health care utilisation, predominantly due to off-label use of PH drugs, is significant.

Cost-effectiveness analysis of a lidocaine 5% medicated plaster compared with gabapentin and pregabalin for treating postherpetic neuralgia: a german perspective.

OBJECTIVE: This study set out to assess the cost effectiveness of using a 5% lidocaine (lignocaine) medicated plaster for the treatment of postherpetic neuralgia (PHN) compared with gabapentin, pregabalin 300 mg/day or 600 mg/day in German primary care. The analysis took the perspective of the Statutory Health Insurance scheme (GKV). METHODS: A Markov model was used to calculate the costs (2007) and benefits of the lidocaine plaster, gabapentin 1800 mg/day and pregabalin 300 or 600 mg/day over a 6-month time horizon in elderly patients with PHN who experienced insufficient pain relief with standard analgesics and could not tolerate or had contraindications to tricyclic antidepressants. The model calculated the cost per quality-adjusted life-year (QALY) gained and the cost per additional month without symptoms or intolerable adverse effects. The majority of transition probabilities were obtained from randomized controlled trials identified from a systematic literature review. Further model inputs, including resource use, concomitant medication and long-term efficacy/adherence data, were obtained from a Delphi panel. Utility values were taken from a previous study and age adjusted. Cost data were obtained from official price tariffs. Mortality, indirect costs and costs associated with inpatient treatment were not considered in the present analysis due to the perspective and time horizon employed. RESULTS: Over the 6-month period modelled, the mean total therapy cost per patient treated with the lidocaine plaster was euro911, compared with euro728 for gabapentin, euro875 for pregabalin 300 mg/day and euro977 for pregabalin 600 mg/day. Treatment with the lidocaine plaster was related to greater numbers of QALYs and more months without symptoms or intolerable adverse effects (mean 0.300 QALYs and 4.06 months per patient) than with gabapentin (mean 0.247 QALYs and 2.72 months), pregabalin 300 mg/day (mean 0.253 QALYs and 3.02 months) or pregabalin 600 mg/day (mean 0.256 QALYs and 3.22 months). The lidocaine plaster cost euro3453/QALY gained and euro137 per additional month without adverse effects or symptoms relative to gabapentin and euro766/QALY and euro35 per month without adverse effects or symptoms relative to pregabalin 300 mg/day. The lidocaine plaster dominated pregabalin 600 mg/day, being less costly and more effective. Probabilistic sensitivity analysis indicated that there is a 99.36% chance that the lidocaine plaster is the most clinically effective treatment considered in the analysis and a 99.09% chance that the lidocaine plaster is the most cost-effective treatment of the four therapies considered in the analysis if the GKV is willing to pay at least euro20 000/QALY gained. Extensive deterministic sensitivity analyses demonstrated that the findings are robust. CONCLUSIONS: The 5% lidocaine-medicated plaster is a cost-effective treatment option for the management of PHN in Germany compared with gabapentin and both 300 and 600 mg/day of pregabalin.

Mu-opioid receptor mRNA regulation during morphine tolerance in the rat peripheral nervous system.

UNLABELLED: In vivo data on opioid receptor mRNA regulation after agonist exposure in the peripheral nervous system are lacking. Therefore, we studied the impact of morphine treatment on the regulation of mu-opioid receptor mRNA during behavioral signs of tolerance in rat peripheral sensory ganglia. Nineteen rats were treated in 2 groups with either morphine (10 mg/kg subcutaneously) or saline over 4 days, and a subset of rats received naloxone on the fifth day followed by either morphine injection on the sixth day or death to obtain dorsal root ganglia for mRNA analysis. Animals were tested on the hot plate during treatment days. To assess the levels of mu-opioid receptor mRNA, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used with the co-amplification of the "housekeeping" gene cyclophilin as internal control. Morphine treatment over 4 days induced tolerance as reflected on the hot-plate test by a significant reduction of paw-withdrawal latency from 242% to 99% above baseline. Using RT-PCR we demonstrated a down-regulation of mu-opioid receptor mRNA by 62% after morphine exposure (P < 0.05). After acute withdrawal of morphine from the mu-receptor by naloxone, the mu-opioid receptor mRNA levels in the dorsal root ganglia were restored to control levels within 24 h and the paw-withdrawal latency also returned to 280% above control. These data suggest that the peripheral nervous system may be an important site of opioid tolerance development. IMPLICATIONS: The peripheral nervous system is a possible site of opioid receptor tolerance. We show the development of behavioral tolerance and mu-opioid receptor mRNA down-regulation in the dorsal root ganglia in rats after chronic morphine treatment. Both this mRNA down-regulation and behavioral tolerance reverse after 24 h of naloxone treatment.

Gene structure, dual-promoters and mRNA alternative splicing of the human and mouse regulator of G protein signaling GAIP/RGS19.

Here we report the gene structure and transcription regulation of the human and mouse G protein-signaling regulator GAIP/RGS19. The GAIP/RGS19 gene is adjacent to and in an opposite orientation to the opioid-receptor-like receptor 1 (ORL1) gene. In both human and mouse, the GAIP/RGS19 gene is composed of seven exons. The first two exons are under the control of two different promoters and are alternatively employed to start the transcription of two 5' distinctive mRNAs. The two promoters appear to compete with and inhibit each other. We have also identified in mice an alternatively spliced short GAIP/RGS19 mRNA that lacks the exon 2 region and utilizes an ATG in exon 3 as its translation initiation codon. As a result, the short GAIP/RGS19 protein does not have the N-terminal 22 amino acid residues of a full-length isoform. GAIP/RGS19 alternative splicing patterns are differentially expressed in various tissues. The mRNA alternative splicing to produce multiple isoforms may play a significant role in regulating the function and selectivity of GAIP/RGS19.

5-HT7 receptors are involved in mediating 5-HT-induced activation of rat primary afferent neurons.

The purpose of this study was to determine whether the 5-hydroxytryptamine7 (5-HT7) receptor is expressed by nociceptor-like neurons in the rat PNS and whether 5-HT activates these nociceptors via the 5-HT7 receptor subtype. Using a polyclonal antibody and the method of immunofluorescence staining, we demonstrated that the 5-HT7 receptor appears predominately on "nociceptor-like" neurons of the rat lumbar dorsal root ganglia. Using immunocytochemical methods, we showed that the immunoreactivity of the 5-HT7 receptor antibody complex is localized in the superficial layers of the spinal cord dorsal horn, which corresponds with laminae I, IIouter and IIinner. Furthermore, we demonstrated that noxious stimulation produced by knee injection of 5-HT or a 5-HT7 agonist dose-dependently increases c-Fos production of the rat spinal cord dorsal horn. This effect was significantly inhibited by the preinjection of a 5-HT7 antagonist. We conclude that the 5-HT7 receptor is expressed by rat primary afferent nociceptors which terminate in the superficial layers of the spinal cord dorsal horn and that the 5-HT7 receptor subtype is involved in nociceptor activation by 5-HT.

Involvement of endogenous opioid systems in nociceptin-induced spinal antinociception in rats.

The present study investigates the involvement of opioid receptors in the antinociceptive effects of nociceptin in the spinal cord of the rat. Intrathecal administrations of 5 and 10 nmol of nociceptin significantly increase the withdraw response latencies to noxious thermal and mechanical stimulations. This nociceptin-induced antinociceptive effect is significantly attenuated by intrathecal injection of (Nphe(1))nociceptin(1-13)-NH(2), a selective antagonist of the nociceptin receptor (opioid receptor-like receptor ORL1), indicating an ORL1 receptor-mediated mechanism. This antinociceptive effect is also significantly attenuated by intrathecal injections of naloxone (a nonselective opioid receptor antagonist), naltrindole (a selective delta-opioid receptor antagonist), and beta-funaltrexamine (a selective mu-opioid receptor antagonist) in a dose-dependent manner, but not by the selective kappa-opioid receptor antagonist norbinaltorphimine. Since it is unlikely that nociceptin acts by direct binding to opioid receptors, these results suggest a possible interaction between the nociceptin/ORL1 and opioid systems in the dorsal horn of the rat spinal cord.

Localization of the tandem pore domain K+ channel KCNK5 (TASK-2) in the rat central nervous system.

Tandem pore domain K+ channels (2P K+ channels) are responsible for background K+ currents. 2P K+ channels are the most numerous encoded K+ channels in the Caenorhabditis elegans and Drosophila melanogaster genomes and to date 14 human 2P K+ channels have been identified. The 2P K+ channel TASK-2 (also named KCNK5) is sensitive to changes in extracellular pH, inhibited by local anesthetics and activated by volatile anesthetics. While TASK-1 has been shown to be involved in controlling neuronal cell excitability, much less is known about the cellular expression and function of TASK-2, originally cloned from human kidney. Previous studies demonstrated TASK-2 mRNA expression in high abundance in human kidney, liver, and pancreas, but only low expression in mouse brain or even absent expression in human brain was reported. In this study we have used immunohistochemical methods to localize TASK-2 at the cellular level in the rat central nervous system. TASK-2 immunoreactivity is prominently found in the rat hippocampal formation with the strongest staining observed in the pyramidal cell layer and in the dentate gyrus, and the Purkinje and granule cells of cerebellum. Additional immunofluorescence studies in cultured cerebellar granule cells demonstrate TASK-2 localization to the neuronal soma and to the proximal regions of neurites of cerebellar granule cells. The superficial layers of spinal cord and small-diameter neurons of dorsal root ganglia also showed strong TASK-2 immunoreactivity. These results suggest a possible involvement of TASK-2 in central mechanisms for controlling cell excitability and in peripheral signal transduction.