СИСТЕМА ЛЕЧЕНИЯ ХРОНИЧЕСКОЙ БОЛИ В США

The article describes the system of pain management in the USA, and it highlights the fact that despite the difference in organization of medical care provision, Russia and the USA aim at similar objectives in this field. Managing patients with pain syndrome is an important part of medicine; anesthesiology is a core of pain management, but only the collaborative approach involving different specialists can provide the required result. Treatment of patients suffering from chronic pain can be a success if it is comprehensively planned and coordinated.В статье представлена система лечения пациентов с болевым синдромом в США и показано, что, несмотря на разницу в организации медицины, у России и США есть одинаковые задачи в этой области. Лечение пациентов с болевым синдромом − необходимая часть медицины; анестезиология − ядро лечения боли, но только коллективный подход с участием разных специалистов дает нужные результаты. Лечение больных с хронической болью успешно, если оно производится с использованием общего планирования и при координированном исполнении

Контроль периоперационной боли

Objective: analysis of the current pharmacological approaches to perioperative pain control, including in patients with chronic pain and opioid dependenceResults: An assessment of pregabalin, gabapentin, celecoxib, and other medications utilized in perioperative pain control as well as a characterization of methods used in pain control in opioid-dependent individuals, including chronic buprenorphine therapy. Detailing how multiple preparations are employed and their effectiveness in intraoperative and postoperative pain management. Also, addressing the increased role of pharmacogenomics in individualized pain management.Цель: анализ современных сведений о фармакологических подходах к контролю периоперационной боли, в том числе у пациентов с хроническим болевым синдромом и опиоидной зависимостью.Результаты: оценена ниша для применения прегабалина, габапентина, целекоксиба и некоторых других средств предоперационного контроля боли; описана тактика подготовки к операции пациентов, находящихся на хронической опиоидной терапии, в том числе получающих бупренорфин. Рассмотрены эффективность различных медикаментозных средств, используемых с целью потенцирования анальгезии в интраоперационном периоде, и подходы к контролю послеоперационной боли. Уделено внимание возрастающей роли фармакогеномики для обеспечения индивидуального подхода к обезболиванию

Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials

An analysis of the activity of compounds tested in pre-clinical in vivo and in vitro assays by the National Cancer Institute's Developmental Therapeutics Program was performed. For 39 agents with both xenograft data and Phase II clinical trials results available, in vivo activity in a particular histology in a tumour model did not closely correlate with activity in the same human cancer histology, casting doubt on the correspondence of the pre-clinical models to clinical results. However, for compounds with in vivo activity in at least one-third of tested xenograft models, there was correlation with ultimate activity in at least some Phase II trials. Thus, an efficient means of predicting activity in vivo models remains desirable for compounds with anti-proliferative activity in vitro. For 564 compounds tested in the hollow fibre assay which were also tested against in vivo tumour models, the likelihood of finding xenograft activity in at least one-third of the in vivo models tested rose with increasing intraperitoneal hollow fibre activity, from 8% for all compounds tested to 20% in agents with evidence of response in more than 6 intraperitoneal fibres (P< 0.0001). Intraperitoneal hollow fibre activity was also found to be a better predictor of xenograft activity than either subcutaneous hollow fibre activity or intraperitoneal plus subcutaneous activity combined. Since hollow fibre activity was a useful indicator of potential in vivo response, correlates with hollow fibre activity were examined for 2304 compounds tested in both the NCI 60 cell line in vitro cancer drug screen and hollow fibre assay. A positive correlation was found for histologic selectivity between in vitro and hollow fibre responses. The most striking correlation was between potency in the 60 cell line screen and hollow fibre activity; 56% of compounds with mean 50% growth inhibition below 10–7.5 M were active in more than 6 intraperitoneal fibres whereas only 4% of compounds with a potency of 10–4 M achieved the same level of hollow fibre activity (P< 0.0001). Structural parameters of the drugs analysed included compound molecular weight and hydrogen-bonding factors, both of which were found to be predictive of hollow fibre activity. © 2001 Cancer Research Campaign www.bjcancer.co

ОПИОИДНЫЕ АНАЛЬГЕТИКИ В ТЕРАПИИ БОЛЕВЫХ СИНДРОМОВ (часть 1)

The goal of this review is to inform doctors about new opioids currently used for routine medical practice in the most developed countries. This publication contains brief history, describes main mechanisms of opioid action, types and specific functioning of opioid receptors, it presents pharmacological parameters of the most frequently used opioids and their specific use in the clinical practice. In the light of increased interest towards pain management with opioids, the article will be useful for broad audience of doctors treating acute and chronic pain. Предлагаемый обзор имеет цель ознакомить врачей с современными опиоидными препаратами, применяемыми в настоящее время в повседневной медицинской практике ведущих стран мира. В представленной публикации дана краткая историческая справка, освещены основные механизмы действия опиоидов, типы и специфика функционирования опиоидных рецепторов, приведены фармакологические характеристики наиболее часто используемых опиоидных препаратов и особенности их применения в клинической практике. Учитывая возросший интерес к терапии боли опиоидными препаратами в последние годы, публикация будет полезна для широкого круга врачей, занимающихся лечением острой и хронической боли.

Infusional 5-fluorouracil, cisplatin and mitomycin C in advanced gastric cancer : A low cost effective regimen

Recently, we reported a highly active regimen in advanced gastric cancer including a weekly administration of cisplatin, epidoxorubicin, leucovorin, 5-fluorouracil with the support of filgrastim. In order to simplify the administration and to decrease the toxicity of these drugs, mainly epidoxorubicin-induced alopecia, we designed a regimen including an infusional 5-fluorouracil schedule according to the de Gramont regimen, cisplatin and mitomycin C replacing epidoxorubicin. Forty-five patients with advanced or metastatic gastric cancer were treated with cisplatin 50 mg m−2 i.v. on day 1, every 2 weeks, 6S-stereoisomer-leucovorin 100 mg m−2 i.v. followed by 5-fluorouracil 400 mg m−2 i.v. bolus and 600 mg m−2 i.v. in a 22-h infusion, on days 1 and 2, every 2 weeks, and mitomycin C 7 mg m−2 i.v. bolus on day 2, every 6 weeks. Grades 3–4 toxicities (National Cancer Institute-Common Toxicity Criteria) consisted mainly of neutropenia and thrombocytopenia. Five patients had a complete response and 16 had a partial response for an overall response rate of 46.7% (95% confidence interval, 32.1–61.2%). The median survival was 11 months. The combination of cisplatin, 5-fluorouracil and leucovorin according to de Gramont, and mitomycin C seems to be an active and safe regimen in the treatment of advanced gastric cancer. Because of its low cost it may be suggested for patients not enrolled into clinical trials

Synergistic activity of troxacitabine (Troxatyl™) and gemcitabine in pancreatic cancer

<p>Abstract</p> <p>Background</p> <p>Gemcitabine, a deoxycytidine nucleoside analog, is the current standard chemotherapy used as first-line treatment for patients with locally advanced or metastatic cancer of the pancreas, and extends life survival by 5.7 months. Advanced pancreatic cancer thus remains a highly unmet medical need and new therapeutic agents are required for this patient population. Troxacitabine (Troxatyl™) is the first unnatural L-nucleoside analog to show potent preclinical antitumor activity and is currently under clinical investigation. Troxacitabine was recently evaluated as a first-line therapy in 54 patients with advanced adenocarcinoma of the pancreas and gave comparable overall results to those reported with gemcitabine in recently published randomized trials.</p> <p>Methods</p> <p>The human pancreatic adenocarcinoma cell lines, AsPC-1, Capan-2, MIA PaCa-2 and Panc-1, were exposed to troxacitabine or gemcitabine alone or in combination, for 72 h, and the effects on cell growth were determined by electronic particle counting. Synergistic efficacy was determined by the isobologram and combination-index methods of Chou and Talalay. Mechanistic studies addressed incorporation of troxacitabine into DNA and intracellular levels of troxacitabine and gemcitabine metabolites. For <it>in vivo </it>studies, we evaluated the effect of both drugs, alone and in combination, on the growth of established human pancreatic (AsPC-1) tumors implanted subcutaneously in nude mice. Statistical analysis was calculated by a one-way ANOVA with Dunnett as a post-test and the two-tailed unpaired <it>t </it>test using GraphPad prism software.</p> <p>Results</p> <p>Synergy, evaluated using the CalcuSyn Software, was observed in all four cell-lines at multiple drug concentrations resulting in combination indices under 0.7 at Fa of 0.5 (50% reduction of cell growth). The effects of drug exposures on troxacitabine and gemcitabine nucleotide pools were analyzed, and although gemcitabine reduced phosphorylation of troxacitabine when cells were exposed at equal drug concentrations, there was no effect on phosphorylated pools at drug combinations that were synergistic. The amount of troxacitabine incorporated into DNA was also not affected by the presence of gemcitabine. <it>In vivo </it>testing against a human pancreatic (AsPC-1) xenograft mouse tumor model indicated that both drugs were more than additive at well-tolerated doses and schedule. The biological basis for this synergy is unclear as we did not observe changes in apoptosis, DNA repair, troxacitabine incorporation into DNA or troxacitabine metabolism in the presence of gemcitabine.</p> <p>Conclusion</p> <p>These data, together with phase I clinical data showing tolerability of both agents when combined, suggest combination therapy with troxacitabine and gemcitabine warrants further evaluation in advanced pancreatic cancer patients.</p

Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathological subtypes: a pooled analysis

IntroductionObesity is an unfavorable prognostic factor in breast cancer (BC) patients regardless of menopausal status and treatment received. However, the association between obesity and survival outcome by pathological subtype requires further clarification.MethodsWe performed a retrospective analysis including 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906, GEICAM/9805, GEICAM/2003–02, and BCIRG 001) evaluating anthracyclines and taxanes as adjuvant treatments. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect differences of such prognostic effects by subtype.ResultsMultivariate survival analyses adjusting for age, tumor size, nodal status, menopausal status, surgery type, histological grade, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, chemotherapy regimen, and under-treatment showed that obese patients (BMI 30.0 to 34.9) had similar prognoses to that of patients with a BMI < 25 (reference group) in terms of recurrence (Hazard Ratio [HR] = 1.08, 95% Confidence Interval [CI] = 0.90 to 1.30), BCM (HR = 1.02, 0.81 to 1.29), and OM (HR = 0.97, 0.78 to 1.19). Patients with severe obesity (BMI ≥ 35) had a significantly increased risk of recurrence (HR = 1.26, 1.00 to 1.59, P = 0.048), BCM (HR = 1.32, 1.00 to 1.74, P = 0.050), and OM (HR = 1.35, 1.06 to 1.71, P = 0.016) compared to our reference group. The prognostic effect of severe obesity did not vary by subtype.ConclusionsSeverely obese patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM, and OM than patients with BMI < 25. The magnitude of the harmful effect of BMI on survival-related outcomes was similar across subtypes

Control of perioperative pain

Objective: analysis of the current pharmacological approaches to perioperative pain control, including in patients with chronic pain and opioid dependenceResults: An assessment of pregabalin, gabapentin, celecoxib, and other medications utilized in perioperative pain control as well as a characterization of methods used in pain control in opioid-dependent individuals, including chronic buprenorphine therapy. Detailing how multiple preparations are employed and their effectiveness in intraoperative and postoperative pain management. Also, addressing the increased role of pharmacogenomics in individualized pain management