Side Effects Of Combination Therapy Research Articles

Research Progress of B-Cell Lymphoma/Leukemia-2 Inhibitor Combined with Azacytidine in the Targeted Therapy of Acute Myeloid Leukemia.

Objective To investigate the efficacy and safety of azacytidine and B-cell lymphoma/leukemia-2 inhibitors in the treatment of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods The clinical data of 31 patients with AML/MDS who were clearly diagnosed with AML/MDS were analyzed from 2018.10 to 2021.02, and the total amount of azacyclonol and B-cell lymphoma/leukemia-2 inhibitor was used for single or combined chemotherapy, with a total amount of 75 mg/m2∗7 d, divided into 7-10 days of continuous subcutaneous injection, every 28-30 days for a course of treatment. Overall response rate (ORR), median survival, poor response, and genetic mutations were observed. Results A total of 104 courses of treatment were completed in 31 patients, the median course was 3 (1–12), and 6 patients who did not complete 2 courses of treatment were not counted in the statistics. After 2 courses, ORR was 72.0%, CRES was 2 (8.0%), mCR was 16 (64.0%), disease stable was 5 (20.0%), treatment failures were 2 (8.0%), mortality was 40.0%, and median survival time was >5 months. Single-agent and combined ORR was 64.3% and 81.8%, respectively, with median survival of 7.25 and 9 months; ORR for MDS and AML was 66.7% and 76.9%, respectively, median survival of 8 and 11 months was 66.7% and 80.0% of ORRs at 260 and V60 years, respectively, and median survival of 7 and 11.5 months; MDS-EB-1. The ORR of MDS-EB-2 was 75.0% and 62.5%, respectively, with median survival times of 11.5 and 6.5 months. During 2 courses and 4 courses, the rate of transfusion dependence was 64.0% and 55.5%, respectively. Fifteen cases were detected by second-generation sequencing, and the results were 14 cases of combined gene mutations. Conclusion Azacytidine and B-cell lymphoma/leukemia-2 inhibitors have good efficacy and high safety in the treatment of AML and MDS, and the combined treatment is better than that of monotherapy, but the side effects of combination therapy are large.

Combined use of 177 Lu-DOTATATE peptide receptor radionuclide therapy and fluzoparib for treatment of well-differentiated neuroendocrine tumors: A preclinical study.

Peptide receptor radionuclide therapy (177 Lu-DOTATATE) causes DNA strand breaks and has been validated for well-differentiated neuroendocrine tumor treatment. Poly-(ADP-ribose)-polymerase inhibitors have also been used for malignant tumors with deficient DNA repair. We aimed to determine whether the poly-(ADP-ribose)-polymerase inhibitor fluzoparib could enhance the anti-tumor effects of 177 Lu-DOTATATE in neuroendocrine tumor cells and xenografts. The neuroendocrine characteristics of NCI-H727 bronchial carcinoid cells were evaluated by immunofluorescence staining. The synergistic effects of fluzoparib and 177 Lu-DOTATATE were evaluated by cell proliferation and flow cytometry assays. Tumor response and the side effects of combination therapy were also assessed in xenograft mice treated with 77 Lu-DOTATATE and fluzoparib alone or in combination. Somatostatin receptors were specifically expressed in NCI-H727 cells and tumor xenografts. 177 Lu-DOTATATE (22.20MBqmL-1 ) and fluzoparib (50µm) inhibited cell proliferation by 16.6% and 35.6%, respectively, compared to 73.2% in cells treated with their combination. Tumor cell proliferation was significantly suppressed by 177 Lu-DOTATATE (22.20MBqmL-1 , 4.4-fold) and fluzoparib (50µm, 2.1-fold). 177 Lu-DOTATATE caused cell cycle arrest mainly at G1 phase, whereas fluzoparib caused arrest at G2/M phase, and combined treatment with both agents caused cell cycle arrest at G1 phase, similar to 177 Lu-DOTATATE alone. The volume of tumor xenografts was reduced by 18.6% in mice receiving combined treatment, compared to 4.9% and 11.4% in mice treated with 177 Lu-DOTATATE or fluzoparib alone. Fluzoparib can potentiate the anti-tumor effect of 177 Lu-DOTATATE in NCI-H727 cells in a synergistic manner by arresting the cell cycle at G1 phase. Further preclinical and clinical studies are warranted to validate these findings.

A Retrospective Study on Chronic Pelvic Pain Treated with Traditional Chinese Medicine Combined Therapy: 179 Cases (2016–2018)

PurposeThis study aims to evaluate clinical efficiency and side effects of combined therapy of traditional Chinese medicine in female treating chronic pelvic pain.MethodsA retrospective study was conducted by analyzing 179 patients with chronic pelvic pain. They were divided into the 3-course group and the 1-course group. Patients in the 3-course group received combined therapy of traditional Chinese medicine 10 days per menstrual cycle for three months, while the 1-course group received the same combined therapy for only one menstrual cycle. VAS scores of five kinds of pain were compared between the two groups. Meanwhile, SF-36 scores, menstruation, leucorrhea and major accompanying symptoms were analyzed. To assess side effects of the combined therapy, safety indices were recorded before and after treatment as well.ResultsVAS scores of patients in the 3-course group after treatment were significantly lower than that before the treatment. Total scores of SF-36 were significantly improved after the treatment, and persistently improved even after the discontinuation of the treatment. The menstrual and leucorrhea condition improved as well after the treatment. In addition, among the concomitant symptoms, insomnia, loss of appetite, mental fatigue symptoms were significantly improved after the treatment. More importantly, significances were observed in the improvement of most VAS scores between patients who underwent a 1-course treatment and patients with a 3-course treatment. Meanwhile, no significant change was observed in safety indices before and after treatment. Possible adverse events related to the treatment plan for all enrolled patients included mild skin rash in 16 patients, stomachache in 3 patients after taking medicine on an empty stomach, and oral ulcer in 1 patient.ConclusionCombined therapy of traditional Chinese medicine alleviated symptoms of chronic pelvic pain, soothed the accompanying symptoms, and hence helped to improve the life quality of women.

Simultaneous Use of Herbal Medicines and Antihypertensive Drugs Among Hypertensive Patients in the Community: A Review.

In various countries, approximately 80% of patients use herbal medicine, both in single form or in combination with antihypertensive drugs, for the treatment of hypertension. Therefore, this research summarized studies on the simultaneous use of herbal medicines and antihypertensive drugs among hypertensive patients in the community. A literature search was conducted on PubMed in April 2020, and the following keywords were used: “herbal medicines” and “antihypertensive patients.” In total, 15 of 263 articles were found to be eligible in the initial research. Results showed that studies were performed in different countries worldwide including America and those in Europe, Asia, and Africa between 1960 and 2020. The factors associated with the use of herbal medicines and antihypertensive drugs were age, gender, education level, income, and residence. Herbal medicines and antihypertensive drugs are simultaneously utilized primarily due to their safety and high efficacy. Herbal medicine is frequently recommended by friends or colleagues, herbalists, advertisements, and health workers. Garlic is the most common herbal medicine used along with antihypertensive drugs. The side effects of combination therapy with herbal medicines and prescription drugs for the management of antihypertension include shortness of breath and cough, ulcers, diarrhea, knee cramps, and abdominal discomfort. The lack of communication between patients and health care workers could cause an increase in the simultaneous use of herbal medicines and antihypertensive drugs. Therefore, effective communication among health care workers and appropriate care are important in preventing the side effects and other risks of combined therapy.

A Boron-10 nitride nanosheet for combinational boron neutron capture therapy and chemotherapy of tumor

Combination cancer therapy (e.g., radiochemotherapy) is widely used to enhance the therapeutic effects and prevent the recurrence of cancer. However, the side effects of monotherapy are also amplified when treating cancer with combination therapy. A locally activated drug delivery strategy that can release the payload in a tumor-selective manner is greatly needed to overcome the side effects of combination therapy. Here, we explore the potential of combining boron neutron capture therapy and chemotherapy as a new type of radiochemotherapy. Two-dimensional (2D) boron-10-rich nanosheets (BNNSs) were fabricated as a dual-functional delivery system: targeted boron-10 delivery systems for boron neutron capture therapy (BNCT) and drug delivery vehicles to load doxorubicin for chemotherapy. Irradiated by low-energy thermal neutron, BNNSs can produce high linear energy transfer (LET) particles to kill tumor cells, and the loaded doxorubicin can be released in situ at the same time. This neutron-triggered radiochemotherapy shows noteworthy efficacy in suppressing tumor growth in triple-negative breast cancer. To the best of our knowledge, this is the first report to combine BNCT with chemotherapy as a new type of radiochemotherapy. We hope this study could inspire additional BNCT-induced combination cancer therapies and provide insight for the further clinical translation of BNCT.

Effects of double-dose antihistamine or combined therapy in allergic rhinitis

Objective:To compare the efficacy and side effects of combined therapy with single-dose oral antihistamine and intranasal corticosteroid to monotherapy with double-dose oral antihistamine in the treatment of seasonal allergic rhinitis. Method:Eighty-two patients with seasonal allergic rhinitis caused by cypress pollen were enrolled in a randomized, parallel-group studycomparing 2 weeks therapy of either 10mg oral ebastine plus 200 μg intranasal mometasone furoate once daily (combined group) or 20 mg oral ebastine once daily (double-dose group) during the pollen season. Daily rhinoconjunctivitis symptom score and rescue medication use were recorded in both groups. After the treatment period, questionnaires were used to survey the side effects of medicines and dosage form preference of the patients. The levels of IL-6, IL-8 and TNF-α in the peripheral blood were measured before and after the therapy. Result:During the cypress pollen season, the daily rhinoconjunctivitis symptom score of the combined group (n=42, 3.7±0.4) was significantly lower than that of double-dose group (n=40, 4.5±0.5), P<0.001. The daily rescue medication score of the combined group (1.3±0.6) was also significantly lower than double-dose group(1.7±0.7), P<0.001. The daily medication cost of combined group was 7.08±0.33 Yuan, which was less than that of double-dose group (7.28±0.51 Yuan, P=0.002). There was no statistical difference in the rate of adverse reactions between the two groups. The peripheral levels of IL-6, IL-8 and TNF-α in two groups did not show significant difference at the end of therapy . Conclusion:The combined therapy with single-dose oral antihistamine and intranasal corticosteroid was superior to the monotherapy with double-dose oral antihistamine in the treatment of seasonal allergic rhinitis in our study.

Retreatment of Chronic Hepatitis C Infection with Telaprevir: Preliminary Results in Turkey.

The use of pegylated interferon alpha and ribavirin (PegIFN/RBV) for the retreatment of chronic hepatitis C virus (HCV) infection without a sustained virological response (SVR) prior to PegIFN/RBV treatment has resulted in low success rates. To investigate the efficacy and safety of telaprevir (TVR) in combination with PegIFN/RBV in patients infected with HCV genotypes 1 and 4 who were previously treated with PegIFN/RBV and failed to achieve SVR. Multi-center, retrospective, cross-sectional study. The study included 111 patients: 80 prior relapsers, 25 prior null responders, and six prior partial responders to PegIFN/RBV treatment. The patients were given TVR/PegIFN/RBV for 12 weeks, followed by a 12-week PegIFN/RBV treatment; virological response results were assessed at weeks 4, 12, and 24. Treatment was discontinued in patients with HCV RNA >1000 IU/mL at week 4 or with negative RNA results at week 4 but >1000 IU/mL at week 12. Rapid virological response (RVR), early virological response (EVR), extended rapid virological response (eRVR), and virological response at 24th week of treatment were evaluated. The side effects of combination therapy and the rates of treatment discontinuation were investigated. The mean age of the patients was 56.02±9.96 years and 45.9% were male. Ninety-one percent of the patients were infected with viral genotype 1, 69.6% with the interleukin (IL) 28B genotype CT and 20.2% were cirrhotic. The RVR rate was 86.3% in prior relapsers, 56% in prior null responders, and 50% in prior partial responders (p=0.002). EVR rates in those groups were 91.3%, 56%, and 83.3%, respectively (p<0.001). eRVR rates were 83.8% in prior relapsers, 48% in prior null responders, and 50% in prior partial responders (<0.001). The virological response at the 24th week of treatment was found to be the highest in prior relapsers (88.8%); it was 56% in prior null responders and 66.7% in prior partial responders (p<0.001). Common side effects were fatigue, headache, anorexia, malaise, anemia, pruritus, dry skin, rash, dyspepsia, nausea, pyrexia, stomachache, and anorectal discomfort. All treatments were discontinued due to side effects in 9.9% of patients. High virological response rates were obtained with TVR/PegIFN/RBV treatment. Although side effects were frequently observed, the discontinuation rate of combination therapy was low.

Optimal treatment scheduling of ionizing radiation and sunitinib improves the antitumor activity and allows dose reduction.

The combination of radiotherapy with sunitinib is clinically hampered by rare but severe side effects and varying results with respect to clinical benefit. We studied different scheduling regimes and dose reduction in sunitinib and radiotherapy in preclinical tumor models to improve potential outcome of this combination treatment strategy. The chicken chorioallantoic membrane (CAM) was used as an angiogenesis in vivo model and as a xenograft model with human tumor cells (HT29 colorectal adenocarcinoma, OE19 esophageal adenocarcinoma). Treatment consisted of ionizing radiation (IR) and sunitinib as single therapy or in combination, using different dose-scheduling regimes. Sunitinib potentiated the inhibitory effect of IR (4 Gy) on angiogenesis. In addition, IR (4 Gy) and sunitinib (4 days of 32.5 mg/kg per day) inhibited tumor growth. Ionizing radiation induced tumor cell apoptosis and reduced proliferation, whereas sunitinib decreased tumor angiogenesis and reduced tumor cell proliferation. When IR was applied before sunitinib, this almost completely inhibited tumor growth, whereas concurrent IR was less effective and IR after sunitinib had no additional effect on tumor growth. Moreover, optimal scheduling allowed a 50% dose reduction in sunitinib while maintaining comparable antitumor effects. This study shows that the therapeutic efficacy of combination therapy improves when proper dose-scheduling is applied. More importantly, optimal treatment regimes permit dose reductions in the angiogenesis inhibitor, which will likely reduce the side effects of combination therapy in the clinical setting. Our study provides important leads to optimize combination treatment in the clinical setting.

Cutaneous side effects of combination therapy of pegylated interferon 2α and ribavirin

Background Hepatitis C virus infection is the main cause of chronic liver disease, and patients are at risk of developing liver cirrhosis and hepatocellular carcinoma. The treatment in CHC is the combination of pegylated interferon 2a (peg-IFN) and ribavirin (RBV), the standard therapy with 24 to 48 weeks regimen. Cutaneous adverse effects are common, with a higher incidence in combination therapy than in IFN alone, and when serious, discontinuation of therapy is mandatory.

Hepatitis C Virus Treatment in the ‘Real-World’: How Well Do ‘Real’ Patients Respond?

Published clinical trials of the treatment of HCV are largely multicentre prospective pharmaceutical trials. Patients in clinical trials tend to have more favorable outcomes than patients in the 'real-world', due to strict patient selection and differences in treatment conditions and available resources. To assess the outcomes of Hepatitis C infected patients treated at the Barwon Health Liver Clinic with combination Pegylated interferon (PEG-IFN) and Ribavirin (RBV) therapy and to determine factors associated with a treatment response. Retrospective review of patients who received treatment for Hepatitis C at our institution's Liver Clinic from January 2001-September 2011. Patient demographics, comorbidities, treatment-related parameters and side effects were extracted from medical records and analyzed. A total of 190 patients (120 male, 70 female) with a mean age of 42.8 years (range 20-68 years) commenced treatment. The most common genotype was genotype 3 (48.9%), followed by genotype 1 (42.6%). 150 of 190 patients (78.9%) completed treatment and had end of treatment data available. 107 of 182 patients, (58.8%) for whom sustained virologic response (SVR) rate data was available achieved an SVR. Overall response rates were; 46.9%, 68.8% and 62.4% in genotypes 1, 2 and 3 respectively. The response rate was significantly lower in 29 patients with documented cirrhosis (20.7%). Age, diabetes and alcohol abuse did not predict treatment response in our cohort. Side effects reported in 81.6% of patients included general malaise, hematological disturbance and psychiatric issues, and necessitated cessation of therapy in 16 patients (8.4%) and dose reduction in 26 patients (13.7%). Response rates to combination PEG-IFN and RBV therapy at our institution are comparable to other 'real-world' and pharmaceutical registration trials. Side effects of combination therapy were prominent but resulted in fewer discontinuations of therapy compared to pharmaceutical trials.

Cutaneous side effects of combined therapy with sorafenib and pegylated interferon alpha‐2b in metastatic melanoma (phase II DeCOG trial)

During a clinical study with combined therapy of sorafenib and pegylated interferon alpha-2b (SoraPeg study) of the German Dermatologic Oncology Group (ADO/DeCOG), multiple and severe cutaneous side effects were observed. This study sought to analyze these cutaneous side effects, particularly because future studies with combinations of interferon alpha and targeted therapies are planned. In a multicenter phase-II-DeCOG study (NCT00623402) in 10 dermato-oncology centers, 55 patients with metastatic melanoma received a combination of sorafenib (2 x 400 mg/day orally) and pegylated interferon alpha-2b (3 μg/kg body weight 1 x/week subcutaneously). All cutaneous side effects were documented. Forty-one patients (74.5 %) developed cutaneous side effects, particularly exanthems (51.2 %), hand-foot syndrome (36.5 %), alopecia (36.5 %) and pruritus (24.4 %). Due to the cutaneous side effects, dose reductions were required in 10 patients, interruption of therapy in 10 cases and permanent discontinuation of therapy and in one patient with extensive follicular-cystic lesions. Exanthems were seen more frequently in women (76.2 %) than in men (23.8 %). The occurrence of cutaneous side effects was not correlated with clinical outcome or prognosis. The combination of sorafenib/pegylated interferon alpha-2b caused more cutaneous side effects than have been reported for single agents. Despite intensive dermatologic management of the cutaneous side effects 24 % of patients required a dose modification.

Is Combination Therapy Interferon and Ribavirin in Patients with Chronic Hepatitis C Infection Toxic for Eyes?

Many side effects of combination therapy using pegylated interferon (IFN) and ribavirin for treatment of chronic hepatitis C virus (HCV) infection have been well described. Ocular complications are fairly common. Diabetes mellitus (DM) and systemic hypertension are possible suggested risk factors for development of these complications. To determine the frequency of retinopathy and its risk factors in patients treated with combined pegylated IFN and ribavirin for chronic hepatitis C infection. Eligible 98 patients for HCV treatment with pegylated IFN a-2a, a-2b, and ribavirin between October 2011 and March 2012 were included. All patients underwent a baseline full ophthalmological examination, and any visual complaints during treatment prompted a repeat eye examination. Out of the eligible 98 patients, 48 (48.78%) patients received pegylated IFN alpha-2a, and the other 50 (51.21%) patients were treated with pegylated IFN alpha-2b. Out of 98 patients, 21 (21.42%) had diabetes; 19 (19.38%) patients had hypertension and 16 (16.32%) patients had both diabetes; and hypertension. Only 8 patients (8.16%) had documented retinopathy [2 had DM; one had hypertension; 4 had both hypertension and diabetes; and one patient without DM or hypertension]. Univariate logistic regression analysis revealed that diabetic, hypertensive patients are at increased risk for development of IFN-associated retinopathy (IAR) (P=0.007, Odds ratio=6.5, 95% confidence interval=1.56-27. Retinopathy in chronic HCV-infected patients undergoing treatment with combination of pegylated IFN-alpha and ribavirin therapy appears to be relatively low, and treatment cessation is rarely needed. Diabetic, hypertensive patients are at increased risk for IAR and are recommended to be ophthalmologically followed-up.

The effect of combined therapy with deferoxamine and deferiprone on serum ferritin level of beta-thalassemic patients

ObjectiveTo determine the effect of combined therapy with deferoxamine and deferiprone on serum ferritin level of beta-thalassemic patients.Method and materialsThis controlled clinical trial was conducted on 26 major beta-thalassemic patients. Twelve patients in case group received deferiprone 75 mg/kg/day three times a day (TDS) orally with deferoxamine 30–50 mg/kg subcutaneously every other day. Fourteen patients in control group received deferoxamine 30–50 mg/kg/day subcutaneously for 6–12 hours/day and 5–6 days per week. Serum ferritin level was measured at the beginning and at the end of the third and the sixth months of study. Side effects of combined therapy were assessed. Data were analyzed by SPSS software v: 16.0 and t-Student and compared t-tests.ResultsThe mean of serum ferritin level in case group significantly decreased from 7539.8 ± 3434.9 µg/l at the beginning of study to 4848.7 ± 2706.2 µg/l (P < 0.001) and to 4338.3 ± 2308.8 µg/l (P < 0.001) at the end of the third and the sixth months of study, respectively. The mean of serum ferritin level in control group insignificantly increased from 5668 ± 3613.8 to 6210.8 ± 3940.9 µg/l and to 5742 ± 3205.9 µg/l at the end of the third and the sixth months of study, respectively. The common side effects of combined therapy were nausea (8.3%) and arthropathy (8.3%). A mild transient neutropenia and liver enzymes elevation happened in four patients of case group.ConclusionCombined therapy with deferoxamine and deferiprone significantly decreases serum ferritin level. It has little side effect and is suggested for major beta-thalassemic patients as a suitable therapy.

C 型 肝炎ウイルスの抗ウイルス療法

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis and liver cancer. Previously, the consensus strategy against HCV infection was interferon mono-therapy. Now, pegylated interferon (PEG-IFN) with ribavirin combination therapy for 24-48 weeks is used against chronic hepatitis C and can achieve a sustained viral response (SVR) in about 50% of patients with genotype 1b and high viral loads. The number of elderly Japanese patients with chronic hepatitis C has increased compared to that in western countries. The efficacy of IFN therapy for elderly patients with genotype 1 and high viral titers is lower than in young patients, because the side effects of combination therapy with PEG-IFN and ribavirin are pronounced with a reduction in blood count. To avoid discontinuation of therapy and overcome the low SVR in elderly patients, ribavirin dosing, based on the total clearance of ribavirin (CL/F), may be considered to be increasingly valuable. Approximately 25% of HCV carriers have normal ranges of serum alanine amino transferase (ALT). The rate of SVR in patients with persistently normal serum ALT (PNALT) is almost as same as that in HCV carriers, in terms of IFN therapy. This evidence suggests that patients with PNALT should be considered for IFN therapy. Novel treatment options currently in development are focused on inhibition of HCV-specific enzymes, NS3 protease and NS5B polymerase, and several drugs have entered clinical trials. Now, patients with HCV and liver cirrhosis can be given IFN therapy, except in the case of genotype 1b and high viral loads. This therapy should contribute to an improvement in the prognosis. It would appears that interferon will remain an element of anti-HCV therapy for the immediate future, although new regimens will be necessary for advanced combination therapy. It is hoped that new forms of interferon that are more effective, less toxic, and more convenient can be developed.

The Use of Growth Factors to Manage the Hematologic Side Effects of PEG-Interferon Alfa and Ribavirin

Hematologic side effects (anemia, neutropenia, and thrombocytopenia) of combination therapy with pegylated (PEG)-interferon alfa and ribavirin are commonly encountered during antiviral therapy for chronic hepatitis C (HCV). An important consequence of these side effects is dose modification of PEG-interferon alfa, ribavirin, or both. Dose modification (including discontinuation) diminishes the efficacy of optimal treatment regimen for HCV and may have a negative impact on sustained virologic response. Additionally, fatigue associated with anemia may impair patients' quality of life. The clinical implications of neutropenia or thrombocytopenia are less clear than for anemia; nevertheless, severe infection and bleeding are uncommon. Dose adjustments effectively treat these hematologic side effects, but the resulting suboptimal dosing and potential impact on virologic response are major concerns. Recent attempts to maximize adherence to the optimal treatment regimen have used hematopoietic growth factors rather than dose adjustment to treat side effects. Research on growth factor support has focused on anemia and neutropenia. Epoetin alfa and darbepoetin alfa are erythropoietic growth factors that effectively increase hemoglobin while maintaining the optimal ribavirin dose and improving patients' quality of life. Preliminary work suggests that filgrastim, granulocyte colony stimulating factors, may be an effective treatment of interferon-induced neutropenia. Although this early work shows tremendous promise for managing hematologic side effects of combination therapy for HCV, and potentially enhancing adherence, further research is needed to clarify the efficacy, safety, and cost-effectiveness of growth factors in the management of patients with chronic HCV.

Impact of Adherence on the Outcome of Antiviral Therapy for Chronic Hepatitis C

Nearly 4 million people in the United States have evidence of hepatitis C infection (HCV), representing a significant cause of cirrhosis and liver cancer as well a major burden to our healthcare systems and society. Antiviral therapy can successfully eradicate HCV over the long term, potentially reducing the risk of progression and improving patients' quality of life. The currently preferred HCV treatment is a combination of pegylated interferon alfa and ribavirin, which can achieve an overall sustained viral eradication rate of 55%. The duration of this treatment is typically determined by HCV genotype and the patient's early virologic response to the antiviral regimen. Evidence has accumulated over the past few years to indicate that close adherence to the optimal antiviral regimen can enhance sustained virologic response. But optimal treatment outcomes require diligence and careful management of side effects related to combination therapy. Although reducing the dose of pegylated interferon alfa, ribavirin, or both can effectively treat side effects, suboptimal doses of this regimen, especially ribavirin, may negatively affect virologic response. An alternative strategy is to use growth factors to treat cytopenias. This strategy can obviate dose reductions while potentially improving patients' quality of life. Patient support seems especially important early after the initiation of antiviral therapy. Encouraging study findings involving the growth factors, epoetin alfa and darbepoetin alfa, suggest improved anemia and quality of life while maintaining the optimal ribavirin dose. Future work should be aimed at providing stronger evidence for the use of these "supportive products" during anti-HCV therapy. As we strive to develop better treatment options for our HCV patients, the importance of adhering to the treatment regimen continues to play a central role. Effective side effect management is crucial for the success of this treatment because adherence is negatively affected by side effects related to the antiviral regimen. By identifying and addressing the important side effects of combination therapy for HCV, adherence to treatment can be improved and optimal outcomes can be achieved.

Combination therapy with ribavirin and interferon in a cohort of children with hepatitis C and haemophilia followed at a pediatric haemophilia treatment center.

Nearly all children with bleeding disorders who received factor concentrates prior to the late 1980s were infected with hepatitis C. Treatment of adults infected with hepatitis C with combination therapy consisting of ribavirin and interferon has shown sustained response rates of 30-60%. Little data is available on the response of children infected with hepatitis C treated with combination therapy, especially those with bleeding disorders. We wish to report a single paediatric haemophilia treatment center's results of treatment of adolescents with haemophilia and hepatitis C infection with combination therapy. All patients followed at the haemophilia treatment center with hepatitis C, who were human immunodeficiency virus (HIV) negative and had a measurable hepatitis C viral load were eligible. Study patients received at least 6 months of 3 MU interferon-alpha via subcutaneous injection three times per week and 1000 mg day(-1) of ribavirin. Eleven patients agreed to participate in the study. Three patients had an un measurable viral load after 6 months of combination therapy. All three completed 12 months of medication and continued to remain free of hepatitis C for 12 months after discontinuation of therapy. Side-effects of combination therapy were significant but tolerable. The sustained response rate in this study is similar to the historical response rate seen in adults but less than the other reported response rates seen in children treated with combination therapy. Given the toxicity of combination therapy, and natural history of hepatitis C infection in children, consideration of a liver biopsy to evaluate disease progression prior to considering antiviral medications is warranted.

Is multimodal analgesia necessary to facilitate postoperative recovery?

Nociception can be defined as the detection of noxious stimuli and the subsequent transmission of information to the brain. The activity in the nociceptive pathways leads to the experience of pain. Such activity can be modulated by endogenous (eg, neuronal and nonneuronal damage) and exogenous (eg, psychosocial, environmental) stress. The resultant pain behaviors and suffering can be measured and provide useful parameters for clinical assessment. Based on the understanding that basic pain pathophysiology is a complex of interrelated systems, it is clear that one method of analgesia cannot be sufficient to provide optimal pain relief. Therefore, additive and synergistic effects of different types of analgesics would provide sufficient analgesia with fewer side effects. Over the last decade, there have been several studies on the efficacy and side effects of combination therapy compared with the traditional unimodal approach. From the available data, it seems advantageous to use multimodal pain therapy, although more needs to be known on the regimens used, optimal drug composition, and interpatient variability. The introduction of hospital acute pain services has been instrumental for optimizing postoperative pain treatment. Realization by our surgical and nursing colleagues that efficient analgesia is associated with beneficial physiologic effects has prompted several institutions to recognize pain relief as an indicator of patient outcome. The effect of multimodal pain relieving techniques on postoperative morbidity has been studied with the intent to show that patient outcome would be influenced by the type and quality of analgesia. The lack of significant positive results, so far reported, might be explained by the lack of integrating pain relief within an overall recovery program tailored for each specific type of surgery. At this point, it might be necessary to revise the concept of multimodal analgesia in the context of surgical rehabilitation. In this article, all these aspects are reviewed critically to provide the reader with some basis for improving perioperative care so that the benefits of good pain relief become evident.

Combined therapy with prospidin and methotrexate in rheumatoid arthritis (12 months controlled study)

Objective. To study efficacy of combined therapy with prospidin (P) and methotrexate (MT) in rheumatoid arthritis (RA). Methods. 60 pts with RA (53 female and 7 male) aged 20 to 72 years were included. The mean disease duration was 5,6 years. 51 patients had 2 and 9-3 degree of RA activity. The pts received P 200-300 mg/week intravenously dropwise with 200 ml of 5% glucose solution during 4 weeks. Intramuscular injections of MT 10 mg/week were given at the third day after the administration of P. Maintenance treatment included P 100-200 mg/week and MT 10 mg/week. Results. Combined therapy provided fast and marked clinical effect in pts with unfavorable variants of RA. 50-70% improvement according to ACR criteria was achieved in 50% of pts received P and MT during 12 months. Amelioration of some laboratory indices of RA activity was also noted. Side effects of combined therapy were reversible and not severe. They led to discontinuation of therapy only in 14,8% .

Saga de la découverte de l’IL-1 et du TNF et de leurs inhibiteurs spécifiques dans la pathogénie et dans le traitement de la polyarthrite rhumatoïde

In the seventies, the molecule subsequently termed IL-1 was among the first cytokines to attract the attention of rheumatologists due to its biological role in tissue destruction and bone resorption. In the mid-eighties, cachectin/tumor necrosis factor was found to share some of these biological activities, and a strong synergism between the two cytokines became evident. While IL-1 appeared to be more important at the local level, TNF played a more prominent part at the systemic level. In 1984, we became aware of the existence of an antagonist to IL-1 - subsequently termed IL-1Ra (interleukin-1 receptor antagonist) - in urine of febrile patients; its mechanism of action was elucidated in 1987 and the molecule cloned in 1990. The natural inhibitors of TNF were identified in 1996/97 by different investigators and proved to be soluble fragments of the TNF receptor. A concept, commonly accepted at present, is that disease activity and clinical outcome are controlled by the balance between agonistic and antagonistic cytokines, and at present the principal goal is to understand the underlying mechanisms. This concept is illustrated by observations in numerous animal models. The control of IL-1 and TNF is strongly dependent on the contact between activated lymphocytes and monocytes, the main source of these cytokines. Inhibiting this interaction by interfering with ligand and counter-ligand may be a useful approach if it is possible to maintain the production of the cytokine antagonist. Apolipoproteins A-I and A-II as well as β2-integrins are molecules that block ligand/counterligand interaction. According to animal experiments and clinical data, blocking either IL-1 or TNF, or both, is beneficial. However, to determine not only the benefit but also the side effects of combination therapy in the human system, long-term clinical trials will be required.