Occurrence Of Severe Adverse Effects Research Articles

Evaluation of Therapeutic Response Under Biologic Therapy in Patients with Rheumatoid Arthritis

Biotherapy has revolutionized the therapeutic management of rheumatoid arthritis (RA). The objective of the study was to evaluate and compare the efficacy and tolerance of biological disease modifying antirheumatic drugs (bDMARDs) and conventional disease modifying antirheumatic drugs ( cDMARDs) used in RA.
 It was a retrospective study covering 13 years at the level of the immunology unit of the UHU Hassiba Ben Bouali Blida and functional rehabilitation service of the CHU Frantz Fanon Blida. We identified 1866 records of patients with RA, 75 receiving biotherapy and 71 receiving conventional treatment. The therapeutic response was evaluated by the DAS 28-ESR (disease activity score based on erythrocyte sedimentation rate) and interpreted according to the EULAR (European league against rheumatism) judgements criteria.
 A female predominance of 83%, the average age of RA patients was 49.3 ±13.42 years, the mean starting DAS28-ESR was 5.625± 1.4. 84% of patients initially received MTX (methotrexate) on the front line, the decrease in DAS28-ESR was non- significant, with patients exhibiting intolerance (41%), and (45%) ineffectiveness. The introduction of biotherapy mainly Actemra allowed a decrease of DAS28-ESR of - 1.842±0.3812, a significant decrease according to the criteria of the EULAR. Humira had an adverse efficacy and tolerance profile (including the occurrence of severe adverse effects (AEs)).
 In conclusion, biotherapy is more effective than conventional treatments, while in terms of tolerance data are insufficient to make a judgment on it.
 Keywords: Rheumatoid arthritis – Biotherapy.

New Scaffolds of Proteasome Inhibitors: Boosting Anticancer Potential by Exploiting the Synergy of In Silico and In Vitro Methodologies.

Cancer is a complex multifactorial disease whose pathophysiology involves multiple metabolic pathways, including the ubiquitin-proteasome system, for which several proteasome inhibitors have already been approved for clinical use. However, the resistance to existing therapies and the occurrence of severe adverse effects is still a concern. The purpose of this study was the discovery of novel scaffolds of proteasome inhibitors with anticancer activity, aiming to overcome the limitations of the existing proteasome inhibitors. Thus, a structure-based virtual screening protocol was developed using the structure of the human 20S proteasome, and 246 compounds from virtual databases were selected for in vitro evaluation, namely proteasome inhibition assays and cell viability assays. Compound 4 (JHG58) was shortlisted as the best hit compound based on its potential in terms of proteasome inhibitory activity and its ability to induce cell death (both with IC50 values in the low micromolar range). Molecular docking studies revealed that compound 4 interacts with key residues, namely with the catalytic Thr1, Ala20, Thr21, Lys33, and Asp125 at the chymotrypsin-like catalytic active site. The hit compound is a good candidate for additional optimization through a hit-to-lead campaign.

The pharmacokinetics of levobupivacaine 0.5% after infraorbital or inferior alveolar block in anesthetized dogs.

Data are lacking on the pharmacokinetic profile and safety of levobupivacaine (LB) used for regional anesthesia of the maxilla and mandibles in dogs. Infraorbital block (n = 10), inferior alveolar block (n = 10) or both infraorbital and inferior alveolar blocks (n = 10) were administered to dogs undergoing dental surgery under isoflurane anesthesia. The dose of LB was calculated as 0.11 ml/kg2/3 for the infraorbital block and 0.18 ml/kg2/3 for the inferior alveolar block. Blood samples were collected before and immediately after administration of the oral blocks, and 3, 4, 7, 12, 17, 32, 47, 62, 92, and 122 min thereafter. Quantification of LB in plasma was performed by LC-MS/MS. The results are presented as median and interquartile range. In dogs in which all four quadrants of the oral cavity were desensitized with LB, the C max was 1,335 (1,030-1,929) ng/ml, the T max was 7 (4-9.5) min, and the AUC(0 → 120) was 57,976 (44,954-96,224) ng min/ml. Plasma concentrations of LB were several times lower than the reported toxic concentrations, and no signs of cardiovascular depression or neurotoxicity were observed in any of the dogs, suggesting that the occurrence of severe adverse effects after administration of LB at the doses used in this study is unlikely.

Risk Factor Analysis for the Occurrence of Severe Adverse Effects in Eribulin Treatment.

Eribulin is an effective chemotherapeutic agent for the treatment of metastatic breast cancer and advanced or metastatic soft-tissue sarcomas. However, severe adverse effects (SAEs) occur in 30-40% of the patients, and significantly reduce the patients' quality of life and disturb the recommended treatment schedules. Neutropenia is the main cause of treatment suspension, delay, and/or dose reductions, also leading to relative dose intensity reduction. This study aimed to examine the risk factors for SAE occurrence after eribulin treatment. Eighty patients with metastatic breast cancer or advanced or metastatic soft tissue sarcoma who received eribulin were retrospectively evaluated. Risk factors for SAE occurrence in the first cycle were primarily assessed. In addition, factors associated with SAE occurrence during all treatment cycles were evaluated. SAEs in the first cycle occurred in 45% of patients. The primary SAE was neutropenia (91.7%). The incidence of SAEs during all treatment cycles was 61.3%. Multivariate analyses suggested that lower baseline neutrophil and hemoglobin levels were risk factors for SAE occurrence and severe neutropenia incidence in the first cycle. An independent factor associated with SAE occurrence during all cycles was age ≥65 years and a tendency was confirmed for baseline anemia. Baseline neutropenia and anemia were risk factors for SAE occurrence during the first eribulin treatment cycle. Age ≥65 years was also associated with SAE occurrence during all treatment cycles. Patients with these risk factors should be carefully monitored for assessment and prophylaxis.

Pharmacologic Control of CAR T Cells.

Chimeric antigen receptor (CAR) therapy is a promising modality for the treatment of advanced cancers that are otherwise incurable. During the last decade, different centers worldwide have tested the anti-CD19 CAR T cells and shown clinical benefits in the treatment of B cell tumors. However, despite these encouraging results, CAR treatment has also been found to lead to serious side effects and capricious response profiles in patients. In addition, the CD19 CAR success has been difficult to reproduce for other types of malignancy. The appearance of resistant tumor variants, the lack of antigen specificity, and the occurrence of severe adverse effects due to over-stimulation of the therapeutic cells have been identified as the major impediments. This has motivated a growing interest in developing strategies to overcome these hurdles through CAR control. Among them, the combination of small molecules and approved drugs with CAR T cells has been investigated. These have been exploited to induce a synergistic anti-cancer effect but also to control the presence of the CAR T cells or tune the therapeutic activity. In the present review, we discuss opportunistic and rational approaches involving drugs featuring anti-cancer efficacy and CAR-adjustable effect.

Analysis of severe adverse effects following community-based ivermectin treatment in the Democratic Republic of Congo

BackgroundThe progress of mass, community-directed, treatment with ivermectin (CDTI) for onchocerciasis control was disrupted by severe adverse effects (SAE) in the Democratic Republic of Congo (DRC). The study aimed at determining the frequency of post-CDTI SAE as well as factors associated with the occurrence of SAE.MethodsOur retrospective study relied on SAE collection cards, as archived by the DRC Ministry of Health, and compiled for people who benefited from ivermectin treatment then further developed SAE. The study included 945 post-CDTI SAE recorded in DRC between 2003 and 2017. These cases occurred in 15 projects out of 22 projects implemented in the country. All cards were reviewed and analysed.ResultsBetween the years 2003 and 2017, the total average population treated was around 15,552,588 among which 945 cases of SAE were registered in DR Congo, i.e. 6 cases of SAE for 100,000 persons treated per year. 55 deaths related to post-CDTI SAE were recorded, which represents 5.8% of all cases of SAE. Non-neurological SAE were dominated by severe headaches (74.8%), myalgia (64.0%) and arthralgia (62.7%). Neurological SAE were mainly coma (94.1%), motor deficit (75.4%) and palpebral subconjunctival haemorrhages (38.8%). Factors associated with the occurrence of SAE were: male, age over 18 years old, alcohol consumption, hemp intake and the presence of loiasis. The study also highlighted weaknesses of the National Program for Onchocerciasis Control (NPOC) in terms of awareness campaigns among the population.ConclusionCo-endemicity of loiasis and onchocerciasis is one of the key factors responsible for the occurrence of SAE following ivermectin treatment. Mobilization of resources necessary to the appropriate management of SAE and awareness of populations are essential to achieve onchocerciasis control in DRC.

Integrating data from the Investigational Medicinal Product Dossier/investigator's brochure. A new tool for translational integration of preclinical effects.

Integrating data from the Investigational Medicinal Product Dossier/investigator's brochure. A new tool for translational integration of preclinical effects.

The influence of detoxification agents on the intensity of side effects caused by medium-high doses of methotrexate in children with acute lymphoblastic leukemia: case series

SUMMARY Objective The treatment of childhood acute lymphoblastic leukemia (ALL) in Serbia is conducted according to protocol ALL IC BMF-2009. The therapy includes the application of cytostatic drugs methotrexate and 6-mercaptopurine, and drug detoxifying Calcium Folinate. At the moment, 80% of affected children could be cured with current treatment, but resistance to the therapy and its toxic effects remain serious clinical problems. The aim of the study was to investigate the influence of detoxification agents (Calcium Folinate, silymarin and ursodeoxycholic acid) on the side effects of methotrexate, applied in this protocol. Methods A modified acute toxicity form (GPOH) was used for side effects monitoring. The research included children with either standard or intermediate risk ALL in the consolidation therapy phase, who were hospitalised at the Institute for Child and Youth Health Care of Vojvodina in Novi Sad during the period from July 2010 to February 2011. Results The most frequent side effect after 40 applications of methotrexate in ten children was bone marrow depression. Methotrexate caused: leukopenia in 10 patients, thrombocytopenia in 5 patients; after the use of folic acid, platelet count grew in 8 patients, leukocyte in 2 patients. Less frequent side effects: an increase serum transaminase activity, the state of fever, bronchopneumonia, diarrhoea with mild cramps and hypercalcaemia. Conclusion The application of Calcium Folinate, silymarin and ursodeoxycholic acid prevented the occurrence of severe adverse effects caused by medium-high doses of methotrexate. Observed adverse effects were of mild to moderate intensity, reversible and did not significantly disturb the quality of life in treated patients.

The influence of detoxification agents on the intensity of side effects caused by medium-high doses of methotrexate in children with acute lymphoblastic leukemia: Case series

Objective The treatment of childhood acute lymphoblastic leukemia (ALL) in Serbia is conducted according to protocol ALL IC BMF-2009. The therapy includes the application of cytostatic drugs methotrexate and 6-mercaptopurine, and drug detoxifying Calcium Folinate. At the moment, 80% of affected children could be cured with current treatment, but resistance to the therapy and its toxic effects remain serious clinical problems. The aim of the study was to investigate the influence of detoxification agents (Calcium Folinate, silymarin and ursodeoxycholic acid) on the side effects of methotrexate, applied in this protocol. Methods A modified acute toxicity form (GPOH) was used for side effects monitoring. The research included children with either standard or intermediate risk ALL in the consolidation therapy phase, who were hospitalised at the Institute for Child and Youth Health Care of Vojvodina in Novi Sad during the period from July 2010 to February 2011. Results The most frequent side effect after 40 applications of methotrexate in ten children was bone marrow depression. Methotrexate caused: leukopenia in 10 patients, thrombocytopenia in 5 patients; after the use of folic acid, platelet count grew in 8 patients, leukocyte in 2 patients. Less frequent side effects: an increase serum transaminase activity, the state of fever, bronchopneumonia, diarrhoea with mild cramps and hypercalcaemia. Conclusion The application of Calcium Folinate, silymarin and ursodeoxycholic acid prevented the occurrence of severe adverse effects caused by medium-high doses of methotrexate. Observed adverse effects were of mild to moderate intensity, reversible and did not significantly disturb the quality of life in treated patients.

SYSTEMIC BETA-BLOCKERS MAY REDUCE THE NEED FOR REPEATED INTRAVITREAL INJECTIONS IN PATIENTS WITH WET AGE-RELATED MACULAR DEGENERATION TREATED BY BEVACIZUMAB

To evaluate the effect of concomitant systemic therapy in patients with choroidal neovascularization secondary to age-related macular degeneration (AMD) treated by intravitreal bevacizumab and to propose a mechanism for different interindividual response. Retrospective, nonrandomized, single-center, consecutive interventional case series study. Forty-six eyes from 46 patients with choroidal neovascularization secondary to age-related macular degeneration were treated by monthly intravitreal 1.25 mg bevacizumab injections on a pro re nata regime. Patients' files were revised and changes in Early Treatment Diabetic Retinopathy Study best-corrected visual acuity, central foveal thickness as determined by spectral domain optical coherence tomography, number of injections performed, occurrence of severe adverse effects, and systemic concomitant medication were recorded. The effect of systemic medication on final best-corrected visual acuity, central foveal thickness, and number of injections performed was evaluated. The most frequent systemic medications recorded were angiotensin-converting-enzyme inhibitors in 19 patients, beta-adrenergic blocking agents (n = 18), nonsteroidal antiinflammatory drugs (n = 17), diuretics (n = 16), calcium channel blockers (n = 14), benzodiazepines (n = 11), proton-pump inhibitors (n = 9), and statins (n = 8). Thirty-two patients had arterial hypertension. Average follow-up was 25.1 months (standard deviation [SD] = 8.9). Average gain in best-corrected visual acuity was 0.9 (SD = 13.6) and -2.1 letters (SD = 15.9) at 12 months and 24 months, respectively. The average reduction in central foveal thickness was 111 μm (SD = 54) and 105 μm (SD = 71) at 12 months and 24 months, respectively. The average number of intravitreal injections required was 6.7 (SD = 3.2). Patients on treatment with systemic beta-adrenergic blocking agents required less intravitreal injections (5.2, SD = 2.4 vs. 7.9, SD = 3.4) and this difference was statistically significant (P = 0.0068, multiple linear regression). Concomitant systemic beta-adrenergic blocking agents treatment may reduce the need for repeated intravitreal injections of bevacizumab in patients with choroidal neovascularization associated with age-related macular degeneration.

Two cases of opioid rotation applied to patients with chronic pain

Two cases of opioid rotation applied to patients with chronic pain

Long-Term Efficacy and Tolerance of Efavirenz- and Nevirapine-Containing Regimens in Adult HIV Type 1 Senegalese Patients

Owing to their low toxicity, low price, and ease of use, efavirenz (EFV) and nevirapine (NVP) are frequently used as part of antiretroviral regimens for AIDS treatment. Several clinical trials have already studied their efficacy and tolerance. However, long-term observations of the effects of these drugs in patients are limited. We used data from a prospective Senegalese cohort to analyze long-term tolerance and efficacy of these two drugs in a low-resources setting. Patients were included if they started their therapy with EFV or NVP. They were censored after treatment discontinuation. The primary endpoint was the time to treatment discontinuation. Secondary endpoints included time to death, time to disease progression, occurrence of severe adverse effects, CD4 cell recovery, and virological response. Confounding factors were controlled using marginal structural models. The median follow-up time in both EFV and NVP arms was 48 months. The hazard ratio (HR) of drug discontinuation in the EFV arm vs. the NVP arm was 0.84 (0.34; 1.87). There was a borderline difference in virological response [HR 1.38 (0.999; 1.89)] but no differences in time to death [HR 1.15 (0.41; 3.24)], time to AIDS progression [HR 1.25 (0.61; 2.58)], or time to increase in CD4 cell count above 500 cells/mm3. Adverse effects were different between NVP and EFV, but long-term tolerance was good for both. This analysis provided further information on long-term tolerance and efficacy of EFV and NVP in a resource-limited setting.

Acute Adverse Effects of Radiation Therapy and Local Recurrence in Relation to Dietary and Plasma Beta Carotene and Alpha Tocopherol in Head and Neck Cancer Patients

There is a debate concerning the effects of antioxidant vitamins during radiation therapy: Can they reduce the adverse effects of therapy without reducing treatment efficacy? We examined whether dietary and plasma beta carotene and alpha tocopherol were related to severe acute adverse effects of radiation therapy and to cancer local recurrence. We conducted a prospective study of 540 head and neck cancer patients treated by radiation therapy. Dietary intakes of beta carotene and alpha tocopherol were measured by a validated food frequency questionnaire and plasma levels were determined. Acute adverse effects of radiation therapy and local recurrence were documented. A higher beta carotene dietary intake was associated with fewer severe acute adverse effects: odds ratio (OR) = 0.61 [95% confidence interval (CI) = 0.40–0.93]. There was a tendency for a similar effect for plasma beta carotene: OR = 0.73 (95% CI = 0.48–1.11). Participants with higher plasma beta carotene had a significantly lower rate of local recurrence (hazard ratio = 0.67; 95% CI = 0.45–0.99). Alpha tocopherol was not related to severe adverse effects or to cancer recurrence. This study suggests that a higher usual dietary beta carotene intake can reduce the occurrence of severe adverse effects of radiation therapy and decrease local cancer recurrence.

PD5-3-6: Compliance with adjuvant chemotherapy for completely resected non-small cell lung cancer

study. The median age of the study group was 60.9 years and 76.7 % of the patients enrolled were male. 34.9%, 28.8% and 36.2% of the patients were in stage IB, II and III respectively. In addition, 142 of the patients (61.2%) completed all planned cycles, whereas 65 patients (28%) received no therapy. The causes of start failure for adjuvant chemotherapy consisted of decreased postoperative performance status (n=39), refusal (n=13) and distant metastasis at the initial follow-up (n=2). The causes of cessation during adjuvant chemotherapy included the occurrence of severe adverse effects (n=12), aggravation of the disease with newly developed metastasis (n=4) and others (n=6). The mortality related to the adjuvant chemotherapy was 1.3 % (n=3), all of the fatalities were due to pneumonia and sepsis. Univariate analysis showed that age, postoperative complications and pathologic staging were the significant factors that determined whether the adjuvant chemotherapy was completed. Multivariate analysis demonstrated statistically significant differences in compliance when age and pathologic staging were considered. Conclusion: Adjuvant chemotherapy for completely resected NSCLC was performed with satisfactory compliance in approximately 60% of the patients included in this study, and age plays an important role in the compliance of adjuvant chemotherapy. Elderly subsets will be examined to help determine the effect of age on compliance and outcome. In addition, the medical oncologist tended to complete the adjuvant chemotherapy for more advanced cases of lung cancer than for stage IB lung cancer.

Les glucocorticoïdes et leur récepteur : mécanismes d'action et conséquences cliniques

Background. – Glucocorticoids are used as anti-inflammatory, immuno-modulatory, anti-proliferative and cytotoxic drugs, but they also trigger important side-effects. These hormones bind to glucocorticoid receptor α (GRα), an intracellular protein, which acts essentially in the nucleus. Main points. – GRα is a ligand-activated transcription factor that positively or negatively regulates gene expression by distinct mechanisms. Stimulation of gene transcription occurs after direct binding of the receptor to specific responsive DNA elements. Gene activation by glucocorticoids is mainly responsible for certain adverse effects. In contrast, the therapeutic effects of glucocorticoids are predominantly mediated through repression of genes encoding inflammatory mediators. Inhibitory protein–protein interaction between the hormone-activated receptor and the transcription factors NF-κB and AP-1 was found to be the underlying mechanism. However, inhibition of other transcription factors may account for deleterious effects of glucocorticoids, such as adrenal suppression and osteoporosis. GRα also mediates rapid non-genomic effects of glucocorticoids. Side-effects are reduced by using topical glucocorticoids which have a low systemic bioavailability. Moreover, it is important to determine the lowest effective maintenance dose of systemic and topical glucocorticoids to further decrease the risk of adverse effects. This is particularly justified because inhibition of AP-1 and NF-κB activities, that is the anti-inflammatory effect, occurs at much lower hormone concentrations than transactivation. Perspectives. – Clinical use of glucocorticoids is limited by occurrence of severe adverse effects. Therefore, the current aim is to design GRα ligands that retain only the anti-inflammatory activities of GC.