Development Of Serious Adverse Effects Research Articles

Nanobiotechnology and Immunotherapy: Two Powerful and Cooperative Allies against Cancer.

Simple SummaryConventional anti-cancer treatments for metastatic tumors include chemotherapy and radiation. These approaches can result in harmful side-effects and, in the vast majority of cases, are not curative. Recently, novel treatments have been developed in order to stimulate the host immune system to fight cancer. This type of therapeutic approach, called immunotherapy, has gained a lot of attention in recent years due to discoveries that have deciphered the immunosuppressive role of the tumor microenvironment and underpinning molecular signals. To enhance the delivery of therapeutic drugs to the tumor site, nanoparticle-based delivery systems can be used to reduce off-target effects, and to modulate immune cells present in the tumor microenvironment. This novel therapeutic approach can synergize with other immunotherapies such as immune checkpoint blockade inhibitors and adoptive cell therapy, by enhancing the infiltration of activated immune cells to the tumor site, and by limiting local immunosuppression.A number of novel cancer therapies have recently emerged that have rapidly moved from the bench to the clinic. Onco-immunotherapies, such as immune checkpoint blockade inhibitors and adoptive cell therapies, have revolutionized the field, since they provide a way to induce strong anti-tumor immune responses, which are able to fight cancer effectively. However, despite showing great efficacy in hematological and some solid tumors, unresponsiveness, development of therapy resistance and the development of serious adverse effects, limit their capacity to impact the vast majority of tumors. Nanoparticle-based delivery systems are versatile vehicles for a wide variety of molecular cargoes and provide an innovative strategy to improve conventional onco-immunotherapies. They can be finely tuned to release their contents in the tumor microenvironment, or to deliver combinations of adjuvants and antigens in the case of nanovaccines. In this review, we summarize the recent advancements in the field of nanobiotechnology, to remodel the tumor microenvironment and to enhance immunotherapies.

Benefits and potential risks of intensive goals in the treatment of arterial hypertension. Systematic review and meta-analysis of clinical trials

There is controversy regarding the most appropriate goals for blood pressure control. We assess the benefits and risks of chossing different therapeutic thresholds. We perform a systematic review and meta-analysis of large clinical trials in order to assess the impact of different therapeutic strategies on the reduction of cardiovascular events and the development of serious adverse effects. Four trials with 29,820 participants were included, with mean age of 65 ± 7.9 years; 42.2% were women and 22% were diabetic. Overall, intensive goals showed a non-significant trend towards reducing cardiovascular mortality (relative risk [RR]: 0.89; 95% confidence interval [CI]: 0.68-1.07; p=0.16) with non-impact in total mortality (p=0.45) and with moderate heterogeneity among the included trials (I index [I]2:44 and 59% respectively). Nevertheless, intensive goals reduce non-fatal cardiovascular events (RR: 0.82; 95% CI: 0.70-0.91; p=0.0003), being consistent in all the analyzed trials (I2: 0%). Regarding adverse effects, intensive goals caused more emergency consultations or hospitalization (RR: 1.98; 95% CI: 1.59-2.46; p<0.0001; I2: 14%), with no clear increase in renal failure (RR: 1.65; 95% CI: 0.94-2.89) but with increase in falls and syncope (RR: 2.39; 95% CI: 1.56-3.67; p<0.0001; I2: 28%). Intensive blood pressure goals reduce non-fatal cardiovascular events, without reduction in mortality, and with an increase of risk of adverse events. These results suggest that individual goals should be set according to the risk of each patient. ­ PROSPERO (CRD42020149134).

Glucocorticoid-Induced Leucine Zipper as a Druggable Target in Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex pathogenesis, affecting people of all ages. They are characterized by alternating phases of clinical relapse and remission, depending on the fine balance between immune cells and the gut microbiota. The cross talk between cells of the immune system and the gut microbiota can result in either tolerance or inflammation, according to multifactorial triggers, ranging from environmental factors to genetic susceptibility. Glucocorticoid (GC) administration remains the first-line treatment for IBDs, although long-term use is limited by development of serious adverse effects. Recently, new alternative pharmacological therapies have been developed, although these are not always effective in IBD patients. There is a constant demand for effective new drug targets to guarantee total remission and improve the quality of life for IBD patients. The glucocorticoid-induced leucine zipper (GILZ) has been implicated as a promising candidate for this purpose, in view of its powerful anti-inflammatory effects that mimic those of GCs while avoiding their unwanted adverse reactions. Here we present and discuss the latest findings about the involvement of GILZ in IBDs.

10-летний опыт лечения фиброзной дисплазии челюстно-лицевой области препаратами алендроновой кислоты

Fibrous dysplasia is a benign rare hamartom disease of bones, characterized by a combination of fibrous tissue elements in the focis. At the present time surgical treatment is the most preferable, however, in the case of small foci or subtotal skull bone affected this approach is not rational or impossible. The accumulated foreign and our experience of conservative treatment of patients with bisphosphonate series increases the possibilities for choosing the tactics of treating patients with this congenital pathology. When using this drug, there was no development of serious adverse effects and in a number of cases, surgical treatment was avoided.

POSSIBILITIES OF THERAPY OF HER-2-POSITIVE REGIONAL BREAST CANCER

Breas t cancer heads the list of malignant neoplasms in women. In this connection the regional forms of cancer are diagnosed in one fourth of the patients. The treatment of regional cancer begins with systemic therapy and aimed at gaining of state fit for operation. The choice of modern treatment strategy is based on determination of molecular subtype of the tumor. One of them is referred to HER-2-positive cancer, requiring the administration of additional targeted therapy. This form of cancer is referred to prognostically pejorative tumors, as it’s more aggressive, leads to fast metastasis and early death of the patients. The “golden standard” of systemic chemotherapy is defined as administration of docetaxel and trastuzumab, and antracyclic drugs, which also prove to be efficient. However concomitant administration of trastuzumab and antracyclines is limited due to their cardiotoxicity. Chemotherapy is not always efficient and, upon recommendations both of Russian and international oncologists, radiotherapy is the next stage of treatment. The question about radiosensibility of HER-2-positive tumors is still open and worth studying. Addition of radiotherapy to regional cancer treatment regimen in combination with the targeted therapy and chemotherapy may contribute to obtaining better survival rate and disease control. There are still no clearly defined standard for the sequence of chemo-radiation therapy. Simultaneous chemo-radiatiojn therapy results in reliably better loco-regional control of tumor and enables to gain a higher degree of pathomorphological response on the one hand, and it may result in development of serious adverse effects on the other hand. Striving for improvement of immediate results of antineoplastic therapy, including that of regional cancer, by combining various methods, one should keep in mind the increasing action toxicity, which may have a considerable impact on the patients’ quality of living. Continuation of experiments and clinical trials in this direction is rather actual, as it allows getting new data for treatment of regional breast cancer.

Antiviral treatment of feline immunodeficiency virus-infected cats with (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine.

Feline immunodeficiency virus (FIV), the causative agent of an acquired immunodeficiency syndrome in cats (feline AIDS), is a ubiquitous health threat to the domestic and feral cat population, also triggering disease in wild animals. No registered antiviral compounds are currently available to treat FIV-infected cats. Several human antiviral drugs have been used experimentally in cats, but not without the development of serious adverse effects. Here we report on the treatment of six naturally FIV-infected cats, suffering from moderate to severe disease, with the antiretroviral compound (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine ([R]-PMPDAP), a close analogue of tenofovir, a widely prescribed anti-HIV drug in human medicine. An improvement in the average Karnofsky score (pretreatment 33.2 ± 9.4%, post-treatment 65±12.3%), some laboratory parameters (ie, serum amyloid A and gammaglobulins) and a decrease of FIV viral load in plasma were noted in most cats. The role of concurrent medication in ameliorating the Karnofsky score, as well as the possible development of haematological side effects, are discussed. Side effects, when noted, appeared mild and reversible upon cessation of treatment. Although strong conclusions cannot be drawn owing to the small number of patients and lack of a placebo-treated control group, the activity of (R)-PMPDAP, as observed here, warrants further investigation.

Frequent-relapsing, steroid-dependent minimal change disease: is rituximab the answer?

In patients with minimal change disease, development of steroid-dependency or frequent relapses pose difficult therapeutic problems. Prolonged administration of corticosteroids or the use of additional immunosuppressive therapy can result in significant toxicity. Recent data point to the use of rituximab as an important treatment option to induce long-term remission in patients with minimal change diseases who are either frequent relapsers or require significant immunosuppression to remain in remission. Minimal change disease (MCD) accounts for the majority of cases of idiopathic nephrotic syndrome (NS) in children and up to 20% of cases of idiopathic NS in white adults [1]. On kidney biopsy, MCD is characterized by widespread effacement of epithelial cell foot processes on electron microscopy, while glomeruli appear normal on light microscopy and immunoglobulin and complement deposition are absent on immunofluorescence. Most cases of MCD are idiopathic, although drugs (such as non-steroidal anti-inflammatory drugs), hematological malignancies (mainly Hodgkin lymphoma) and thymoma are well-recognized causes of secondary MCD. While most patients respond to corticosteroid therapy, up to 25% of treated patients have frequent relapses and up to 30% of patients become steroid dependent [2, 3]. In these patients, alternative therapies aimed at minimizing corticosteroid toxicity have been used, including alkylating agents, antimetabolites and calcineurin inhibitors. While these agents may be beneficial, some patients respond poorly or not all, and their use may be complicated by the development of serious adverse effects, e.g., infertility and malignancy with the use of cyclophosphamide. With calcineurin inhibitors, steroid de

Infliximab for severe, treatment-resistant psoriasis: a prospective, open-label study

Infliximab, a mouse-human chimeric monoclonal antibody directed against tumour necrosis factor-alpha, has been shown to be effective for moderate to severe psoriasis, but there are few data published on its use in recalcitrant, treatment-resistant disease or in combination with other antipsoriatic therapies. To report our experience with infliximab in the treatment of patients attending a tertiary referral service with severe recalcitrant disease. All patients attending a tertiary referral service for severe psoriasis who were treated with infliximab between 2002 and July 2005 were entered into a prospective, open-label study. Details on disease phenotype, clinical course and adverse events were recorded together with measures of disease severity [Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index, clinical photography] at baseline, weeks 2 and 6, and then at 2-monthly intervals throughout the treatment period. Twenty-three patients were treated with infliximab during the study; one patient had pustular psoriasis and was therefore excluded from statistical analysis. All had severe disease (baseline PASI 26.5+/-6.7, mean+/-SD, n=22) and had received at least two systemic therapies for psoriasis in the past; 16 were taking one or more concomitant therapies at the time of treatment initiation. At week 10, 95% had achieved a 50% or greater improvement in baseline PASI (PASI 50), and 77% had achieved a 75% or greater improvement (PASI 75). Efficacy was sustained in the longer term, with eight of 10 patients on treatment for more than 11 months maintaining at least a PASI 50. Only one patient had treatment withdrawn due to lack of efficacy, two suffered severe systemic infections including extrapulmonary tuberculosis (splenic abscess) and cellulitis, and six have discontinued due to adverse effects including infusion reactions (two), severe thrombocytopenia (one), hepatitis (one) and malignancy (two). Data from this open-label study suggest that infliximab is a rapidly effective treatment for patients with severe, treatment-resistant disease, although approximately 25% of patients had to discontinue therapy due to the development of serious adverse effects. Long-term follow-up, continued pharmacovigilance, and further controlled comparative studies will be required to evaluate fully the risks associated with infliximab in the context of this already difficult to treat population.

Do Corticosteroids Prevent Oesophageal Stricture After Corrosive Ingestion?

The most serious complication of corrosive damage to the oesophagus besides perforation is stricture formation. The role of corticosteroids in preventing corrosive-induced strictures is controversial. This review evaluates the usefulness of corticosteroid treatment by critically assessing clinical reports published between 1991 and 2004 in the English, German, French and Spanish literature. Inclusion criteria were the presence of second- or third-degree oesophageal injuries documented by endoscopy and management involving either at least an 8-day course of corticosteroids or no steroid therapy. Ten studies with a total of 572 patients fulfilled the inclusion criteria: six studies employed corticosteroids, two studies did not use corticosteroids, and two studies compared the outcome with and without corticosteroid treatment. In those patients with second-degree burns, the incidence of stricture in the corticosteroid-treated patients was 13.8% and in the non-corticosteroid-treated patients was 6.3%. In those patients with third-degree burns, significantly worse results were found in the corticosteroid-treated group (71.0%) than in the non-corticosteroid-treated group (23.1%). As all studies did not separate second- and third-degree burns, re-analysis of the outcome was undertaken. In the 305 patients treated with corticosteroids, 35.1% developed strictures, whereas 33.3% of the 267 non-corticosteroid-treated patients developed strictures. These data suggest that systemic corticosteroids are not beneficial for second- and third-degree corrosive oesophageal burns. Therefore, the use of corticosteroids in the management of corrosive ingestions should be abandoned as they do not prevent the development of strictures and may lead to the development of serious adverse effects.