Glucocorticoids are potent anti-inflammatory drugs, although their use is associated with severe side effects. Loading glucocorticoids into suitable nanocarriers can significantly reduce these undesirable effects. Macrophages play a crucial role in inflammation, making them strategic targets for glucocorticoid-loaded nanocarriers. The main objective of this study is to develop a glucocorticoid-loaded PLGA nanocarrier specifically targeting liver macrophages, thereby enabling the localized release of glucocorticoids at the site of inflammation. Dexamethasone acetate (DA)-loaded PLGA nanospheres designed for passive macrophage targeting are synthesized using the nanoprecipitation method. Two types of PLGA NSs in the size range of 100-300 nm are prepared, achieving a DA-loading efficiency of 19 %. Sustained DA release from nanospheres over 3 days is demonstrated. Flow cytometry analysis using murine bone marrow-derived macrophages demonstrates the efficient internalization of fluorescent dye-labeled PLGA nanospheres, particularly into pro-inflammatory macrophages. Significant down-regulation in pro-inflammatory cytokine genes mRNA is observed without apparent cytotoxicity after treatment with DA-loaded PLGA nanospheres. Subsequent experiments in mice confirm liver macrophage-specific nanospheres accumulation following intravenous administration using in vivo imaging, flow cytometry, and fluorescence microscopy. Taken together, the data show that the DA-loaded PLGA nanospheres are a promising drug-delivery system for the treatment of inflammatory liver diseases.
- MeSH
- Anti-Inflammatory Agents pharmacology chemistry MeSH
- Dexamethasone * pharmacology chemistry analogs & derivatives MeSH
- Liver * drug effects metabolism MeSH
- Polylactic Acid-Polyglycolic Acid Copolymer * chemistry MeSH
- Macrophages * drug effects metabolism MeSH
- Mice MeSH
- Nanospheres * chemistry MeSH
- Drug Carriers chemistry pharmacology MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Sdělení prezentuje případ 72leté pacientky s těžkým průběhem onemocnění pemphigus vulgaris. Během systémové léčby (glukokortikoidy, azathioprin, rituximab a intravenózní imunoglobuliny) došlo k závažným komplikacím – dřeňovému útlumu po azathioprinu, k infekci covidem-19 a dvěma břišním operacím pro perforaci divertiklu a ileus. I přes všechny komplikace se stav pacientky stabilizoval na nízké dávce systémových kortikosteroidů. V druhé části sdělení se autoři věnují současným terapeutickým možnostem léčby pemphigus vulgaris.
The authors present the case of a 72-year-old patient with severe pemphigus vulgaris. During systemic treatment (glucocorticoids, azathioprine, rituximab and intravenous immunoglobulins) serious complications occurred – azathioprine-induced bone marrow suppression, COVID-19 infection and two abdominal surgeries for diverticular perforation and ileus. Despite all the complications, the patient’s condition stabilized on a low dose of systemic corticosteroids. In the second part of the communication, the authors discuss the current therapeutic options for the treatment of pemphigus vulgaris.
- MeSH
- Azathioprine administration & dosage pharmacology adverse effects therapeutic use MeSH
- Immunoglobulins, Intravenous administration & dosage pharmacology therapeutic use MeSH
- Humans MeSH
- Disease Management MeSH
- Pemphigus * diagnosis drug therapy complications MeSH
- Prednisone administration & dosage pharmacology therapeutic use MeSH
- Rituximab administration & dosage pharmacology therapeutic use MeSH
- Aged MeSH
- Check Tag
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- MeSH
- Child MeSH
- Lower Extremity pathology MeSH
- Edema etiology MeSH
- Humans MeSH
- Nephrotic Syndrome * diagnosis drug therapy MeSH
- Face pathology MeSH
- Prednisone administration & dosage pharmacology therapeutic use MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Case Reports MeSH
Aims: To investigate the efficacy and safety of intravitreal Dexamethasone implant (DEX-I) therapy in the treatment of diabetic macular edema (DME) refractory to intravitreal bevacizumab (IVB). Material and methods: This retrospective and cross-sectional study included 37 eyes of 37 patients who received 3 loading doses of IVB injections for DME with no response and underwent DEX-I implant. Best-corrected visual acuity (BCVA), intraocular pressure (IOP) measurements and central foveal thickness (CFT) measured by spectral domain optical coherence tomography (SD-OCT) were recorded and compared before DEX-I, at the first week, first, second, third and sixth months. Duration of DME, glycated hemoglobin (HbA1c) levels, DME types and lens status (phakic, pseudophakic) were also recorded. Results: The mean age of the patients was 61.14 ±8.69 years (59.5% male, 40.5% female). 35.1% of the patients had cystoid macular edema, 64.9% had diffuse macular edema and 73 % were phakic and 27% were pseudophakic. BCVA, CFT and IOP values before DEX-I injection were 0.78 ±0.16 LogMAR, 493.73 ±107.6 μm and 13.05 ±2.59 mmHg, respectively. At 6 months after DEX-I, BCVA, CFT and IOP values were 0.64 ±0.11 LogMAR, 397.35 ±59.72 μm and 16.3 ±2.51 mmHg, respectively. In all follow-ups, there was a significant improvement in BCVA, a significant decrease in CFT and a significant increase in IOP compared to pre-injection. Ocular hypertension was observed in 0.8 % of patients and progression of cataract progression in 1% of patients after treatment. Conclusion: DEX-I therapy is an effective and safe treatment option for DME refractory to IVB treatment.
Chronic bronchitis is increasingly reported as a healthcare challenge in clinical settings partially due to the disease's bad prognosis and unresponsiveness to therapy, including the ineffectiveness of glucocorticoids. The ineffectiveness could have a link with genetic polymorphism of receptor genes resulting in inappropriate glucocorticoid pharmacodynamics. We sought to identify the role of gene polymorphism in the response of patients with chronic bronchitis to prednisolone therapy. To do so, a total of 60 newly diagnosed chronic bronchitis patients enrolled in the present study. Prednisolone at a dose of 30mg/day for two weeks was given and respiratory parameters [forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC were measured before and after therapy. Blood samples were withdrawn for genetic profiling of genes involved in glucocorticoids pharmacodynamics, including BCII (rs41423247), N363S (rs56149945), and ER22/23EK (rs6189/rs6190) measured for their homozygous versus heterozygous gene splice variants.Results: Gene splice variants for BCII (rs41423247), N363S (rs56149945), and ER22/23EK (rs6189/rs6190) homozygous (73.3%, 98.7%, and 95%) represented a higher percentage than heterozygous (26.7%, 1.7%, and 5%). The respiratory parameters FEV1, FVC, and FEV1/FVC have shown significantly (p<0.05) better values at baseline in homozygous versus heterozygous, correspondingly, the responsiveness to therapy has shown significantly (p<0.05) better values in homozygous versus heterozygous.Conclusion: The study has provided a good template for genetic behaviour toward individualised medicine in our locality providing that these genes could be a cornerstone for discovering issues related to the pharmacodynamics profiling of drugs in clinical settings.
- MeSH
- Bronchitis, Chronic * diagnosis genetics MeSH
- Glucocorticoids pharmacology MeSH
- Humans MeSH
- Polymerase Chain Reaction methods MeSH
- Polymorphism, Genetic genetics MeSH
- Prednisolone pharmacology therapeutic use MeSH
- Protein Isoforms genetics MeSH
- Receptors, Glucocorticoid * genetics drug effects MeSH
- Respiratory Function Tests methods MeSH
- Check Tag
- Humans MeSH
- Publication type
- Clinical Study MeSH
- Research Support, Non-U.S. Gov't MeSH
Díky novým technologiím a vyššímu důrazu kladenému na bezpečnostní profil léčiv dochází k postupnému zlepšování lékových forem, což je také případ inhalačního kortikosteroidu beklometason dipropionátu, kdy jeho extra-fine formulace vede vklinické praxi ke snížení jeho nominální dávky až 2,5krát. Článek podrobněji popisuje dopady této transformace vefixních kombinovaných přípravcích, tj. depozici extra-fine částic vcentrální i periferní části plic, nižší systémovou expozici a v neposlední řadě taky pozitivní vliv u skupiny pacientů s astmatem, CHOPN a snížení rizika výskytu pneumonie.
Thanks to advancements and increased emphasis on the safety profile of medications, there is a gradual improvement in the development of pharmaceutical forms. One such change has been implemented in the inhaled corticosteroid beclomethasone dipropionate, resulting in a 2.5× reduction in its nominal clinical dose. The article provides a detailed description of the effects of this transformation in fixed combination preparations, i.e., the deposition of extra-fine particles in both the central and peripheral parts of the lungs, lower systemic exposure, and, last but not least, the positive impact on patients with asthma, COPD, and a reduced risk of pneumonia.
- MeSH
- Administration, Inhalation MeSH
- Beclomethasone * administration & dosage pharmacology therapeutic use MeSH
- Asthma * drug therapy MeSH
- Pulmonary Disease, Chronic Obstructive * drug therapy MeSH
- Drug Combinations MeSH
- Formoterol Fumarate administration & dosage pharmacology therapeutic use MeSH
- Humans MeSH
- Pneumonia prevention & control MeSH
- Randomized Controlled Trials as Topic MeSH
- Check Tag
- Humans MeSH
Východiska: Castlemanova choroba (Castleman disease – CD) nese název po autorovi prvního popisu. Používá se pro ložisko či ložiska charakteru nemaligní lymfoproliferace. Dle rozsahu postižení organizmu se dělí na dvě základní formy, unicentrickou formu (unicentric Castleman disease – UCD) a multicentrickou formu, přičemž UCD je tvořena hyalinně vaskulárním typem CD. Pozorování: Prvním symptomem v popsaném případě UCD byly bolesti vyzařující do levé horní končetiny, obzvláště při pohybu. Vyšetření krční páteře pomocí MR odhalilo jako příčinu patologickou expanzi na pomezí krku a horního mediastina, více vlevo. Cílená biopsie prokázala CD, hyalinně vaskulární typ. Dle PET/CT zobrazení s využitím fluorodeoxyglukózy (FDG-PET/CT) se jednalo o jediné patologické ložisko v těle. Velikost tumorózní rezistence neumožnovala bezpečnou resekci, a tak jediným řešením bylo podávání adjuvantní léčby. Pacientka zahájila léčbu ve složení rituximab 850 mg v den 1 28denního cyklu, cyklofosfamid 600 mg v dny 1 a 15 a dexametazon 20 mg také v dny 1 a 15 28denního cyklu. Pro individuální intoleranci cyklofosfamidu v prvním cyklu bylo podávání tohoto léku přerušeno a od třetího cyklu dostávala místo cyklofosfamidu bendamustin v celkové dávce 100 mg v dny 1 a 15. Výsledky: Zobrazení pomocí FDG-PET/CT po devíti cyklech léčby prokázalo výrazné zmenšení velikosti infiltrátu a zmenšení míry akumulace FDG. To umožnilo týmu hrudního chirurga a kardiochirurga kompletní odstranění až do zdravé tkáně. Závěr: Léčbou volby pro UCD je operační odstranění. V případě, že uložení či velikost ložiska neumožnuje radikální operaci, je možné dosáhnout zmenšení uvedenou medikamentózní léčbou. V popsaném případě kombinace rituximabu, bendamustinu a dexametazonu zmenšila velikost ložiska, což umožnilo jeho kompletní resekci.
Background: Castleman disease (CD) is a historical name derived from the name of the surgeon who first described it. It is used for lesions or foci of the character of non-malignant lymphoproliferative activity. According to the extent of the affliction, it is divided into two basic forms, the unicentric form (UCD) and the multicentric form of Castleman disease, where UCD is formed by the hyaline vascular type of CD. Observation: The first symptom in the described case of UCD was pain radiating to the left upper limb, especially when moving. MRI of the cervical spine revealed pathological expansion on the border between the neck and the upper mediastinum, more on the left. Targeted biopsy showed Castleman disease, hyaline vascular type. According to PET/CT imaging with fluorodeoxyglucose (FDG-PET/CT), it was the only pathological lesion in the body. The size of the tumour resistance did not allow safe resection, so the only solution was to administer adjuvant treatment. The patient started treatment with rituximab 850 mg on day 1 of a 28-day cycle, cyclophosphamide 600 mg on days 1 and 15 and dexamethasone 20 mg, also on days 1 and 15 of a 28-day cycle. Due to individual intolerance of cyclophosphamide in the first cycle, the administration of this drug was discontinued, and from the third cycle onwards, instead of cyclophosphamide, she received bendamustine at a total dose of 100 mg on days 1 and 15. Results: FDG-PET/CT imaging after 9 cycles of treatment showed a marked reduction in the infiltrate size and a decrease in the rate of FDG accumulation. This allowed the team of thoracic and cardiac surgeons to completely remove it down to healthy tissue. Conclusion: The treatment of choice for UCD is surgical removal. If the location or size of the lesion does not allow radical surgery, it is possible to achieve reduction by the mentioned drug treatment. In the case described, the combination of rituximab, bendamustine and dexamethasone reduced the size of the lesion, which allowed its complete resection.
- MeSH
- Bendamustine Hydrochloride pharmacology therapeutic use MeSH
- Dexamethasone pharmacology therapeutic use MeSH
- Diagnosis, Differential MeSH
- Castleman Disease * diagnosis drug therapy classification MeSH
- Drug Therapy, Combination * methods MeSH
- Middle Aged MeSH
- Humans MeSH
- Lymphoproliferative Disorders diagnosis drug therapy classification MeSH
- Rituximab pharmacology therapeutic use MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
Perikarditida představuje nejčastější patologický proces postihující perikard. Diagnostika toho onemocnění se opírá o splnění dvou ze čtyř klasifikačních kritérií. Akutní perikarditida může být spojena s infekčními, systémovými či autoimunitními chorobami, dále třeba také s malignitami nebo metabolickými poruchami. Základem diagnostiky akutní perikarditidy je echokardiografické vyšetření, které nám případně pomůže vyloučit jiné akutní stavy v kardiologii. Nejčastější formou ve vyspělých zemích je idiopatická či povirová perikarditida, jejíž léčba je založena na podávání nesteroidních antiflogistik a kolchicinu. Kortikoidy jsou druhou linií léčby a jejich největší úskalí spočívá ve zvýšení rizika vzniku rekurentní perikarditidy, která se vyskytuje až v 30 % případů.
Pericarditis is the most common pathological process affecting the pericardium. The diagnosis is based on the fulfillment of two of the four classification criteria. Acute pericarditis may be associated with infectious, systemic, or autoimmune diseases, as well as malignancies or metabolic disorders. The basis of the diagnosis of acute pericarditis is an echocardiographic examination, which can help to exclude other acute cardiac conditions. The most common form in developed countries is idiopathic or post-viral pericarditis, the treatment of which is based on the administration of nonsteroidal anti-inflammatory drugs and colchicine. Corticosteroids are the second line of treatment, and their biggest pitfall is the increased risk of recurrent pericarditis, which occurs in up to 30 % of cases.
- MeSH
- Anti-Inflammatory Agents, Non-Steroidal administration & dosage MeSH
- Echocardiography MeSH
- Colchicine administration & dosage MeSH
- Drug Therapy, Combination methods MeSH
- Humans MeSH
- Pericarditis * diagnostic imaging etiology drug therapy pathology MeSH
- Prednisone administration & dosage MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
BACKGROUND: In the phase 3 ALCYONE study, the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) significantly improved outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma. Here, we present results from the final analysis of ALCYONE. METHODS: ALCYONE was an international, multicentre, randomised, open-label, active-controlled, phase 3 trial in adults aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or presence of substantial comorbidities, and had an Eastern Cooperative Oncology Group performance status of 0-2. Patients were enrolled between Feb 9, 2015, and July 14, 2016, and were randomly assigned (1:1) by randomly permuted blocks using an interactive web-based randomisation system to receive bortezomib, melphalan, and prednisone (VMP) alone or D-VMP, with randomisation stratified by International Staging System disease stage, geographical region, and age. Patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area, twice per week on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2-9), oral melphalan (9 mg/m2, once daily on days 1-4 of each cycle), and oral prednisone (60 mg/m2, once daily on days 1-4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab at a dose of 16 mg/kg once weekly during cycle 1, once every 3 weeks in cycles 2-9, and once every 4 weeks thereafter until disease progression, unacceptably toxicity, or the end of study. The primary endpoint, progression-free survival, has been previously reported. The ALCYONE study has completed; presented here are final analyses for selected secondary endpoints related to overall survival, depth of response, subsequent therapy, and safety. The intention-to-treat population was the primary analysis population (including for overall survival), defined as all patients who were randomly assigned to study treatment. The safety population, consisting of patients who received any dose of study treatment, was used in safety analyses. This trial is registered with ClinicalTrials.gov, NCT02195479. FINDINGS: In total, 706 patients were enrolled and randomly assigned to receive D-VMP (n=350) or VMP (n=356). Baseline characteristics were balanced between the two treatment groups; most participants were female (379 [54%] of 706 patients) and White (601 [85%] of 706 patients). At a median follow-up of 86·7 months (IQR 28·5-85·2), median overall survival was 83·0 months (95% CI 72·5-not estimable) with D-VMP versus 53·6 months (46·3-60·9) with VMP (hazard ratio [HR] 0·65 [95% CI 0·53-0·80]; p<0·0001). The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (140 [40%] of 346 patients in the D-VMP group vs 138 [39%] of 354 patients in the VMP group), thrombocytopenia (120 [35%] vs 134 [38%]), and anaemia (63 [18%] vs 70 [20%]). Serious treatment-related adverse events occurred in 74 (21%) of 346 patients in the D-VMP group and 56 (16%) of 354 patients in the VMP group. Deaths due to treatment-related adverse events occurred in five (1%) of 346 patients in the D-VMP group (pneumonia, acute myocardial infarction, neuroendocrine tumour, tumour lysis syndrome, and acute respiratory failure) and three (1%) of 354 patients in the VMP group (acute myeloid leukaemia, pulmonary embolism, and bacterial pneumonia). INTERPRETATION: With more than 7 years of follow-up, D-VMP continued to elicit clinical benefits in transplant-ineligible patients with newly diagnosed multiple myeloma, supporting the efficacy and safety of frontline daratumumab-based therapy in this patient population. FUNDING: Janssen Research & Development.
- MeSH
- Bortezomib administration & dosage adverse effects MeSH
- Progression-Free Survival MeSH
- Middle Aged MeSH
- Humans MeSH
- Melphalan administration & dosage adverse effects MeSH
- Multiple Myeloma * drug therapy pathology mortality MeSH
- Antibodies, Monoclonal administration & dosage adverse effects MeSH
- Prednisone administration & dosage adverse effects MeSH
- Antineoplastic Combined Chemotherapy Protocols * therapeutic use adverse effects MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Randomized Controlled Trial MeSH
Daratumumab, lenalidomid (Revlimid) a dexamethason (DRd) je léčebná kombinace indikovaná pro pacienty s nově diagnostikovaným, ale i relabujícím mnohočetným myelomem. Účinnost DRd v léčbě myelomu nelze zpochybnit. U pacientky, kterou popisuje náš příspěvek, byl diagnostikován kromě myelomu i nekrobiotický xantogranulom (NXG) se závažnými komplikacemi. Vzhledem k raritnímu výskytu této histocytární nemoci není stanoven žádný optimální léčebný postup. S cílem léčby mnohočetného myelomu a s ním spojeného NXG jsme použili režim DRd v kombinaci s intravenózní aplikací imunoglobulinů. Kombinovaná léčba vedla k významné regresi NXG a k vymizení potíží, které byly s NXG spojeny.
Daratumumab, lenalidomid and dexamethason (DRd) is a combination treatment indicated for newly diagnosed as well as relapsed multiple myeloma. The efficacy of DRd in the treatment of myeloma is unquestionable. In the case of the patient described in our report, in addition to myeloma, necrobiotic xanthogranuloma (NXG) with significant complications was also diagnosed. Given the rare occurrence of this histiocytic disease, no optimal treatment protocol has been established. With the aim of myeloma treating and associated NXG, we used the DRd regimen in combination with intravenous administration of immunoglobulins. The combined treatment led to significant regression of NXG and the disappearance of symptoms associated with NXG.
- Keywords
- daratumumab,
- MeSH
- Dexamethasone pharmacology therapeutic use MeSH
- Adult MeSH
- Immunoglobulins, Intravenous administration & dosage pharmacology therapeutic use MeSH
- Lenalidomide pharmacology therapeutic use MeSH
- Humans MeSH
- Multiple Myeloma * drug therapy MeSH
- Antibodies, Monoclonal pharmacology therapeutic use MeSH
- Necrobiotic Xanthogranuloma * drug therapy physiopathology MeSH
- Antineoplastic Combined Chemotherapy Protocols MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Female MeSH
- Publication type
- Case Reports MeSH
