Long-term Drug Administration Research Articles

The evaluation of risk factors for prolonged viral shedding during anti-SARS-CoV-2 monoclonal antibodies and long-term administration of antivirals in COVID-19 patients with B-cell lymphoma treated by anti-CD20 antibody

BackgroundThe global impact of the coronavirus disease 2019 (COVID-19) pandemic has resulted in significant morbidity and mortality. Immunocompromised patients, particularly those treated for B-cell lymphoma, have shown an increased risk of persistent infection with SARS-CoV-2 and severe outcomes and mortality. Multi-mutational SARS-CoV-2 variants can arise during the course of such persistent cases of COVID-19. No optimal, decisive strategy is currently available for patients with persistent infection that allows clinicians to sustain viral clearance, determine optimal timing to stop treatment, and prevent virus reactivation. We introduced a novel treatment combining antivirals, neutralizing antibodies, and genomic analysis with frequent monitoring of spike-specific antibody and viral load for immunocompromised patients with persistent COVID-19 infection. The aim of this retrospective study was to report and evaluate the efficacy of our novel treatment for immunocompromised B-cell lymphoma patients with persistent COVID-19 infection.MethodsThis retrospective descriptive analysis had no controls. Patients with B-cell lymphoma previously receiving immunotherapy including anti-CD20 antibodies, diagnosed as having COVID-19 infection, and treated in our hospital after January 2022 were included. We selected anti-SARS-CoV-2 monoclonal antibodies according to subvariants. Every 5 days, viral load was tested by RT-PCR, with antivirals continued until viral shedding was confirmed. Primary outcome was virus elimination. Independent predictors of prolonged viral shedding time were determined by multivariate Cox regression.ResultsForty-four patients were included in this study. Thirty-five patients received rituximab, 19 obinutuzumab, and 26 bendamustine. Median treatment duration was 10 (IQR, 10–20) days; 22 patients received combination antiviral therapy. COVID-19 was severe in 16 patients, and critical in 2. All patients survived, with viral shedding confirmed at median 28 (IQR, 19–38) days. Bendamustine use or within 1 year of last treatment for B-cell lymphoma, and multiple treatment lines for B-cell lymphoma significantly prolonged time to viral shedding.ConclusionsAmong 44 consecutive patients treated, anti-SARS-CoV-2 monoclonal antibodies and long-term administration of antiviral drugs, switching, and combination therapy resulted in virus elimination and 100% survival. Bendamustine use, within 1 year of last treatment for B-cell lymphoma, and multiple treatment lines for B-cell lymphoma were the significant independent predictors of prolonged viral shedding time.

Chronic pyogenic spondylitis in patients with spinal gout: a case series and literature review

Background. Spinal gout is a rare and poorly described group of noninfectious inflammatory spinal lesions characterized by the deposition of monosodium urate crystals in the epidural space, paravertebral soft tissues, and by facet joints damage. There is no systematized data on the course of infectious spondylitis and spinal gout in the literature. The aim of the study — to present long-term outcomes of surgical treatment of chronic pyogenic spondylitis in patients with spinal gout and systematize the literature data on the issue. Methods. The clinical part of the study included 6 consecutively operated patients in the period from 2018 to 2021. The diagnosis of spinal gout and chronic pyogenic spondylitis was verified according to the results of histologic and bacteriologic studies of surgical material. Catamnesis accounted for at least 12 months. We studied the peculiarities of clinical and laboratory, radiological and histologic manifestations of the disease. Literature data systematization was carried out in the databases PubMed, Google Scholar, eLIBRARY from 2013 to 2023. Inclusion criteria: level of evidence II B-IV, catamnesis more or equal to 6 months, information on diagnostic and treatment measures. Results. The average age of the patients was 55±9 years. The duration of the diagnostic pause was 8±5 years. Multisegmented lesions of the lumbar (n = 6) spine prevailed. According to the classification of Pola E. et al. (2017) the following types of spondylitis were identified: B.3 (n = 1), C.1 (n = 1), C.3 (n = 2) and C.4 (n = 2). The clinical manifestation was dominated by chronic back pain with an intensity of 6,1±1,4 VAS scores. Neurologic disorders of the lower extremities and pelvic (ASIA scale) corresponded to types B (n = 1) and C (n = 4). The type of surgery: three-column reconstruction through combined approach in 2 cases and isolated anterior column reconstruction in 2 cases, 360° fusion in 1 case, and debridement of the epidural space and anterior column through posterior approach in 1 case. The follow-up results show the absence of recurrence of spondylitis in 4 cases, in 2 patients there were postoperative complications that required revision, after which no recurrence of spondylitis was noted. We selected 17 publications for literature review. Conclusion. The combination of chronic pyogenic spondylitis and spinal gout is a rare and poorly described pathology in the literature. Long therapeutic pause, chronic character of vertebrogenic pain syndrome in combination with increased uric acid level and formation of tophi of vertebral localization are distinctive features of the disease. Neurologic disorders with the combination of spondylitis and gout result from stenosis of the spinal canal due to two factors — epidural abscesses and tophi. Achieving local control of the combined pathology is possible with a combination of surgical intervention and long-term administration of hypouricemic drugs.

Long-Term Pharmacokinetic Follow-Up of Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer.

This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate cancer patients (81 patients). It was observed that individual AA concentrations remained constant over treatment time, with no noticeable changes during repeated long-term drug administration for up to 120 days. There was no correlation between AA concentrations and survival outcomes. However, a significant association between higher AA concentrations and better clinical benefit was observed (p = 0.041). The safety data did not correlate with the AA PK data. A significant positive correlation (r = 0.40, p < 0.001) was observed between mean AA concentration and patient age: the older the patient, the higher the AA concentration. Patient age was found to impact steady-state AA concentration: the older the patient, the higher the mean AA concentration. Altogether, these data may help to guide future research and clinical trials in order to maximize the benefits of AA metastatic castration-resistant prostate cancer patients.

Long-term toxicity evaluation of aristolochic acid-IIIa in mice

Aristolochic acid (AA)-IIIa is an AA analog present in Aristolochiaceae plants. To evaluate the chronic toxicity of AA-IIIa, mice were intragastrically administered with media control, 1 mg/kg AA-IIIa, and 10 mg/kg AA-IIIa, and designated as the control (CTL), AA-IIIa low dose (AA-IIIa-L), and AA-IIIa high dose (AA-IIIa-H) groups, respectively. AA-IIIa was administered three times a week, every other day, for 24 weeks (24-week time point). Thereafter, some mice were sacrificed immediately, while others were sacrificed 29 or 50 weeks after AA-IIIa withdrawal (53- or 74-week time point). Serum and organs were collected for biochemical and pathological analyses, respectively. Whole-genome sequencing was performed on the kidney, liver, and stomach tissues of AA-IIIa-treated mice for single-nucleotide polymorphism (SNP) detection. AA-IIIa-H mice died at 66 weeks, and the remaining mice showed moribund conditions at the 69 weeks. AA-IIIa induced minor kidney tubule injury, fibroblast hyperplasia, and forestomach carcinoma in mice. Bladder, intestine, liver, heart, spleen, lung, and testis tissues were not pathologically altered by AA-IIIa. In addition, AA-IIIa increased the C:G > A:T mutation in the kidney; however, no SNP mutation changes were observed in the liver and forestomach tissues of AA-IIIa-H mice at the 24-week time point compared with control mice. Therefore, we suspect that AA-IIIa is potentially mutagenic for mice after overdose and long-term administration. On the other hand, the forestomach is a unique organ in mice, but it does not exist in humans; thus, we hypothesize that the stomach toxicity induced by AA-IIIa is not a suitable reference for toxicological evaluation in humans. We recommend that Aristolochiaceae plants containing AA-IIIa should be properly supervised, and overdosing and long-term administration of drugs containing AA-IIIa should be avoided.

Reactive Oxygen Species-Responsive Dual Anti-Inflammatory and Antioxidative Nanoparticles for Anterior Uveitis.

Anterior uveitis (AU) is an immune-mediated inflammatory disease that results in iritis, cyclitis, glaucoma, cataracts, and even a loss of vision. The frequent and long-term administration of corticosteroid drugs is limited in the clinic owing to the side effects and patient noncompliance with the drugs. Therefore, specifically delivering drugs to inflammatory anterior segment tissues and reducing the topical application dosage of the drug are still a challenge. Here, we developed dual dexamethasone (Dex) and curcumin (Cur)-loaded reactive oxygen species (ROS)-responsive nanoparticles (CPDC NPs) to treat anterior uveitis. The CPDC NPs demonstrated both anti-inflammatory and antioxidative effects, owing to their therapeutic characteristics of dexamethasone and curcumin, respectively. The CPDC NPs could effectively release dexamethasone and curcumin in the oxidizing physiological environment of the inflammation tissue. The CPDC NPs can effectively internalize by activated macrophage cells, subsequently suppressing the proinflammatory factor expression. Moreover, the CPDC NPs can inhibit ROS and inflammation via nuclear transcription factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway activation. In an endotoxin-induced uveitis rabbit model, the CPDC NPs show a therapeutic effect that is better than that of either free drugs or commercial eye drops. Importantly, the CPDC NPs with a lower dexamethasone dosage could reduce the side effects significantly. Taken together, we believe that the dual-drug-loaded ROS-responsive NPs could effectively target and inhibit inflammation and have the potential for anterior uveitis treatment in clinical practice.

Comparison of a brand-name drug and its generic drugs - Impact of anti-human immunodeficiency virus drug exposure on the intestinal epithelial barrier

The use of unapproved anti-human immunodeficiency virus (HIV) drugs for its treatment and prevention has recently increased in Japan. Our research group investigated generic drugs of the Truvada combination tablet (TVD) that have not been approved in Japan, and reported differences in the pharmaceutical properties of their formulations. We also demonstrated that the pharmaceutical excipients in generic drugs may differ from those in TVD, and showed that some pharmaceutical excipients may affect epithelial cell barrier function. The present study investigated differences in the effects of TVD and its generic drugs (Generic A and Generic B) on epithelial cell barrier function. No significant differences were observed in epithelial cell barrier function following exposure to TVD, Generic A, and Generic B. However, significant increases in the mRNA levels of ABCB1 and Occludin, which regulate the epithelial cell barrier, were detected following exposure to Generic B. Therefore, the administration of Generic B for a longer duration or at a higher concentration may lead to changes in epithelial barrier function. Since the treatment and prevention of HIV requires the long-term (chronic) administration of drugs, the drugs used may change, such as from a brand-name drug to a generic drug and also from one generic drug to another. The present results suggest that the effects of brand-name and generic drugs, such as on intestinal epithelial barrier function, may differ with changes in the drugs being administered.

Elimination of transmission of onchocerciasis (river blindness) with long-term ivermectin mass drug administration with or without vector control in sub-Saharan Africa: a systematic review and meta-analysis

WHO has proposed elimination of transmission of onchocerciasis (river blindness) by 2030. More than 99% of cases of onchocerciasis are in sub-Saharan Africa. Vector control and mass drug administration of ivermectin have been the main interventions for many years, with varying success. We aimed to identify factors associated with elimination of onchocerciasis transmission in sub-Saharan Africa. For this systematic review and meta-analysis we searched for published articles reporting epidemiological or entomological assessments of onchocerciasis transmission status in sub-Saharan Africa, with or without vector control. We searched MEDLINE, PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials, African Index Medicus, and Google Scholar databases for all articles published from database inception to Aug 19, 2023, without language restrictions. The search terms used were "onchocerciasis" AND "ivermectin" AND "mass drug administration". The three inclusion criteria were (1) focus or foci located in Africa, (2) reporting of elimination of transmission or at least 10 years of ivermectin mass drug administration in the focus or foci, and (3) inclusion of at least one of the following assessments: microfilarial prevalence, nodule prevalence, Ov16 antibody seroprevalence, and blackfly infectivity prevalence. Epidemiological modelling studies and reviews were excluded. Four reviewers (NM, AJ, AM, and TNK) extracted data in duplicate from the full-text articles using a data extraction tool developed in Excel with columns recording the data of interest to be extracted, and a column where important comments for each study could be highlighted. We did not request any individual-level data from authors. Foci were classified as achieving elimination of transmission, being close to elimination of transmission, or with ongoing transmission. We used mixed-effects meta-regression models to identify factors associated with transmission status. This study is registered in PROSPERO, CRD42022338986. Of 1525 articles screened after the removal of duplicates, 75 provided 282 records from 238 distinct foci in 19 (70%) of the 27 onchocerciasis-endemic countries in sub-Saharan Africa. Elimination of transmission was reported in 24 (9%) records, being close to elimination of transmission in 86 (30%) records, and ongoing transmission in 172 (61%) records. I2 was 83·3% (95% CI 79·7 to 86·3). Records reporting 10 or more years of continuous mass drug administration with 80% or more therapeutic coverage of the eligible population yielded significantly higher odds of achieving elimination of transmission (log-odds 8·5 [95% CI 3·5 to 13·5]) or elimination and being close to elimination of transmission (42·4 [18·7 to 66·1]) than those with no years achieving 80% coverage or more. Reporting 15-19 years of ivermectin mass drug administration (22·7 [17·2 to 28·2]) and biannual treatment (43·3 [27·2 to 59·3]) were positively associated with elimination and being close to elimination of transmission compared with less than 15 years and no biannual mass drug administration, respectively. Having had vector control without vector elimination (-42·8 [-59·1 to -26·5]) and baseline holoendemicity (-41·97 [-60·6 to -23·2]) were associated with increased risk of ongoing transmission compared with no vector control and hypoendemicity, respectively. Blackfly disappearance due to vector control or environmental change contributed to elimination of transmission. Mass drug administration duration, frequency, and coverage; baseline endemicity; and vector elimination or disappearance are important determinants of elimination of onchocerciasis transmission in sub-Saharan Africa. Our findings underscore the importance of improving and sustaining high therapeutic coverage and increasing treatment frequency if countries are to achieve elimination of onchocerciasis transmission. The Bill & Melinda Gates Foundation and Neglected Tropical Diseases Modelling Consortium, UK Medical Research Council, and Global Health EDCTP3 Joint Undertaking. For the Swahili, French, Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Long-Term Constant Subcutaneous Drug Administration.

In this chapter, a long-term drug delivery system for preclinical therapeutic research is introduced. By using a subcutaneously implanted ALZET® Osmotic Pumps osmotic pump, continuous zero-order delivery of drugs under investigation that need repeated oral or intravenous dosing is realizable. Compared to traditional delivery systems, implanted osmotic pumps present several advantages, such as that no external connections or researcher intervention is required during infusion and that it is possible to save time by eliminating the need for frequent animal handling and repetitive injection schedules. Most importantly, a stable peripheral concentration of a drug can be obtained using this constant drug delivery system, which would benefit researchers in verifying the efficiency of anti-rheumatoid drugs and establishing safety profiles in preclinical studies.

Platelet membrane encapsulated curcumin nanomaterial-mediated specific thrombolysis and anti-thrombotic treatment among pregnant women.

The current treatment for venous thrombosis during pregnancy is ineffective, primarily, due to the unique physiology of pregnant women. Most clinical medications have fetal side effects when they circulate in the body. We first synthesized nanomaterials (Cur-PFP@PC) using poly lactic-co-glycolic acid (PLGA) as the base material, with curcumin (Cur) and perfluoropentane (PFP) as core components. Subsequently, we encapsulated Cur-PFP@PC into the platelet membrane to synthesize P-Cur-PFP@PC. Under ultrasound guidance, in combination with low-intensity focused ultrasound (LIFU), PFP underwent a phase change, resulting in thrombolysis. The generated microbubbles enhanced the signal impact of ultrasound, and P-Cur-PFP@PC showed better performance than Cur-PFP@PC. P-Cur-PFP@PC can target thrombosis treatment, achieve visually and precisely controlled drug release, and repair damaged blood vessels, thus avoiding the adverse effects associated with traditional long-term drug administration.

A ROS-responsive microsphere capsule encapsulated with NADPH oxidase 4 inhibitor ameliorates macrophage inflammation and ferroptosis

Inflammatory macrophages within the synovium play a pivotal role in the progression of arthritis inflammation. Effective drug therapy targeting inflammatory macrophages has long been a goal for clinicians and researchers. The standard approach for treating osteoarthritis (OA) involves systemic treatment and local injection. However, the high incidence of side effects associated with long-term drug administration increases the risk of complications in patients. Additionally, the rapid clearance of the joint cavity poses a biological barrier to the therapeutic effect. NADPH oxidase 4 (NOX4) is an enzyme protein regulating the cellular redox state by generating reactive oxygen species (ROS) within the cell. In this study, we designed and fabricated a hydrogel microsphere consisting of methyl methacrylate (MMA) and polyvinyl acetate (PVA) as the outer layer structure. We then loaded GLX351322 (GLX), a novel selective NOX4 inhibitor, into hydrogel microspheres through self-assembly with the compound polyethylene glycol ketone mercaptan (mPEG-TK) containing a disulfide bond, forming nanoparticles (mPEG-TK-GLX), thus creating a two-layer drug-loaded microspheres capsule with ROS-responsive and slow-releasing capabilities. Our results demonstrate that mPEG-TK-GLX@PVA-MMA effectively suppressed TBHP-induced inflammation, ROS production, and ferroptosis, indicating a promising curative strategy for OA and other inflammatory diseases in the future.

Toxicity study of compound granules of Hedyotis diffusa: Acute toxicity and long-term toxicity

Ethnopharmacological relevanceThe clinical efficacy of the hospital preparation compound granules of Hedyotis diffusa (CGHD), which is composed of Hedyotis diffusa Willd, Smilax china L., Solanum lyratum Thunb., has accumulated a good reputation over the past decades. However, because it is a hospital preparation, few researchers have paid attention to it, resulting in a lack of systematic basic research studies. Thus, it is not clear whether there are safety concerns that restrict its clinical application, and toxicological evaluation of CGHD is needed. Aim of the studyThe aim of this study was to evaluate the safety of CGHD by conducting acute toxicity and long-term toxicity experiments, with the objective of providing evidence for its clinical safety and a theoretical foundation for its clinical application. Materials and methodsKM mice were selected for the acute toxicity experiment and were administered water or CGHD-E 3 times within 24 h. The reactions of the animals to CGHD treatment were observed and recorded within 1 h after administration and then once a day for 14 consecutive days. SD rats were selected to conduct the long-term toxicity experiment. The drug-treated groups were administered different doses of CGHD-E, which were equivalent to 10 times, 20 times and 50 times the clinical dose in humans. The rats were administered the drug for 28 consecutive days. After 28 days, the animals were sacrificed, and routine blood tests, blood coagulation function analysis, liver and kidney function tests, and glycolipid metabolism related tests were conducted. The major organs of the rats were collected to calculate organ coefficients and perform hematoxylin-eosin (HE) staining. ResultsIn the CGHD-E acute toxicity experiment, the drug-treated groups did not show adverse reactions or poisoning symptoms, and the maximum tolerated dose of CGHD-E in mice was greater than 45.072 g/kg. In the long-term toxicity experiment, drug-treated rats generally exhibited a good condition, but continuous administration decreased on body weight and food intake, especially in male rats. Coagulation function alterations and the impact on the liver during long-term drug administration were also assessed, which should be emphasized in clinical applications. No significant toxic effects were observed according to routine blood tests or test of liver and kidney function, glucose and lipid metabolism, or ion metabolism. ConclusionsThe results of this study showed that CGHD was nontoxic or had low toxicity, providing not only a scientific basis for its clinical application, determining the appropriate clinical dose and monitoring clinical toxicity but also theoretical support for subsequent clinical drug trials.

Detection of Aspergillus Sp Fungus in Tuberculosis Patients with A Treatment Length of 2 Months using the Polymerace Chain Reaction (Pcr) Method

This study aims to detect the presence or absence of the Aspergillus sp fungus in Tuberculosis Patients within a 2 month treatment period. This research was carried out in the Microbiology Laboratory at Hasanuddin University Teaching Hospital. Laboratory methods. Samples were obtained from the Tabaringan and Pattingaloang Community Health Centers in Makassar City. Then testing was carried out using culture techniques and polymerace chain reaction techniques. The research results showed that by using the culture method from 30 samples, 9 samples obtained growing media, for 2 samples it was suspected that Aspergillus sp fungus was growing. Then for the polymerace chain reaction (PCR) method, from 30 samples the presence of Aspergillus sp fungus was detected, 4 samples using ASAP primers, then carried out again using ASPU primers (ASPU+Af3r, ASPU+Ni1r, ASPU+Fl2r) which resulted in 1 Aspergillus niger sample. From the results of this research, it can be concluded that the factor that causes the growth of fungus is the long-term administration of anti-tuberculosis drugs which only suppress bacteria from pulmonary tuberculosis.

Intravitreal injectable hydrogel rods with long-acting bevacizumab delivery to the retina.

Retinal vascular diseases such as neovascular age-related macular degeneration (nAMD) are the leading cause of blindness worldwide. They can be treated with intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) agents by inhibiting VEGF which is a major agent of abnormal blood vessel growth. However, because of drug's short half-life, clinical treatment often requires monthly repeated intravitreal injections, causing treatment burden and undertreatment. Among various kinds of drug carriers, in situ forming hydrogels have been studied as potential intravitreal drug carriers for the high drug loading, easy injection, controlled drug release, and protection of encapsulated drugs from the environment. However, gelation time, crosslinking degree, and drug release patterns following injection of a liquid that will be subsequently gelled in situ are susceptible to be hindered by dilution of the hydrogel precursor solution with body fluids (e.g., blood or vitreous). Here, we report an injectable pre-crosslinked hydrogel rod to overcome the limitations of in situ forming hydrogels and to extend intravitreal half-life of anti-VEGF for reducing intraocular injection frequency. Hydrogel rods can be simply prepared using in situ forming hydrogels, and injectable using a designed rod injector. The adjustable crosslinking degree of hydrogel rods easily controlled bevacizumab release profiles in a sustained manner. Compared with in situ forming hydrogels, hydrogel rods effectively reduced initial burst release, and showed sustained release with long-term drug efficacy in vitro. From the 4-month in vivo pharmacokinetic analysis, following the intravitreal injection of hydrogel rods, the half-life of bevacizumab in the vitreous and retina was significantly extended, and drug elimination to aqueous humor was effectively reduced. Finally, intraocular stability, degradation, and inflammatory response of hydrogel rods were evaluated. We expect that the hydrogel rod can be a potential drug delivery system for the treatment of nAMD and other conditions that need long-term and local sustained drug administration. STATEMENT OF SIGNIFICANCE: Herein, we report an injectable pre-crosslinked hydrogel rod based on an in situ forming hydrogel to achieve intravitreal long-acting anti-VEGF delivery to reduce injection frequency and improve the long-term visual outcomes of patients with retinal vascular diseases. Hydrogel rods were readily prepared using removable molds and injected using customized injectors. Compared to the in situ forming hydrogel, hydrogel rods showed significantly reduced initial burst release, controllable release profiles for several months, physical stability, and a long-acting anti-angiogenic effect. Animal studies demonstrated that the hydrogel rods dramatically prolonged the intraocular drug half-life while significantly reducing drug elimination for up to four months. Moreover, the biodegradability and safety of the hydrogel rods suggest their suitability as an advanced intravitreal DDS for treating retinal vascular diseases.

Role of Potassium-competitive Acid Blockers in the Treatment of Gastric Acid-related Disorders

Owing to their superior pharmacokinetic and pharmacodynamic profiles, potassium-competitive acid blockers (P-CABs) score over proton pump inhibitors (PPIs) in the treatment of gastric acid-related disorders and may provide clinical benefit in the management of these conditions. Previous studies have compared P-CABs with PPIs for treatment of gastric acid-related disorders, and current data show that P-CABs are non-inferior to PPIs in the treatment of erosive esophagitis and as maintenance therapy. P-CABs are useful for effective healing and as maintenance medications in patients with severe esophagitis. These drugs also aid with healing of peptic ulcers and artificial ulcers secondary to gastric endoscopic submucosal dissection (ESD). Few studies have discussed prevention of delayed ulcer bleeding after gastric ESD and ulcers associated with long-term nonsteroidal anti-inflammatory drug administration. Well-controlled, large-scale prospective studies are warranted in future to compare P-CABs with PPIs.

Epigenetic Effects of Psychoactive Drugs.

Currently, and globally, we are facing the worst epidemic of psychoactive drug abuse resulting in hundreds of thousands of lives annually. Besides alcohol and opioid use and misuse, there has been an increase in illicit abuse of psychostimulants. Epigenetics is a relatively novel area of research that studies heritable alterations in gene expression. Long-term administration of psychoactive drugs may lead to transcriptional changes in brain regions related to drug-seeking behaviors and rewards that can be passed down transgenerationally. Epigenetic biomarkers such as DNA methylation and histone modifications contribute to disease diagnoses. This review aims to look at the epigenetic modifications brought forth by psychoactive drug abuse.

ПАЦИЕНТКА С ПРОГРЕССИРУЮЩИМ МИКОБАКТЕРИОЗОМ ЛЕГКИХ: ВОЗМОЖЕН ЛИ УСПЕХ В ЛЕЧЕНИИ?

Pulmonary mycobacteriosis has become a new global health challenge. The development of severe lung pathology, which requires long-term complex therapy with broad-spectrum antibiotics, can only be caused by some of the currently described nontuberculous mycobacteria. The treatment for mycobacteriosis requires long-term administration of combined antibacterial drugs, may cause adverse drug reactions, or fail. A clinical case of progressive pulmonary mycobacteriosis in a 53-year-old female patient is described in the article.

Fabrication of hesperidin hybrid lecithin-folic acid silver nanoparticles and its evaluation as anti-arthritis formulation in autoimmune arthritic rat model

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease that results in synovitis, cartilage destruction and loss of joint function. The frequent and long-term administration of anti-rheumatic drugs often leads to adverse effects and patient non-compliance. Hesperidin (HP) is a naturally occurring bioflavonoid having anti-inflammatory and antioxidant properties. In this study, Hesperidin loaded hybrid lecithin-folic acid silver nanoparticles (L-HP-FA-AgNPs) formulation has been developed to deliver HP to inflamed jointsspecifically.Thein vivo anti-inflammatory and anti-arthritic effectsof the formulation were validated in the CFA arthritis rat model by giving oral treatment of L-HP-FA-AgNPs (1 and 3mg/kg) which alleviated the joint swelling, cartilage destruction and reduced influx of inflammatory cells. The results showed decreased pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) in the peritoneal and spleen cells coupled with an increase in anti-inflammatory cytokine TGF-β1. Additionally, the treatment caused the decline in M1 macrophage activation with a concomitant increment in M2 macrophage activation. Further, hybrid L-HP-FA-AgNPs suppressed the production of RANKL, OPG and MMP-2/9, which supported its anti-osteoclastic effects. Collectively, our data revealed that L-HP-FA-AgNPs significantly inhibited the progression of arthritis by reducing inflammationand bone damage. The protective effects of hybrid L-HP-FA-AgNPs highlight its potential as an ideal new anti-arthritic agent for human RA.

Extracorporeal photopheresis in the treatment of chronic graft-versus-host-disease

Introduction. Chronic graft versus host disease (GVHD) is a frequently occurring complication after transplantation of allogeneic hematopoietic cells associated with a decrease in the quality of life and long-term administration of immunosuppressive drugs. Extracorporeal photopheresis (ECP) is a second line of therapy after treatment failure with glucocorticoids.Aim — to evaluate the effects of ECP treatment in patients with glucocorticosteroids (GCS)-refractory, GCS-dependent or GCS -intolerant chronic GVHD.Materials and methods. 24 patients with GCS-refractory, GCS-dependent or GCS-intolerant chronic GVHD were included in the therapy with ECP. Nine patients had moderate chronic GVHD, and 15 had a severe chronic GVHD. Skin and mucous membranes were the most frequently targeted organs, 21 and 20 of 24 patients respectively, liver damage was detected in 8 patients. The maximum duration of treatment was 33 months (median — 8.5 months). The number of procedures of ECP ranged from 6 to 48 (median — 22).Results. A response was determined in 23 patients with one patient being excluded from the assessment due to a relapse of acute leukemia. 16 (69.5 %) patients achieved an overall response to ECP treatment. Three patients had complete response and full reduction of immunosuppressive therapy. When assessing organ-specific response, the most notable improvement was observed in the mucous membranes of 17 patients (89.4 %), skin — 17 (85 %), and liver — 7 (75 %). Along with achieving a general overall response, 78.2 % of patients partly reduced or completely canceled immunosuppressive therapy.Conclusion. ECP is an effective and promising second line treatment method for chronic GVHD in patients with GCS-refractory, GCS-dependent or GCS-intolerant forms.

50 Years Ago in TheJournalofPediatrics: Rickets and Antiepileptic Drugs: What Have We Learned?

Borgstedt AD, Bryson MF, Young LW, Forbes GB. Long-term administration of antiepileptic drugs and the development of rickets. J Pediatr 1972;81:9-15. In 1972, Borgstedt et al reported 2 neurologically impaired children who developed rickets after years of antiepileptic drug therapy. The diagnosis was based on physical findings, radiographs, and serum calcium, phosphate, and alkaline phosphatase levels. Rickets resolved with daily doses of calcium and large amounts of vitamin D, despite continuance of the antiepileptic drugs. Missing were measures of vitamin D metabolites, presumably owing to a lack of available clinical assays at that time. Our knowledge of vitamin D metabolism has progressed far beyond the already established metabolic pathways of hepatic 25-hydroxylation and renal 1-hydroxylation of that era. As the authors suspected, antiepileptic drugs, and other drugs, cause rickets by increased hepatic vitamin D catabolism. Induction of catabolic enzymes leaves less vitamin D for eventual renal conversion to the active metabolite 1,25 dihydroxyvitamin D (1,25-D). With inadequate 1,25-D, calcium absorption is impaired, contributing to inadequate bone mineralization. As extracellular calcium decreases, parathyroid hormone responds, but this response causes phosphaturia, further under mineralizing bone. In vitamin D disorders, bone chondrocyte function is also altered, leading to metaphyseal abnormalities explaining many hallmark features of vitamin D rickets, such as widened wrists and rachitic rosary. Other bone health issues in children with epileptic disorders, not related to vitamin D deficiency, include seizure-associated trauma, nonambulatory status, and nutritional deficiencies. The measurement of the main circulating metabolite, 25-hydroxyvitamin D (25-D), is widely available. Problems remain, including assay variability and an inconsistent relationship of level to clinical impact; for example, a 25-D level of 12 ng/mL may cause rickets in 1 individual and no notable signs in another. The 25-D levels are, at best, a surrogate for potential 1,25-D production. Another issue is that 25-D is measured in nanograms per milliliter, with acceptable levels in children generally considered to be more than 20 ng/mL. However, 1,25-D is measured in picograms per milliliter, or a 1000-fold less concentration. Why is a 25-D level of 10 000 pg/mL (=10 ng/mL) not enough substrate to provide adequate 1,25-D production to the 20-80 pg/mL reference range? From their inference of vitamin D deficiency, Borgstedt et al helped to identify an important preventable complication of antiepileptic drug use in children. Incorporating these findings into clinical guidelines remains to be completed.

Metronomic chemotherapy regimens and targeted therapies in non-Hodgkin lymphoma: The best of two worlds.

Novel drugs are rapidly moving forward the treatment-paradigm of non-Hodgkin-lymphomas (NHLs). Notwithstanding, especially in aggressive subtypes, chemotherapy remains the pillar of treatment. Indeed, the combination of highly effective Maximum-Tolerated-Dose Chemotherapy (MTD-CHEMO)+"novel drugs", has so far, fallen short from expectations, often because it caused excessive toxicity. Metronomic chemotherapy (mCHEMO), which is the frequent, long-term administration of low dose cytotoxic drugs, may allow more effective and tolerable combinations. mCHEMO pharmacodynamics, has been described as pleiotropic. In fact, it may have different cellular and molecular targets, when drugs or their schedules are modified. Although mCHEMO has been little explored in NHLs, pre-clinical studies - in lymphoma models - which addressed the activity of mCHEMO in combination with novel drugs, have shown very promising results. These included inhibitors of histone deacetylase, mTOR and PI3K/mTOR, as well as the immune checkpoint inhibitor anti-PD-L1. Moreover, a few impressive reports have recently shown all-oral mCHEMO schedules, with or without rituximab, can effectively shrink both B and T-cell aggressive NHLs. Indeed, these regimens allowed elderly-frail patients to achieve sustained remission, while toxicity proved manageable. In our opinion, all-oral mCHEMO, is an active, easy-to start, well-tolerated, and inexpensive therapeutic approach, which deserves further investigation. Most importantly, mCHEMO, holds promise to empower the activity of novel targeted therapies, without causing excessive toxicity.