Chronic Diseases and Translational Medicine最新文献

Cytarabine is one of the most used drugs for the treatment of hematological malignancies such as leukemia and non-Hodgkin's lymphoma. In cells, cytarabine is activated into ara-CTP, which can replace deoxycytidine triphosphate (dCTP) and become incorporated into the DNA of proliferating cells. Thus, it can block DNA synthesis, resulting in proliferation arrest and cell death.¹ High doses of cytarabine usually induce dermatological toxicity commonly reported as morbilliform eruptions, acral erythema, neutrophilic eccrine hidradenitis, vasculitis, toxic epidermal necrolysis, and eccrine squamous syringome taplasia.^2-5 Of these toxicity effects, violaceous erythema is especially rare.^{6, 7} Herein, we present a case of delayed generalized violaceous erythema associated with cytarabine and discuss its necessary treatment.

An 11-year-old boy came to the hospital complaining of an ache in the lower limb. Bone marrow puncture results confirm that he has acute lymphoblastic leukemia. He received a chemotherapy with cyclophosphamide, cytarabine, and 6-mercaptopurine (according to the Chinese Children Cancer Group [CCCG]-Acute lymphoblastic leukemia [ALL]-2015) for induction chemotherapy. The treatment course lasted 7 days, with cytarabine (100 mg/m²) and 6-mercaptopurine (60 mg/m²) given daily. Cyclophosphamide (1 g/m²) was given on the first day. On the seventh day of chemotherapy, he developed a high fever (39.8°C). The next day, a florid, diffuse, nonpruritic erythematous macule eruption appeared on his face, ears, and scalp. Antihistamines have no effect on the erythematous macule. Over the next 24 h, erythematous macules spread over his neck, arms, chest, abdomen, and back (Figure 1A). The percentage of eosinophils (6%; reference value, 0–5%) increased transiently on the eighth day of chemotherapy. On the ninth day of chemotherapy, erythematous macules coalesced into purpuric plaques and spread throughout the body (Figure 1B). The color of the erythema turned to bright red as well as a growing facial edema was observed. Histopathological examination of skin biopsy tissue demonstrated neutrophilic, lymphocytic infiltration and erythrocytic extravasation (Figure 2). C-reactive protein (CRP) level (56.7 mg/L; reference value, 0–8 mg/L) and D-dimer (2860 µg/L; reference value, 0–550 µg/L) were high throughout the period of erythema. Meanwhile, anti-infective therapy showed no effect on the progression of erythema or the reduction of CRP. On the 12th day of initial cytarabine exposure, dry desquamation was noted (Figure 1C), with complaints of slight pruritus. Then, the eruption faded away and disappeared on the 17th day after initial exposure to cytarabine (Figure 1D). However, in the later stage of erythema, the patient developed a liver injury and lasted for 13 days. After 28 days of initial exposure to cytarabine, the patient recovered. Subs

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease, and the “four-hit” theory represents its currently accepted pathogenic mechanism. Mucosal immunity triggered by infections in the respiratory tract, intestines, or other areas leads to antigen presentation, T cell stimulation, B cell maturation, and the production of IgA-producing plasma cells. The proteins B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) are involved in this process, and alternative complement and lectin pathway activation are also part of the pathogenic mechanism. Kidney Disease Improving Global Outcomes guidelines indicate that a specific effective treatment for IgAN is lacking, with renin–angiotensin–aldosterone system inhibitors being the primary therapy. Recent research shows that biological agents can significantly reduce proteinuria, stabilize the estimated glomerular filtration rate, and reverse some pathological changes, such as endocapillary proliferation and crescent formation. There are four main categories of biological agents used to treat IgA nephropathy, specifically anti-CD20 monoclonal antibodies, anti-BLyS or APRIL monoclonal antibodies, monoclonal antibodies targeting both BLyS and APRIL (telitacicept and atacicept), and monoclonal antibodies inhibiting complement system activation (narsoplimab and eculizumab). However, further research on the dosages, treatment duration, long-term efficacy, and safety of these biological agents is required.

Insulin is used as a therapeutic agent in patients with diabetes, and cutaneous lipohypertrophy (LH) and localized insulin-derived amyloidosis (LIDA) are well-known adverse effects associated with insulin injections. The clinical implications, management, assessment methods, and pathological differentiation of LH and LIDA have been recently updated. This review was to update our knowledge of the pathological differentiation, effects of insulin absorption, hypoglycemic events, and recent assessment methods for LH and LIDA. A scoping review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses extension for Scoping Reviews guidelines. Original studies and case reports in English were also included. PubMed and Scopus databases were searched for keywords to identify papers published up to January 2022. A total of 113 studies were identified through a database search, and 31 were eligible for inclusion in this scoping review. In the 31 studies included in this review, patients with type 2 diabetes had high frequencies of LH and LIDA. LH outcome parameters were assessed using pathological findings and imaging. LIDA is mainly determined by pathological methods, such as hematoxylin and eosin and Congo red staining. Several in vitro and in vivo LIDA models of LIDA have been developed. These results suggest that pathological analysis is required to identify LH and LIDA. It is important to consider LIDA, as it likely influences insulin adsorption and glycemic control. Although several studies have evaluated the LIDA process, little is known about the mechanisms underlying the development of adverse effects associated with insulin injections.

The American College of Cardiology/American Heart Association defines resistant hypertension (RH) as a clinical blood pressure (BP) reading of >130/80 mmHg in patients taking three antihypertensive drugs, including a renin–angiotensin system inhibitor, a calcium channel blocker (CCB), and a diuretic at well-tolerated doses.^{1, 2} It is reported from multiple population-based surveys that in the United States, there is an approximately 12%–15% prevalence of RH among adults diagnosed with hypertension.² A prospective study demonstrates that 20% of people diagnosed with RH had primary hyperaldosteronism.^{3, 4} In addition to the classic three antihypertensive drugs, spironolactone and mineralocorticoid are also administered for RH. However, with respect to the safety profile of spironolactone, it has been reported to have several side effects such as low testosterone production, menstrual irregularities, and excessively raised serum potassium levels, leaving the drug unfit for the longitudinal therapeutic purpose of treating RH.⁵

Clinical research has demonstrated that aldosterone synthesis inhibitors lower circulating aldosterone levels by directly blocking the synthesis of aldosterone rather than blocking its receptor activity, subsequently lowering BP.⁶ The first aldosterone synthase inhibitor to be developed was Osilodrostat (LCI699), which was intended to reduce serum aldosterone levels and manage hypertension. It was soon discovered, nevertheless, that Osilodrostat also inhibits 11-beta hydroxylase (CYP11B1), which lowers serum cortisol levels.⁷

Perhaps due to decreased cortisol levels, there were many reasons for the administration of Osilodrostat; thus, what was needed for the resistance was a selective aldosterone inhibitor, which was conceived and licensed by CinCor Pharma Inc. Baxdrostat, a drug in phase 2 clinical trials, exemplifies exceptional selective suppression of aldosterone synthase without blocking 11-beta hydroxylase.⁸

Animal model studies conducted on cynomolgus monkeys suggested that this drug inhibits the production of aldosterone without influencing the increase in cortisol caused by adrenocorticotropic hormone.⁹ Furthermore, research involving healthy volunteers validated these findings (ClinicalTrials.gov Identifier: NCT01995383).⁸ Multiple ascending doses of Baxdrostat were later investigated for safety, pharmacokinetics, and pharmacodynamics in a Phase I trial, which found that Baxdrostat was well tolerated, safe, and caused a dose-dependent decrease in plasma aldosterone but not cortisol.

Baxdrostat was tested in a Phase II trial^{8, 10} that was randomized, double-blind, placebo-controlled, and dose-ranging in adults with treatment-resistant hypertension (Brig