Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line drug isoniazid

AbstractIsoniazid (INH) is a first-line anti-tuberculosis drug used for nearly 70 years. However, the mechanism underlying the side effects of INH has remained elusive. Here, we report that INH and its metabolites induce a post-translational modification (PTM) of histones, lysine isonicotinylation (Kinic), also called 4-picolinylation, in cells and mice. INH promotes the biosynthesis of isonicotinyl-CoA (Inic-CoA), a co-factor of intracellular isonicotinylation. Mass spectrometry reveals 26 Kinic sites in histones in HepG2 cells. Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone Kinic, while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase sensitivity assay and RNA-seq analysis show that histone Kinic relaxes chromatin structure and promotes gene transcription. INH-mediated histone Kinic upregulates PIK3R1 gene expression and activates the PI3K/Akt/mTOR signalling pathway in liver cancer cells, linking INH to tumourigenicity in the liver. We demonstrate that Kinic is a histone acylation mark with a pyridine ring, which may have broad biological effects. Therefore, INH-induced isonicotinylation potentially accounts for the side effects in patients taking INH long-term for anti-tuberculosis therapy, and this modification may increase the risk of cancer in humans.

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Dual orexin receptor antagonist in treatment of insomnia

Engrami ◽

10.5937/engrami41-29093 ◽

2020 ◽

Vol 42 (2) ◽

pp. 57-68

Author(s):

Nikola Trajanović

Keyword(s):

Circadian Rhythm ◽

Side Effects ◽

Receptor Antagonist ◽

Safety Profile ◽

The Elderly ◽

First Line ◽

Future Studies ◽

Good Safety Profile ◽

Circadian Rhythm Disorders

A novel group of medications, dual orexin receptor antagonists, emerged as a competent group that challenges current first-line hypnotics. They have relatively infrequent and mostly well-tolerated side effects, primarily in the form of residual somnolence, fatigue and nightmares/disturbing dreams. The advantage over conventional hypnotics stems from the specifics of their target receptors, which translates into lack of tolerance after long term use and good safety profile. They are particularly favoured in some specific populations, including the elderly. Ongoing and future studies are set to explore their effect on selected conditions, such as addiction and psychiatric disorders, dementias, perimenopausal condition and circadian rhythm disorders, to name a few.

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Complementary drugs—herbs, vitamins, and dietary supplements for pain and symptom management

Oxford Textbook of Paediatric Pain ◽

10.1093/med/9780199642656.003.0059 ◽

2013 ◽

pp. 613-622

Author(s):

Joy A. Weydert

Keyword(s):

Side Effects ◽

Dietary Supplements ◽

Symptom Management ◽

Nutritional Supplements ◽

First Line ◽

Pharmacological Agents ◽

First Line Therapy ◽

Line Therapy

Because of the interest of patients and physicians, there has been increasing research into the use of botanical agents, nutritional supplements, and diet as a means to manage pain. Pharmacological agents typically are chosen as first-line therapy for pain and symptom management; however, for some patients these agents may not work well long term or have side effects that are not tolerated. Other patients may prefer non-pharmacological therapies. Most clinicians are not trained or may not be comfortable recommending these complementary agents.

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INHIBITION OF REDD1 EXPRESSION FOR THE REDUCTION OF GLUCOCORTICOID-INDUCED SIDE EFFECTS

Siberian Journal of Oncology ◽

10.21294/1814-4861-2020-19-6-73-81 ◽

2020 ◽

Vol 19 (6) ◽

pp. 73-81

Author(s):

E. S. Lylova ◽

A. V. Savinkova ◽

E. M. Zhidkova ◽

K. I. Kirsanov ◽

M. G. Yakubovskaya ◽

...

Keyword(s):

Side Effects ◽

Biological Effects ◽

Remission Induction ◽

Therapeutic Effects ◽

Antitumor Effects ◽

Bone Atrophy ◽

Promising Area ◽

Potential Inhibitors

Glucocorticoids (GC ) have been an integral component of the treatment of leukemias and lymphomas for several decades. Specific cytotoxic effect of GC on transformed lymphoblasts mediates their use at the stage of the remission induction as well as consolidation of treatment. However, the main problem of the long-term GC use is the development of atrophic and metabolic side effects as well as GC resistance. The biological effects of GC are realized via activation of the glucocorticoid receptor (GR) by two mechanisms: transrepression (TR) associated with the therapeutic effects of GC , and transactivation (TA ), which mediates the development of metabolic and atrophic complications. It was demonstrated that an increase in the expression of the GC - dependent gene REDD1 associated with GC -induced skin, muscle and bone atrophy of the skin, muscle and bone tissue was realized via the induction of transactivation. Therefore, identification of potential inhibitors of REDD1 expression and study of their biological effects in combination with GC in models of leukemia and lymphoma is of particular interest. In our recent study we have selected a number of drugs from the class of PI 3K/Akt/mTO R modulators using bioinformatic screening. These drugs effectively inhibited REDD1 expression, modulated GR activity and shifted it towards transrepression, and prevented the development of GC -induced side effects in mice. Here we aimed to study the effects of potential inhibitors of REDD1 expression from different pharmacological groups, the compounds Emetine and CGP -60474, on leukemia and lymphoma cells in combination with GC . We demonstrated antitumor effect of the compounds in vitro, a decrease in the expression of TA -associated genes and an increase in TR induction. Further studies of the antitumor effects of REDD1 expression inhibitors (Emetine and CGP -60474 is a promising area of research.

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Complementary drugs

Oxford Textbook of Pediatric Pain ◽

10.1093/med/9780198818762.003.0055 ◽

2021 ◽

pp. 585-595

Author(s):

Joy A. Weydert

Keyword(s):

Side Effects ◽

Symptom Management ◽

Nutritional Supplements ◽

Evidence Based ◽

First Line ◽

Pharmacological Agents ◽

Safety And Efficacy ◽

First Line Therapy ◽

Line Therapy

Research into the use of botanical agents, nutritional supplements, and diet to manage pain has increased owing to the interest and demand of patients and physicians. Pharmacological agents are typically used as first-line therapy for pain and symptom management; however, for some patients these agents may not work well in the long term or have side effects that are not tolerated. Other patients may prefer nonpharmacological therapies. Most clinicians are not trained or may not be comfortable recommending these complementary agents. It is the goal of this chapter to introduce to practitioners the evidence-based data that support the safety and efficacy of these complementary drugs.

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Triple Immunosuppressive Therapy in Patients with Chronic Resistant Immune Thrombocytopenic Purpura; a Case Series of 11 Patients.

Blood ◽

10.1182/blood.v104.11.2059.2059 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2059-2059

Author(s):

Howard H.W. Chan ◽

Nancy M. Heddle ◽

John G. Kelton

Keyword(s):

Side Effects ◽

Immunosuppressive Therapy ◽

Case Series ◽

Adult Patients ◽

First Line ◽

Thrombocytopenic Purpura ◽

First Line Therapy ◽

Line Therapy ◽

Impaired Liver

Introduction: Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by destruction of opsonized platelets. The first-line therapy for adult patients with chronic ITP includes steroid, IVIG and anti-D. Splenectomy is reserved for patients not responding to the first-line therapy. However, approximately 20–30% of patients are resistant or relapsed after splenectomy. In this subgroup of patients, more aggressive immunosuppressive therapy is indicated. Methods: This is a case series of patients with chronic resistant ITP receiving multiple immunosuppressive treatments in a tertiary medical referral center. The diagnosis of ITP was established by excluding other thrombocytopenic diseases. Adult patients with chronic resistant ITP presenting with life threatening thrombocytopenia were selected for a therapeutic trial of immunosuppressive therapy. The therapy included azathioprine 100–200 mg daily; cyclosporine 100–200 mg daily; and mycophenolate 1–2 gm daily (triple immunosuppressive therapy). All of these patients failed 1st line therapy; splenectomy; and other immunosuppressive treatments. Patients with uncontrolled hypertension; impaired liver functions; impaired renal functions; and those who have not completed family were excluded from triple immunosuppressive therapy. A response to the therapy was defined as persistent platelet count above 30 without other concurrent treatments. When patients responded to the triple immunosuppressive therapy, the doses of the medications were gradually tapered to minimize the long-term side effects. Results: Since July of 2000, 11 patients with chronic resistant ITP have received triple immunosuppressive therapy for a variable duration (table 1). Five out of these 11 patients (45.5%) achieved a response within 4 to 6 weeks after the initiation of the treatments. One of the five patients eventually had a break-through during the tapering of triple immunosuppressive therapy. This patient was stabilized by further doses of IVIG and prednisone. The treatments were well tolerated. The most common side effects were mildly elevated blood pressure; and mildly impaired liver function tests. None of the patients suffered from serious side effects that resulted in termination of the treatments. Conclusion: Combining low-dose azathioprine, cyclosporin and mycophenolate can induce long-term remission in patients with chronic ITP resistant to steroid, IVIG, splenectomy and other immunosuppressive agents. This combination regimen is safe and well-tolerated. In adult patients with chronic resistant ITP, the immune dysfunction may need multiple immune blockades. Summary of Treatments ID Rx Prior to Triple Rx Concurrent Rx with Triple Rx Mean (mg OD) Mean (mg OD) Mean (gm OD) Response Duration of Triple Rx Triple Rx:Triple Immunosuppressive Therapy; PRD:Prednisone; DAN:Danazol; AnD:Anti-D; SPN:Splenectomy; VCR:Vincristine; CTX:Cyclophosphamide; LUF:Luflunomide 1 PRD, IVIG, DAN, SPN PRD, IVIG 66.7 63.8 1 No 77 2 PRD, IVIG, DAN, SPN, VCR 75 25 0.8 No 20 3 PRD, AnD, SPN, CTX PRD (taper) 75 50 0.9 Yes 91 4 PRD, SPN, DAN, CTX, LUF 100 100 2 No 106 5 PRD, IVIG, SPN, DAN PRD, IVIG 144.2 236.1 1.9 No 217 6 PRD, IVIG, SPN, DAN, VCR IVIG 91.7 120.5 1.4 No 406 7 PRD, IVIG, DAN, SPN, VCR PRD (taper) 140.9 156.6 1.6 Yes 296 8 PRD, IVIG, SPN, DAN, VCR DAN (taper) 150 100 2 Yes 1351 9 PRD, DAN, SPN, AnD, CTX IVIG 100 150 2 No 130 10 PRD, IVIG, SPN, VCR, CTX PRD (taper) 85.6 121.1 1.4 Yes 1456 11 PRD, DAN, IVIG, SPN, AnD IVIG, PRD (taper) 125.6 225 1.9 Yes 875

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Declining Rates of Adverse Events (AEs), Rare Occurrence of Serious AEs (SAEs), and No Unexpected Long-Term Side Effects at 5 Years in Patients with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Initially Treated with Imatinib (IM) in the International Randomized Study of Interferon vs STI571 (IRIS).

Blood ◽

10.1182/blood.v108.11.2136.2136 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2136-2136 ◽

Cited By ~ 2

Author(s):

Hagop M. Kantarjian ◽

Richard A. Larson ◽

Francois Guilhot ◽

Stephen G. O’Brien ◽

Brian J. Druker ◽

...

Keyword(s):

Side Effects ◽

Randomized Study ◽

Chronic Phase ◽

Study Drug ◽

Fluid Retention ◽

Upper Respiratory Tract ◽

Newly Diagnosed ◽

First Line ◽

Grade 3

Abstract The IRIS trial compared interferon alfa + cytarabine (IFN+Ara-C) and imatinib (IM) in patients (pts) with newly diagnosed CML-CP. Among 553 pts randomized to receive 400 mg IM, 157 (28%) discontinued for reasons which included AEs or deaths unrelated to CML and treatment (6%) and unsatisfactory therapeutic effect (11%). Only 2.4% discontinued due to drug-related AEs. The average daily dose was 389±71 mg, suggesting that no major dose modifications were required due to toxicity. In pts still on IM, the average doses was 382±50 mg. Average duration of exposure is 50 mos (median 60 mos). Table 1 summarizes the most frequently reported non-hematologic AEs (regardless of relationship to study drug) in pts who started IM therapy and those who were still on IM at 2 and 4 years (n=456 and 409 respectively). Table 1. AEs (≥ 20%) on First-Line Imatinib Therapy AE All grades N= 551 (%) All grades, after 2 yrs N = 456 (%) All grades, after 4 yrs N = 409 (%) Grades 3/4 N= 551 (%) Fluid retention 61.7 20.2 5.6 2.5 – Superficial edema 59.9 18.2 5.1 1.5 – Other fluid retention events 6.9 2.4 0.7 1.3 Nausea 49.5 15.4 3.4 1.3 Muscle cramps 49.2 22.8 7.3 2.2 Musculoskeletal pain 47.0 20.8 6.1 5.4 Diarrhea 45.4 23.0 5.1 3.3 Rash and related terms 40.1 13.8 2.4 2.9 Fatigue 38.8 11.4 2.9 1.8 Headache 37.0 12.1 3.4 0.5 Abdominal pain 36.5 15.4 3.4 4.2 Joint pain 31.4 9.2 2.0 2.5 Nasopharyngitis 30.5 14.3 3.7 0 Hemorrhage 28.9 14.3 5.1 1.8 Myalgia 24.1 4.6 1.5 1.5 Vomiting 22.5 9.2 3.7 2.0 Upper respiratory tract infection 21.2 11.2 2.7 0.2 Cough 20.0 7.7 3.4 0.2 Hematologic toxicities were the most frequently occurring grade 3/4 AEs (Table 2). Table 2. Grade 3/4 laboratory abnormalities on First-line Imatinib Overall N = 551 (%) After 2 years N= 456 (%) After 4 years N= 409 (%) Hematologic – Neutropenia 16.7 7 1.0 – Thrombocytopenia 8.9 1.5 0.2 – Anemia 4.4 1.8 0.5 Biochemical – ↑ SGOT/SGPT 5.3 0.4 0 – ↑Total bilirubin 1.1 0.4 0.2 The most frequent reported AEs as well as grade 3/4 hematological and biochemical toxicities were observed at decreasing frequencies throughout therapy. After 4 years, 8% of pts experienced an SAE, compared with 14%, 12%, 7.5%, and 9% during year one through four of therapy. Overall, only 6% of pts had SAEs considered related to study drug (1.5% pts after 4 years of IM). Congestive heart failure/cardiac dysfunction (incl. pulmonary edemas) were reported for 3% of pts (<1% grade 3/4) and pleural effusion in 1% (<1% grade 3/4). Despite much shorter average exposure (12 mos), similar % of these AEs were noted for IFN+Ara-C. Although it should be considered that pts more likely to experience grade 3/4 events may have discontinued from the study prematurely, the 5-year data with IM in pts with newly diagnosed CML-CP show declining frequencies of AEs and SAEs over time. Occurrence of SAEs and laboratory abnormalities with long-term follow-up was rare. No unexpected long-term side effects were noted. These results confirm the IM tolerability and safety profile for durations exceeding 4 years.

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Duration of Corticosteroid Tapering as First Line Treatment In Idiopathic Thrombocytopenic Purpura.

Blood ◽

10.1182/blood.v116.21.3688.3688 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3688-3688

Author(s):

Selay Lam ◽

Cyrus C. Hsia

Keyword(s):

Side Effects ◽

Idiopathic Thrombocytopenic Purpura ◽

Therapy Group ◽

Term Therapy ◽

Line Treatment ◽

First Line ◽

Short Term ◽

Thrombocytopenic Purpura ◽

First Line Treatment

Abstract Abstract 3688 Background: Idiopathic Thrombocytopenic Purpura (ITP) is a relatively common benign hematologic disorder. Management of ITP is difficult as many treatment regimens present risks that may pose more harm than the disease itself. Typically, corticosteroid is used as first line treatment, but there is currently no evidence-based guideline to direct the optimal duration of therapy. Objective: To investigate the effectiveness and relative safety of various lengths of corticosteroid therapy. Methods: In a retrospective cohort study, charts of all ITP patients seen in the general hematology clinic at the London Health Sciences Centre (LHSC) from January 1, 2004 to December 31, 2009 were reviewed. Results : A total of 312 patients with ITP were reviewed. 128 of the patients (52 male, 76 female), age range 4–94 at time of diagnosis, required corticosteroid treatment. Of those, 35 patients were treated with short term steroid regimen (< 8 weeks); 32 patients had 8–16 weeks of therapy, and 64 patients received long term steroid tapering regimen (>16 weeks). Based on results, 63%, 56% and 39% of patients achieved complete response in each group respectively. The follow-up duration from diagnosis ranged from 1 month to 29 years (with median of 1 year). Interestingly, the same proportion of patients experienced side effects as a result of steroid use in all groups. However, frequency of serious complications such as avascular necrosis and infections, occurred at a higher rate in the long term therapy group (9%) compared to 0% in short term therapy group. Conclusions: Rapid corticosteroid taper is as effective as a slow corticosteroid taper and has less serious side effects. Disclosures: No relevant conflicts of interest to declare.

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Cutaneous ulcers following hydroxyurea therapy

Phlebologie ◽

10.1055/s-0037-1621559 ◽

2004 ◽

Vol 33 (06) ◽

pp. 202-205 ◽

Cited By ~ 2

Author(s):

K. Hartmann ◽

S. Nagel ◽

T. Erichsen ◽

E. Rabe ◽

K. H. Grips ◽

...

Keyword(s):

Side Effects ◽

Side Effect ◽

Antineoplastic Agent ◽

Limited Time ◽

Myeloproliferative Diseases ◽

Dermatological Side Effects ◽

Chronic Myeloproliferative Diseases ◽

Hydroxyurea Therapy

SummaryHydroxyurea (HU) is usually a well tolerated antineoplastic agent and is commonly used in the treatment of chronic myeloproliferative diseases. Dermatological side effects are frequently seen in patients receiving longterm HU therapy. Cutaneous ulcers have been reported occasionally.We report on four patients with cutaneous ulcers whilst on long-term hydroxyurea therapy for myeloproliferative diseases. In all patients we were able to reduce the dose, or stop HU altogether and their ulcers markedly improved. Our observations suggest that cutaneous ulcers should be considered as possible side effect of long-term HU therapy and healing of the ulcers can be achieved not only by cessation of the HU treatment, but also by reducing the dose of hydroxyurea for a limited time.

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