Givinostat or gavinostat (originally ITF2357) is a histone deacetylase inhibitor

Histone deacetylase inhibitor

Histone deacetylase inhibitors are a class of compounds that interfere with the function of histone deacetylase.HDIs have a long history of use in psychiatry and neurology as mood stabilzers and anti-epileptics...

 with potential anti-inflammatory

Anti-inflammatory

Anti-inflammatory refers to the property of a substance or treatment that reduces inflammation. Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as opposed to opioids, which affect the central nervous system....

, anti-angiogenic, and antineoplastic activities. It is a hydroxamate used in the form of its hydrochloride

Hydrochloride

In chemistry, hydrochlorides are salts resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base . This is also known as muriate, derived from hydrochloric acid's other name: muriatic acid....

.

Givinostat is in numerous phase II clinical trials (including for relapsed leukemias and myelomas), and has been granted orphan drug

Orphan drug

An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease...

 designation in the European Union

European Union

The European Union is an economic and political union of 27 independent member states which are located primarily in Europe. The EU traces its origins from the European Coal and Steel Community and the European Economic Community , formed by six countries in 1958...

 for the treatment of systemic juvenile idiopathic arthritis

Juvenile idiopathic arthritis

Juvenile idiopathic arthritis is the most common form of persistent arthritis in children. JIA is a subset of arthritis seen in childhood, which may be transient and...

 and polycythaemia vera.

ITF2357 was discovered at Italfarmaco of Milan, Italy. It was patented in 1997 and first described in the scientific literature in 2005.

Adverse effects

In clinical trials of givinostat as a salvage therapy

Salvage therapy

Salvage therapy is a form of treatment given after an ailment does not respond to standard treatment. The most common diseases that require salvage therapy are HIV and various tumors...

 for advanced Hodgkin's lymphoma

Hodgkin's lymphoma

Hodgkin's lymphoma, previously known as Hodgkin's disease, is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes...

, the most common adverse reactions

Adverse drug reaction

An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

 were fatigue (seen in 50% of participants), mild diarrhea or abdominal pain (40% of participants), moderate thrombocytopenia

Thrombocytopenia

Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...

 (decreased platelet

Platelet

Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes.  The average lifespan of a platelet is normally just 5 to 9 days...

 counts, seen in one third of patients), and mild leukopenia

Leukopenia

Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....

 (a decrease in white blood cell

White blood cell

White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...

 levels, seen in 30% of patients). One-fifth of patients experienced prolongation of the QT interval

QT interval

In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...

, a measure of electrical conduction in the heart, severe enough to warrant temporary suspension of treatment.

Mechanism of action

Givinostat inhibits class I and class II histone deacetylase

Histone deacetylase

Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...

s (HDACs) and several pro-inflammatory cytokine

Cytokine

Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s. This reduces expression of tumour necrosis factor (TNF), interleukin 1α and β, and interleukin 6

Interleukin 6

Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...

.

It also has activity against cells expressing JAK(2V617F), a mutated form of the janus kinase 2

Janus kinase 2

Janus kinase 2 is a human protein that has been implicated in signaling by members of the type II cytokine receptor family , the GM-CSF receptor family , the gp130 receptor family , and the single chain receptors...

 (JAK2) enzyme that is implicated in the pathophysiology of many myeloproliferative disease

Myeloproliferative disease

The myeloproliferative diseases are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases on the whole have a much better prognosis than...

s, including polycythaemia vera. In patients with polycythaemia, the reduction of mutant JAK2 concentrations by givinostat is believed to slow down the abnormal growth of erythrocytes and ameliorate the symptoms of the disease.