Gusperimus is an

immunosuppressive drug Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified into ...

. It is a derivative of the naturally occurring

HSP70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an importa ...

inhibitor spergualin, and inhibits the interleukin-2-stimulated maturation of T cells to the S and G2/M phases and the polarization of the T cells into IFN-gamma-secreting Th1 effector T cells, resulting in the inhibition of growth of activated naive CD4 T cells. Gusperimus was developed by Bristol-Myers Squibb. Currently, it is manufactured and sponsored for use as an

orphan drug An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases. The assignment of ...

and for clinical studies by the Japanese company Euro Nippon Kayaku. The patent claim (see quotation) is that Gusperimus may be useful for a variety of hyperreactive inflammatory diseases such as autoimmune diseases. The drug is available in vials containing 100 mg each. There is little information about the

pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

properties of gusperimus.

Overview

The

European Commission The European Commission (EC) is the executive of the European Union (EU). It operates as a cabinet government, with 27 members of the Commission (informally known as "Commissioners") headed by a President. It includes an administrative body o ...

assigned

status to Gusperimus in 2001 for the treatment of

granulomatosis with polyangiitis Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis (WG), is a rare long-term systemic disorder that involves the formation of granulomas and inflammation of blood vessels (vasculitis). It is a form of vasculitis ...

, a serious form of

vasculitis Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily caused b ...

frequently associated with permanent disability and/or fatal outcome. There have been many cases of patients resistant to all forms of usual treatment responding very well to Gusperimus. It has been proposed that gusperimus may benefit patients with the neurological disease

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

(ALS or Lou Gehrig's disease). ALS causes permanent motor deficits and disabilities up to the point that almost all motor functions, including breathing and bladder control, are lost. Patients usually have no intellectual impairments. Currently, there are no results from controlled studies in ALS patients. There have also been positive and negative anecdotal reports in patients with

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

. As with ALS, there are no sufficient studies in MS patients. Gusperimus may possibly be of use in more common diseases and conditions such as

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...

, lupus erythematosus, and the prevention and therapy of

transplant rejection Transplant rejection occurs when Organ transplant, transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between don ...

graft-versus-host disease Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants. White blood cells of the donor's immune system which remain wit ...

Adverse effects

Currently, only provisional and preliminary data about side-effects is available. The following side-effects have been noticed so far: * Dysgeusia (abnormal or bad taste) * Drug induced

leukopenia Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...

(very common) * Significant infections related to therapy. It is not known if therapy with gusperimus may increase the risk of malignant diseases (lymphoma, leukemia, solid tumors), as is the case with other highly potent immunosuppressant agents such as ciclosporin or tacrolimus.

Interactions

There has been little experience about clinically relevant interactions. These might be: * Other immunosuppressant drugs : Risk of infections increased. * Myelotoxic drugs like 6-Mercaptopurin : Risk of serious

bone marrow Bone marrow is a semi-solid tissue found within the spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It is composed of hematopoietic ce ...

damage increased. * Certain NSAIDs : Increased risk of hepatotoxic reactions.

Dosage

Gusperimus is used in therapeutic cycles. The daily dose and the length of each cycle as well as the length of the treatment free interval depend on the degree of leukopenia/neutropenia caused by gusperimus. It is recommended to obtain complete WBC (White Blood Cell) counts during and after each cycle frequently.

Synonyms

2Common references are: * (+−)-15-Deoxyspergualin, * 1-Amino-19-guanidino-11-hydroxy-4,9,12-triazanonadecane-10,13-dione, * 15-Deoxyspergualin, * 15-Deoxyspergualin Hydrochloride, * 7-{(Aminoiminomethyl)amino]-N- -4-[(3-aminopropyl)aminoutyl">4-[(3-aminopropyl)amino.html" ;"title="-4-[(3-aminopropyl)amino">-4-[(3-aminopropyl)aminoutylmino-
1-hydroxy-2-oxoethyl]heptanamide, * Gusperimus (Trihydrochloride), * N-[4-[(3-Aminopropyl)amino]-butyl]carbamoyl]hydroxymethyl-
7-guanidinoheptanamide, * Spanidin

Synthesis

*The BOC derivative of 4-aminobutanol is oxidized with

Collins reagent Collins reagent is the complex of chromium(VI) oxide with pyridine in dichloromethane. This metal-pyridine complex, a red solid, is used to oxidize primary alcohols to the corresponding aldehydes and secondary alcohols to the corresponding ket ...

to afford the aldehyde. *Condensation with the

ylide An ylide or ylid () is a neutral dipolar molecule containing a formally negatively charged atom (usually a carbanion) directly attached to a heteroatom with a formal positive charge (usually nitrogen, phosphorus or sulfur), and in which both atoms h ...

obtained from reaction of 3-triphenylphosphonium propionic acid with lithium hexamethyldisilazane leads to the chain extended acid. *The carboxylic acid is then activated by conversion to its N-hydroxysuccinimide ester; That group is displaced by ammonia to give the corresponding amide and the BOC group is removed by acid to give the intermediate. *Treatment of the aminoamide with 1-amidino-3,5-dimethylpyrazole leads to an exchange of the amidine function and formation of the corresponding guanidine. *The saturated guanidino-amide is obtained by catalytic hydrogenation. Amides are well known to participate in the formation of

carbinolamine In organic chemistry, a hemiaminal (also carbinolamine) is a functional group or type of chemical compound that has a hydroxyl group and an amine attached to the same carbon atom: . R can be hydrogen or an alkyl group. Hemiaminals are intermediat ...

s and aminals. *Reaction with the glyoxilamide from

spermidine Spermidine is a polyamine compound () found in ribosomes and living tissues and having various metabolic functions within organisms. It was originally isolated from semen. Function Spermidine is an aliphatic polyamine. Spermidine synthase (SPDS) ...

(shown as its hydrate) leads to displacement of one of the hydroxyl groups and formation of the corresponding

, gusperimus.

References

* https://web.archive.org/web/20120204123305/http://www.bizbozos.com/nci_Gusperimus * http://ec.europa.eu/enterprise/pharmaceuticals/register/o034.htm * https://web.archive.org/web/20060109201017/http://www.als.net/research/treatments/treatmentDetail.asp?treatmentID=858 * {{immunosuppressants Orphan drugs Guanidines Immunosuppressants