Ciclosporin
Systematic (IUPAC) name
(E)-14,17,26,32-tetrabutyl-5-ethyl-8-(1-hydroxy-2-methylhex-4-enyl) -1,3,9,12,15,18,20,23,27-nonamethyl-11,29-dipropyl-1,3,6,9,12,15,18,21,24,27,30- undecaazacyclodotriacontan-2,4,7,10,13,16,19,22,25,28,31-undecaone
Identifiers
CAS number	59865-13-3
ATC code	L04AA01
PubChem	2909
DrugBank	BTD00003
Chemical data
Formula	C62H111N11O12
Mol. mass	1202.61
Pharmacokinetic data
Bioavailability	variable
Metabolism	hepatic
Half life	variable (about 24 hours)
Excretion	biliary
Therapeutic considerations
Pregnancy cat.	C(AU) C(US)
Legal status	Prescription Only (S4)(AU) POM(UK) ℞-only(US)
Routes	oral, IV, ophthalmic

Ciclosporin, cyclosporine (USAN) or cyclosporin (former BAN), is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the patient’s immune system and so the risk of organ rejection. It has been studied in transplants of skin, heart, kidney, liver, lung, pancreas, bone marrow and small intestine. Initially isolated from a Norwegian soil sample, Ciclosporin A, the main form of the drug, is a cyclic nonribosomal peptide of 11 amino acids (an undecapeptide) produced by the fungus Tolypocladium inflatum Gams, and contains D-amino acids, which are rarely encountered in nature.

Indications

The immuno-suppressive effect of cyclosporin was discovered on January 31, 1972, by employees of Sandoz (now Novartis) in Basel, Switzerland, in a screening test on immune-suppression designed and implemented by Dr.Hartmann F. Stähelin, M.D. The success of Cyclosporin A in preventing organ rejection was shown in liver transplants performed by Dr. Thomas Starzl at the University of Pittsburgh hospital. The first patient, on March 9, 1980, was a 28-year-old woman. Cyclosporin was subsequently approved for use in 1983.

Apart from in transplant medicine, cyclosporin is also used in psoriasis, severe atopic dermatitis and infrequently in rheumatoid arthritis and related diseases, although it is only used in severe cases. It has been investigated for use in many other autoimmune disorders. Cyclosporin has also been used to help treat patients with ulcerative colitis who do not respond to treatment with steroids. This drug is also used as a treatment of posterior or intermediate uveitis with non-infective etiology.

Cyclosporin A has been investigated as a possible neuroprotective agent in conditions such as traumatic brain injury, and has been shown in animal experiments to reduce brain damage associated with injury. Cyclosporin A blocks the formation of the mitochondrial permeability transition pore, which has been found to cause much of the damage associated with head injury and neurodegenerative diseases.

Mode of action

Cyclosporin is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of ciclosporin and cyclophylin inhibits calcineurin, which under normal circumstances is responsible for activating the transcription of interleukin-2. It also inhibits lymphokine production and interleukin release and therefore leads to a reduced function of effector T-cells. It does not affect cytostatic activity.

It also has an effect on mitochondria. Cyclosporin A prevents the mitochondrial PT pore from opening, thus inhibiting cytochrome c release, a potent apoptotic stimulation factor. However, this is not the primary mode of action for clinical use but rather an important effect for research on apoptosis.

Biosynthesis

Figure 1: Cyclosporine A Biosynthesis. Bmt = butenyl-methyl-threonine, Abu = L-alpha-aminobutyric acid, Sar = sarcosine

Cyclosporine A is synthesized by a nonribosomal peptide synthetase, cyclosporine synthetase. The enzyme contains an adenylation domain, thiolation domain, condensation domain, and an N-methyltransferase domain. The adenylation domain is responsible for substrate recognition and activation. While the thiolation domain covalently binds the adenylated amino acids to phosphopantetheine and the condensation domain elongates the peptide chain. Cyclosporine synthetase substrates includes: L-Valine, L-Leucine, L-Alanine, L-Glycine, 2-aminobutyric acid, 4-methylthreonine, and D-Alanine. With the adenylation domain, cyclosporine synthetase generates the acyl adenylated amino acids then covalently binds the amino acid to phosphopantetheine through a thioester linkage. Some of the amino acid substrates become N-methylated by S-adenosylmethionine. The cyclization step releases cyclosporine A from the enzyme. Amino acids such as D-Ala and butenyl-methyl-L-threonine indicates that cyclosporine synthetase requires the action of other enzymes such as a D-Alanine racemase. The racemization of L-Ala to D-Ala is PLP dependent. The formation of butenyl-methyl-L-threonine is performed by a butenyl-methyl-L-threonine polyketide synthase that utilizes acetate/malonate as its starting material.

Figure 2: Butenyl-methyl-L-Threonine Biosynthesis

Adverse Effects and Interactions

Treatment may be associated with a number of potentially serious adverse drug reactions (ADRs) and adverse drug interactions. Ciclosporin interacts with a wide variety of other drugs and other substances including grapefruit juice. There have been studies into the use of grapefruit juice to increase the blood level of cyclosporin.

ADRs can include gum hyperplasia, convulsions, peptic ulcers, pancreatitis, fever, vomiting, diarrhea, confusion, breathing difficulties, numbness and tingling, pruritus, high blood pressure, potassium retention and possibly hyperkalemia, kidney and liver dysfunction (nephrotoxicity & hepatotoxicity), and obviously an increased vulnerability to opportunistic fungal and viral infections.

An alternate form of the drug, ciclosporin G (OG37-324), has been found to be much less nephrotoxic than the standard ciclosporin A. Ciclosporin G (Mol. mass 1217) differs from ciclosporin A in the amino acid 2 position, where an L-nor-valine replaces the α-aminobutyric acid.

Formulations

The drug is marketed by Novartis under the brand names Sandimmune, the original formulation, and Neoral for the newer microemulsion formulation. Generic ciclosporin preparations have been marketed under various trade names including Cicloral (Sandoz/Hexal) and Gengraf (Abbott). Since 2002 a topical emulsion of ciclosporin for treating keratoconjunctivitis sicca has been marketed under the trade name Restasis. Annual sales of ciclosporin are around $1 billion.

The drug is also available in a dog preparation manufactured by Novartis called Atopica. Atopica is indicated for the treatment of atopic dermatitis in dogs. Unlike the human form of the drug, the lower doses used in dogs mean the drug acts as an immuno-modulator and has fewer side effects than in man. The benefits of using this product include the reduced need for concurrent therapies to bring the condition under control.

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Ciclosporin

Vinorelbine

Systematic (IUPAC) name

4-(acetyloxy)-6,7-didehydro-15- ((2R,6R,8S)-4-ethyl-1,3,6,7,8,9-hexahydro- 8-(methoxycarbonyl)-2,6-methano- 2H-azecino(4,3-b)indol-8-yl)-3-hydroxy- 16-methoxy-1-methyl-,methyl ester, (2beta,3beta,4beta,5alpha,12R,19alpha)- aspidospermidine-3-carboxylic acid

Vinorelbine (Navelbine) is an anti-mitotic chemotherapy drug that is given as a treatment for some types of cancer, including breast cancer and non-small cell lung cancer.

Pharmacology

Vinorelbine is the first 5´NOR semi-synthetic vinca alkaloid. It is obtained by semi-synthesis from alkaloids extracted from the rosy periwinkle, Catharanthus roseus.

History

Vinorelbine was invented by the Pharmacist Pierre Potier and his team from the CNRS in France in the 1980s and was licensed to the oncology department of the Pierre Fabre Group. The drug was approved in France in 1989 under the brand name Navelbine for the treatment of bronchial cancer. It gained approval to treat non-small cell lung cancer in 1991. The drug is now primarily used to treat this cancer. Vinorelbine received approval by the United States Food and Drug Administration (FDA) in December 1994 sponsored by GlaxoSmithKline. The drug went generic in the U.S. in February 2003.
In Europe is approved to treat non-small cell lung cancer, breast cancer and, in some countries, prostate cancer.
Since 2004 an oral formulation has been marketed and registered in Europe for the same settings. It has been shown a similar efficacy and safety profile between both intravenous and per os formulations, avoiding local toxicity induced by the intravenous vinorelbine.

Side effects

Vinorelbine has a number of side-effects that can limit its use:

Lowered resistance to infection, bruising or bleeding, anaemia, constipation, diarrhoea, nausea, numbness or tingling in hands or feet (peripheral neuropathy), tiredness and a general feeling of weakness (asthenia), inflammation of the vein into which it was injected (phlebitis).Seldom severe hyponatriamia is seen

Less common effects are hair loss and allergic reaction.

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Vinorelbine

Serine
IUPAC name	(S)-2-amino-3-hydroxypropanoic acid
Identifiers
CAS number	56-45-1
PubChem	617
SMILES	[show] OCC(N)C(=O)O
Properties
Molecular formula	C3H7NO3
Molar mass	105.09 g mol−1
Supplementary data page
Structure and properties	n, εr, etc.
Thermodynamic data	Phase behaviour Solid, liquid, gas
Spectral data	UV, IR, NMR, MS
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references

Serine (abbreviated as Ser or S) is an organic compound with the formula HO2CCH(NH2)CH2OH.

Occurrence

It is one of the 20 naturally occurring proteinogenic amino acids. Its codons are UCU, UCC, UCA, UCG, AGU and AGC. Only the L-stereoisomer appears naturally in proteins. It is not essential to the human diet, since it is synthesized in the body from other metabolites, including glycine. Serine was first obtained from silk protein, a particularly rich source, in 1865. Its name is derived from the Latin for silk, sericum. Serine’s structure was established in 1902. By virtue of the hydroxyl group, serine is classified as a polar amino acid.

Biosynthesis

The biosynthesis of serine starts with the oxidation of 3-phosphoglycerate to 3-phosphohydroxypyruvate and NADH. Reductive amination of this ketone followed by hydrolysis gives serine. Serine hydroxymethyltransferase catalyzes the reversible, simultaneous conversions of L-serine to glycine (retro-aldol cleavage) and 5,6,7,8-tetrahydrofolate to 5,10-methylenetetrahydrofolate (hydrolysis).

Chemical synthesis

Racemic serine can be prepared from methyl acrylate via several steps.

Function

Metabolic

Serine is important in metabolism in that it participates in the biosynthesis of purines and pyrimidines. It is also the precursor to several amino acids, including glycine, cysteine, and, in bacteria, tryptophan. It is also the precursor to numerous of other metabolites, including sphingolipids. Serine is also a precursor to folate, which is the principal donor of one carbon fragments in biosynthesis.

Structural role

Serine plays an important role in the catalytic function of many enzymes. It has been shown to occur in the active sites of chymotrypsin, trypsin, and many other enzymes. The so-called nerve gases and many substances used in insecticides have been shown to act by combining with a residue of serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. The unmetabolized acetylcholine cannot be recycled into the nerve for signaling. This results in depletion of acetylcholine at the neuromuscular junction, resulting in the inability to control muscles, which results in asphyxiation, and death.

As a constituent (residue) of proteins, its side chain can undergo O-linked glycosylation, which may be functionally related to diabetes. It is one of three amino acid residues that are commonly phosphorylated by kinases during cell signaling in eukaryotes. Phosphorylated serine residues are often referred to as phosphoserine. Serine proteases are a common type of protease.

Signaling

D-serine, synthesized by serine racemase from L-serine, serves as a neuronal signal by activating NMDA receptors in the brain.

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Serine

360 – 365 °C

Adenine is a purine with a variety of roles in biochemistry including cellular respiration, in the form of both the energy-rich adenosine triphosphate (ATP) and the cofactors nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD), and protein synthesis, as a chemical component of DNA and RNA. the shape of adenine is complementary to either thymine or uracil.

Structure

It forms several tautomers, compounds that can be rapidly interconverted and are often considered equivalent.

Biosynthesis

The Purine metabolism involves the formation of Adenine and Guanine. Both adenine and guanine are derived from the nucleotide inosine monophosphate (IMP), which is synthesised on a pre-existing ribose through a complex pathway using atoms from the amino acids glycine, glutamine, and aspartic acid, as well as formate ions transferred from the coenzyme tetrahydrofolate.

Function

Adenine is one of the two purine nucleobases (the other being guanine) used in forming nucleotides of the nucleic acids. In DNA, adenine binds to thymine via two hydrogen bonds to assist in stabilizing the nucleic acid structures. In RNA, which is used in the cytoplasm for protein synthesis, adenine binds to uracil.

Adenine forms adenosine, a nucleoside, when attached to ribose, and deoxyadenosine when attached to deoxyribose. It forms adenosine triphosphate (ATP), a nucleotide, when three phosphate groups are added to adenosine. Adenosine triphosphate is used in cellular metabolism as one of the basic methods of transferring chemical energy between chemical reactions.

History

In older literature, adenine was sometimes called Vitamin B4. It is no longer considered a true vitamin or part of the Vitamin B complex. However, two B vitamins, niacin and riboflavin, bind with adenine to form the essential cofactors nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD), respectively.

Some think that, at the origin of life on Earth, the first adenine was formed by the polymerization of five hydrogen cyanide (HCN) molecules. However, this has been criticized by some chemists.

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Adenine

Dutasteride

Systematic (IUPAC) name

Dutasteride (marketed as Avodart, Avidart, Avolve, Duagen, Dutas, Dutagen, Duprost) is a 5-alpha-reductase inhibitor, a drug which inhibits the conversion of testosterone into dihydrotestosterone (DHT). It is used to treat conditions caused by DHT, such as benign prostatic hyperplasia (BPH). Avodart is manufactured and marketed by GlaxoSmithKline.

Classification and Method of Action

Dutasteride belongs to a class of drugs called 5-alpha-reductase inhibitors, which block the action of the 5-alpha-reductase enzymes that convert testosterone into dihydrotestosterone (DHT). Finasteride also belongs to this group. Dutasteride inhibits both isoforms of 5-alpha reductase, while finasteride inhibits only one. But a clinical study done by GlaxoSmithKline, the EPICS trial, did not find dutasteride to be more effective than finasteride in treating BPH.

Uses

While dutasteride is only officially approved to treat enlargement of the prostate gland (at a dose of 0.5mg/day), phase I and II clinical trials for dutasteride as a hair loss drug were also undertaken, but called off in late 2002. The reason the trials were called off is not publicly known. Industry sources speculate that Avodart would have been seen as too similar to Propecia to have proved profitable as a hair loss treatment. However, phase II results indicated that dutasteride 2.5mg/day generated a superior hair count to finasteride 5mg at 12 and 24 weeks.

In December 2006, GlaxoSmithKline started a new Phase III, six month study in Korea to test the safety, tolerability and effectiveness of a once-daily dose of dutasteride (0.5mg) for the treatment of male pattern baldness in the vertex region of the scalp (types IIIv, IV and V on the Hamilton-Norwood scale). The future impact that this study will have on the FDA’s approval or disapproval of Avodart for the treatment of male pattern baldness in the United States is yet to be determined.

Dutasteride is also in development for Prostate cancer risk reduction.

Side Effects

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.

The most common adverse reactions reported in subjects receiving AVODART were impotence, decreased libido, breast disorders (including gynecomastia), and ejaculation disorders. Study withdrawal due to adverse reactions occurred in 4% of subjects receiving AVODART and 3% of subjects receiving placebo. The most common adverse reaction leading to study withdrawal was impotence (1%).

(Before Avodart)

(After 6 months treatment with Avodart)

Teratogenic effect

The teratogenic effect from Dutasteride is a very large risk for male children. The effect would be similar to 5-alpha-reductase deficiency, where a developing male child naturally is deficient in 5-alpha reductase type 2, and thus unable to synthesize DHT Type 2. As Dutasteride blocks the same process (although type 1 and 2 DHT) a developing male would have this deficiency as a result of medication, rather than simply naturally.

Women who are pregnant or in their childbearing years, or children should not be allowed to handle the capsules. This can cause major birth defects.

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Dutasteride