Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic    group:   Antineoplastic           and     immunomodulating         agents, immunostimulants, ATC code: L03AX

Mechanism of action
Methoxsalen is a photosensitising agent. Although photochemotherapy has been used clinically for many years, the mechanism by which the therapy is effective remains to be fully elucidated. The general assumption is that the molecular processes which lead to apoptotic cell death involve the intercalating of methoxsalen into the double-stranded DNA molecule within the nucleus. The nucleic acid-furocoumarin complexes formed in this intercalation process involve weak bonding forces such as van der Waals‘ forces, hydrogen bonding and hydrophilic forces. These bonding forces are easily reversed and, in the absence of photoactivation, they are without pharmacological consequence. However, upon activation by absorption of UVA light, methoxsalen binds to the pyrimidine bases of the nucleic acid (thymine, cytosine and uracil) and forms covalent cross-links between the two DNA strands.
The reaction occurs in a few micro-seconds, and when the radiation is turned off, the active substance returns to its inert form immediately.
The mechanism by which the photopheresis procedure acts was investigated by observing certain proteins which induce apoptosis (bcl-2 and fas). Lymphocytes present in peripheral blood were isolated immediately before and 24 hours after treatment, and the numbers of bcl-2 and fas were recorded in comparison to an untreated control group. It was shown that the portion of fas-proteins was significantly higher after treatment, whereas that of bcl-2 remained unchanged. The photopheresis procedure was also shown to increase the portion of apoptotic cells in cultured lymphocytes. These apoptotic cells appear to be absorbed by dendritic cells and presented as antigens so that a specific cell-mediated immune response is triggered and put into operation immediately.
The exact mechanism has not been elucidated in detail.

Pharmakodynamic effects
The formation of photoadducts results in the proliferative arrest of lymphocytes and, over a period of about 72 hours, they die. This acute effect on the T-cell is probably a minor effect with regard to therapeutic efficacy. There is an increasingly large body of evidence suggesting that photopheresis may act as an immune-modulator leading to the augmentation of systemic anti-tumour responses.

Clinical efficacy and safety
41 patients with various diseases (CTCL, GVHD, systemic sclerosis) had a total of 1,210 photopheresis treatments. The CTCL patients with erythroderma and intact immune competence were the ones who responded most favourably, but even advanced tumour- stage CTCL was treated successfully.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Administration
During photopheresis the whole-blood components are separated. Erythrocytes and excess plasma are reinfused into the patient immediately, while the buffy coat (leucocyte-enriched blood) and some plasma are collected, treated with methoxsalen, exposed to UVA light (320 to 400 nm) and then reinjected or reinfused into the patient.

In an investigation conducted in 16 patients, the quantity of methoxsalen required for extracorporeal use was compared to the quantity of oral methoxsalen required in order to achieve similar levels of active substance in the leucocyte fraction. It was shown that for the extracorporeal technique, between 1/250 and 1/500 of the oral quantity were used.

Distribution and biotransformation
Plasma half-life is approximately 2 hours.
Methoxsalen is almost completely metabolised in the liver by hydroxylation and glucuronidation.

Elimination
The metabolites are eliminated predominantly via the kidneys. 90% of the dose administered is found in the urine after 6 to 8 hours.

Specific pharmacokinetic studies in patients with hepatic or renal insufficiency, elderly patients or the paediatric population have not been conducted.