27 november 2011: Opvallend dat nu november 2011 een Nederlandse oncoloog chirurg een manier promoot die toen al werd toegepast. Klik hier voor artikel: Kankercellen doen oplichten met fluorescerende kleurstoffen helpt oncologische chirurgen bij opereren om zo de snijvlakken schoon te krijgen

17 september 2004:

Van de directeur van Radapharma en bio-chemist/onderzoeker Andrei Reshetnickov, en 'uitvinder' van de meerwaarde van radachlorin in een PDT-behandeling of deze pagina over CLT en nu PDT - kreeg ik onderstaande informatie over de geschiedenis van radachlorin en photostim.  De resp. intraveneuze 'agent' en orale 'agent' die gebruikt worden bij de Photodynamische Therapie met niet toxische fotosensitizers. Deze middelen en aanpak zijn afgelopen jaar door de Ierse oogdokter Dr. Bill Porter geprobeerd in de markt te zetten onder de naam Cytoluminescent Therapie - CLT, maar deze man blijkt er een potje van gemaakt te hebben en lijkt puur op eigen winstbejag uit geweest te zijn zonder goede kennis van zaken. Radapharma bevestigde dat zij absoluut niet meer samenwerken met de CLT-organisatie van Bill Porter. Zie ook officiële bericht van Radapharma daarover. Zie ook uw verhaal-Karen. en uw verhaal van meneer A. Maar ondanks de slechte afloop voor Karen lijkt deze aanpak toch nog veelbelovend - wij hebben inzage gehad in dierstudies en fase I trials en in 2004 worden aldus woordvoerder van Radapharma fase II trialresultaten bij plaveiselcarcinomen bekend gemaakt. Daarom ook zetten we deze informatie ongewijzigd op onze website. We tekenen er wel bij aan dat dit alles voor volle verantwoordelijkheid komt van Radapharma Rusland en wij nemen geen enkele verantwoording voor het waarheidsgehalte van de geleverde informatie. Ook is uiteraard onze disclaimer van toepassing hier.  

Bron: Dir. Radapharma Rusland/Ierland 

Water-soluble derivatives of chlorophyll were first introduced as potential drugs by E. Snyder (USA) in 1942 [1]. The other important step was done by E.A. Allen [2]. He revealed that chlorin mixtures, mainly containing chlorin e6, under peroral and intravenous administration possess low toxicity and hypotensive, antisclerotic, spasmolytic, anaesthetic, antirheumathoid action. The first PDT usage of chlorins relates to phaeophorbide a derivatives. Some of them were patented as prospective photosensitizers for PDT in Japan in 1984 by I. Sakata et.al. [3]. In 1986 an American group reported about a photosensitizer meeting crucial PDT requirements: good tumor affinity and intensive absorption in the middle red part of the spectrum [4]. Their choice was mono-L-aspartyl-chlorin  e6 [5]. At present it is at stage III of clinical studies in Japan. Afterwards the group has patented more functionally advanced chlorin and bacteriopheophorbide a derivatives as photosensitizers for PDT6. In 1990s a Byelorussian group at first headed by G. Gurinovich reported about their search on a water-soluble chlorin type photosensitizers derived from nettle [6]. As far as there was not reported about clear chemical composition of the drug substance, the investigators probably dealt with mixtures similar to chlorin e mixtures described in the above-mentioned works of E. Snyder [1] and E. Allen [2].

Starting from the only chlorophyll a containing cyanobacteria of Spirulina species, the first chlorin e6 -based water-soluble preparations for the medical purposes have been developed in 1994-2002 by A.Reshetnickov in Russia [7]. Radachlorinâ is, to our opinion, the most advanced water-soluble chlorin e6-based drug substance sponsored and patented by "RADA-PHARMA" Co. Ltd., Russia [8]. 

In 2000 by I.Zalevsky and S.Goncharov (Russia) to activate Radachlorin laser diode module "ML500-SP" emitting at 662 nm was first designed and assembled [8]. The module is presently produced by companies "MILON LASER" (St.Petersburg, Russia) and "SIGM PLUS" (Moscow, Russia). It emits at 662±3 nm, and available in two modifications with output power 1.2 or 2.5 W from the standard SMA-905 connector, aperture 0.22 in 250 µm
fibre, weight of modules 3-6 kg. It can be optionally equipped with additional channel of 808 or 980 nm with output power of 3 to 15 W for laser thermal therapy or laser surgery.

 

N ) ses.

Photodynamic therapy (PDT) of tumours is based on the administration of a photosensitizer (PS), followed by its accumulation in sufficient amounts by malignant tissues, and photoirradiation of the tumour area with light having wavelengths specifically absorbed by the photosensitizer. The cumulative action leads to tumour necrosis and certain systemic effects.

Clinical applications of PDT mainly involve derivatives of hematoporphyrin (HpD) or its partially purified version, known as "Photofrin II" [[i]], as phototherapeutic agents. The intrinsic limitations of "Photofrin", such as the reduced selectivity of tumour targeting and the heterogeneous chemical composition, prompted investigations aimed at the research and development of second- and third-generation photosensitizers with improved photo­therapeutic properties. In general, such photosen­sitizers, including chlorins, bacteriochlorins, benzoporphyrins, texaphyrins, etiopurpurins, phthalocyanines and naphthalocyanines, are typically associated with cell membranes, being the cause of cell damage upon irradiation with light [].

 Recent studies have shown that “Radachlorin” pro­vokes the efficient photodynamic inactivation of cancer cell lines, murine experimental tumours, as well as certain types of cancer in humans [[iii

DESCRIPTION

«Radachlorin»’s active ingredient is a natural (organic) liquid extract derived from Spirulina Platensis micro-algae powder.

Species of Spirulina platensis Gom. Geitleri., class of Hormogoniophyceae, division of Ceanophycophyta, order of Oscillatoriales, family of  Oscillatoriaceae is a widely known food supplement used in natural (herbal) medicine for healing and supporting the organism. The liquid extract contains a mixture of three chlorins (chlorophyll a derivatives) in the form of sodium salts: 

sodium 13-carboxy-17-[2-carboxyethyl]-15-carboxymethyl-17,18-trans-dihydro-3-vinyl-8-ethyl-2,7,12,18-tetramethyl-porphyrin (chlorin e6);

sodium 13-carboxy-17-[2-carboxyethyl]-15-carboxy-17,18-trans-dihydro-3-vinyl-8-ethyl-2,7,12,18-tetramethyl-porphyrin (chlorin p6);

and a third chlorin preferred not to be disclosed.

«Radachlorin»  is a novel second generation photosensitizing agent.  

The photosensitizer is chemically stable, water soluble, with l 662 nm at physiological conditions.  It has been shown to possess a high efficacy against cancer cell lines upon photoirradiation (Table I, Spectrum 1).

 

Table 1. Photophysical properties, partition coefficients and in vitro activity

 

 

PS

lmax, nm

E,  1%1cm

(0.01 M borate buffer, pH 9.18)

 

1-Octanol/

pH 7.4 phosphate buffer partition coefficient (Kp)

Cytotoxicity

(dark toxicity),

% from control

at 5 mM

Photocytotoxicity, EC50, mM

 

«Radachlorin»

654,5 (407)

1.40

96

1.80

Comparison – sulfonated AlCl-phthalocyanine

670 (1360)

0.05

72

2.00

Spectrum 1. Absorption spectrum of  0.037% solution of  CLE in ethyl alcohol with chlorin active substance concentration of 25.9 mg/ml.

In vivo acute toxicity (LD50) of «Radachlorin » was 147 mg/kg (male Bulb/c mice) allowing for its classifying as "Slightly toxic" and  "Non-pyrogenic"  at the test-dose of 0.7 mg/ml/kg (Table 2).

 

Table 2. Acute toxicity and pyrogenity of  «Radachlorin»  in vivo.

 

PS

Acute toxicity

Pyrogenity*

LD10 mg/kg

LD50 mg/kg

«Radachlorin»

119

147

Non-pyrogenic

*for the test-dose of 0.7 mg/kg

 

Pharmacokinetics and biodistribution studies have been done using the same line of mice. Maximum tumour accumulation of «Radachlorin» (0.70 mM) was achieved by 5 h p.i. at i.p. administration at the dose of 40 mg/kg, and 0.32 mM by 0.5 h p.i. at i.v. administration of the dose twice as lower (Table 3). 

 

Table 3. Accumulation of «Radachlorin», mM

 

 Tissue

i.p. administration at the dose of 40 mg/kg

i.v. administration at the dose of 20 mg/kg

0.5 h

3  h

5 h

18 h

0.5 h

3  h

5 h

18 h

Tumour

0.100

0.550

0.700

0.480

0.320

0.290

0.260

0.018

Blood

1.200

0.900

0.610

0.010

1.500

0.540

0.060

0.030

Skin

0.280

0.110

0.180

0.011

0.045

0.020

0.020

0.001

Muscle

2.800

0.410

0.230

0.015

0.200

0.100

0.001

0.001

 

 

These values are enough for efficient PDT procedure with this drug. It is noteworthy that by 18 h p.i. at i.p. administration tumour concentration was still high enough to perform PDT efficiently (0.48 mM), being only 1.5 times lower than at its absolute maximum by 5 h p.i.

Maximum contrast with «Radachlorin» was observed at i.p. way of administration 18 h p.i. with the maximum tumour-to-muscle ratio about 32, and tumour-to-skin ratio about 44 (Table 4). In the clinic, at i.v. way of administration, however, from the accumulation point, PDT should be given within the interval of 0.5-5 h.

 

Table 4. «Radachlorin» therapeutic ratios.

 

Dose, mg/kg

Tumour-to-skin ratio p.i.

 

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