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Biomedical subjects

R Bonnett

Publications and source records attributed to R Bonnett.

At least 19 recordsLinked to original sources
PubMed1993

Photodynamic therapy with m-tetrahydroxyphenylchlorin in vivo: optimization of the therapeutic index.

The therapeutic index of meta-tetrahydroxyphenylchlorin-mediated photodynamic therapy (mTHPC-PDT) was assessed in BALB/c nude mice bearing human malignant mesothelioma xenografts. Equal doses of 650 nm laser light were delivered to the tumour and to an equal-sized area of the hind leg (control site) after i.p. administration of mTHPC. Twenty-one groups of 6 animals each were treated under various drug-light conditions and at drug-light intervals ranging from 4 hr to 6 days. After light delivery the extent of tumour necrosis and the depth of alterations in normal tissue were assessed by light microscopy of standardized histological sections. A therapeutic index (TI) of mTHPC-PDT was defined as the cross-sectional area of tumour necrosis per depth of visible tissue injury at the control site. This TI was strongly related to the conditions of treatment. In particular, it was increased by prolonging the drug-light interval up to 5 days and by increasing the dose of light for any dose of drug. The most profound increase of TI was obtained by increasing the intensity of light administered at the chosen interval while reducing the dose of drug. Our findings suggest that threshold conditions operate in PDT and have important implications for clinical application of the treatment.

Animals↗
PubMed1992

Protective effects of a novel perfluorochemical emulsion in photodynamic therapy.

The effects of pre-injection of mice with a novel perfluorodecalin-based emulsion on the responses to photodynamic therapy (PDT) using the photosensitizer, metatetra (hydroxyphenyl) porphyrin (m-THPP), have been studied. Injection of emulsion after m-THPP and before illumination (activating wavelength 648 nm) protected skin against PDT-induced inflammatory effects, as reflected by decreases (P less than 0.05) in vascular permeability and oedema formation. However, there was no protection against epidermal cell loss. In contrast, injection of emulsion before sensitizer had no corresponding effect. A fall in mean dermal temperature of up to 6 degrees C occurred in mice injected with emulsion 1-2.5 h before illumination suggesting a decrease in skin blood flow which would reduce oedema formation. Possible mechanism(s) for this apparent protective effect are discussed.

Animals↗
PubMed1991

Photodynamic therapy with chlorins for diffuse malignant mesothelioma: initial clinical results.

Four patients underwent intraoperative photodynamic therapy after surgery with meso-tetra-(hydroxyphenyl)-chlorin (mTHPC-PDT) for diffuse malignant mesothelioma. Preliminary procedures were performed in two patients in order to establish the efficacy of mTHPC-PDT and to optimise its tumoricidal effect. The tumoricidal effect was related to the mTHPC dose, light dose and the time interval between sensitation and activation. 0.3 mg kg-1 mTHPC activated after 48 h with 10 Joules cm-2 of non-thermal laser light at 650 nm resulted in a 10 mm deep tumour infarction, due to tumour vessel necrosis and thrombosis. The mTHPC tissue concentration was up to 14 times higher in the tumour than in normal tissues. Skin photosensitivity was mild, dose dependent and occurred 3 to 10 days after administration of mTHPC. According to the results obtained, intraoperative mTHPC-PDT was performed following pleuropneumonectomy in two, pleurectomy and lobectomy in one and pleurectomy in one patient. Ten Joules cm-2 were delivered to the diaphragm and the costophrenic sulcus and 5 Joules cm-2 to the remaining thoracic cavity. The postoperative course was marked by loss of appetite, fluid retention, hypoproteinemia and severe chest pain. One patient succumbed from aspiration pneumonia. The remaining patients developed no neural or vascular alterations and no bronchial stump insufficiency during follow-up. mTHPC-PDT following surgical tumour resection deserves further evaluation in good risk patients with diffuse malignant mesothelioma.

Combined Modality Therapy↗
PubMed1991

Photodynamic therapy of a mouse glioma: intracranial tumours are resistant while subcutaneous tumours are sensitive.

Subcutaneous and intracranial VMDk tumours were treated with photodynamic therapy (PDT) using a new sensitiser, m-THPP. Subcutaneous tumours were highly sensitive to PDT but intracranial tumours were much more resistant, requiring a 30-fold increase in sensitiser dose to produce equivalent levels of necrosis. Resistance of intracerebral tumours was not due to failure of the sensitiser to enter tumours. Necrosis of intracranial tumours was increased when mice breathed 100% oxygen during PDT while subcutaneous tumour necrosis was unaffected.

Animals↗
PubMed1990

Perfluorochemicals and photodynamic therapy in mice.

The effects of pre-treatment with a novel PFC emulsion on PDT-induced tumor necrosis have been studied in mice. Injection of emulsion either 2.5 hr or 24 hr before PDT did not affect the depth of tumour necrosis. However, pre-treatment with the emulsion appeared to protect skin against photodynamic damage although the mechanism(s) and active principle(s) involved were not identified. These results suggest that there may be specific advantages in using emulsified PFCs in conjunction with PDT which may be independent of changes in tumour oxygenation.

Animals↗
PubMed1990

Porphyrin sensitizers in tumour phototherapy. Novel sensitizers of the chlorin and bacteriochlorin class with amphiphilic properties.

The requirements for activity in a tumour-photosensitizing drug are outlined. A series of metallo tetrasulphonatophthalocyanines are shown to be inactive in an in vivo assay of tumour photosensitization; however, some less water-soluble compounds (hydroxylated derivatives of octaethylchlorin and octaethylbacteriochlorin) are shown to possess promising activity.

Animals↗
PubMed1989

Porphyrins as photosensitizers.

The porphyrins have two important roles in photobiology: in photosynthesis, which has evolved and is highly organized morphologically; and in the photodynamic effect, which is adventitious. The damage to tissue that results from photodynamic action is regarded as arising from a number of pathways, but singlet oxygen generation is a major route. Even for the latter mechanism, a number of target molecules are possible. Compared with photosynthesis, it is a very disorganized process. Since the mid 1970s there have been increasing efforts to turn the photodynamic effect to good use as the basis of a phototherapy for cancer. The field has been dominated by the photosensitizer haematoporphyrin derivative. This is a complex mixture of molecules, and although we are learning more about it, it seems unlikely that it will be possible to separate out a useful single substance. A second generation of porphyrin sensitizers is emerging, which, unlike haematoporphyrin derivative, is designed for the job in hand. Some of these photosensitizers, especially the hydroporphyrins, look quite promising.

Photochemotherapy↗
PubMed1986

meso-Tetra(hydroxyphenyl)porphyrins, a new class of potent tumour photosensitisers with favourable selectivity.

We compared para-, meta- and ortho-isomers of meso-tetra(hydroxyphenyl)porphyrin (p-, m- and o-THPP) and the potassium salt of the para compound (K-p-THPP) with haematoporphyrin derivative (HpD) and Photofrin II in their ability to sensitise tumours, skin and brain to light. HpD and Photofrin II induced modest tumour photosensitisation at the cost of substantial skin and brain sensitisation. At doses low enough to keep sensitisation of these normal tissues within acceptable limits, tumour sensitisation was sufficient to give necrosis only approximately 2 mm deep after exposure to 10 J cm-2 light. In contrast, doses of p-THPP, K-p-THPP and m-THPP that produced skin and brain sensitivity within acceptable limits sensitised tumours enough to give 4-9 mm necrosis after 10 J cm-2 light. m-THPP was, on a molar basis, about 25-30 times as potent as HpD and Photofrin II in sensitising tumours. o-THPP was also a potent tumour photosensitiser, but induced a prohibitive degree of skin photosensitivity even at low doses. It is unlikely that these differences in relative selectivity are due to differences in such photophysical parameters as optimum activating wavelength (which would affect tissue penetration by light), or light absorption, and physicochemical factors that determine tissue localisation may be involved. The high tumour sensitising potency and favourable tissue selectivity of m-THPP, p-THPP and K-p-THPP make them promising candidates for clinical tumour phototherapy.

Animals↗
PubMed1985

The effect on photohaemolysis of variation in the structure of the porphyrin photosensitizer.

A comparison of the photosensitizing ability of a variety of porphyrins for photohaemolysis gives the following order of activity: protoporphyrin greater than deuteroporphyrin, mesoporphyrin, haematoporphyrin dimethyl ester much greater than haematoporphyrin diacetate, haematoporphyrin greater than haematoporphyrin monoacetate, coproporphyrin III, haematoporphyrin derivative, coproporphyrin III tetramethyl ester greater than uroporphyrin I, meso-tetra-(N-methyl-4-pyridinium)porphyrin tetratoluene-p-sulphonate, meso-tetra-(p-carboxyphenyl)porphyrin, protoporphyrin dimethyl ester, meso-tetra-(p-hydroxy-sulphonylphenyl)porphyrin tetrasodium salt, uroporphyrin III, deuteroporphyrin-3,8-disulphonic acid and protohaemin. The results for the metal-free porphyrins are rationalized in terms of solubility and partition properties, and a model is proposed for the incorporation of amphipathic porphyrins into the membrane lipid bilayer. Experiments with erythrocytes from patients with erythropoeitic protoporphyria and with normal erythrocytes to which porphyrin was added in a deuterium oxide medium do not lead to an increase in the rate of photohaemolysis. A possible explanation for this somewhat surprising observation is outlined.

Deuterium↗
PubMed1984

Photobilirubin II.

An improved preparation of photobilirubin II in ammoniacal methanol is described. Evidence is presented which distinguishes between the two structures proposed earlier for photobilirubin II in favour of the cycloheptadienyl structure. Nuclear-Overhauser-enhancement measurements with bilirubin IX alpha and photobilirubin II in dimethyl sulphoxide are complicated by the occurrence of negative and zero effects. The partition coefficient of photobilirubin II between chloroform and phosphate buffer (pH 7.4) is 0.67.

Bilirubin↗
PubMed1982

Concerning the structure of photobilirubin II.

Evidence is presented which supports the postulate that the photobilirubins IIA and IIB are diastereoisomers in which the C-3 vinyl group has cyclized intramolecularly. The evidence comes principally from proton n.m.r. spectroscopy at 400 MHz and from chemical considerations. The cyclic structures require the E-configuration at the C-4 double bond in the precursor; this is the first structural evidence for the Z leads to E isomerization in bilirubin and supports the view that the precursor (photobilirubin IA or IB) is (4E, 15Z)-bilirubin. Brief irradiation of photobilirubin II gives bilirubin, a new compound (photobilirubin III) and unchanged starting material. The various photoisomers are discussed in terms of their inter-relationships and biological fates.

Bilirubin↗
PubMed1982

In vivo biological activity of the components of haematoporphyrin derivative.

The in vivo biological activity of various fractions and components of haematoporphyrin derivative (HpD) have been determined by measuring the depth of necrosis of implanted tumours in mice exposed to light after the administration of standard doses of porphyrins dissolved in alkali. In this assay, haematoporphyrin, hydroxyethylvinyldeuteroporphyrin and protoporphyrin are inactive, but the mono- and di-acetates of haematoporphyrin (which are major components of HpD) and acetoxyethylvinyldeuteroporphyrin are active. However, the situation appears to be more complex than this. The normal method for preparing HpD for injection involves an alkali treatment which causes hydrolysis and elimination of the acetoxy functions, and the only recognized products (haematoporphyrin, hydroxyethylvinyldeuteroporphyrin and protoporphyrin) are inactive in the in vivo assay. It is concluded that the active component here is a porphyrin, possibly a dimer or oligomer, which is retained on the column during the normal separation by HPLC. This conclusion is supported by the observations that (i) the crude material obtained from the spent column is active without further alkali treatment, and (ii) activity develops over 30 min, when HpD or the mono- or diacetates of haematoporphyrin are treated with sodium bicarbonate in aqueous DMSO. The advantages of working with a pure substance (e.g. haematoporphyrin diacetate) rather than a mixture (HpD) are stressed.

Animals↗