Dorset Family Search

Weinberg, Gerald M.

Dorset House Publishing

2006

194 pages

$24.95

Paperback

PN145

Weinberg, a former professor of computer science who now leads writing seminars, reveals his secrets for gathering, organizing, and discarding writing ideas. Drawing an analogy to the stone-by-stone method of building fieldstone walls, he shows how to construct fiction and nonfiction manuscripts from key insights, stories, and quotes. The elements, or stones, are collected nonsequentially, over time, and eventually find logical places in larger pieces.

In clinical 5-aminolevulinic acid (ALA)-based photodynamic therapy (PDT) of skin tumors it is desirable to develop vehicles that minimize the penetration of ALA through normal stratum corneum and maximize it through the compromised stratum corneum of the tumors to improve tumor selectivity. We have designed a bioadhesive patch, which may be able to achieve this aim. It induces levels of protoporphyrin IX (PpIX) in skin overlying tumors similar to those induced by the proprietary cream (Porphin®) but at the same time induces less PpIX to form in normal skin and at distant sites. The mechanisms of action of the patch, as compared with that of the cream, were studied by means of Cuprophan® barriers that mimic compromised tumor stratum corneum and in a mouse model with transplanted tumors.

INTRODUCTION

5-Aminolevulinic acid (ALA), a naturally occurring precursor in the biosynthesis of heme, is a commonly used agent in clinical photodynamic therapy (PDT) (1). Administration of exogenous ALA, systemically or topically, is reported to cause rapid and highly selective accumulation of the potent photosensitizer protoporphyrin IX (PpIX) in neoplastic cells. The reasons cited for the high selectivity of PpIX accumulation include enhanced porphobilinogen deaminase activity and reduced ferrochelatase activity in neoplastic cells (2,3). A compromised stratum corneum barrier to drug diffusion is reported to further enhance the selectivity of PpIX accumulation in neoplastic skin lesions by allowing increased ALA penetration following topical application (4). ALA is most commonly administered to neoplastic skin lesions in a topical semisolid vehicle in Europe and in a hydroalcoholic solution in the United States.

Because of the inability of semisolid or liquid vehicles to persist at moist or irregularly shaped regions of the body, we have previously described a bioadhesive patch system containing ALA, which allowed efficient delivery of the drug to the vulva (5-7) and mouth (8). In this paper, we compare the selectivity of PpIX accumulation in normal skin and skin overlying tumors in vivo following topical application of patch and semisolid cream systems containing ALA.

MATERIALS AND METHODS

Chemicals. Gantrez® AN-139, a copolymer of methylvinylether and maleic anhydride (PMVE/MA), was provided by ISP Co. Ltd. Guildford, UK. Tripropyleneglycol methyl ether (TPM; Dowanol(TM) TPM) was purchased from Sigma Aldrich, Dorset, UK. Plastisol® medical grade polylvinyl chloride) emulsion, containing diethylphthalate as plasticizer, was provided by BASF Coatings Ltd., Clwyd, UK. 5-Aminolevulinic acid, hydrochloride salt and Porphin® cream (20% w/w ALA in Unguentum Merck®) were purchased from Crawford Pharmaceuticals, Milton Keynes, UK. Unguentum Merck® was obtained from Merck, Darmstadt, Germany.

Patch and cream manufacture. Bioadhesive patches evaluated in this study were prepared by a conventional casting technique (9) using a 20% w/w PMVE/MA and 10% wt/wt TPM gel. PMVE/MA was added to ice-cooled water (reagent grade 1), stirred vigorously and heated to 95°C until a clear solution was formed. Upon cooling, the required amount of TPM was added and the casting blend adjusted to a final weight with water. Appropriate amounts of ALA were dissolved directly into defined volumes of this aqueous blend immediately prior to casting.

Determination of approximate loadings of ALA to be included in bioadhesive patches was by consultation with a clinician experienced in the use of topical creams in PDT. It was decided to load each square centimeter of the patch with a dose of ALA equivalent to that contained in the amounts of proprietary creams typically applied per square centimeter to neoplastic lesions.

A cream (Unguentum Merck®) was applied in the thickness used clinically to each of 25 square centimeters, ruled out on the back of a gloved hand. Each square centimeter was individually cleared of cream using a microspatula and each aliquot of cream was weighed. Because Porphin® cream, the most commonly used ALA product in the UK, contains 20% wt/wl ALA, the mean ALA dose per square centimeter was determined by calculation. This estimation of drug loading was then used as a starting point in the patch design process. Patches containing ALA loadings of 38 mg cm^sup -2^ were prepared as a result of this process.

In his foreword to the catalogue of John Hubbard’s Spirit of Trees, Duncan Robinson, the director of the Fitzwilliam Museum, invokes John Constable. Indeed if Constable were alive today he might be John Hubbard. Although Hubbard is American, he has lived in Dorset for 45 years and although his paintings are far more abstract than Constable’s and have been inspired by foreign places as well as British - the Atlas Mountains, Spanish gardens, the Vaucluse in France - they approach nature in a similar way, with romantic feelings but a pragmatic eye.

They express the artist’s deep passion for and curiosity about elusive nature, almost as a force or idea, but never lose sight of its more mundane reality - its branches in your face, its hard and uneven surfaces, its absolute determination to grow.

Hubbard is himself a gardener as well as an artist. The garden of his house in Dorset is well known to connoisseurs and has often been written about as well as filmed for TV. Again like Constable, he mostly prefers to paint and draw nature as it has been trimmed and ordered by man, but is constantly aware of its innate wildness, its capacity, if man relaxes his control, to smother and swallow the gardener, the farmer, the landscapist and all their works.

Hubbard’s large charcoal drawings are perhaps the best way to approach his art, for they are themselves - some of them made directly in front of the motif, some developed and abstracted in the studio from pencil sketches - approaches to his paintings. ‘I draw to sharpen my eye, ‘ he says, ‘to fix an image on my unconscious mind. . .’

and ‘I adore drawing outside, it’s the most enjoyable aspect of my working life.’

The exhibition at Kew, beautifully hung in a spacious, light-filled pavilion called White Peaks, which apparently (I can hardly believe this) is threatened with being turned into a shop, consists of a selection of charcoal drawings made over the last quarter century. The earliest as well as the latest are taken from Kew itself, including ‘Kew Gardens no.5′ (1980) - a wonderful deep vista into an ash grove, characteristic of Hubbard’s work in its upward and inward movement towards a source of light - and ‘Palm House’ (2005) - an explosion of diagonal stems against the light, barred with the fierce tiger-stripes of the palm’s fronds. In between are drawings from the subtropical gardens at Abbotsbury in Dorset and Tresco in the Isles of Scilly. The huge ‘Abbotsbury Gardens no.2′ is almost abstract, a play of light and foliage (or white paper, swirling lines and smears of grey), as is the denser ‘Twisting, Gripping no.1′ from Tresco, nicely described in Andrew Lambirth’s excellent catalogue text as ‘a dark, meaty drawing’. Two drawings made in Hubbard’s garden, the large abstract ‘Plant Forms’ (1984) and the smaller figurative ‘Weeping Pears’ (2005) - an open gate framed by writhing trees - show how easily he can switch between supposedly antipathetic styles with equal authority in pursuit of his own vision.

But for mastery of the medium - light, shade, trunks, bark, branches, foliage, the bumpy contours of the ground beneath, and his special sense of penetration, of pressing inwards and being surrounded by nature - perhaps ‘Olive Grove, Corfu’ (1994) is the most complete. And all executed, ladies and gentlemen, as if by nature itself, with mere sticks of charred wood! It’s a pity this show can’t be transferred to Tate Britain to coincide with the Constable exhibition at the beginning of June, though it wouldn’t look as good there as it does at Kew.