Soft drugs. 21. Design and evaluation of soft analogs of propantheline.

The soft drug approach was applied to synthesize seven soft analogs of propantheline, which by design display predictable and controllable decomposition to inactive metabolites. Their synthesis involved the quatemization of several different amine groups with the chloromethyl ester of 9-methylxanthene-9-carboxylic acid. The rates of disappearance were measured for all of the compounds and were found to be more rapid than that of propantheline bromide in a variety of chemical and biological media under in vitro conditions. One of the soft analogs was found to be equipotent with propantheline in an in vitro assay. This soft analog was found to be equipotent with propantheline, in vivo, in protecting the rats against indomethacin-induced gastric ulceration and in inducing mydriasis in rabbits on intravenous administration. The pupil sizes returned faster to predrug levels with the soft analog than with propantheline, indicating increased metabolic lability of the soft analog. The equipotency of this soft analog coupled with increased metabolic lability proves the rationality of the soft drug approach for the design of safer therapeutic agents with higher therapeutic indices.

Novel 'soft' anticholinergic agents.

The concepts involved in the design of 'soft' drugs (drugs which, after achieving their therapeutic role, are metabolised in a predictable manner and at a controlled rate to non-toxic moieties) have been further applied in the case of atropine. Selected aliphatic and cycloaliphatic esters of a hypothetical, inactive acidic metabolite of atropine were designed and found to have atropine-like activity, and to revert to the inactive metabolite in rat liver homogenates. Peak anticholinergic activity, measured by the degree of antagonism of carbachol-induced spasms of guinea pig ileum strips, was observed when the esters contained a quaternary group. The in vitro stability of the esters was determined in human plasma, in pH 12 buffer solution, and in rat liver homogenate; the fastest rate of hydrolysis occurred in rat liver homogenate, and least sterically hindered esters degraded more rapidly than hindered esters. Synthesis of the esters was achieved in two stages. Phenylmalonic acid and the appropriate alcohol gave phenylmalonic acid monoesters, which, after reaction with tropine, afforded the required diesters. The tertiary amine group on the tropine moiety of the diesters then allowed the preparation of quaternary derivatives.

Long-term results of modified trabeculectomy with supramid implant for neovascular glaucoma.

Sixteen patients with neovascular glaucoma and residual visual function underwent modified trabeculectomy, including insertion of a Supramid sheet under the scleral flap. After 1 to 8.5 years of follow-up the intraocular pressure was substantially reduced in 12 patients and was maintained at 22 mm Hg or less in 10. Four patients were able to discontinue their medical therapy, and in 10 others it was considerably reduced. Functional filtering blebs were obtained in 12 patients. Visual acuity was about the same after surgery as before surgery in 8 of the 12; among the 4 others, visual loss was attributed to progressive cataracts in 2 and to macular degeneration in 2.

Combined trabeculectomy and cataract extraction: modified technique.

Two groups of patients with chronic open-angle glaucoma and cataract underwent combined surgery. Compared with the 11 who underwent the classic technique, the 11 who underwent a modified technique in which the cataractous lens was extracted through an incision in clear cornea obtained better control of their intraocular pressure and were less likely to have postoperative hyphema; however, their residual astigmatism was greater. The modified technique took a mean of 30 minutes less operating time and consistently produced a high-quality filtration bleb.

Ciliary block glaucoma: malignant glaucoma in the absence of a history of surgery and of miotic therapy.

A 45-year-old woman had malignant glaucoma but no history of glaucoma surgery or of treatment with miotics. The attack responded promptly and dramatically to cycloplegic therapy, the anterior chamber deepening and the intraocular pressure dropping. This is only the second such case reported in the literature.

[Sarcoidosis and rubeosis iridis]. / Sarcoïdose et rubeosis iridis.

In this case of sarcoidosis the prominent ophthalmologic manifestation was neovascularization of the iris and of the angle, with glaucoma.

[Transitory closed-angle glaucoma following a central retinal vein thrombosis]. / Glaucome par fermeture transitoire de l'angle consécutif à une thrombose de la veine centrale de la rétine.

This article reports a case in which an occlusion of the central retinal vein of one eye was accompanied by transitory shallowness of the anterior chamber, partial closure of the angle and elevation of the intraocular pressure.

[Neovascular glaucoma. Surgical technic]. / Glaucome neo-vasculaire. Une technique chirurgicale.

We describe a surgical technique we have used in eight cases of neo-vascular glaucoma. Under the scleral flap of a trabeculectomy we insert a sheet of supramid. After a follow-up period of 8 to 24 months, half of the cases have a good functioning filtration bleb.

[Papillary hemorrhage associated with posterior vitreous detachment]. / Hémorragie papillaire associée au décollement du vitré postérieur.

Three cases of papillary hemorrhage associated with posterior vitreous detachment are reported. One still has a visual field defect after two years. The resemblance between these hemorrhages and those found in some cases of chronic simple glaucoma is discussed.