Retina drugs

ADH also has clinical significance in the metabolism of methanol and ethylene glycol, two drugs with toxic metabolites. Methanol is oxidized by ADH to formaldehyde, which damages the retina and can cause blindness. Ethylene glycol is metabohzed by ADH to oxalic acid, which has renal tox-... 

K. Hosoya, T. Kondo, M. Tomi, H. Takanaga, S. Ohtsuki, and T. Terasaki. MCT1-mediated transport of L-lactic acid at the inner blood-retinal barrier A possible route for delivery of monocarboxylic acid drugs to the retina. Pharm. Res. 18 1669-1676 (2001). 

Currently, there is only one antisense drug on the market— Vitravene (active ingredient fomivirsen) for the treatment of cytomegalovirus (CMV)-induced retinitis (inflammation of the retina) in AIDS patients. Fomivirsen has 21 nucleotides complementary to a CMV mRNA sequence, which is necessary for the production of infectious virus. Two examples of experimental antisense drugs are provided in Exhibit 3.15, while Table 3.1 lists other antisense drugs in clinical phase. 

Topical application is the most common route of administration for ophthalmic drugs. Advantages include convenience, simplicity, noninvasive nature, and the ability of the patient to self-administer. Because of blood and aqueous losses of drug, topical medications typically do not penetrate in useful concentrations to posterior ocular structures and therefore are of no therapeutic benefit for diseases of the retina, optic nerve, and other posterior segment structures. 

Parasympatholytics are used to induce a mydriasis in the ophthalmology for the examination of the retina. They are applied locally as drops or ointment. The drug-induced inability of the eyes to accommodate results in a serious, although transient, impairment of the visus. Therefore the long-acting atropine (7-10 days) is replaced by short-acting compounds like homatropine (1-3 days), cyclopentolate (1 day) or tropicamide (6 hours). 

Fomivirsen is injected directly into the vitreous humor of the eye. Animal studies have shown that this drug accumulates in the retina and iris over 3 to 5 days and is cleared from the vitreous humor within 7 to 10 days. Fomivirsen exhibits minimal systemic absorption and is degraded locally by cellular exonucleases. 

All these parameters are very close to the requirements which a long-term ocular endotamponade has to fulfil. Also the in vivo tests in a rabbit eye model were extremely promising no emulsification, no changes in the vascular structure of the retina and no increase of the intra-ocular pressures. All negative side effects, seen with the monomeric FCLs, seemed to be eliminated. In addition, some additional advantages could be claimed reduced tissue penetration and the potential to dissolve drugs [44,45]. 

The ocular endotamponades of the future could be a combination of tampo-nading and drug delivery device. Vitrectomy removes the natural vitreous after it has become opaque, inflamed, or unable to keep the retina in place. In many cases, the necessity to remove it is the result of retinal disorders, which are still existent after vitrectomy [50]. In equivalence to the blood-brain barrier, there is also a blood-retina barrier, with the effect that it is difficult to treat retinal disorders systemically. Therefore, the delivery of appropriate drugs via the vitreous cavity would open new treatment options. 

We recently proposed a completely electronic model for the excitability of nerve membranes that is based on the assumption of electron-donating, electron-accepting, and electron-storing properties of macromolecules or of protein-lipid complexes which constitute the ionic channels of the nerve membrane (63). This model, which is based on simple physical concepts with easily defined parameters, reproduces the empirical Hodkgin-Huxley equations rather well and also explains how different types of drugs may work on nerves. The model is easily extended to other excitable complexes like the receptor protein complex at nerve synapses and the rodopsin molecules in the retina. Nor is it inconceivable to build a model for the function of smell that is based on electronic triggering of ionic channels which are affected by molecules adsorbed onto or dis-... 

In the first part of our chapter the occurrence of H3 heteroreceptors in the CNS and in the retina will be described. Then the location of the H3 heteroreceptors will be discussed. (The term "heteroreceptor" will be used in a relatively broad sense in this article, i.e. regardless of whether the presynaptic location on the nerve endings themselves has been proven or not.) Next, interactions between H3 heteroreceptors and other types of presynaptic receptors will be considered. Finally, some general remarks with respect to H3 heteroreceptors as targets for new drugs will be given. 

To investigate drug action at the most peripheral sites, i.e., the light receptors and synapses in the retina, they stim-... 

---