Phase I study using desferrioxamine and iron sorbitol citrate in an attempt to modulate the iron status of tumor cells to enhance doxorubicin activity.

A novel approach to enhance the activity of doxorubicin is to increase the availability of cellular "chelatable" iron to participate in doxorubicin-mediated free-radical generation. To achieve this, we designed a regimen consisting of desferrioxamine (DFO, 50 mg/kg daily given as an i.v. infusion over 72 h) to increase cellular iron uptake. Thereafter, the combination of iron sorbitol citrate (ISC) and doxorubicin (as a single agent or as part of the CHOP regimen) was given. In a phase I study we investigated the toxicity of this regimen in nine patients with refractory malignant disease. Severe but reversible ocular toxicity (i.e., acute maculopathy) was observed in two patients. As these patients were the only ones who were pretreated with cisplatin, we caution against the use of DFO in cisplatin-pretreated patients. Severe phlebitis was encountered in five of nine patients. A partial remission was observed in two of four patients with refractory Non-Hodgkin's lymphoma who were treated with DFO, ISC, and doxorubicin as part of the CHOP regimen. We conclude that pretreatment with DFO and iron sorbitol citrate may be of benefit in the treatment of malignancies with doxorubicin-containing regimens, but ocular toxicity and severe phlebitis limits the use of DFO in this approach. The attachment of DFO to biocompatible polymers may be a method of overcoming the observed toxicity and warrants further study.

Bandage lenses: collagen shield vs. hydrogel lens.

We compared the behavior of a 70% water content hydrogel lens to a 24-hour collagen shield in 11 healthy volunteers. Corneal swelling was measured by means of ultrasound pachymetry. After 24 hours of continuous wear, mean corneal thickness increased 26.4 microns (4%) with the hydrogel lens and 17.9 microns (3%) with the collagen shield, a difference that was not significant at the P less than 0.05 level. Both the hydrogel lens and the corneal shield were well tolerated. Ocular discomfort was slightly greater with the collagen shield. We assume that this is related to the reduction in visual acuity and subsequent loss of binocular vision with the collagen shield. The development of a fully transparent collagen shield would enhance patient compliance and facilitate assessment of the corneal and intraocular status in eye disease.

Long-term treatment with Pilogel/beta-blocker in glaucoma patients.

In a multicentre clinical trial thirteen patients with primary open angle glaucoma or ocular hypertension were followed during at least six months while selfinstilling Pilogel (once daily) and topical beta-blocker (twice daily). After six months of combination therapy there was an average decrease in intra-ocular pressure (IOP) of 33.6% 9.5 hours after Pilogel administration and an IOP decrease of 23.4% 22.5 hours after Pilogel administration. With topical beta-blocker alone, an average IOP decrease of 15% was measured. Throughout the study we observed in six patients (46.1%) a superficial punctate keratitis which mostly spontaneously cleared. We did not see any serious side-effects after six months of combination therapy.

Efficacy and safety of the combination therapy Pilogel/beta-blocker: interim results.

The interim results of a multicentered clinical trial with the combination therapy therapy Pilogel/topical beta-blocker (twice daily) in patients with primary open angle glaucoma or ocular hypertension are discussed. Six patients were treated with Pilogel and a topical beta-blocker for one month. Four out of six patients responded well to the combination therapy. Most patients experienced some difficulty in applying the gel and their eyelids stuck together on awakening. In two patients a superficial punctate keratitis was observed. We found an average decrease in intra-ocular pressure (IOP) of 22.5% 22.5 hours after Pilogel administration, but there was some tendency towards higher evening values compared to morning values. In view of the appearance of a corneal haze as described by Johnson et al. during long-term treatment, longer follow-up is necessary.

Ocular penetration of beta-adrenergic blocking agents. An experimental study with atenolol, metoprolol, timolol and propranolol.

A comparison was made between the ocular penetration of topically applied 14C-atenolol, 14C-timolol, 14C-propranolol and 3H-metoprolol by means of liquid scintillation counting. Only one eye was treated, the fellow eye served as a control. Blood plasma levels were measured as well. We could detect a relationship between the ocular penetration and the degree of lipophilicity of the drugs used, as was to be expected. Drugs with a higher degree of lipophilicity penetrated more readily into the eye, whereas they also achieved higher blood plasma levels. Relatively high concentrations of atenolol were found in the nicitating membrane, thus reflecting its poor ocular penetration. The concentrations detected in the untreated eye were low and probably cannot explain the marked reduction in intraocular pressure observed after unilateral instillation of active beta-adrenergic blocking drugs, as for instance timolol. Our findings suggest that the ocular penetration of beta-adrenergic blocking agents on topical application only plays a minor part in their ocular hypotensive effect.

Timolol eye drops: bradycardia or tachycardia?

26 eyes of 14 patients--8 with primary open angle glaucoma, 6 glaucoma suspects--were treated for at least 6 months with either twice daily timolol 0.25% in both eyes or twice daily timolol 0.50% in one eye. None of the patients received concomitant local or oral drugs. Special attention was paid to tachyphylaxis and to blood pressure and pulse rate. We could detect a slight although not significant tendency to tachyphylaxis (1-2 mm Hg) after 1 week of timolol treatment. It takes at least 1-2 weeks to reach the initial I.O.P. level after withdrawal of timolol therapy. Blood pressure did not change significantly. The pulse rate showed a slight although not significant tendency to decrease (a few beats/minute), but we detected a reflex tachycardia (10 beats/minute) after withdrawal of timolol therapy which was very significant. This rebound phenomenon has not been referred to in the literature. It seems reasonable to conclude that one should take care in treating glaucoma patients with concomitant arrhythmias with timolol eye drops.

Dermatitis as a side-effect of long-term topical treatment with certain beta-blocking agents.

Three groups of glaucoma patients, treated topically with various beta-blocking agents, were studied for mucocutaneous side-effects of long-term therapy. In five of eleven patients with ocular and/or periocular dermatitis as an adverse reaction to long-term treatment with metoprolol eye drops a dermatitis, reproducible by patch tests with pure metoprolol 3%, was demonstrable. Histopathological examination of positive patch tests examined in three cases showed a picture compatible with a delayed type of hypersensitivity. Four atenolol treated patients showed adverse reactions, but negative patch tests to atenolol were found. In addition new data are reported in favour of cross-reactivity between certain beta-blocking agents.

Penetration of atenolol in the rabbit eye.

The ocular penetration of topically applied [14C]-atenolol in the rabbit was determined by means of liquid scintillation counting. Only one eye was treated, the fellow eye serving as a control. Blood plasma levels were measured as well. The absolute amount of atenolol which penetrated the eye was very low, but a relatively high concentration was achieved in the tissues of the nictitating membrane. We could only detect an increase in the amount of atenolol with time in the aqueous humor. In all other ocular tissues, including iris and ciliary body, the atenolol level remained constant with time. Hardly any atenolol could be detected in the untreated eye and none in the blood plasma. These findings suggest that the ocular penetration of atenolol administered as an eye drop is very poor. Ocular penetration, therefore, hardly seems to play a part in the antiglaucomatous effect of atenolol.

Metoprolol eye drops in the treatment of glaucoma. A double-blind single-dose trial of a beta1-adrenergic blocking drug.

A double-blind single-dose trial was performed on 13 patients with primary open-angle glaucoma. Metoprolol 1%, 2%, and 4% produced a median fall in IOP of 5.6, 5.4, and 6.8 mm Hg, respectively, in the treated eye. The differences in effect between the 1%, 2%, and 4% solutions were not statistically significant. There was no significant fall in IOP in the untreated eyes. There were no significant changes in blood pressure, pulse rate, or pupillary diameter. We could not detect any local objective or subjective side effects during the single-dose study. The clinical usefulness of metoprolol may be limited due to local toxic reactions after treatment with multiple doses. Furthermore, there is the problem of tachyphylaxis that could limit extended treatment with topical beta-adrenergic blocking drugs.

Atenolol 4% eye drops and glaucoma. A double-blind short-term clinical trial of a new beta1-adrenergic blocking agent.

We studied the effect of a single dose of atenolol 4% eye drops on 21 patients with primary open-angle glaucoma during a double-blind clinical trial. We monitored intraocular pressure (IOP), blood pressure, and pulse rate. At three and six h after medication, the average reduction of IOP was 7.3 and 4.1 mm Hg, respectively, compared to the baseline readings without medication. The reduction of IOP at four h after medication was 6.3 mm Hg compared to the pretreatment value. This corresponds to an average change from the pretreatment value of 22%. Blood pressure and pulse rate did not change significantly. We observed no subjective or objective ocular side effects. The duration of the effect of a single dose of atenolol 4% eye drops is approximately six h. Atenolol 4% eye drops may become a useful agent in the medical treatment of glaucoma if a long-term effect and no ocular side effects (especially a local anesthetic effect) can be proven.