Tafluprost, a new potent prostanoid receptor agonist: a dose-response study on pharmacodynamics and tolerability in healthy volunteers.

OBJECTIVE: Prostaglandin receptor analogs lower intraocular pressure (IOP) and are used for the treatment of glaucoma. This study aimed to compare the safety, tolerability and pharmacodynamics of four doses of the new, selective-prostanoid receptor agonist, tafluprost (AFP-168) in a Phase I placebo-controlled study. METHODS: Healthy volunteers (n = 16) received sequentially ascending doses of tafluprost (0.0001%, 0.0005%, 0.0025% and 0.005%) in one eye, and placebo in the other. Each treatment period consisted of 2 days of treatment, with 5 days between the treatment periods. Safety and tolerability assessments, as well as IOP measurements, were performed at defined intervals. RESULTS: Tafluprost was generally well tolerated and no volunteer discontinued due to adverse events (AEs). The most common ocular AE was ocular hyperemia, which was mild-to-moderate, and highly concentration-dependent. All doses of tafluprost decreased IOP, with the maximum effect occurring 12 hours after treatment. The decrease in IOP relative to placebo was significantly more effective with tafluprost 0.0025% and 0.005%, compared with tafluprost 0.0001% (p pound 0.005). CONCLUSION: Tafluprost was well tolerated and effective in lowering IOP. These data support further testing of tafluprost 0.0025% and 0.005%.

Ophthalmic timolol: plasma concentration and systemic cardiopulmonary effects.

Timolol maleate is a non-selective beta-adrenoceptor antagonist currently used mainly as an ocular preparation for the treatment of glaucoma and ocular hypertension. Despite the topical administration, ophthalmic timolol causes systemic adrenergic beta-blocking because of absorption from the eye into the systemic circulation. Gel formulations of ophthalmic timolol have been developed to reduce systemic absorption and adverse effects in comparison with conventional aqueous solution formulations. Timolol is metabolized by the polymorphic cytochrome P450 2D6 enzyme (CYP2D6). The changes in heart rate (HR) are the most striking effects of the systematically absorbed fraction of ophthalmic timolol, with 0.5 % aqueous formulations presenting larger effects than 0.1 % hydrogel formulations, especially during exercise. Plasma levels of ophthalmic timolol correlate with the changes in HR. Neither 0.5 % aqueous nor 0.1 % hydrogel formulations of timolol have exerted noteworthy effects on systolic (SAP) or diastolic (DAP) arterial pressures, probably because of a compensatory increase in systemic vascular resistance due to the attenuation of HR. Ophthalmic timolol does not exert remarkable effects on pulmonary parameter peak expiratory flow (PEF) and forced expiratory volume in 1 s (FEV1) in non-asthmatic patients. CYP2D6 activity is clearly associated with the pharmacokinetic parameters, particularly when 0.5 % aqueous solution of timolol is used: peak plasma concentration, elimination half-life and area-under-the-curve are highest in CYP2D6 poor metabolizers. Finally, since there is a correlation between the plasma level of timolol and several haemodynamic effects - especially HR in the state of elevated beta-adrenergic tonus - the CYP2D6 poor metabolizers may be more prone to bradycardia during treatment with (aqueous) ophthalmic timolol.

Cardiovascular effects of ophthalmic 0.5% timolol aqueous solution and 0.1% timolol hydrogel.

The objective of this randomized, double-masked, cross-over study was to compare the cardiovascular effects of two glaucoma formulations, ophthalmic 0.5% timolol aqueous solution and 0.1% timolol hydrogel. Twenty-four young healthy subjects received for 2 weeks either twice daily 0.5% timolol solution or once daily 0.1% timolol hydrogel. Heart rate (HR), blood pressure, atrio-ventricular conduction (PR interval), corrected QT time (QTc) and heart rate variability (HRV) were measured in supine position and during head-up tilted position. The mean peak concentrations of timolol in plasma were significantly higher after administration of 0.5% aqueous solution than after 0.1% hydrogel. A 0.5% timolol aqueous solution decreased HR on average by 3 bpm in supine position and by 7 bpm in head-up tilted position while no significant effects were observed with 0.1% timolol hydrogel. During tilt test HR was significantly lower after administration of timolol aqueous solution than after timolol hydrogel (mean +/- SD, 77 +/- 11 bpm versus 86 +/- 13 bpm, P < 0.05). Timolol aqueous solution slightly decreased QTc during tilt (5.9 +/- 5.6 ms, P < 0.01). During tilt tests, timolol aqueous solution slightly increased atrio-ventricular conduction (7.2 ms, P = 0.02). No significant differences were found in HRV. These results indicate that in healthy volunteers, ophthalmic 0.5% timolol aqueous solution produces more pronounced cardiac beta-blocking effects than 0.1% timolol hydrogel.

Timolol hemihydrate vs timolol maleate to treat ocular hypertension and open-angle glaucoma.

PURPOSE: We compared the therapeutic efficacy and safety of timolol hemihydrate to timolol maleate in patients with ocular hypertension and chronic open-angle glaucoma. METHODS: We conducted this three-month study as a multicentered, masked, parallel group comparison. Both the 0.25% and 0.5% concentrations were evaluated against similar concentrations of timolol maleate. Dosing was twice daily. An open-label, nine-month study followed the masked portion of the protocol, in which all patients received either 0.25% or 0.5% timolol hemihydrate. A total of 371 patients were included in both the 0.25% and 0.5% studies. RESULTS: We found statistically similar intraocular pressures with both the 0.25% (18.3 and 18.6 mm Hg for the hemihydrate and maleate groups, respectively) and 0.5% (19.9 and 19.5 mm Hg for the hemihydrate and maleate groups, respectively) concentrations of timolol hemihydrate and timolol maleate after three months of masked treatment. Likewise, peak intraocular effect at two hours after taking the medication was statistically similar between medicines at both concentrations. Likewise, both ocular and systemic safety were similar between the maleate and hemihydrate preparations at both concentrations. In the nine-month open-label protocol, therapeutic efficacy (19.9 and 19.1 mm Hg for the 0.25% and 0.5% concentrations, respectively) and safety of timolol hemihydrate were similar to effect and safety of the three-month protocol. CONCLUSIONS: This study suggests that timolol hemihydrate had an ocular hypotensive efficacy and safety profile statistically equivalent to that of timolol maleate for up to three months of therapy. Timolol hemihydrate showed efficacy and safety similar to that observed within the first three months, for up to one year of therapy.

Comparison of etidocaine and bupivacaine + lidocaine in retrobulbar anaesthesia.

Etidocaine (15 mg/ml) was compared with bupivacaine (5 mg/ml) combined with lidocaine (10 mg/ml) in retrobulbar anaesthesia. One hundred and twelve patients were randomised into two groups. Supplemental anaesthesia was needed in 41% of cases of the etidocaine group and 32% of the bupivacaine-lidocaine group. Akinesia was evaluated by the surgeon both pre- and postoperatively and was found to be good or complete in more than 95% of both groups. Recovery from the motor and sensory block was investigated three times during the first 24 postoperative hours. The motor block of the orbicular muscle disappeared earlier than that of the globe. Akinesia lasted significantly longer in the etidocaine group than in the bupivacaine-lidocaine group: after 14 h 69% vs 100%, respectively, of the eyes showed normal movements. Sensation in the cornea was also regained more rapidly in patients treated with the mixture.

Visual evoked potentials after retrobulbar or periocular anaesthesia.

The effect of the local anaesthetic agent, etidocaine, on the optic nerve function was examined at regional ophthalmic anaesthesia. Visual evoked potential (VEP) was recorded before and 15 minutes after injection of the anaesthetic agent in 19 patients scheduled for elective cataract surgery (seven retrobulbar and 12 periocular). Both the anaesthetised--that is, the eye to be operated on--and the fellow eye were examined. In the retrobulbar group, two patients displayed non-recordable VEPs while one had virtually non-detectable waves following the anaesthesia. In two retrobulbarly anaesthetised eyes, later peaks were unidentifiable while two other eyes had decreased amplitudes. In the periocular group, in nine patients, there was no clearcut effect on VEP resulting from the anaesthetic. In three patients of this group mild changes in the anaesthetised eyes were found. The differences in the effect of retrobulbarly or periocularly injected anaesthetics on VEP are probably due to the different concentration of the anaesthetic agent around the optic nerve.

Orbicular muscle akinesia: a comparison, using electromyography, of three techniques.

Ninety patients scheduled for elective cataract extraction under local anesthesia received an inferolateral intraconal injection of 4 mL of etidocaine mixed with hyaluronidase. They were divided into three groups of 30 patients each according to the method used to provide orbicular akinesia. Those in group I had a nasal, intraorbital injection; those in group II underwent electrostimulation to locate branches of the facial nerve in the eyelids; and those in group III had the anesthetic agent injected subcutaneously into the lids. Ten minutes after the regional blockade, orbicular muscle activity of the upper eyelid, as measured by electromyography, was found to be higher in group I than in the other two groups. The muscular activity of the lower lid at 10 minutes, or of either of the lids at 20 minutes, was similar in all three groups. The use of electrostimulation did not yield better orbicular akinesia than the infiltration technique alone. Nasal injection improved globe akinesia.

Ptosis following periocular or general anaesthesia in cataract surgery.

The incidence and duration of postoperative ptosis was investigated in 64 patients undergoing cataract surgery. Thirty-two patients had a 2-point periocular regional anaesthesia while 32 others were given general anaesthesia. The palpebral aperture and the levator muscle function were measured preoperatively and then on the 1st, 2nd, 4th and 7th postoperative days or as long as ptosis persisted. On the 1st postoperative day, about half of the patients in both groups demonstrated ptosis. On the 2nd day, ptosis was more common in the general anaesthesia group. The ptosis persisted 1 week postoperatively in 2 patients, both belonging to the general anaesthesia group. It is concluded that postoperative ptosis is common both after local and general anaesthesia. In most cases it is shortlasting and may be related to the volume or myotoxicity of a local anaesthetic drug. The use of a superior rectus muscle bridle suture and/or lid speculum may be important in provoking ptosis of longer duration.

Comparison of retrobulbar and periocular injections of lignocaine by computerised tomography.

Ten patients undergoing cataract surgery were given a local anaesthetic with lignocaine solution which was mixed with iohexol contrast medium. The location of the needle and the substance injected was determined by computerised tomography following retrobulbar or periocular anaesthesia. The retrobulbarly inserted needles were within the muscle cone, directed towards the optic foramen. The periocular needles were outside the muscle cone, tangentially along the orbital floor or pointing slightly upwards. After the retrobulbar injection the contrast medium was seen within the cone immediately after the injection and outside the cone as early as 3 minutes after the injection. With the periocular technique, however, diffusion of the anaesthetic in the opposite direction (that is, into the muscle cone) was rapid. The contrast medium was identified inside the muscle cone 2 minutes after the injection. Compression with an intraocular pressure reduction device after both of these techniques prevented exophthalmos. It is concluded that retrobulbar-like anaesthesia can also be induced by an appropriate periocular technique.

Periocular anaesthesia: technique, effectiveness and complications with special reference to postoperative ptosis.

The effectiveness of periocular anaesthesia and its complications were examined in 100 successive cataract operations. The patients were divided into 3 groups according to the duration of ocular compression with an Autopressor device after administration of periocular anaesthesia. In the control group, no compression was used (C-O, n = 36 patients). In the other two groups, compression was used for 10 (C-10, n = 32) and for 20 (C-20, n = 32) min. No differences in globe or orbicular akinesia were found between the groups. At 10 min, immobilisation of the globe in different directions was attained in 60.1-84.5% of the patients. Compression for an additional 10 min did not significantly improve the akinesia. In contrast, the hitherto undescribed loss of light perception increased with time: 15 patients at 10 min and 22 at 20 min were unable to see light. Chemosis and haematomas in the upper eyelid occurred more often in C-0 than in the other 2 groups. One day postoperatively the average palpebral aperture was smaller in C-0 than in the other two groups. The frequent postoperative ptosis (74.3% on the 1st day) decreased rapidly, but on postoperative day 7, 9 patients still had ptosis. In only one patient was ptosis still recognizable at 6 weeks postoperatively. No serious complications occurred. This study demonstrates that periocular anaesthesia with ocular compression is a suitable method for cataract surgery.

Effect of ocular compression (Autopressor) on intraocular pressure in periocular anaesthesia.

One hundred successive patients were operated on for cataract under periocular anaesthesia. The patients were divided into 3 groups to study the effect of extraocular compression on intraocular pressure. In the control group (C-O), no compression was used. In the other 2 groups, compression was applied immediately after local injection of the anaesthetic for either 10 (C-10) or 20 min (C-20). In the control group, a periocular local anaesthetic increased the IOP in 27 of 36 patients, the average increase being 3.8 mmHg (at 10 min). Postanaesthetic compression of the eye led to a decrease in intraocular pressure, which is beneficial for the operative procedure. During the first 10 min, the mean intraocular pressure decreased by 3.1 and 4.0 mmHg in groups C-10 and C-20, respectively. In the C-20 group, there was a further (1.3 mmHg) reduction in intraocular pressure between 10 and 20 min.