Ocular safety and efficacy of an HSV-1 gD vaccine during primary and latent infection.

One potential complication of systemic herpes simplex virus (HSV) vaccination is that subsequent ocular infection may lead to increased immunogenic corneal scarring. Therefore, V52, a genetically engineered vaccinia virus that expresses the HSV-1 glycoprotein gD, was tested for ocular safety and for protection against ocular challenge with a stromal-disease-producing strain (McKrae) of HSV-1. To maximize immune response, rabbits were vaccinated by a series of inoculations. V52-vaccinated rabbits developed significant HSV-1 neutralizing antibody titers; however, they were not as high as those induced by vaccination with live HSV-1 McKrae. One month after the final vaccination, all rabbits were challenged ocularly. Eyes were monitored for 35 days for epithelial keratitis, stromal keratitis, and iritis. In no case was epithelial keratitis, stromal keratitis, or iritis significantly exacerbated by vaccination. The gD V52 recombinant vaccine provided protection against HSV-1 induced epithelial keratitis (P = 0.02) and long-term stromal scarring (P = 0.04). There was no significant reduction in the incidence of trigeminal ganglionic latency in the vaccinated rabbits (P greater than 0.05). Thus, our results indicate that V52, a gD recombinant vaccine probably is safe with regard to corneal scarring, and may provide a small amount of protection against ocular HSV-1 infection. The amount of protection provided was less than that reported in mice and guinea pigs. This suggests that to provide high levels of ocular protection in rabbits (and probably in humans), HSV-1 vaccines may have to elicit a more vigorous immune response than that produced by normal HSV-1 infection.

Long-term acyclovir use to prevent recurrent ocular herpes simplex virus infection.

OBJECTIVE: To evaluate the effectiveness of more than 12 months of oral acyclovir therapy in reducing recurrences of ocular herpes simplex virus. METHODS: We retrospectively compared ocular herpes simplex virus recurrence in 2 groups of patients. In group 1, patients used oral acyclovir for at least 12 months and then discontinued the treatment. In group 2, patients received the treatment for at least 18 months. We compared recurrences when both groups were using acyclovir (period 1) and when only group 2 was receiving the drug (period 2). Statistical analysis was performed with the t test, chi2 test, and Kaplan-Meier method. RESULTS: Group 1 had 18 patients and a mean +/- SD follow-up of 45.2 +/- 22.2 months. Group 2 had 22 patients and a mean +/- SD follow-up of 42.4 +/- 30.2 months. Six patients (33%) in group 1 and 4 patients (18%) in group 2 had recurrence in period 1 (P =.3). In period 2, 14 patients (78%) in group 1 and 8 patients (36%) in group 2 had recurrence (P =.01). Mean +/- SD recurrence-free survival in period 2 was 15.3 +/- 5.5 months in group 1 and 37.3 +/- 6.3 months in group 2 (P =.001). CONCLUSIONS: Long-term oral acyclovir use seems to remain effective in decreasing the number of ocular herpes simplex virus recurrences beyond 12 months.

A controlled trial of oral acyclovir for the prevention of stromal keratitis or iritis in patients with herpes simplex virus epithelial keratitis. The Epithelial Keratitis Trial. The Herpetic Eye Disease Study Group.

OBJECTIVE: To evaluate the efficacy of oral acyclovir in preventing stromal keratitis or iritis in patients with epithelial keratitis caused by herpes simplex virus (HSV). METHODS: Patients with HSV epithelial keratitis of 1-week or less duration were treated with topical trifluridine and were randomly assigned to receive a 3-week course of oral acyclovir, 400 mg 5 times a day (hereafter referred to as the acyclovir group), or placebo (hereafter referred to as the placebo group). The development of HSV stromal keratitis or iritis was assessed during 12 months of follow-up. RESULTS: Stromal keratitis or iritis developed in 17 (11%) of the 153 patients in the acyclovir group and in 14 (10%) of the 134 patients in the placebo group. Compared with the placebo group, the adjusted rate ratio for the development of stromal keratitis or iritis in the acyclovir group was 1.16 (95% confidence interval, 0.56-2.43). The development of stromal keratitis or iritis was more frequent in patients with a history of HSV stromal keratitis or iritis than in those without such a history (23% vs 9%; P = .01). CONCLUSIONS: For patients with HSV epithelial keratitis treated with topical trifluridine, no apparent benefit of a 3-week course of oral acyclovir in preventing HSV stromal keratitis or iritis was seen during the subsequent year. The 1-year rate of development of stromal keratitis or iritis was lower than previously reported in the literature, except in patients with a history of HSV stromal keratitis or iritis.

Prophylactic topical cyclosporine in experimental herpetic stromal keratitis.

We determined the anti-inflammatory prophylactic effect of topical cyclosporine in a rabbit model of herpetic stromal keratitis. In a first study, we established that presensitization of rabbits prior to corneal intrastromal injection of herpes simplex virus produced a severe stromal keratitis beginning on day 7 after the intrastromal challenge. Twenty-four presensitized rabbits were thereafter divided into three groups for topical treatment five times a day: (1) 1% cyclosporine in a vehicle solution, started on day 4 after intrastromal challenge, plus 1% trifluridine started on day 7 after challenge, (2) the vehicle solution for cyclosporine, started on day 4, plus 1% trifluridine started on day 7, and (3) the vehicle solution for cyclosporine alone, started on day 4. The severity of stromal disease was significantly decreased in eyes treated with combined cyclosporine-trifluridine, whereas trifluridine alone had no effect on the stromal disease. Epithelial disease did not seem to be worse in eyes treated with combined cyclosporine-trifluridine; the incidence and duration of positive cultures, however, were increased in this group.

Penicillin therapy in icteric leptospirosis.

A prospective, controlled randomized study of penicillin therapy in icteric human leptospirosis was carried out between 1 October 1983 and 31 December 1986. Thirty-eight patients received intravenous crystalline penicillin for 5 days, while 41 assigned to a control group received intravenous fluids only. A comparison of the results of laboratory tests made on the day of admission revealed no significant differences between the 2 groups. There was no significant difference in time for defervescence, return of biochemical parameters to normal, incidence of iritis, or mortality in the 2 groups. Three patients (7.3%) in the control group and 1 patient (2.6%) in the treatment group died. The overall mortality rate was 5.9%. Leptospira were recovered from urine cultures in 6 control patients but from none of the treated patients' post-treatment cultures. We conclude that penicillin has little effect on clinical outcome in icteric leptospirosis.

Effects of nitric oxide synthase inhibitor on intraocular pressure and ocular inflammation following laser irradiation in rabbits.

PURPOSE: To examine the effects of nitric oxide synthase (NOS) inhibitors on intraocular pressure (IOP) and ocular inflammation following laser irradiation of the rabbit iris, and to investigate the involvement of nitric oxide (NO). METHODS: Thirty min after the intravenous administration of a nonselective inhibitor of NOS, N omega-nitro-L-arginine methyl ester (L-NAME, 1-100 mg/kg), or a selective inhibitor of iNOS, aminoguanidine (AG, 100 mg/kg), Q-switched Nd:YAG laser irradiation was applied to the iris of albino rabbits at an energy level of 48 mJ. IOP was measured prior to and for 24 h after irradiation. In separate groups of rabbits, aqueous humor was withdrawn 30 min after irradiation to determine protein and prostaglandin (PG) E2 concentrations. RESULTS: Intravenously administered L-NAME dose-dependently inhibited the acute increase in IOP, the peak of which was observed at 30 min, following laser irradiation. The IOP increase was completely abolished by 100 mg/kg of L-NAME. This dose of L-NAME significantly reduced the elevation of protein concentration in aqueous humor following irradiation; however, this dose failed to affect the increase in PGE2 concentration On the other hand, the inhibitory effects of AG (100 mg/kg) on the increase in IOP and aqueous protein following laser irradiation were not significant. CONCLUSIONS: Intravenous administration of L-NAME significantly inhibits the IOP rise and the increase in protein concentration in aqueous humor following laser irradiation, but AG does not, suggest the involvement of cNOS in these ocular responses to laser irradiation.

Cyclosporin-augmented laser peripheral iridoplasty.

BACKGROUND AND OBJECTIVE: Almost all patients develop iritis following argon laser peripheral iridoplasty. Numerous adverse effects, particularly elevated intraocular pressure (IOP) and reduced microbial resistance, complicate therapy with topical corticosteroids. An immunomodulator, such as cyclosporin A (CsA), avoids these undesirable effects, yet may suppress ocular inflammation. MATERIALS AND METHODS: Argon laser peripheral iridoplasty was performed on anesthetized rabbits with pigmented iris epithelium. Rabbits were randomly assigned to the untreated control, CsA (2%), or dexamethasone (0.1%) groups. Postoperative inflammation was documented by digital photography, IOP, and protein in aqueous humor. RESULTS: Iris injection, aqueous flare, and fibrin decreased most rapidly in the control group, as did protein in aqueous humor. Decreases in IOP of 49% to 58% were similar in all three groups. There were no differences in conjunctival congestion between the CONCLUSION: Neither treatment with antiinflammatory drugs that inhibit phagocytosis (e.g., topical steroids) nor treatment with anti-inflammatory drugs that suppress T-lymphocytes (e.g., topical sA) significantly attenuated inflammation following iridoplasty.

Efficacy of polyacrylamide vs. sodium hyaluronate in cataract surgery.

A prospective randomized study was conducted in 137 patients who underwent cataract surgery and implantation of a polymethylmethacrylate intraocular lens with either polyacrylamide (Orcolon) (68 patients) or sodium hyaluronate (Healon) (69 patients) as the viscoelastic material. Both viscoelastics were aspirated at the end of surgery. Patients were examined before surgery and 1 and 14 days after surgery. Endothelial cell counts were obtained before surgery and 3 months after surgery in 34 patients (16 in the polyacrylamide group and 18 in the sodium hyaluronate group). There were no reports of a flat or shallow anterior chamber intraoperatively in either group. There was no statistically significant difference between the two groups in the incidence of corneal edema or iritis on any visit or in endothelial cell loss. Although there was a significant reduction in intraocular pressure across postoperative visits for the overall sample, there was no significant difference in pressure between the polyacrylamide and sodium hyaluronate groups. The results indicate that no untoward effects on corneal edema, endothelial cell count, iritis or intraocular pressure are to be expected when polyacrylamide is used as an aid to cataract surgery.

[Laser trabeculoplasty: therapeutic options and adverse effects]. / Behandlungsmethoden und Komplikationen der Lasertrabekuloplastik.

Laser trabeculoplasty is a simple method for treating glaucoma and ocular hypertension and has few adverse effects. There are different laser systems for reducing the intraocular pressure of patients with glaucoma and ocular hypertension. Complications include transient intraocular pressure elevation, iritis, and anterior synechiae.

[Effect of corticoids on protein concentration in rabbit aqueous humor after argon laser surgery of the iris (author's transl)]. / Einfluss von Corticoiden auf die Proteinkonzentration im Kammerwasser des Kaninchens nach Laserkoagulation der Iris.

A high dose of corticoid premedication was applicated intramuscularly five hours before laser surgery. Following laser coagulation of the pigmented iris the protein concentration in the aqueous humor was measured every hour. The initial increase in protein concentration was found to be lower than in earlier experiments without premedication. In contrast to earlier results without corticoid premedication, the reaction of the untreated contralateral eye was suppressed.

Effect of heparin surface modification of polymethylmethacrylate intraocular lenses on signs of postoperative inflammation after extracapsular cataract extraction. One-year results of a double-masked multicenter study.

PURPOSE: A heparin surface modified posterior chamber intraocular lens (IOL) was compared with a conventional polymethylmethacrylate (PMMA) IOL regarding postoperative complications caused by inflammation. METHODS: Five hundred twenty-four patients from 10 different centers were included in a parallel group, double-masked, multicenter study. RESULTS: The cumulative number of patients with inflammatory cellular deposits on their IOLs during the first postoperative year differed significantly in favor of the heparin surface modified group, with 29.8% of the patients having cellular deposits compared with 48.8% of patients in the control group. Cellular deposits were observed most frequently at 3 months after surgery, and the difference between the groups was most pronounced and statistically significant at this time. The same results were seen at 1 year, but the difference was not significant. The number of cellular deposits per patient, however, was significantly lower in the heparin surface modified group at 1 year. Cumulatively, there were significantly more patients with posterior synechiae in the PMMA group than in the heparin surface modified group during the 1-year follow-up. Complications were few and comparable between the groups. CONCLUSION: The results of this study indicate that heparin surface modification reduces the inflammatory response to PMMA IOLs.

Acyclovir for the prevention of recurrent herpes simplex virus eye disease. Herpetic Eye Disease Study Group.

BACKGROUND: Long-term treatment with antiviral agents has been shown to prevent recurrences of genital and orofacial herpes simplex virus (HSV) disease, but it is uncertain whether prophylactic treatment can prevent recurrences of ocular HSV disease. METHODS: We randomly assigned 703 immunocompetent patients who had had ocular HSV disease within the preceding year to receive 400 mg of acyclovir or placebo orally twice daily. The study outcomes were the rates of development of ocular or nonocular HSV disease during a 12-month treatment period and a 6-month observation period. RESULTS: The cumulative probability of a recurrence of any type of ocular HSV disease during the 12-month treatment period was 19 percent in the acyclovir group and 32 percent in the placebo group (P<0.001). Among the 337 patients with a history of stromal keratitis, the most common serious form of ocular HSV disease, the cumulative probability of recurrent stromal keratitis was 14 percent in the acyclovir group and 28 percent in the placebo group (P=0.005). The cumulative probability of a recurrence of nonocular (primarily orofacial) HSV disease was also lower in the acyclovir group than in the placebo group (19 percent vs. 36 percent, P<0.001). There was no rebound in the rate of HSV disease in the six months after treatment with acyclovir was stopped. CONCLUSIONS: After the resolution of ocular HSV disease, 12 months of treatment with acyclovir reduces the rate of recurrent ocular HSV disease and orofacial HSV disease. Long-term antiviral prophylaxis is most important for patients with a history of HSV stromal keratitis, since it can prevent additional episodes and potential loss of vision.

The effects of endotoxin, glucocorticoids and prostaglandin metabolism in the rabbit iris.

Superoxide dismutase activity (SOD) was measured in the irides of control animals (n = 16) and 24 hours after the intravitreal administration of endotoxin (n = 12). Nearly a twofold increase in SOD was noted in the endotoxin-treated animals (p less than 0.001). In order to assess the induction of SOD while protecting against the inflammatory process, topical dexamethasone (dex) was administered t.i.d. for 2 days before and 1 day after endotoxin (n = 6). Dex prevented the conjunctival hyperemia, vascular injection and iritis seen with endotoxin treatment alone and blocked the induction of SOD. A similar medrysone (med) application (n = 4) failed to prevent the visible signs of ocular inflammation yet also blocked the elevation of SOD. Pretreatment with either of the cyclooxygenase inhibitors, indomethacin (n = 4) or aspirin (n = 7), failed to block the induction in SOD (p less than 0.001 and p less than 0.01, respectively). However, the induction of SOD was prevented by the phospholipase A2 inhibitor, quinacrine, and the lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA). The data indicate that a product of the lipoxygenase pathway may be mediating the induction of SOD seen with endotoxin-induced ocular inflammation.

Anterior nongranulomatous uveitis after intravitreal HPMPC (cidofovir) for the treatment of cytomegalovirus retinitis. Analysis and prevention.

BACKGROUND AND OBJECTIVE: The authors characterize and analyze the incidence of a previously reported mild anterior nongranulomatous uveitis associated with intravitreal injections of (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC), also termed cidofovir (Vistide, Gilead Sciences, Foster City, CA). This is an acyclic nucleoside phosphonate analogue with a potent anticytomegalovirus effect. The authors also analyzed the effects of probenecid therapy, as well as prophylaxis with probenecid plus topical corticosteroids and cycloplegics on the course and outcome of the uveitis. METHODS: Prospective case series from a tertiary referral center, which included 46 consecutive patients with acquired immune deficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis. There was a total of 130 injections in 69 eyes treated with 20 micrograms of intravitreal HPMPC. Forty-one patients (119 injections) received oral probenecid, 5 patients (11 injections) did not, and 21 patients (53 injections) received topical corticosteroids and cycloplegics as an adjuvant to probenecid in the prophylaxis of iritis. RESULTS: Mild to moderate nongranulomatous iritis was seen in 26% of patients after their first injection (n = 12). Patients receiving probenecid prophylaxis after first injection had a significantly lower frequency of iritis versus patients who did not receive probenecid at the time of first injection (P = 0.0089). In contrast, treatment with topical corticosteroid and cycloplegics after injection did not statistically significantly affect the frequency of iritis in patients (P = 0.44). The development of iritis after a second injection of HPMPC was more likely if it had occurred after the initial injection (P = 0.015; Fisher's exact test). All cases of iritis were treated with topical corticosteroids and cycloplegics, and there was no permanent impairment of vision secondary to iritis after HPMPC injection in any eyes. CONCLUSIONS: Anterior uveitis was seen in 26% of patients after first-time HPMPC injection. Concomitant use of probenecid appears to decrease the frequency of the iritis from 71% to 18% in patients with AIDS and CMV retinitis after the first intravitreal injection of HPMPC. Topical corticosteroid administration after injection (before iritis) was ineffective in preventing iritis treatment with topical corticosteroids and cycloplegics resulted in resolution of all iritis cases.

Effect of local corticosteroids on antibody-forming cells in the eye and draining lymph nodes.

Significant numbers of antibody-forming cells (AFC) have been found in the cornea, uveal tract, and draining lymph nodes after the intracorneal injection of bovine gamma-globulin (BGG). To study the effect of locally administered corticosteroids on these antibody-forming tissues, we made unilateral intracorneal injections of rabbit eyes with BGG. These we followed immediately with subconjunctival injections of 10 mg. of triamcinolone suspension, and then with a second round of 10 mg. injections seven days later. A control group of animals received the BGG injections followed by two subconjunctival saline injections. We killed the animals on postinjection days 6, 9, 12, 15, and 21, and tested the draining lymph nodes, homolateral uveal tissue, and homolateral cornea for AFC by a modification of the Jerne placque technique. The local steroids had no effect on the number of AFC produced in the draining lymph nodes or on the circulating antibody response, but they reduced the number of AFC in the homolateral uveal tracts and corneas. Clinically there was less inflammatory response in the steroid-treated eyes than in the control eyes. The possible mechanisms by which corticosteroids achieve their anti-immunologic and anti-inflammatory benefits are discussed.

Effects of nilvadipine, nicardipine and verapamil on acute rise of aqueous flare induced by iris photocoagulation or intravenous lipopolysaccharides in pigmented rabbits.

The effects of nilvadipine, nicardipine and verapamil on the acute rise of aqueous flare induced by argon laser photocoagulation of the iris or by intravenous injection of lipopolysaccharides (LPS, 0.5 microg/kg) were investigated in pigmented rabbits. Nilvadipine, nicardipine and verapamil were injected intravenously. Aqueous flare was measured with a laser flare cell meter. Following photocoagulation, aqueous flare increased, reached its maximum at 45-75 min and then decreased. After administration of LPS, aqueous flare increased, reached its maximum at 4 h and then returned to baseline levels at about 24 h. Flare reactions were inhibited by nilvadipine in a dose-dependent manner. The elevations were maximally inhibited by nilvadipine 30 min before photocoagulation or intravenous LPS. Two hundred micrograms per kilogram of nilvadipine inhibited 81% of photocoagulation-induced flare elevation, while the same dose of nicardipine and verapamil inhibited 19 and 9% of the elevation, respectively. The same dose of nilvadipine inhibited 51% of LPS-induced flare elevation, while the same dose of nicardipine and verapamil inhibited 6 and 4% of the elevation, respectively. In conclusion, nilvadipine inhibited the experimental elevation of aqueous flare more effectively than did nicardipine and verapamil.