Combination benefit of treatment with the cytokine inhibitors interleukin-1 receptor antagonist and PEGylated soluble tumor necrosis factor receptor type I in animal models of rheumatoid arthritis.

OBJECTIVE: To determine the potential for additive or synergistic effects of combination therapy with the recombinant anticytokine agents interleukin-1 receptor antagonist (IL-1Ra) and PEGylated soluble tumor necrosis factor receptor type I (PEG sTNFRI) in established type H collagen-induced arthritis (CIA) and developing adjuvant-induced arthritis (AIA) in rats. METHODS: Rats with established CIA or developing AIA were treated with various doses of IL-1Ra in a slow-release hyaluronic acid vehicle or with PEG sTNFRI, either alone or in combination with the IL-1Ra. The effects of treatment were monitored by sequential caliper measurements of the ankle joints or hind paw volumes, final paw weights, and histologic evaluation with particular emphasis on bone and cartilage lesions. RESULTS: Combination therapy with IL-1Ra and PEG sTNFRI in rats with CIA resulted in an additive effect on clinical and histologic parameters when moderately to highly efficacious doses of each protein were administered. Greater-than-additive effects were seen when an inactive dose of IL-1Ra was given in combination with moderately to minimally active doses of PEG sTNFRI. Plasma levels associated with the latter effect (for both proteins) were similar to those seen in rheumatoid arthritis (RA) patients in clinical trials with these agents. Combination therapy in the AIA model generally resulted in additive effects, but some parameters showed a greater-than-additive benefit. CONCLUSION: The results provide preclinical support for the hypothesis that IL-1Ra administered in combination with PEG sTNFRI might provide substantially more clinical benefit to RA patients than either agent alone at blood levels that are currently achievable in patients.

Filgrastim prevents severe neutropenia and reduces infective morbidity in patients with advanced HIV infection: results of a randomized, multicenter, controlled trial. G-CSF 930101 Study Group.

OBJECTIVE: To assess the effect of filgrastim treatment on the incidence of severe neutropenia in patients with advanced HIV infection, and the effect of initial filgrastim treatment on prevention of infectious morbidity. DESIGN: Randomized, controlled, open-label, multicenter study. SETTING: Outpatient centers and physician offices. PATIENTS: Men and women aged > 13 years, who were HIV antibody-positive, and had a CD4 cell count < 200 x 10(6)/l, absolute neutrophil count (ANC) 0.75-1.0 x 10(9)/l, and platelet count > or = 50 x 10(9)/l within 7 days of randomization were eligible. Two hundred and fifty-eight patients entered and 201 completed the study. INTERVENTION: Daily filgrastim (starting at 1 microg/kg daily, adjusted up to 10 microg/kg daily) or intermittent filgrastim (starting at 300 microg daily one to three times per week to a maximum of 600 microg daily 7 days weekly) was administered to maintain an ANC between 2 and 10 x 10(9)/l. Patients in the control group received filgrastim if severe neutropenia developed. MAIN OUTCOME MEASURES: Incidence of severe neutropenia (ANC < 0.5 x 10(9)/l) or death, incidence of bacterial and fungal infections, duration of hospitalization and intravenous antibacterial use, and safety. RESULTS: The primary endpoint of severe neutropenia or death was less frequent in patients who received daily (12.8%) or intermittent (8.2%) filgrastim compared with control patients (34.1%; P<0.002 and P<0.0001 for comparison with daily and intermittent groups, respectively). Filgrastim-treated patients developed 31% fewer bacterial infections and 54% fewer severe bacterial infections than control patients, required 26% less hospital days including 45% fewer hospital days for bacterial infections, and needed 28% fewer days of intravenous antibacterials. Filgrastim was not associated with an increase in HIV-1 plasma RNA level in a subset of patients in whom this was measured or any new or unexpected adverse events. CONCLUSION: Filgrastim was safe and effective in preventing severe neutropenia in patients with advanced HIV infection, and may reduce the incidence and duration of bacterial infections, incidence of severe bacterial infections, duration of hospital days for infections, and days of intravenous antibacterial agents.

Lens epithelial cells adhere less to HEMA than to PMMA intraocular lenses.

Following cataract surgery proliferation of residual lens epithelial cells may occur causing secondary opacification and loss of visual acuity. Using an in vitro system the abilities of bovine and porcine lens epithelial cells to adhere to two types of intraocular lens have been assessed. Lens epithelial cells adhere significantly less to lenses composed of poly 2 hydroxyethylmethacrylate (HEMA) than to polymethylmethacrylate (PMMA).

Bacterial contamination of intraocular and extraocular fluids during extracapsular cataract extraction.

Fluid aspirated from the anterior chamber and fluid drained from the conjunctival sac during 101 extracapsular cataract operations was examined for bacterial contamination. Bacteria were grown by enrichment culture from the conjunctival sac of 90 eyes and from the anterior chamber aspirate of 29 eyes. Conjunctival fluid, stained with fluorescein, was demonstrated to flow into the anterior chamber during the aspiration stage of extracapsular cataract extraction and during intraocular lens implantation. It is suggested that this fluid from the conjunctival sac, contaminated with bacteria, routinely enters the anterior chamber during extracapsular cataract extraction and is the likely source of some cases of post-operative endophthalmitis.

Single stage insertion of the Molteno tube for glaucoma and modifications to reduce postoperative hypotony.

Severe glaucoma was controlled in all 13 cases following insertion of a Molteno drain in a single stage procedure. One eye required a repeat operation. A modified technique to minimise early postoperative hypotony and prevent flat anterior chambers is described.

Hydrogel intraocular lens experience with endocapsular implantation.

The experience is presented of three independent surgeons using Hydrogel posterior chamber intraocular lenses in a combined series of 157 endocapsular cataract extractions. One hundred and fifty of these eyes were examined after a minimum follow-up period of one year and 92.0% achieved visual acuity of 6/12 or better, and 98.6% achieved this if pre-existing pathology was excluded. Insertion of this lens has proved to be simple, the adaptions of technique required are described and the complications are presented and analysed.

Raised intraocular pressure and other problems with sodium hyaluronate and cataract surgery.

Raised intraocular pressure is confirmed to be the principal complication following the use of sodium hyaluronate in cataract surgery and the value of the 'piping technique' limiting the use of sodium hyaluronate to the wound edges is demonstrated in reducing this hypertensive response. Difficulties with technique, differentiation between vitreous and sodium hyaluronate, damping effects and has dissipation fall into the category of problems rather than complications. A double cannula is described to remove as much sodium hyaluronate as possible at the end of surgery.

Prevention of postoperative ocular hypertension by prostaglandin inhibitors.

The Pneumatonometer of Langham was used to monitor intraocular pressure in the operating theatre and in the early postoperative period after cataract surgery. Both indomethacin and aspirin were shown to prodcue a significant reduction in the acute ocular hypertension which can be expected to follow 6 hours after routine cataract surgery. It is suggested that the inhibition of prostaglandin synthesis by these drugs is probably responsible for this effect.

Effect of lid specula and superior rectus traction on intraocular pressure.

The Pneumatonometer of Langham was used to record the effect upon intraocular pressure of a range of eyelid specula, lid sutures, and eyelid clamps. It was concluded that all methods tested produced a rise in intraocular pressure in most patients, and that the degree of rise was related to the degree to which the eyelids were separated. It was therefore recommended that a method of eyelid retraction which allows adjustment is to be preferred, and that specula which do not allow this, such as the Barraquer speculum, are not to be recommended. Traction upon the superior rectus suture was shown to lead to a considerable rise in intraocular pressure and this should therefore be avoided unless strictly necessary. The traction produced by two limbal sutures pulling tangentially downwards, rotates the eye downwards for intraocular surgery without inducing a rise in intraocular pressure. Measurement of intraocular pressure in the operating theatre is recommended in order to ascertain whether the method used to retract the eyelids or to rotate the eye to the field of surgery is having an adverse effect.