Visual disturbances associated with oval-optic poly(methyl methacrylate) and round-optic silicone intraocular lenses.

A prospective, randomized, double-masked clinical trial of 182 patients compared the frequency of visual disturbances associated with two small incision intraocular lenses (IOLs): the Alcon MZ20BD 5 mm x 6 mm oval-optic poly(methyl methacrylate) (PMMA) IOL and the STAAR AQ1016 round-optic silicone IOL. The samples were similar at baseline. There were no significant differences in visual acuity, mean keratometric cylinder, or surgically induced cylinder between the two groups postoperatively. Patients completed a satisfaction questionnaire and visual symptom inventory of ten items three months postoperatively. Those with the oval-optic PMMA IOL reported significantly more visual symptoms than those with the round-optic silicone IOL (P = .03). The oval-optic group reported three symptoms more frequently: reflections, halos or rings around lights, and objects at arm's length appearing blurry (P < or = .010). The status of the fellow eye (cataract or pseudophakic) did not differ by randomization group, and the distribution of visual symptoms did not differ by status of the fellow eye. Frequency and severity of visual complaints were modest overall; only 1% in each group was unsatisfied with the visual results.

WY-50,295 tromethamine, a novel, orally active 5-lipoxygenase inhibitor: biochemical characterization and antiallergic activity.

WY-50,295 tromethamine demonstrates significant 5-lipoxygenase inhibitory activity with IC50 values ranging from 0.055 microM in rat peritoneal exudate cells, to 0.16 microM in mouse macrophages, 1.2 microM in human peripheral neutrophils and 8.1 microM in rat blood leukocytes. This activity appeared selective for 5-lipoxygenase as concentrations up to 10 microM in rat peritoneal exudate cells, and 1 microM in mouse macrophages did not effect prostaglandin generation. In non-cellular enzyme assays, WY-50,295 tromethamine displayed inhibitory activity against a soluble 5-lipoxygenase from guinea pig peritoneal exudate cells (IC50 = 5.7 microM), while it was essentially inactive against 12-lipoxygenase, 15-lipoxygenase, or prostaglandin H synthetase at concentrations up to 500 microM, or against human phospholipase A2 at concentrations up to 50 microM. In purified human blood neutrophils the inhibitory activity was reversible but did not appear dependent upon substrate concentration. IN contrast, in the guinea pig cell-free 5-lipoxygenase assay changing the arachidonic acid substrate concentration from 5 to 500 microM produced a concentration-dependent reduction in inhibitory activity. WY-50,295 tromethamine inhibited the release of peptidoleukotrienes from fragmented guinea pig lung with an IC50 of 0.63 microM. When administered p.o. with a 4 h pretreatment time, WY-50,295 tromethamine inhibited ex vivo leukotriene B4 production in rat blood leukocytes with an ED50 of 19.6 mg/kg. Against an ovalbumin-induced leukotriene dependent bronchoconstriction in anesthetized sensitized guinea pigs, WY-50,295 tromethamine inhibited the ovalbumin-induced bronchoconstriction with an i.v. ED50 of 2.5 mg/kg (5 min pretreatment) and a p.o. ED50 of 7.3 mg/kg (4 h pretreatment). Significant activity was also evident with an 18 h pretreatment. Thus WY-50,295 tromethamine is an potent and selective 5-lipoxygenase inhibitor in a number of in vitro systems. Additionally the compound is orally efficacious and has a long duration of action in an allergic bronchoconstriction model. This data suggests that WY-50,295 tromethamine may have utility in the treatment of asthma and other leukotriene-dependent pathologies.

VLA-4-dependent adhesion activities of U937 cells and guinea pig bronchoalveolar lavage leukocytes.

VLA-4-dependent binding to fibronectin (FN) and to a human vascular cell adhesion molecule (hVCAM-1)-transfected murine cell line was measured using U937 cells and guinea pig (GP) bronchoalveolar lavage (BAL) cells. A species cross-reactive, blocking monoclonal antibody directed against human VLA-4 (TY 21.6) inhibited U937/FN binding by 71 +/- 7%. The presence of TY21.6 inhibited the stimulated binding of U937 cells to hVCAM-1 by 84%. However, TY 21.6 was unable to inhibit the BAL/FN binding. With the addition of TY 21.6, the binding of PMA-stimulated BAL cells to hVCAM-1 was inhibited by 57 +/- 5%. In summary, human and guinea-pig leukocytes express binding activity to both FN and hVCAM-1. A specific VLA-4 blocking monoclonal antibody, TY 21.6, inhibited U937 and BAL cell binding to hVCAM-1, but only inhibited FN binding with U937 cells.

Strategies for the development of new antiarthritic agents.

Therapeutic advances in rheumatoid arthritis (RA) have largely focused on the development of non-steroidal antiinflammatory drugs (NSAIDs) with improved characteristics compared with aspirin [Brooks & Day, New Engl. J. Med., 324, 1716-1725 (1991)]. For example, greater potency, safety, improved tolerance in the elderly and reduced frequency of dosing have been achieved. However, these agents are generally considered to be palliative treating of the symptoms of the disease. The development of disease modifying drugs (DMD), also known as second line drugs, for RA has not been very successful. Most of the agents that are currently used in this category were originally used to treat other diseases such as malignancy (cyclophosphamide, methotrexate), Wilson's disease (d-penicillamine) and tuberculosis (gold salts) [Pullar, Br. J. clin. Pharmac., 30, 501-510 (1990)]. Unfortunately, none of the agents is ideal and each has potentially serious side-effects. There have been several attempts to develop agents with new mechanisms of action that hopefully will greatly improve these current therapies.

Rat peritoneal neutrophils selectively relax vascular smooth muscle.

A vascular relaxing factor from oyster glycogen-elicited rat peritoneal neutrophils has been shown previously to possess a pharmacologic profile similar to that described for endothelium-derived-relaxing factor. The present experiments were designed to determine the in vitro tissue and species selectivity effects of the neutrophil-derived nitric oxide. Neutrophils (1 x 10(5) to 1 x 10(8) cells/10-ml organ chamber) were added to organ chambers filled with a physiological salt solution (37 degrees C; pH 7.4; 21% O2; 100 U/ml of superoxide dismutase) containing a ring or strip of an isolated tissue contracted with an appropriate contractile agent. Neutrophils caused relaxations in all vascular tissues tested, with the dog coronary artery being the most sensitive (IC50 approximately 1 x 10(5) cells), followed by the dog femoral artery, rabbit aorta and dog saphenous vein, respectively. In the rabbit fundic strip, approximately 1 x 10(7) cells were required to induce 50% relaxation, with 1 x 10(8) cells producing less than 35% relaxation in the dog, guinea pig and rat tracheas. In contrast, nitroprusside- and cromakalim-induced relaxations in all the smooth muscle tissues tested. The response to cromakalim was similar in all tissues with nitroprusside being more active in the vascular tissues. Methylene blue (1 x 10(-5) M) abolished the neutrophil induced relaxations in the rabbit aorta and dog femoral artery but had no effect on the responses to nitroprusside or cromakalim in the rabbit aorta, dog femoral artery or guinea pig trachea. Neutrophils, nitroprusside and cromakalim had limited effects on the spontaneously beating guinea pig right atria.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of selective phosphodiesterase inhibitors on the polymorphonuclear leukocyte respiratory burst.

Modulation of the human polymorphonuclear leukocyte (PMN) respiratory burst by selective cyclic 3',5' adenosine monophosphate (cAMP) phosphodiesterase (PDE) inhibitors was studied with respect to PDE isozyme characteristics. Zaprinast, an inhibitor of a cyclic guanosine monophosphate (cGMP)-specific PDE (PDE I), at concentrations up to 100 mumol/L, had no significant effect on the respiratory burst. Milrinone and imazodan, inhibitors of cAMP-metabolizing, cGMP-sensitive PDE (PDE III), reduced the respiratory burst to 60% of control magnitude but only had significant effects when they were introduced at high (100 mumol/L) concentrations. In contrast, rolipram and RO 20-1724, inhibitors of a cAMP-metabolizing, cGMP-insensitive PDE (PDE IV), had significant effects at low concentrations (0.1 mumol/L) and caused marked reduction of the respiratory burst at higher concentrations (25% of control at 10 mumol/L). The selective PDE IV inhibitors significantly potentiated PMN inhibition by isoproterenol. Diethylaminoethyl (DEAE)-Sepharose chromatography demonstrated a predominant PDE isozyme with high affinity and selectivity for cAMP that was insensitive to cGMP and was completely inhibited by rolipram, a PDE IV inhibitor. These results are consistent with the conclusion that the PMN respiratory burst is inhibited by an elevation of cAMP induced by PDE IV inhibition.

Neutrophil-derived relaxing factor relaxes vascular smooth muscle through a cGMP-mediated mechanism.

Neutrophils harvested from the peritoneal cavities of rats have been shown to release a factor that relaxes precontracted aorta and has a pharmacologic profile similar to that previously reported for endothelium-derived relaxing factor (EDRF). The present study was designed to determine if this neutrophil-derived relaxing factor (NDRF) relaxes rat aortic smooth muscle by affecting the intracellular cGMP levels. Aortic sheets (endothelium removed) were incubated in organ chambers in a physiological salt solution containing phenylephrine (1 x 10(-7) M) and superoxide dismutase (10 or 100 U/ml). Basal cGMP levels (10-15 pmoles/g tissue) were not affected by the incubation reagents. Neutrophils (3 x 10(6) to 1 x 10(8) cells/10 ml) increased cGMP, but not cAMP, levels in a cell number-dependent manner. Peak induction occurred at 5 min of incubation. Methylene blue (1 x 10(-5) M) inhibited and zaprinast (1 x 10(-5) M) potentiated the neutrophil-induced increases in cGMP. The data thus support the hypothesis that neutrophil-induced vascular smooth muscle relaxation is mediated through a factor, NDRF, which increases intracellular cGMP levels.

Potential regulatory role of inflammatory cells on local vascular smooth muscle tone.

A neutrophil-derived relaxing factor (NDRF) from oyster glycogen (OG)-elicited rat PMN, which causes an endothelium independent relaxation of rat aorta, and which is pharmacologically indistinguishable from endothelium-derived relaxing factor (EDRF) has been described. Experiments were designed to evaluate the presence of NDRF in PMN from rat -whole blood, -carrageenan pleurisy, -OG peritonitis, and guinea pig (GP) -OG peritonitis, as well as in OG-elicited rat macrophages (M phi). Significant vascular relaxing activity was found using rat PMN from OG peritonitis and carrageenan pleurisy, as well as from OG-M phi. Little or no activity was found in rat whole blood PMN or PMN from GP-OG peritonitis. These results suggest that NDRF activity may be expressed upon cellular migration to an inflammatory site in the rat, and may not be present in all species. Also, all inflammatory cells examined were capable of reversing EDRF-dependent relaxations when stimulated to produce superoxide anion suggesting a dual regulatory role for these cells on local vascular tone.

Interaction of neutrophils with vascular smooth muscle: identification of a neutrophil-derived relaxing factor.

Experiments were designed to study the interaction of rat peritoneal neutrophils with the vascular smooth muscle of the rat aorta. Rings of aorta, suspended in 10-ml organ chambers containing a physiologic salt solution, were precontracted with phenylephrine. Neutrophils (1 X 10(5) -4 X 10(7) cells/organ chamber) caused a cell number-dependent relaxation of the rat aorta that was augmented by superoxide dismutase (100 U/ml) or changing the oxygen content from 95 to 21%. The neutrophil-induced smooth muscle relaxation occurred in rings with and without endothelium and in rings precontracted with increasing concentrations of phenylephrine, prostaglandin F2 alpha or KCI. Catalase (1000 U/ml) and mannitol (1 X 10(-3) M) did not block the neutrophil-induced relaxation, whereas phenazine methosulfate (1 X 10(-5) M), hydroquinone (3 X 10(-5) M) and methylene blue (1 X 10(-5) M) reversed the neutrophil-induced relaxation. Pre-exposure of endothelium-rubbed rings to neutrophils (2 X 10(7) cells/organ chamber; 15 min) depressed the subsequent concentration-response curve to phenylephrine but augmented the relaxation induced by the phosphodiesterase inhibitor zaprinast (1 X 10(-5) M). The effluent from a column restraining the neutrophils induced a relaxation of endothelium-rubbed aortic rings that was prevented by methylene blue (1 X 10(-5) M). These results demonstrate that rat neutrophils release a factor that has a pharmacologic profile similar to that previously reported for the relaxing factor released from the vascular endothelium.

Leukotriene B4 production and pharmacologic regulation of reverse passive Arthus pleurisy: importance of antigen dose.

Immunoreactive leukotriene B4 (iLTB4), detected in the pleural cavity following induction of a reverse passive Arthus reaction (RPAR), was inhibited by the mixed lipoxygenase-cyclooxygenase inhibitors, phenidone and BW 755C, but not by cyclooxygenase inhibitors or by chlorpheniramine or methysergide. Both iLTB4 production and the subsequent pleural inflammation were dependent upon the dose of BSA antigen employed to elicit the RPAR pleurisy. However, inasmuch as BW 755C and phenidone were not distinguished from the cyclooxygenase inhibitors in their effects on fluid accumulation and cellular infiltration in RPAR pleurisy, it is doubtful that LTB4 plays a functional role in this inflammation model.

Effect of in vitro differentiation on phorbol diester receptor number in human promyelocytic leukemia (HL-60) cells.

Phorbol diester (PDE) tumor promoters affect cells by interacting with specific receptors on the plasma membrane. Cells are known to regulate their receptor populations in response to many external and internal stimuli, including differentiation. The human promyelocytic leukemia cell line HL-60, which can be induced by dimethyl sulfoxide to differentiate into mature granulocytes, was used as a model to examine whether PDE receptors are regulated as cells differentiate in vitro. PDE binding was measured using [20-3H]phorbol 12,13-dibutyrate ([3H]PDBu). Specific binding of [3H]PDBu to the undifferentiated cells was rapid, reversible, and time and concentration related. One class of noncooperative binding sites was found with approximately 3.3 X 10(5) cells, having a Kd of 27.5 nM. [3H]PDBu could be displaced from the binding sites by a series of biologically active PDEs, but not by inactive ones. The characteristics of [3H]PDBu binding to the differentiated HL-60 cells were almost identical to those of the undifferentiated cells, except that there was an increase in the number of binding sites to 9.1 X 10(5) cells. Production of reactive oxygen metabolites by the cells, as monitored by chemiluminescence (CL) in response to PDEs, was examined before and after dimethyl sulfoxide differentiation, to determine if the change in receptor density was accompanied by a change in cell function. Only the differentiated HL-60 cells produced a quantifiable CL response when exposed to PDEs. The potency of the PDEs in causing CL generation was the same as that for displacing [3H]PDBu. The correlation between CL generation and affinity for the binding site suggests that the PDE binding sites mediate this effect of the PDEs and, therefore, are receptors. These studies indicate that HL-60 cells regulate their PDE receptors as they differentiate in vitro, with minimal extracellular influence. This may reflect a portion of an internal mechanism to enhance or change response to an endogenous ligand for the PDE receptor as cells mature.

Reversibility of phorbol diester-induced macrophage spreading.

Phorbol 12-myristate 13-acetate and phorbol 12, 13-dibutyrate induced spreading of mouse macrophages with 50% effective concentrations of 3 nM and 35 nM, respectively. Macrophages treated with 100 or 1000 nM phorbol 12, 13- dibutyrate showed a time related decrease in spreading after washout. Spreading induced by 1, 10, or 100 nM phorbol 12-myristate 13-acetate was irreversible; however, washed phorbol 12,13-dibutyrate-treated cells respread after a second exposure to this compound. Washout of 3[H]phorbol diesters corroborated these observations in that 5% of 3H-phorbol 12-myristate 13-acetate and only 0.1% 3[H]phorbol, 12,13-dibutyrate remained associated with washed cells. Since phorbol 12-myristate 13 acetate is much more lipophilic than phorbol 12,13-dibutyrate, the reversibility of phorbol diester-induced macrophage spreading may depend upon the lipophilicity of the derivative utilized.

Antagonist of phorbol ester receptor-mediated chemotaxis in mouse peritoneal macrophages.

Biologically active phorbol ester derivatives displace [3H]phorbol-12, 13-dibutyrate from thioglycollate-elicited mouse peritoneal macrophages in a time-, temperature-, and concentration-dependent manner. Scatchard analysis revealed an apparent Kd of 54.1 nM and 8.0 X 10(5) sites/cell, indicating that these macrophages possess saturable, high-affinity phorbol ester-binding sites. These derivatives also act as chemoattractants for the macrophage at equivalent concentrations. A notable exception to this pattern is phorbol-12,13-diacetate. Phorbol-12,13-diacetate inhibits specific binding of [3H]phorbol-12,13-dibutyrate (concentration required for a 50% inhibition of the maximum specific binding of [3H]phorbol-12,13-dibutyrate, 2.6 microM) and chemotaxis to phorbol-12-myristate, 13-acetate (concentration required for a 50% inhibition of the maximum chemotactic response, 0.39 microM) while exhibiting no activity as a chemoattractant at concentrations up to 10(-5) M. The data indicate that phorbol-12,13-diacetate may be an antagonist for receptor-mediated chemotaxis to phorbol-12-myristate, 13-acetate in the macrophage.

Calcium modulation of phorbol ester-induced alterations in murine macrophage morphology.

The phorbol ester tumor promoter phorbol-12-myristate-13-acetate (PMA) induced mouse resident peritoneal macrophage spreading in an in vitro system in a time- and dose-dependent manner; this process was modified by agents which alter intracellular calcium metabolism. After a 35-min incubation with PMA, 50% of the macrophages were spread (as classified by at least a 2-fold increase in cell surface area). Also at 35 min, the median effective concentration for PMA induction of spreading was 1.6 ng/ml. The intracellular calcium antagonist 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate inhibited PMA-induced cell spreading with a one-half maximal inhibitory concentration of 8.0 microM. The calcium ionophore A23187 enhanced PMA-induced spreading by 30% at 0.1 to 10 nM. The histological dye ruthenium red, which purportedly increases intracellular calcium by displacing membrane-bound calcium stores, enhanced PMA-induced spreading up to 75% at 1.0 pM. The cationic chelator ethyleneglycolbis(beta-aminoethylether)-N,N-tetraacetic acid (1.8 and 3.6 mM) had no effect on PMA-induced spreading. Thus, PMA-induced spreading was independent of extracellular calcium but was modulated by agents altering intracellular calcium metabolism. Microfilament formation, a proposed mechanism of cell spreading, also depends on intracellular calcium availability. The microfilament inhibitor cytochalasin B inhibited PMA-induced spreading with a one-half maximal inhibitory concentration of 1 microM. Future experiments should investigate the hypothesis that calcium availability to the cytoskeletal elements regulates the morphological effects of PMA on macrophages.

Toxicity of combined therapy with carbonic anhydrase inhibitors and aspirin.

A 67-year-old woman and a 75-year-old woman taking carbonic anhydrase inhibitors for therapy of glaucoma and high doses of aspirin for therapy of arthritis developed severe acid-base imbalance and salicylate intoxication. Neither patient exhibited ill effects when taking high aspirin doses without carbonic anhydrase inhibitor. Carbonic anhydrose inhibitor-induced acidemia increases the risk of developing salicylate intoxication in patients receiving high aspirin doses.

Raeder's paratrigeminal syndrome.

Three middle-aged patients, 2 of whom are females, with unilateral trigeminal pain and associated isolated oculosympathetic paralysis are presented as characteristic of the benign form of Raeder's paratrigeminal syndrome. Their nonprogressive course is representative of the fact that this syndrome is not likely to be caused by aneurysms or mass lesions, and suggests that neuroradiologic contrast studies are generally not initially required in the investigation of such patients. If atypical features are present, or the pain is protracted, further investigation may be warranted.