Exfoliation syndrome and cataract extraction.

In a prospective study of 351 consecutive cataract operations performed on Finnish patients, the prevalence of exfoliation syndrome was 31% (108 of 351 eyes), increasing from 0% (zero of 54 eyes) in patients younger than 60 years to 15% (12 of 78 eyes) in patients aged 60 to 69 years, 42% (57 of 137 eyes) in patients aged 70 to 79 years, and 48% (39 of 82 eyes) in those aged 80 years or more, than has previously been reported in general populations of the same age in Finland. Exfoliation syndrome was more common in patients aged 70 years or more. Glaucoma was found in 41 of 108 eyes with exfoliation syndrome (38%). Exfoliation syndrome increased the risk of intraoperative complications in extracapsular cataract extraction either directly (rupture of the zonules) or through poor dilation of the pupil (rupture of the posterior lens capsule). The occurrence of vitreous loss was fourfold, and the need to use an anterior chamber intraocular lens instead of a posterior chamber lens because of loss of capsular support was tenfold in eyes with exfoliation as compared to those without exfoliation.

Risk factors for intraoperative and early postoperative complications in extracapsular cataract surgery.

The risk factors for intraoperative and early postoperative complications were evaluated in 351 consecutive cataract operations at the Oulu University Hospital in 1990. Bleeding into the anterior chamber during the operation was recorded in 8.6%, zonular rupture in 6.6%, posterior capsular rupture in 5.4% and vitreous loss in 3.2%, On account of the loss of capsular support an anterior chamber intraocular lens was implanted in 3.1%. Of the early postoperative complications, signs of fibrinous reaction were observed in 24.5%, corneal edema in 53.6% and rise of intraocular pressure to 30 mmHg or more in 27.6%. There was no difference in the complication rate between men and women or in relation to age. The use of anticoagulant (although discontinued before surgery) or antiplatelet medication increased the risk of intraoperative bleeding but no sight-threatening bleeding occurred. The use of acetylsalicylic acid was also associated with an increased risk of postoperative fibrinous reaction. Other systemic diseases like systemic hypertension, diabetes, asthma, or cardiac or mental disorders, or medications, did not increase the complication rate. Of the various ocular parameters, small pupil and exfoliation syndrome were the most important risk factors for both intra- and early postoperative complications, and the presence of glaucoma increased the risk of vitreous loss, postoperative pressure rise and corneal edema. General anesthesia did not seem to reduce the complications rate.

Antiproliferative activity of derivatives of trans-bis(salicylaldoximato)copper(II) in vitro. Some in vivo properties of the parent compound.

Several derivatives and analogs of the recently reported antiproliferative and antitumor agent trans-bis(salicylaldoximato)copper(II) (CuSAO2) have been prepared and tested for antiproliferative activity against L1210 leukemia cells in vitro. The salicylaldimine analog of CuSAO2 had a very strong antiproliferative activity, the 2-day IC50 value being lower than 3 micrograms/ml. The 2,3-dihydroxybenzaldoxime analog was equally active with CuSAO2, while the corresponding 2,5-dihydroxy derivative had a slightly lower activity. The 2,3,4-trihydroxybenzaldoxime derivative had a much lower activity than had the dihydroxybenzaldoxime derivatives. The zinc(II) analog of CuSAO2 had only a low antiproliferative activity. The ligand of CuSAO2, salicylaldoxime, resembles pyridoxal oxime, a vitamin B6 antagonist and a powerful inhibitor of pyridoxal kinase. An attempt to reduce the toxicity of CuSAO2 in vivo with pyridoxal hydrochloride led to increased toxicity.

Biochemical properties and crystal structure of ethylmethylglyoxal bis(guanylhydrazone) sulfate--an extremely powerful novel inhibitor of adenosylmethionine decarboxylase.

Ethylmethylglyoxal bis(guanylhydrazone) (EMGBG) sulfate, an analog of the well-known anti-leukemic drug methylglyoxal bis(guanylhydrazone), was synthesized. It was shown to be an extremely powerful competitive inhibitor of eukaryotic S-adenosylmethionine decarboxylase, with an apparent Ki value 12 nM. Thus, it appears to be the most powerful known inhibitor of the enzyme, being almost an order of magnitude more powerful than the corresponding ethylglyoxal derivative. It neither inhibited the proliferation of mouse L1210 leukemia cells in vitro, nor did it potentiate the growth inhibition produced by alpha-difluoromethyl ornithine. In this respect, its properties are closely related to those of dimethylglyoxal, ethylglyoxal and propylglyoxal bis(guanylhydrazones), while in striking contrast to those of the antiproliferative glyoxal and methylglyoxal analogs. EMGBG also inhibited intestinal diamine oxidase activity (Ki 0.7 microM). EMGBG sulfate was crystallized from water, giving orthorhombic crystals (space group Pbcn). Their crystal and molecular structure was determined by X-ray diffraction methods. The carbon-nitrogen double bonds between the ethylmethylglyoxal part and the aminoguanidine moieties were found to have the same configuration as they are known to have in the salts of glyoxal, methylglyoxal and propylglyoxal bis(guanylhydrazones). The glyoxal bis(guanylhydrazone) chain of the EMGBG cation deviated strongly from planarity, thus differing dramatically from the corresponding chains of the glyoxal, methylglyoxal and propylglyoxal analogs.

Age and CYP3A4 and CYP2A6 activities marked by the metabolism of lignocaine and coumarin in man.

The effect of age on human liver drug-metabolizing ability was investigated by using probe drugs, metabolized by specific isozymes in liver, as an index. Formation of monoethylglycinexylide (MEGX) after i.v. infusion of lignocaine (1 mg/kg), metabolized by CYP3A4, and excretion of 7-hydroxycoumarin (7-OHC) after oral coumarin (5 mg) administration, hydroxylated by CYP2A6, were investigated in healthy young (< 25 years) and elderly (> 65 years) women and men (n = 10 in each group). MEGX content in young subjects (men 57.8 +/- 11.3 and women 52.9 +/- 13.1 ng/ml) did not diverge significantly but was reduced in elderly subjects (men 43.57 +/- 15.8 and women 29.2 +/- 13.6 ng/ml, p < 0.05 and 0.01, respectively). 7-OHC excretion at 2 h averaged 68.1 +/- 13.1 per cent (men) and 65.0 +/- 18.3 per cent (women) of the dose given in young subjects and was delayed in elderly persons (men 46.5 +/- 16.3 per cent and women 44.8 +/- 18.3 percent, p < 0.01 and 0.05, respectively). The change in probe drug metabolism was related to age (MEGX, r = -0.473 (men) and -0.682 (women) and 7-OHC; r = -0.690 (men) and -0.565 (women)). MEGX formation was reduced by 0.92 microgram/L per year and 7-OHC excretion by 0.85 per cent per year. The results indicate a decrease of CYP3A4 and CYP2A6 metabolic activities with age.

Cell reaction and pigment deposits on the posterior chamber intraocular lens.

Cellular reaction and pigment deposits on the intraocular lens were evaluated by biomicroscopy in 220 eyes which had undergone estracapsular cataract extraction and implantation of a posterior chamber intraocular lens 3 months previously. No cells or pigment were observed on the intraocular lens in 32% of the eyes, while small cells and/or pigment were found in 32% and giant cells with or without pigment and small cells were seen in 35%. In a sample of 28 eyes the clinical findings correlated with the findings in specular microphotographs. The corresponding percentages were 32, 36 and 32% in biomicroscopy and 14, 36 and 50% in specular microphotography. The giant cell reaction was notably (p < 0.001) associated with the presence of exfoliation. Previous ocular diseases and operations did not increase the frequency of cellular reaction.

Sociodemographic aspects and systemic diseases of cataract patients.

Sociodemographic analysis of 351 consecutive cataract patients operated on at the Oulu University Hospital in 1990 revealed that 30.0% of the patients lived alone at home, 62.0% lived with some other person and 7.9% were in institutions. The mean age was 70.6 +/- 12.4 years, the sex distribution (62.7% women, 37.3% men) corresponded with that in the general population of the same age. 78.8% of the patients had had surgery on the first eye, 29.0% of them had low vision or blindness (visual acuity less than 0.3 in the better eye). In the second eye surgery group (21.2% of the patients) low vision or blindness was found in 13.0%. Low vision was more common in institutionalized patients and in those with restricted mobility. In 80.9% of the operated eyes and in 41.5% of the fellow eyes the visual acuity was less than 0.3. 76.6% of the patients had medication for cardiovascular diseases, diabetes, asthma or mental disorders. Based on this survey the demand for cataract surgery is expected to increase in coming years. The majority would be suitable for day case surgery, but for patients living alone, having restricted mobility, poor general health, poor vision in the fellow eye or long distance to the hospital, hospitalization still seems to be a better alternative.

Factors affecting the visual outcome after cataract surgery.

Postoperative visual outcome and factors related to poor visual acuity three months after cataract surgery were evaluated in 243 cataract patients operated on at the Oulu University Hospital in 1990. The surgical technique used was a planned extracapsular cataract extraction with implantation of an intraocular lens (IOL) in 240 cases: a posterior chamber IOL in 231 cases and an anterior chamber IOL in 9 cases. The postoperative visual acuity was 0.5 or better in 74.5% of the eyes, 11.9% (29 eyes) had low vision and 2.4% (6 eyes) were blind. The visual outcome was significantly related to age. The most common causes for low vision or blindness were age related macular degeneration and glaucoma. There was one case of postoperative endophthalmitis but other surgical complications did not result in visual loss. Visually significant posterior capsular opacification was observed in 2.5%, and significant postoperative astigmatism (> or = 3.5 D) was present in 11.1%.

Antitumor activity of trans-bis(salicylaldoximato)copper(II): a novel antiproliferative metal complex.

trans-Bis(salicylaldoximato)copper(II) (CuSAO2), the parent compound of a new group of antiproliferative copper(II) complexes, was studied in vivo. It had marked antitumor activity against Ehrlich ascites carcinoma in NMRI mice. Survival was considerably increased, and, in some cases, total cures were encountered. No activity against leukemia L1210 was found in female DBA/2J mice, although CuSAO2 is equally effective against L1210 and Ehrlich carcinoma cells in vitro. The side effects of CuSAO2 included weight loss, weakness, acrodynia, and blindness; all of these side effects were transient.

Biochemical characterization of propylglyoxal bis(guanylhydrazone). Facile synthesis of monoalkylglyoxal bis(guanylhydrazones).

Propylglyoxal bis(guanylhydrazone) sulfate, a novel analog of the well-known antileukemic drug methylglyoxal bis(guanylhydrazone), has been prepared from 2,2-dibromopentanal, and the compound has been characterized biochemically. Although it is a powerful inhibitor of S-adenosylmethionine decarboxylase, its Ki value (0.2 microM) is considerably higher than that of ethylglyoxal bis(guanylhydrazone) (0.06 microM). The compound is only poorly taken up by tumor cells, and its accumulation is not stimulated by a prior exposure of the tumor cells to difluoromethylornithine, a compound that causes polyamine depletion. Thus, the uptake characteristics of the compound are similar to those of ethylglyoxal bis(guanylhydrazone), but in striking contrast to those of methylglyoxal and glyoxal bis(guanylhydrazones). Since the configuration of the double bonds in glyoxal, methylglyoxal and propylglyoxal bis(guanylhydrazones) has been shown to be identical, the different uptake characteristics are probably only due to differences in side chain size and/or hydrophobicity.

Neuroretinal rim area in low tension glaucoma: effect of nifedipine and acetazolamide compared to no treatment.

The purpose of this study was to measure the change of neuroretinal rim area in patients with low tension glaucoma on- and off-treatment. Thirty-two patients were followed up for a mean of 2.6 years. Ten patients received treatment with nifedipine, 11 patients with acetazolamide and 11 patients had no treatment. The total change of rim area and the yearly rate of rim area change did not differ statistically significantly between the three groups. Seven patients in each group suffered from cold hands and feet. The response to cold provocation visual field testing was positive in 25% of patients. Neither the history of cold hands and feet nor the cold provocation test result affected the rate of progression of optic disc abnormalities. Nifedipine and acetazolamide treatment seemed to show no advantage over no-treatment in our patients.

Glyoxal bis(guanylhydrazone) as an inhibitor of polyamine biosynthesis in tumour cells.

Glyoxal bis(guanylhydrazone), the parent compound of methylglyoxal bis(guanylhydrazone), was synthesized and tested for its ability to inhibit the biosynthesis of polyamines. It was found to be a powerful competitive inhibitor of adenosylmethionine decarboxylase (EC 4.1.1.50), yet the lack of the methyl group at the glyoxal portion increased the apparent Ki value for the enzyme by about 30-fold in comparison with methylglyoxal bis(guanylhydrazone). Glyoxal bis(guanylhydrazone) inhibited diamine oxidase (EC 1.4.3.6) activity as effectively as did methylglyoxal bis(guanylhydrazone). The cellular accumulation curves of glyoxal bis(guanylhydrazone) in L1210 cells were practically superimposable with those of methylglyoxal bis(guanylhydrazone), and the uptake of both compounds was distinctly stimulated by a prior treatment with 2-difluoromethylornithine. The drug decreased the concentration of spermidine in a dose-dependent manner and, in contrast with methylglyoxal bis(guanylhydrazone), without a concomitant accumulation of putrescine. The fact that putrescine concentrations were decreased in cells exposed to glyoxal bis(guanylhydrazone) was, at least in part, attributable to an inhibition of ornithine decarboxylase (EC 4.1.1.17) activity in cells treated with the compound. Under these experimental conditions equivalent concentrations of methylglyoxal bis(guanylhydrazone) [1,1'-[(methylethanediylidine)dinitrilo]diguanidine] elicited large increases in the enzyme activity. When combined with difluoromethylornithine, glyoxal bis(guanylhydrazone) potentiated the growth-inhibitory effect of that drug. Taking into consideration the proven anti-leukaemic activity of glyoxal bis(guanylhydrazone), its effectiveness to inhibit spermidine biosynthesis (without raising the concentration of putrescine) as well as its suitability for combined use with inhibitors of ornithine decarboxylase, this drug is apparently worthy of further testing in tumour-bearing animals, especially in combination with difluoromethylornithine or related inhibitors of ornithine decarboxylase.

Charge transfer-oxy radical mechanism for anticancer agents: mAMSA derivatives, rhodamine 123, and nickel salicylaldoximate.

The proposal is advanced that many anticancer agents may function via redox reactions resulting in generation of toxic oxy radicals which destroy neoplastic cells. Cyclic voltammetry was performed with some of the main types: iminium ions (protonated mAMSA derivatives), quinone derivatives (rhodamine 123) and metal complexes (nickel(II) salicylaldoximate). In addition, relevant literature data are provided. A rationale is offered that relates electrochemical data to physiological activity.

Charge transfer-oxy radical mechanism for anti-cancer agents.

The proposal is advanced that anti-cancer drugs generally function by charge transfer resulting in formation of toxic oxy radicals which destroy the neoplasm. Electrochemical studies were performed with some of the main types of agents: iminium ions (adenine iminium from alkylating species, iminium metabolite of 6-mercaptopurine, nitidine, other polynuclear iminiums) and metal complexes (Pt(II)diaquodiammine-guanosine, copper salicylaldoximes). Reduction potentials ranged from -0.4 to -1.2 V. Literature data for quinones are presented and radiation is discussed. Based on the theoretical framework, a rationale is offered for the carcinogen-anti-cancer paradox and the role of antioxidants.