The immunomodulatory effect of topical cyclosporin A in atopic keratoconjunctivitis

PURPOSE: To perform a detailed examination of the immunomodulatory effects of topical cyclosporin A (CsA) in conjunctival tissue from patients with atopic keratoconjunctivitis (AKC). METHODS: Patients with active AKC were randomly allocated into two groups of four patients. For 3 months one group received 2% CsA drops, and the other group received placebo drops. Superior tarsal conjunctival biopsy specimens were harvested before and after treatment and examined by one- and two-color immunohistochemistry to compare leukocyte counts, HLA-DR+ and IL-2R+ cell counts, HLA-DR positivity of conjunctival epithelial cells, and counts of T cells expressing the cytokines interleukin (IL)-2, IL-3, IL-4, IL-5, and interferon (IFN)-gamma. RESULTS: Posttreatment values were significantly less than pretreatment values for the total number of leukocytes and in the numbers of CD3+ T cells, CD4+ cells, CD8+ cells, CD20+ B cells, neutrophils, and macrophages, and there was a decrease in the CD4-CD8 ratio (P = 0.03) in the CsA group. There was a reduction from before CsA treatment to after CsA-treatment in the numbers of HLA-DR+ and IL-2R+ cells (P = 0.03), but the reduction in the epithelial cell HLA-DR expression did not reach significance. The number of T cells staining for IL-3 and IL-5 was reduced, although not to statistical significance, but there was a significant reduction in the number of T cells expressing IL-2 and IFN-gamma (P = 0.03) after CsA treatment compared with initial values. There were no statistically significant differences between pretreatment and posttreatment values in the placebo group. There was a clinical improvement in the CsA group and a clinical worsening in the placebo group. CONCLUSIONS: The in vitro effects of CsA translate into a reduction in T cells, a normalization of the CD4-CD8 ratio, a decrease in T-cell activation, and a reduction in T-cell cytokine expression, especially IL-2 and IFN-gamma. The decrease in HLA-DR expression may be mediated by the change in IFN-gamma. There were fewer B cells but not fewer plasma cells after CsA and no change in IL-4 expression, suggesting minimal effects on type I hypersensitivity responses. There was no significant reduction in mast cell or eosinophil numbers, but direct effects of topical CsA on their function may play a role in the therapy of ocular allergic disease. These results show that the beneficial effects of topical CsA in AKC are accompanied by important changes in conjunctival immune cell profiles.     

The effects of topical steroids on refractive outcome and corneal haze, thickness, and curvature after photorefractive keratectomy with a 6.0-mm ablation diameter

BACKGROUND AND OBJECTIVE: To study the effect of topical prednisolone acetate after photorefractive keratectomy (PRK) using a 6.0-mm ablation diameter on the refractive and visual outcomes, corneal haze, corneal thickness, and corneal curvature in a prospective, double-masked, randomized manner. PATIENTS AND METHODS: Seventy-two eyes of 36 patients who had excimer laser PRK for correction of myopia ranging from -3.00 to -6.00 D (-4.11 +/- 0.84 D in eyes treated with steroids and -4.38 +/- 0.79 D in eyes treated with placebo; mean +/- SD) were enrolled. PRK procedures were performed using a 193-nm argon-fluoride excimer laser with 180-ml/cm2 fluence, a 10-Hz repetition rate, and a 6.0-mm ablation diameter. One eye of each patient was treated with the steroid (prednisolone acetate) and the other eye with placebo. Patients were observed for at least 12 months after PRK. RESULTS: There was no statistically significant difference between the steroid and the placebo groups with regard to refraction measurements that were taken postoperatively at 3 months (P = .39) and 12 months (P = .51). The corneas showed an increase in thickness after PRK in both groups, but the difference was not statistically significant at 12 months postoperatively (P = .45). The corneal haze score was not statistically different at any stage between groups (P = .30 at 3 months, P = .84 at 12 months). Keratometric data derived from corneal topography did not show any statistically significant difference (P = .85 at 3 months, P = .96 at 12 months). The rate of uncorrected visual acuity of 20/40 or more was 79.4% (27 eyes) in the steroid group and 70.5% (24 eyes) in the placebo group (P = .40). The rate of loss of 2 or more lines in best spectacle-corrected visual acuity was 5.85% (2 eyes) in the steroid group and 8.8% (3 eyes) in the placebo group (P = 1.0). CONCLUSION: Topical prednisolone acetate use for 3 months after PRK with a 6.0-mm ablation diameter has no effect on refractive and visual outcome, corneal haze, corneal thickness, and corneal curvature.     

Methotrexate in the management of severe steroid dependent asthma

AIMS: This study was designed to assess the efficacy of low dose methotrexate, 15 mg weekly, as a steroid-sparing agent in asthmatic patients requiring long-term oral prednisone treatment. METHODS: The study was a randomised, double blind, placebo controlled, cross over study of 48 weeks duration. Eleven patients with severe steroid-dependent asthma were included. A successful outcome was defined as a reduction in mean prednisone requirements of 7 mg daily compared to baseline requirements, during active treatment. RESULTS: Two patients were required to be withdrawn owing to methotrexate-related adverse effects. The mean prednisone dose for patients who completed the study was 14.4 mg per day (95% CI; 13.6, 15.1) during active treatment, and 12.9 mg per day (95% CI: 12.2, 13.6) during placebo treatment (NS). Only one patient reduced his individual dose requirements by more than 7 mg per day, whereas in three patients prednisone requirements actually increased during active treatment. There were no significant differences in symptom scores, pulmonary function data, and exacerbations between active and placebo treatments. CONCLUSION: No significant steroid-sparing effect was obtained using low dose methotrexate in this study. This negative outcome may be attributable to the small population of patients studied, low baseline FEV1, and the omission of a steroid minimisation run-in period. Our results highlight the importance of careful patient selection and a painstaking approach in the management of patients with steroid-dependent asthma.     

A randomized controlled trial of verapamil on cyclosporine nephrotoxicity in heart and lung transplant recipients

BACKGROUND: Cyclosporine (CsA) is a potent immunosuppressive drug widely used in organ transplantation and in the treatment of autoimmune diseases (1, 2). However, its common nephrotoxic effect is a major limiting factor. Short-term CsA treatment has been shown to cause reversible renal vasoconstriction, whereas long-term treatment can lead to an afferent arteriolopathy and chronic renal failure. METHODS: We performed a randomized controlled trial to examine the short-term renal effects of verapamil in 32 CsA-treated heart or lung transplant recipients. Sixteen patients each were randomized to receive a 6-week course of verapamil or control treatment (atenolol in hypertensive patients and placebo in normotensive patients) 1-2 months after transplantation. An 8-hr sequential clearance study of inulin and p-aminohippuric acid for estimating glomerular filtration rate and renal plasma flow, respectively, was performed at baseline and at completion of study. The integral area under the curve of the clearance parameter over 8 hr was then calculated to generate a clearance-time index. RESULTS: There was no difference in the clearance-time indices for inulin and p-aminohippuric acid between the two groups at baseline. However, at the completion of study, the within-group change in the glomerular filtration rate clearance-time index was different between the verapamil and control groups (48+/-20 vs. -35+/-17 ml/min/1.73 m2 x hr, respectively; P=0.0038). A similar trend was seen for renal plasma flow, but did not reach statistical significance. Mean arterial blood pressure and whole-blood CsA levels did not differ between the two groups during the study. Verapamil treatment was also associated with a decrease in CsA dose requirement (7.6+/-0.58 mg/kg/day at baseline vs. 4.6+/-0.40 mg/kg/day at completion; P<0.001) without any significant change in trough whole blood CsA levels. Rejection episodes did not differ between the two groups. CONCLUSIONS: The use of verapamil in the heart or lung transplant recipients may therefore provide both renal protective effects and cost savings.     

Differential suppression of dialysis patients' lymphocyte IFN-gamma production by glucocorticoids and cyclosporine

IFN-gamma is a potent pro-inflammatory cytokine involved in the immunologic rejection of transplanted organs. Having previously demonstrated differential suppressive effects of methylprednisolone (MP), prednisolone (P) and cyclosporine (CsA) on dialysis patients' lymphocyte proliferative responses to phytohaemagglutinin (PHA), we studied the effects of these drugs on dialysis patients' lymphocyte IFN-gamma production during mitogenic and allogeneic (MLR) stimulation. The mean +/- SEM 50% inhibitory concentration (ng/ml) on cell proliferation was significantly lower for MP than P in PHA-stimulated haemodialysis (HD) patients' (35 +/- 7 vs 152 +/- 25, P < 0.001) and peritoneal dialysis (PD) patients' (35 +/- 11 vs 134 +/- 33, P = 0.001) cultures and in HD patients' MLR cultures (15 +/- 3 vs 48 +/- 9, P < 0.001). The mean +/- SEM fractional responses (PHA or MLR + drug/PHA or MLR) in culture supernatant IFN-gamma concentrations were significantly lower with 10(-7) M concentrations of MP than P in HD (0.19 +/- 0.05 vs 0.31 +/- 0.06, P = 0.01) and PD (0.30 +/- 0.11 vs 0.46 +/- 0.11, P < 0.05) PHA cultures and in HD MLR cultures (0.15 +/- 0.04 vs 0.28 +/- 0.07, P = 0.01). CsA (400 ng/ml) alone not only caused less than 50% inhibition of IFN-gamma production in 15/27 HD PHA, 6/14 PD PHA and 4/13 HD MLR cultures, but actually stimulated it in 9 HD and 5 PD PHA cultures. The results suggest that: (1) MP has greater immunosuppressive potential than P for renal transplant recipients; (2) the stimulation of IFN-gamma by CsA in some patients could be harmful in patients with initial allograft dysfunction; and (3) pre-transplant in-vitro assessment of recipients' PBMC responsiveness to glucocorticoids and CsA may help individualize the post-transplant immunosuppressive regimen.     

Mycophenolate mofetil. A useful immunosuppressive in inflammatory eye disease

OBJECTIVE: To assess the usefulness of mycophenolate mofetil (MMF) (Cellcept, Roche), a potent selective uncompetitive and reversible inhibitor of ionisine monophosphate dehydrogenase involved in purine synthesis, as an immunosuppressive and steroid-sparing agent in the management of ocular inflammatory disease. DESIGN: Open-label, prospective, uncontrolled pilot study. PARTICIPANTS: Eleven patients with uncontrolled ocular inflammation. INTERVENTION: Mycophenolate mofetil, at a dosage of 1 g twice daily, was given in conjunction with steroids, as a steroid-sparing agent, or as an additional agent with cyclosporine (CsA), or instead of CsA or azathioprine. MAIN OUTCOME MEASURES: The inflammatory response, side effects, and toxicity were monitored. RESULTS: The addition of MMF to immunosuppressive regimens led to the improvement in symptoms and the ability to reduce the dose of prednisone in most patients. Ten of 11 patients showed a favorable response to MMF, with few side effects noted. CONCLUSION: These findings suggest that MMF is a useful immunosuppressive drug for controlling ocular inflammation with minimal side effects.     

Comparison of methotrexate 30 mg per week with placebo in chronic steroid-dependent asthma: a 12-week double-blind, cross-over study

Methotrexate has been shown to have a steroid-sparing effect in chronic steroid-dependent asthmatics at a dose of 15 mg week-1. The aim of this study was to investigate the steroid-sparing activity and adverse events profile of methotrexate 30 mg week-1 in severe steroid-dependent asthma. Eighteen patients who had required 10-50 mg week-1 prednisolone for at least 6 months were asked to participate in a randomized, double-blind, placebo-controlled cross-over study lasting 24 weeks. Daily diary cards of symptoms, peak expiratory flow rate and medication requirements were kept and the patients attended for a chest X-ray, spirometry, lung volumes and gas transfer at commencement and after each 12-week treatment period. Every 3 weeks, adverse events were noted and blood taken for full blood count, urea and electrolytes and liver function tests. Twelve patients completed the trial. Withdrawals were due to non-compliance in two patients, pneumonia in two patients, depression in one patient (on placebo) and severe nausea in one patient. Adverse events were common, probably as a consequence of the higher dosage. Prednisolone requirements were not significantly reduced on methotrexate. Lung function improved on methotrexate with a significant rise in maximal mid-expiratory flow rate and a trend towards improvement in FEV1.     

The treatment with levamisole of frequently recurring steroid-sensitive idiopathic nephrotic syndrome in children

BACKGROUND AND OBJECTIVE: The treatment of frequently relapsing steroid-sensitive nephrotic syndrome in children with established immunosuppressive drugs (steroids, cyclophosphamide, cyclosporin A) sometimes presents problems because of the expected incidence of side effects. Stimulation of the immune system with the anthelminthic drug levamisole in this disease has been documented. Aim of this study was to assess in a prospective but uncontrolled series of observations its value and side effects. PATIENTS AND METHODS: 25 patients (15 boys, ten girls; median age 10 [3.5-22] years) were given levamisole, 2 mg/kg/48 h. Before this treatment was started eight of the children/adolescents (32%) had frequent relapses and 17 (68%) had become steroid-dependent. Treatment was started during steroid-induced remission and continued for 3-24 (median 6) month, while steroids were discontinued after four weeks. RESULTS: Relapse frequency per patient month was reduced from a mean of 0.5 (0.33-0.83) before to 0.31 (0-0.67) during levamisole administration (P < 0.001). In 12 patients (48%) no or considerably fewer relapses were observed. Patients with exclusively frequent relapses responded to levamisole better than those with steroid dependence (7/8 [87.5%] vs. 5/18 [27.7%], P = 0.01). Side effects were reversible leukopenia in two patients and nonspecific skin rash as well as epigastric pain in one patient. CONCLUSION: Levamisole is an efficacious addition or alternative, with a low incidence of side effects, in the treatment of frequently relapsing nephrotic syndrome, particularly so in yet steroid-dependent patients.     

Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma

The anti-asthmatic effect of theophylline may supplement those of inhaled steroids in asthma. The aim of the present trial was to study how the addition of theophylline compares to doubling the dose of inhaled steroid in asthmatics who remain symptomatic on beclomethasone dipropionate (BDP) 400 micrograms/day. The trial was designed as a randomized, double-blind, parallel-group study in several European countries. 69 patients were treated for 6 weeks with theophylline plus BDP 400 micrograms/day, compared to 64 patients treated with BDP 800 micrograms/day. The mean +/- SD serum theophylline concentration was 10.1 +/- 4.2 mg/l. Lung function measurements were made throughout the study and patients kept daily records of peak expiratory flow rate (PEF), symptoms and salbutamol usage. Forced expiratory volume in one second and PEF at week 6 were significantly increased by both treatments (p < 0.01). PEF variability was reduced by about 30% in both groups. There were significant improvements in asthma symptoms and rescue medication use (p < 0.001). There were no significant differences between the treatment groups. The study demonstrated clinical equivalence of theophylline plus beclomethasone dipropionate 400 micrograms/day and beclomethasone dipropionate 800 micrograms/day in patients whose asthma is not controlled on beclomethasone dipropionate 400 micrograms/d. The results support the use of theophylline as steroid-sparing agent. The combination of low-dose inhaled steroid plus theophylline is a suitable treatment for moderate asthma.     

Acarbose in NIDDM patients with poor control on conventional oral agents. A 24-week placebo-controlled study

OBJECTIVE: To determine the efficacy of acarbose, compared with placebo, on the metabolic control of NIDDM patients inadequately controlled on maximal doses of conventional oral agents. RESEARCH DESIGN AND METHODS: In this three-center double-blind study, 90 Chinese NIDDM patients with persistent poor glycemic control despite maximal doses of sulfonylurea and metformin were randomly assigned to receive additional treatment with acarbose 100 mg thrice daily or placebo for 24 weeks, after 6 weeks of dietary reinforcement. Efficacy was assessed by changes in HbA1c, fasting and 1-h postprandial plasma glucose and insulin levels, and fasting lipid levels. RESULTS: Acarbose treatment was associated with significantly greater reductions in HbA1c (-0.5 +/- 0.2% vs. placebo 0.1 +/- 0.2% [means +/- SEM], P = 0.038), 1-h postprandial glucose (-2.3 +/- 0.4 mmol/l vs. placebo 0.7 +/- 0.4 mmol/l, P < 0.001) and body weight (-0.54 +/- 0.32 kg vs. placebo 0.42 +/- 0.29 kg, P < 0.05). There was no significant difference between the two groups regarding changes in fasting plasma glucose and lipids or fasting and postprandial insulin levels. Flatulence was the most common side effect (acarbose vs. placebo: 28/45 vs. 11/44, P < 0.05). One patient on acarbose had asymptomatic elevations in serum transaminases that normalized in 4 weeks after acarbose withdrawal. Another patient on acarbose developed severe hypoglycemia; glycemic control was subsequently maintained on half the baseline dosage of sulfonylurea. CONCLUSIONS: In NIDDM patients inadequately controlled on conventional oral agents, acarbose in moderate doses resulted in beneficial effects on glycemic control, especially postprandial glycemia, and mean body weight. Additional use of acarbose can be considered as a useful alternative in such patients if they are reluctant to accept insulin therapy.     

Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma

The anti-asthmatic effects of theophylline may supplement those of inhaled steroids in asthma. The aim of the present trial was to study how the addition of theophylline compares to doubling the dose of inhaled steroid in asthmatics who remain symptomatic on beclomethasone dipropionate (BDP) 400 microg x day(-1). The trial was designed as a randomized, double-blind, parallel-group study in several European countries. Sixty nine patients were treated for 6 weeks with theophylline plus BDP 400 microg x day(-1), compared to 64 patients treated with BDP 800 micro x day(-1). The mean+/-SD serum theophylline concentration was 10.1+/-4.2 mg x L(-1). Lung function measurements were made throughout the study and patients kept daily records of peak expiratory flow (PEF), symptoms and salbutamol usage. Forced expiratory volume in one second and PEF at week 6 were significantly increased by both treatments (p<0.01). PEF variability was reduced by about 30% in both groups. There were significant improvements in asthma symptoms and rescue medication use (p<0.001). There were no significant differences between the treatment groups. The study demonstrated clinical equivalence of theophylline plus beclomethasone dipropionate 400 microg x day(-1) and beclomethasone dipropionate 800 microg x day(-1) in patients whose asthma is not controlled on beclomethasone dipropionate 400 microg x day(-1). The results support the use of theophylline as a steroid-sparing agent. The combination of low-dose inhaled steroid plus theophylline is a suitable treatment for moderate asthma.     

An in vitro biocompatibility evaluation of double-J stents

This double-blind, randomized, multicenter trial compared clindamycin/primaquine (Cm/Prq) with trimethoprim-sulfamethoxazole (TMP-SMZ) as therapy for AIDS-related Pneumocystis carinii pneumonia (PCP). Forty-five patients received clindamycin (450 mg four times daily [q.i.d.]) and primaquine (15 mg of base/d); 42 received TMP-SMZ (320 mg/1,600 mg q.i.d. if weight of > or = 60 kg or 240 mg/1,200 mg q.i.d. if weight of < 60 kg) plus placebo primaquine. Overall, the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 76% vs. 79%, respectively); Cm/Prq was associated with fewer adverse events (P = .04), less steroid use (P = .18), and more rashes (P = .07). These differences were even greater for patients with PaO2 of > 70 mm Hg (P = .02, P = .04, and P = .02, respectively). For patients with PaO2 of < or = 70 mm Hg (23 Cm/Prq recipients and 21 TMP-SMZ recipients), the efficacy of Cm/Prq was similar to that of TMP-SMZ (success rate, 74% vs. 76%, respectively); Cm/Prq was associated with similar adverse events (P = .57), steroid use (P = .74), and rashes (P = .78). This trial confirms that Cm/Prq is a reasonable alternative therapy for mild and moderately severe PCP.     

Management of steroid-dependent asthma with methotrexate: a meta-analysis of randomized clinical trials

Our objective was to determine whether methotrexate is an effective steroid-sparing agent for patients with severe asthma. Published reports of controlled trials assessing the use of methotrexate in asthma were identified by a search of the MEDLINE, EMBASE, CINAHL, Biological Abstracts on CD, and Current Contents databases. Bibliographies from identified studies and from review articles were manually searched. Published and unpublished reports in any language were identified and assessed for inclusion in the meta-analysis. We selected randomized, double-blind, placebo-controlled trials in which low-dose methotrexate was administered to corticosteroid-dependent asthmatics, and oral steroids were subsequently tapered according to the patients' clinical status. Data were extracted independently by two reviewers. For all eligible trials, the mean reduction in oral corticosteroid dose, the mean change in FEV1, and the standard deviations, were calculated for the treatment and control groups. Data concerning side-effects of therapy were also extracted. Data from 12 studies, reporting on a total of 250 patients, were pooled using a weighted average method, with weights proportional to the inverse of the variance of the treatment effect. Compared to placebo, the use of methotrexate was associated with a pooled 6.0% improvement in FEV1 (95% CI, 1.0-11%) and an 18.2% reduction in oral steroid use (95% CI, 11.7-24.7%). This corresponded to a 3.3 mg day-1 greater reduction in oral steroid use for patients taking methotrexate than for those taking placebo (95% CI, 2.1-4.4 mg day-1). Gastrointestinal complications and transient increases in liver enzymes were more common in patients randomized to methotrexate. Three potentially life-threatening side-effects (two pneumonias and one liver dysfunction) occurred in 159 patients randomized to methotrexate vs. none in those patients on placebo. It was concluded that methotrexate allowed a modest reduction in oral corticosteroid compared to patients receiving placebo. The benefit is relatively small, however, and should be balanced against the potential for side-effects associated with the use of methotrexate.     

Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery

BACKGROUND: Atrial fibrillation occurs commonly after open-heart surgery and may delay hospital discharge. The purpose of this study was to assess the use of preoperative amiodarone as prophylaxis against atrial fibrillation after cardiac surgery. METHODS: In this double-blind, randomized study, 124 patients were given either oral amiodarone (64 patients) or placebo (60 patients) for a minimum of seven days before elective cardiac surgery. Therapy consisted of 600 mg of amiodarone per day for seven days, then 200 mg per day until the day of discharge from the hospital. The mean (+/-SD) preoperative total dose of amiodarone was 4.8+/-0.96 g over a period of 13+/-7 days. RESULTS: Postoperative atrial fibrillation occurred in 16 of the 64 patients in the amiodarone group (25 percent) and 32 of the 60 patients in the placebo group (53 percent) (P=0.003). Patients in the amiodarone group were hospitalized for significantly fewer days than were patients in the placebo group (6.5+/-2.6 vs. 7.9+/-4.3 days, P=0.04). Nonfatal postoperative complications occurred in eight amiodarone-treated patients (12 percent) and in six patients receiving placebo (10 percent, P=0.78). Fatal postoperative complications occurred in three patients who received amiodarone (5 percent) and in two who received placebo (3 percent, P= 1.00). Total hospitalization costs were significantly less for the amiodarone group than for the placebo group ($18,375+/-$13,863 vs. $26,491+/-$23,837, P=0.03). CONCLUSIONS: Preoperative oral amiodarone in patients undergoing complex cardiac surgery is well tolerated and significantly reduces the incidence of postoperative atrial fibrillation and the duration and cost of hospitalization.     

Low-dose cyclosporine and mycophenolate mofetil in renal allograft recipients with suboptimal renal function

BACKGROUND: Cyclosporine (CsA) nephrotoxicity can be identified by functional changes and chronic renal damage. CsA-associated renal fibrosis has been related to the overproduction of transforming growth factor (TGF)-beta1, a fibrogenic cytokine. Mycophenolate mofetil (MMF) may allow CsA dose reduction without increasing the risk of rejection. METHODS: We studied the impact of CsA dose reduction in association with MMF on renal function and TGF-beta1, production in 16 long-term renal allograft recipients with suspected CsA nephrotoxicity. Two grams/day of MMF were introduced, and CsA dose was reduced to reach whole-blood levels between 40 and 60 ng/ml within 1 month. CsA dose and levels, renal function parameters, and platelet-poor plasma TGF-beta1 levels were evaluated before and 6 months thereafter. RESULTS: MMF allowed a decrease in both the mean dose of CsA (3.8+/-1.35 vs. 2.2+/-0.73 mg/kg/day; P<0.01) and CsA levels (148+/-36 vs. 53+/-19 ng/ml; P<0.001). The reduction of CsA was associated with a decrement of serum creatinine levels (210+/-46 vs. 172+/-41 micromol/L; P<0.001) and an increase in both the glomerular filtration rate (32.9+/-12 vs. 39.1+/-14 ml/min/1.73 m2; P<0.02) and renal plasma flow (195+/-79 to 218.6+/-74.02 ml/min/1.73 m2; P<0.02). There was a reduction in plasma TGF-beta1 levels (4.6+/-4.2 vs. 2.0+/-1.4 ng/ml; P=0.003) and CsA levels correlated with TGF-beta1 (r=0.536, P=0.002). No rejection episodes occurred, and an improvement in both systolic (149+/-13 vs. 137+/-12 mmHg; P<0.01) and diastolic blood pressure (89+/-14 vs. 83+/-10 mmHg; P<0.04) were observed. CONCLUSIONS: These short-term results show that MMF introduction allows a CsA dose reduction, which improves renal function, reduces TGF-beta1 production, and improves the control of hypertension, without increasing the incidence of acute rejection.     

A randomized clinical trial of the nonsteroidal eyedrop diclofenac after strabismus surgery

OBJECTIVE: This study aimed to compare the anti-inflammatory and analgesic effects of topical diclofenac sodium 0.1% (Voltaren) with prednisolone sodium phosphate 1% ophthalmic solution after strabismus surgery. DESIGN: A prospective, double-masked, randomized, two-center clinical trial. PARTICIPANTS: Eighty eyes of 52 patients undergoing strabismus surgery were examined. INTERVENTION: For 1 week after surgery, the eye that was operated on received one drop of either diclofenac or prednisolone four times a day. MAIN OUTCOME MEASURES: The diclofenac- and prednisolone-treated eyes were compared on postoperative days 3 and 7 with respect to signs of inflammation (e.g., erythema, edema, discharge), patient comfort, and conjunctival incisional healing. RESULTS: On postoperative day 7, in eyes that received prednisolone, the conjunctival defects were larger (P = 0.004) and more frequent (P = 0.02). For all subjects, despite adequate statistical power, there was no statistically significant difference in inflammatory scores between eyes that received diclofenac or prednisolone. In cases of bilateral surgery, however, there was less postoperative erythema and edema in the diclofenac-treated eyes. CONCLUSIONS: In the first week after strabismus surgery, topical diclofenac proved at least as effective as prednisolone in controlling inflammation and discomfort with less delay in incisional wound healing. Topical diclofenac, a nonsteroidal anti-inflammatory agent, may be considered for use after strabismus surgery in place of corticosteroids.     

Mechanism of the diabetogenic action of cyclosporin A

To investigate the mechanism of diabetogenic action of cyclosporin A (CsA), 7 male Wistar albino rats received 10 mg/kg/day of the drug for 4 weeks (CsA). The results were compared with controls (C); blood CsA levels measured weekly remained stable throughout the experiment (mean +/- SEM) (X = 2657.9+/-155.1 ng/ml). Intravenous glucose load (0.75 g/kg) performed after 2 weeks of CsA therapy showed glucose intolerance in treated animals as evaluated by the glucose area under the curve (CsA = 409.2+/-17.8 vs. C = 313.3+/-12.6 umol x ml(-1) x min(-1)) (p < 0.05) with insulin levels being similar in the two groups (CsA = 8603.9+/-1645.5 vs. C = 9571.9+/-828.5 pmol x ml(-1) x min(-1)). After 4 weeks of CsA administration, glucose intolerance was maintained (CsA = 398.6+/-35.6 vs. C = 301.7+/-23.0 umol x ml(-1) x min(-1)) (p < 0.05) associated with a significant decrease in insulin secretion (CsA = 4404.9+/-2392.0 vs. C = 10075.9+/-2861.0 pmol x ml(-1) x min(-1) (p < 0.05). These results suggest that CsA induced a state of insulin resistance preceding the failure of insulin secretion. After 4 weeks, the pancreatic insulin content was also decreased (CsA = 0.7+/-0.1 vs. C = 1.4+/-0.5 mU/mg) (p < 0.05). Maximal insulin binding to isolated adipocytes was not affected by CsA (CsA = 7.4+/-2.6 vs. C = 6.4+/-2.0%), although glucose transport and oxidation decreased after CsA treatment (p < 0.05). In conclusion, glucose intolerance induced by CsA in Wistar albino rats is due to decreased insulin production and impaired insulin action by a post-binding mechanism.     

Benefit of active compression-decompression cardiopulmonary resuscitation as a prehospital advanced cardiac life support. A randomized multicenter study

OBJECTIVES: We sought to evaluate the effects of intermittent transdermal nitroglycerin (TD-NTG) on the occurrence of ischemia during patch-off hours in patients with stable angina pectoris receiving a beta-adrenergic blocking agent or calcium antagonist, or both. BACKGROUND: The current recommendations for the use of intermittent TD-NTG may be associated with the occurrence of rebound ischemia. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, crossover trial with three study periods. Tolerability to TD-NTG was assessed in Period I. Seventy-two patients were assigned to receive either double-blind transdermal placebo or maximally tolerated TD-NTG for 2 weeks (Period II) and were then crossed over to the alternative treatment for another 2 weeks (Period III). The patients were instructed to apply medication daily at 8 AM, to remove it at 10 PM and to note symptoms and sublingual nitroglycerin (SL-NTG) use in a diary. The occurrence of ischemia was assessed from patient-perceived angina, symptom-limited exercise treadmill test (ETT) and 48-h ambulatory electrocardiographic (AECG) monitoring. RESULTS: Transdermal NTG (0.2 to 0.4 mg/h) significantly reduced the magnitude of ST segment depression at angina onset during ETT compared with placebo. Total angina frequency was not significantly different between TD-NTG (mean [+/-SD] 3.2 +/- 4.2) and placebo (3.3 +/- 5.2). During patch-off hours, angina frequency increased with TD-NTG (1.1 +/- 2.1) compared with placebo (0.7 +/- 1.6) (p = 0.03). Similar trends for an increase in ischemia after TD-NTG were also observed from AECG analyses. Specifically, ischemia frequency tended to be lower during patch-off hours for placebo than with TD-NTG (0.05 +/- 0.09 vs. 0.08 +/- 0.20 episodes/h, respectively, p = 0.08), even though frequency of ischemia tended to be higher during patch-on hours for placebo than with TD-NTG (0.12 +/- 0.19 vs. 0.07 +/- 0.15 episodes/h, respectively, p = 0.11). During placebo, ischemia frequency decreased 58% (patch-on to patch-off, p = 0.01) compared with a 14% increase with TD-NTG. These changes attenuate the usual circadian variation in ischemia. CONCLUSIONS: An increase in ischemia frequency during patch-off hours after use of intermittent TD-NTG was perceived by patients, and this subjective finding was supported by a corresponding trend for AECG ischemia to increase during these same hours.     

Effects of amlodipine on transient myocardial ischaemia in patients with a severe coronary condition treated with a beta-blocker. Amlor-Holter Study Investigators

The purpose of this trial was to study the additional anti-ischaemic effects of amlodipine in coronary patients with ambulant ischaemia despite beta-blocker therapy. Beta-blockers are the most effective drug therapy for reducing the frequency and duration of ambulatory ischaemic episodes. However, the therapeutic advantage of combined calcium antagonist-beta-blocker treatment remains questionable. Three hundred and thirteen patients with documented coronary artery disease, a positive exercise test within 6 months before entry and background beta-blocker therapy, were screened. Inclusion criteria (> or = 4 episodes of transient ST segment depression of > or = 1.0 mm and/or > or = 20 min of ischaemia) were demonstrated in a 48 h ECG during the placebo run-in period in 84 (25%) of the patients. Eighty-nine percent of the ischaemic episodes were silent. The eligible patients were then randomized in a 2-week, double-blind, parallel group study comparing placebo to amlodipine 10 mg daily added to the beta-blocker. The anti-ischaemic efficacy of the combination therapy was assessed by 48 h ECG monitoring and exercise tests. Compared to placebo, amlodipine did not significantly reduce either the frequency (3.7 +/- 4.3 vs 4 +/- 4.8 episodes in the amlodipine group) or the duration of ambulatory ischaemia (mean duration: 43.9 +/- 57.1 vs 39.6 +/- 65.7 min, total duration 3.1 +/- 6.7 vs 2.8 +/- 6.1 h). Exercise-induced ST segment depression tended to decrease with amlodipine (58% vs 73% in the placebo group) and the ischaemia-free workload capacity was increased (+1.7 stage vs 0.7 stage in the placebo group, P = 0.08). These results suggest that 2 weeks treatment with amlodipine may not provide any additional anti-ischaemic benefit in patients with ambulant ischaemia resistant to a beta-blocker therapy.     

The effect of felodipine on renal function and blood pressure in cyclosporin-treated renal transplant recipients during the first three months after transplantation

BACKGROUND: Due to their vasodilatory effect, calcium antagonist may have a renoprotective against cyclosporin (CsA)-induced nephrotoxicity and rise in blood pressure (BP) seen in renal transplantation. METHODS: In order to evaluate the effect of the calcium antagonist felodipine on renal function and BP during cyclosporin treatment, 79 CsA-treated renal transplant recipients were investigated during the first 3 months after transplantation in a randomized, double-blind, placebo-controlled study with two parallel groups. Felodipine (ER tablets, 10 mg) or placebo was given prior to transplantation and each day during the study period. The patients were assessed twice, i.e. at 4-6 weeks and at 10-12 weeks after transplantation. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were measured by constant infusion technique. Tubular function was estimated from clearance of lithium. RESULTS: At 6 weeks after transplantation, felodipine caused a significantly higher RPF [felodipine: 219 +/- 70 ml/min; placebo: 182+/-56 ml/min (mean+/-1 SD); P=0.03]. No differences were found in GFR, filtration fraction (FF), tubular sodium handling, or sodium excretion. Felodipine lowered BP significantly. At 12 weeks after transplantation, felodipine caused a significantly higher GFR (felodipine: 49+/-18 ml/min; placebo: 40+/-16 ml/min; P=0.05) and RPF (felodipine: 225+/-77 ml/min; placebo: 175+/-48 ml/min; P<0.01). No difference was found in FF. Felodipine lowered BP significantly. No differences were found with regard to duration of primary anuria, hospitalization time, number of rejection episodes, plasma creatinine day 7 post-transplant, or treatment doses of CsA. CONCLUSIONS: It is concluded that in renal transplant recipients treated with CsA, felodipine significantly increased both GFR and RPF 3 months after transplantation when compared with placebo, despite a concomitant lowering of BP. A possible antagonizing affect of felodipine against CsA-induced nephrotoxicity in these patients is suggested.