A preliminary study of photodynamic therapy using verteporfin for choroidal neovascularization in pathologic myopia, ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes.

OBJECTIVE: To evaluate short-term safety and the effects on visual acuity and fluorescein angiography of single or multiple sessions of photodynamic therapy with verteporfin for choroidal neovascularization (CNV) not related to age-related macular degeneration (AMD), including pathologic myopia, the ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes. DESIGN: A nonrandomized, multicenter, open-label, dose-escalation phase 1 and 2 clinical trial. SETTING: Four ophthalmic centers in Europe and North America providing retinal care. PARTICIPANTS: Thirteen patients with subfoveal CNV due to pathologic myopia, the ocular histoplasmosis syndrome, angioid streaks, or idiopathic causes. METHODS: Standardized protocol refraction, visual acuity testing, ophthalmic examinations, color photographs, and fluorescein angiograms were used to evaluate the results of photodynamic therapy treatments with verteporfin. Follow-up ranged from 12 weeks for patients who were treated once to 43 weeks for patients who were treated up to 4 times. RESULTS: Verteporfin therapy was well tolerated in patients with CNV not related to AMD. No deterioration in visual acuity was observed; most patients gained at least 1 line of vision. Reduction in the size of leakage area from classic CNV was noted in all patients as early as 1 week after verteporfin therapy, with complete absence of leakage from classic CNV in almost half of the patients. Improvement in visual acuity after verteporfin therapy was greatest (+6, +8, and +9 lines) in 3 patients with relatively poor initial visual acuity (between 20/200 and 20/800). Up to 4 treatments were found to have short-term safety even with retreatment intervals as short as 4 weeks. CONCLUSIONS: Treatment of CNV not related to AMD with verteporfin therapy achieves short-term cessation of fluorescein leakage from CNV in a small number of patients without loss of vision. Further randomized clinical trials including a larger number of patients are under way to confirm whether verteporfin therapy is beneficial for subfoveal CNV not related to AMD.

Photodynamic therapy with verteporfin for choroidal neovascularization caused by age-related macular degeneration: results of retreatments in a phase 1 and 2 study.

OBJECTIVES: To evaluate safety and short-term visual acuity and fluorescein angiographic effects of photodynamic therapy (PDT) after retreatments with verteporfin for choroidal neovascularization (CNV) in age-related macular degeneration (AMD) that demonstrated fluorescein leakage after at least 1 course of PDT. DESIGN: Nonrandomized, multicenter, open-label phase 1 and 2 clinical trial using 2 different retreatment dosage regimens. SETTING: Four ophthalmic centers in Europe and North America providing retinal care. METHODS: Standardized protocol refraction, visual acuity testing, ophthalmic examinations, color photographs, and fluorescein angiograms were used to evaluate the results of multiple PDT treatments. Two regimens (regimens 2 and 4) for treatment and retreatment were chosen from 5 used in a single-treatment study. Both regimens used a verteporfin dose of 6 mg/m2 infused for 10 minutes. However, regimen 2 used a light dose of 100 J/cm2 applied 20 minutes after the start of the verteporfin infusion, whereas regimen 4 used a light dose of 50, 75, or 100 J/cm2 applied 15 minutes after infusion commenced. Posttreatment evaluations were planned in 31 participants up to 3 months after up to 2 retreatments given at 2- or 4-week intervals after initial PDT treatment. Similar posttreatment evaluations were planned after retreatments in 5 additional participants who were reenrolled some time more than 12 weeks after an initial PDT treatment. RESULTS: The average visual acuity change for the 31 participants who had retreatment within 2 to 4 weeks after the initial treatment and a follow-up examination 16 to 20 weeks after the initial treatment was 0.2 lines (range, -4 to 4 lines) in regimen 2 and -1.0 line (range, -5 to 3 lines) in regimen 4. Similar outcomes were noted in the 5 reenrolled participants. Cessation of fluorescein leakage from classic CNV for at least 1 to 4 weeks could be achieved without loss of visual acuity after at least 2 treatments in 2 (6.5%) of 31 patients. Similar to single-treatment effects, the disappearance of leakage was documented regularly at 1 week after each retreatment. Fluorescein leakage reappeared by 4 to 12 weeks after a retreatment in almost all cases. However, compared with baseline, leakage activity appeared to be reduced after multiple PDT courses. For the 31 patients who had follow-up for 3 months after the last retreatment and had received retreatment 2 to 4 weeks after the initial treatment, progression of CNV beyond the area identified before the retreatment was noted in 10 (48%) of the 21 eyes with classic CNV in regimen 2 and 9 (90%) of 10 eyes in regimen 4. The rate and severity of ocular or systemic adverse events were not increased by multiple applications. CONCLUSIONS: Multiple applications of PDT with verteporfin achieve repetitive, short-term cessation of fluorescein leakage from CNV secondary to AMD, without loss of visual acuity. This strategy can be used in randomized clinical trials investigating the efficacy of verteporfin in PDT for recurrent fluorescein dye leakage from persistent or recurrent CNV, following an initial or subsequent PDT treatment, with maintenance of visual acuity. Retreatments may achieve progressive cessation of leakage and prevent further growth of CNV and subsequent visual loss.

Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics.

The bioavailability of some dihydropyridine calcium antagonists can be markedly augmented by grapefruit juice and may involve the bioflavonoid naringin. The pharmacokinetics of nisoldipine coat-core tablet were studied in a Latin square-designed trial in which 12 healthy men were administered the drug with water, grapefruit juice, or encapsulated naringin powder at the same amount as that assayed in the juice. Compared with water, grapefruit juice increased the maximum concentration of nisoldipine to 406% +/- 73% (mean +/- SEM; range, 107% to 836%; p < 0.001), increased the area under the plasma concentration-time curve to 198% +/- 46% (range, 81% to 682%; p < 0.001), and reduced time to reach maximum nisoldipine concentration to 58% +/- 9% (range, 13% to 100%; p < 0.01), probably by inhibition of presystemic metabolism and possibly by enhancement of drug dissolution. The interaction could not be predicted from baseline pharmacokinetics with water and resulted in greater interindividual variability. The naringin capsule did not change nisoldipine pharmacokinetics. All treatments produced minor effects on supine blood pressure and heart rate, probably because subjects were normotensive. Current information supports the cautioning of patients about concomitant ingestion of grapefruit juice and nisoldipine.

Efficacy of once daily nitrendipine in mild hypertension: comparison with placebo.

A randomized, double-blind, parallel group study was carried out to compare the antihypertensive efficacy of nitrendipine with that of placebo in 80 mild hypertensives. The dose of nitrendipine was initially 10 mg once daily and was doubled to 20 mg once daily after four weeks in patients who responded poorly (33% of patients on nitrendipine and 49% of patients on placebo required doubling of dose). Blood pressure was assessed 20 to 24 h after dosing. Mean (+/- standard error) reductions in supine systolic and diastolic blood pressures for patients who completed 10 weeks of therapy were significantly greater for the nitrendipine group than for the placebo group (systolic blood pressure 18.1 +/- 2.7 mmHg versus 4.2 +/- 2.5, P less than 0.0001; and diastolic blood pressure 10.6 +/- 1.1 mmHg versus 6.6 +/- 1.3, P = 0.002). A comparison of mean reductions in standing systolic and diastolic blood pressures produced similar results. Goal of therapy (diastolic blood pressure no more than 90 mmHg or reduction of at least 10 mmHg) was achieved in 71% of nitrendipine-treated and 45% of placebo-treated patients (P less than 0.05). Nine of 80 patients randomized to therapy dropped out during treatment (nitrendipine: four adverse experiences and one moved from the area; placebo: two adverse experiences, and drug ineffective in two). Overall, the incidence of adverse experiences considered by the physician to be related to treatment was higher in the placebo group (32%) than in the nitrendipine group (23%). Only flushing had a higher incidence in the nitrendipine group; however, the overall incidence was low (9%).(ABSTRACT TRUNCATED AT 250 WORDS)

Effectiveness and tolerability of once versus twice daily nitrendipine in the treatment of mild to moderate hypertension. The Canadian Nitrendipine Study Group.

Improved measurement of plasma concentrations of nitrendipine demonstrates a plasma half-life of 17 to 21 h allowing once daily dosing for antihypertensive treatment. To determine the effectiveness and tolerability of nitrendipine given once versus twice daily, 78 patients with mild to moderate essential hypertension were randomized in a double-blind fashion to 12 weeks of treatment with either nitrendipine 20 mg once daily (n = 39) or nitrendipine 10 mg bid (n = 39). Blood pressures measured at the end of the dosing interval were similar on 20 mg once daily and 10 mg bid. Adverse events considered to be drug related (flushing and headaches) occurred mostly at the beginning of active treatment and more frequently on the once daily dosing, resulting in a greater number of patients being withdrawn from the once daily treatment group. Thus, nitrendipine 20 mg once daily lowered blood pressure as effectively as 10 mg bid but was associated with a higher incidence of adverse events. These could be minimized by starting at nitrendipine 10 mg once daily and increasing to 20 mg once daily after two to four weeks.

Pharmacokinetics of lidocaine in children with congenital heart disease.

The purpose of this study was to determine the pharmacokinetics of lidocaine in children with congenital heart disease (CHD). Fifteen children with left to right intracardiac shunting of blood (acyanotic group) and 15 children with right to left intracardiac shunting of blood (cyanotic group) were studied and compared with 15 children without CHD (control group). Lidocaine (1.5 mg.kg-1) was injected into a peripheral vein over 30 sec and serial samples of arterial blood were obtained up to 120 min after completion of the infusion. Total and free lidocaine were analyzed by enzyme immunoassay. The serum concentration of alpha 1-acid glycoprotein (alpha 1-AGP) at induction of anaesthesia was measured in the three groups by radial immunodiffusion. The percent free lidocaine (100 x [free lidocaine]/[total lidocaine]) was greater at 30 sec post-infusion in all three groups (35-37%) than it was at any other time but was not significantly different among the three groups (P less than 0.05). There was no significant difference in either the percent free or the total lidocaine concentration at any sample time or in any of the pharmacokinetic variables among the three groups. The serum concentration of alpha 1-AGP did not differ significantly among the three groups of patients. We conclude that the presence of intracardiac shunts does not alter the pharmacokinetic behaviour of intravenous lidocaine (1.5 mg.kg-1) in children. The percent free lidocaine is greatest immediately post-injection and this may mitigate against rapid bolus administration of intravenous lidocaine in children.

Once- vs. twice-daily nitrendipine in the treatment of mild to moderate hypertension, Canadian Nitrendipine Study Group.

Improved measurement of the plasma concentration of nitrendipine demonstrated a plasma half-life of 17-21 h, allowing once-daily (o.d.) instead of currently twice-daily (b.i.d.) dosing. To determine the effectiveness of nitrendipine given o.d. vs. b.i.d., 78 hypertensive patients, [supine diastolic blood pressure (DBP) of 95-114 mm Hg] were randomized in a double-blind fashion to 12 weeks of treatment with either nitrendipine 10 mg b.i.d. (n = 39) or nitrendipine 20 mg o.d. (n = 39) after a 2-week placebo baseline period. Blood pressures (BPs) were measured in the morning at the end of the dosing interval. Mean +/- SD reduction in supine systolic BP (SBP) and DBP in patients evaluable for efficacy (greater than or equal to 14 days treatment) were 7.2 +/- 16.5 and 7.7 +/- 10.3 mm Hg, respectively, after nitrendipine b.i.d. (n = 38) and 9.4 +/- 15.1 and 9.5 +/- 7.0 mm Hg, respectively, after nitrendipine o.d. (n = 36). Similar falls in BP were found for both regimens in patients completing the full 12 weeks of treatment period (n: o.d. = 28, b.i.d. = 32). Discontinuation due to adverse experiences (AEs) occurred in three patients on b.i.d. and eight patients on o.d., the latter mostly in the first 2 weeks of therapy. Overall, AEs were higher in the o.d. group (% AEs at least possibly related to study medication: o.d. = 44%, b.i.d. = 33%). Most frequent AEs were headache and flushing.(ABSTRACT TRUNCATED AT 250 WORDS)

Alpha 1-acid glycoprotein and the binding of lidocaine in children with congenital heart disease.

The purpose of this study was to evaluate the effect of congenital heart disease (CHD) on the serum concentrations of alpha 1-acid glycoprotein (alpha 1-AGP) and the serum binding of lidocaine. Thirteen children with acyanotic CHD and 12 children with cyanotic CHD were studied and compared with 28 children without heart disease (control). The mean (+/- SD) serum concentration of alpha 1-AGP, as determined by radial immunodiffusion, did not differ significantly among the three groups. Five minutes after administration of 1.5 mg.kg-1 intravenous lidocaine, the free fraction of lidocaine correlated inversely and linearly with the serum concentration of alpha 1-AGP in children with acyanotic CHD (r2 = 0.74; P less than 0.001) cyanotic CHD (r2 = 0.57; P less than 0.005), and control (r2 = 0.63; P less than 0.001). The slopes and intercepts of the linear regressions did not differ significantly among the three groups. We conclude that the serum concentration of alpha 1-AGP in children with CHD does not differ quantitatively or qualitatively from that in children without CHD.

Effects of age on the serum concentration of alpha 1-acid glycoprotein and the binding of lidocaine in pediatric patients.

We determined the effect of age on the serum concentration of alpha 1-acid glycoprotein (alpha 1-AGP) in venous blood from 134 subjects who ranged in age from preterm neonates to 18-year-old adolescents. The mean (+/- SD) serum concentration of alpha 1-AGP, determined by radial immunodiffusion, increased significantly with age: the concentration found in neonates was less than that found in infants which, in turn, was less than that found in older children (p less than 0.001). In addition, we determined the effect of alpha 1-AGP on the free fraction of lidocaine in four groups of infants and children who received intravenous lidocaine (1.5 mg/kg). The percentage of free lidocaine correlated inversely and linearly with the serum alpha 1-AGP concentration (r2 = 0.617; p less than 0.001). The percentage of free lidocaine in the five neonates exceeded that in the older age groups. We conclude that the serum concentration of alpha 1-AGP increases while the free fraction of lidocaine decreases from early infancy to adolescence.

Pharmacokinetics of intravenous dantrolene in children.

To determine the pharmacokinetics of iv dantrolene and its metabolites in children, ten children 2-7 yr of age scheduled for minor elective surgery, were studied. After induction of anesthesia and tracheal intubation, dantrolene (2.4 mg/kg) was administered iv over 10.2 +/- 0.83 min. Venous blood samples (3 ml) were obtained 1, 5, 10, 20, and 30 min and 1, 2, 4, 8, 12, and 20 h after the dantrolene infusion. Whole blood concentrations of dantrolene, 5-hydroxydantrolene, and nitroreduced acetylated dantrolene were measured by high-performance liquid chromatography. The whole blood concentration of dantrolene decreased rapidly from a mean (+/- SD) of 6.03 +/- 0.93 microgram/ml 1 min after the end of the dantrolene infusion to 3.56 +/- 0.49 microgram/ml at 1 h. Between 1 and 4 h, the concentration of dantrolene either remained constant or increased slightly. Thereafter, the concentration of dantrolene decreased slowly with an elimination half-life (mean +/- SD) of 10.0 +/- 2.6 h. The mean (+/- SD) time for the concentration of dantrolene to decrease to 3.0 micrograms/ml was 6.55 +/- 2.88 h. The whole blood concentration of 5-hydroxydantrolene reached a maximum of 0.60 +/- 0.18 microgram/ml approximately 7 h after the dantrolene and decreased thereafter with an elimination half-life of 9.0 +/- 2.5 h. The concentration of nitroreduced acetylated dantrolene was below the limit for detection at all times. All children recovered without complications. Intravenous dantrolene, 2.4 mg/kg, produces safe and predictable blood concentrations in children similar to those reported in adults.

The reduction of sulphinpyrazone and sulindac by intestinal bacteria.

1. Incubation of human or rabbit faeces with sulphinpyrazone gave greater reduction under anaerobic than under aerobic conditions. Reduction of sulindac by human faeces was more extensive than that of sulphinpyrazone. 2. Growth of mixed cultures of intestinal bacteria in nutrient media containing antibiotics produced a marked inhibition in their ability to reduce sulphinpyrazone. Sulphide formation was inhibited by metronidazole and lincomycin for human faeces and by tetracycline for rabbit faeces/caecal contents. 3. The formation of the sulphides of sulindac and sulphinpyrazone ex vivo was decreased in faeces from patients treated with metronidazole. Metronidazole, but not tetracycline, decreased the extent of reduction of sulphinpyrazone by rabbits in vivo. No reduction of either substrate occurred on incubation with ileostomy effluent. These data indicate that anaerobic intestinal bacteria are important in the reduction of these sulphoxide-containing drugs. 4. However, when incubated anaerobically with over 200 strains of bacteria isolated from human faeces, sulphinpyrazone was reduced by most of the aerobic but not the anaerobic organisms. Sulindac was reduced more extensively by the same aerobes and by some anaerobes. 5. The discrepancy between the apparent importance of anaerobes in vivo and in vitro may be due to their very large number present in the hind gut and to the production of an anaerobic environment suitable for the enzymic activity of other organisms, such as aerobes or facultative anaerobes.

Effects of ischaemic heart disease, Crohn's disease and antimicrobial therapy on the pharmacokinetics of sulphinpyrazone.

The renewed interest in sulphinpyrazone in recent years has arisen from its potential to inhibit platelet aggregation. In vivo much of the activity is probably due to the thioether or sulphide metabolite which has a greater potency and a longer half-life than the parent compound. The sulphide metabolite is formed exclusively by the gut microflora in man. The pharmacokinetics of sulphinpyrazone (200 mg orally) have been studied, with particular attention to the formation of the sulphide metabolite, in groups of patients who might be expected to show abnormal formation of this active metabolite due to altered delivery of the drug to the lower gut or altered gut flora. Five patients studied 1 month after a myocardial infarction did not differ markedly from young, normal volunteers with respect to either sulphinpyrazone or its metabolite. Crohn's disease in the quiescent phase did not significantly alter the pharmacokinetics or metabolism of the drug, but 1 patient who had undergone a hemicolectomy formed negligible concentrations of the active metabolite. Antimicrobial therapy produced highly variable results with almost complete suppression of sulphide formation in some subjects but no apparent effect in others.

Sulindac metabolism: the importance of an intact colon.

The pharmacokinetics of sulindac have been studied after a single 200 mg oral dose in six normal subjects and five patients with surgical ileostomies. The plasma concentration-time curves for sulindac were similar in both groups up to 12 hours after dosing, indicating similar absorption of the drug. Higher plasma concentrations of sulindac were found in normal subjects after 12 hours, but this late phase accounted for only 12% of the total AUC in the subjects. The sulfone metabolite showed a similar pattern, with no statistically significant difference in the total AUC, but in patients with ileostomy there was a halving of the AUC after 12 hours. Plasma concentrations of the active sulfide metabolite were similar in both groups up to 12 hours, but negligible concentrations were detected in the plasma of patients with ileostomy after 12 hours. Thus the AUC after 12 hours, which represented 55% of the total AUC in normal subjects, was reduced to only 7% in patients with ileostomy. The rate of reduction of sulindac in vitro by ileostomy effluent was only one hundredth that by normal feces. Our results suggest that the gut microflora are an important site of reduction of sulindac in man. Comparison of AUC values suggests that about half the total sulfide is formed by the gut bacteria, probably from sulindac excreted in the bile.

The site of reduction of sulphinpyrazone in the rabbit.

Comparison of oral and i.v. administration of sulphinpyrazone (10 mg/kg) to rabbits showed that the oral route was associated with an incomplete bioavailability and a six-fold greater formation of the active sulphide metabolite. The bile was an important route of elimination of unchanged sulphinpyrazone in rabbits (18% of an i.v. dose in four hours). Only small amounts of the sulphide appeared in the bile after i.v. administration. Pretreatment with oral antibiotics decreased the area under the plasma concentration-time curve (AUC) for the sulphide but increased that of the parent drug. Excretion of the p-hydroxysulphide metabolite in urine was decreased 30-fold by antibiotic treatment. The contents of the caecum showed the greatest capacity for sulphinpyrazone reduction in vitro. The liver possessed a slight ability to reduce sulphinpyrazone in vitro under anaerobic, but not aerobic, conditions. The gut bacteria are the main site of reduction of sulphinpyrazone to the active sulphide metabolite in the rabbit. These findings contrast with those obtained for sulindac which was reduced extensively under both aerobic and anaerobic conditions by rabbit-liver soluble fraction in vitro. The sulphide metabolites of both sulphinpyrazone and sulindac were oxidized to the parent drug by rabbit-liver microsomes.

Role of the gut flora in the reduction of sulfinpyrazone in humans.

Peak plasma concentrations of sulfinpyrazone occurred about 2 h after administration of a single oral dose (200 mg tablet) to 11 normal volunteers. In contrast, the peak concentrations of the active sulfide metabolite occurred 15 h after dosing. Concurrent oral administration of metoclopramide with sulfinpyrazone resulted in a 4-fold decrease in the time to peak sulfide concentrations and a 3-fold increase in the amounts formed. A slow release formulation showed a low, variable bioavailability, but the proportion of sulfide was 3-fold higher based on the ratio of the area under the plasma concentration-time curve of the sulfide to that of the parent compound. Intravenous administration of sulfinpyrazone demonstrated that the tablets had a high bioavailability (about 90%), and the time to peak plasma concentration of the sulfide and the amount formed were similar to those seen after oral administration. Patients who had undergone surgical removal of the distal part of the intestine had normal plasma concentrations of sulfinpyrazone, but negligible amounts of the sulfide, after oral administration of sulfinpyrazone. The ileostomy effluent of such patients showed little ability to reduce sulfinpyrazone in vitro, in contrast to the extensive reduction detected with normal feces. These data demonstrate that the hind gut microflora are the principal and possibly the only site of reduction of sulfinpyrazone to its active sulfide metabolite in humans.