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Biomedical subjects

N Kassem

Publications and source records attributed to N Kassem.

11 recordsLinked to original sources
PubMed2000

Long-term follow-up of premature infants treated with prophylactic, intratracheal recombinant human CuZn superoxide dismutase.

OBJECTIVE: To examine the long-term effects of treatment with recombinant human CuZn superoxide dismutase (rhSOD) in infants enrolled previously in two placebo-controlled trials. STUDY DESIGN: Records for 46 (88%) infants were examined, with 19 infants having received either single or multiple intratracheal (i.t.) doses of placebo, 12 having received a single i.t. dose of rhSOD, and 15 having received multiple i.t. doses of rhSOD. Mean age at follow-up was 28 months corrected age. Records were examined for neurologic dysfunction, developmental delay, and any significant medical disorders. RESULTS: Four placebo infants (21%) had evidence of neurodevelopmental abnormalities and four infants developed asthma. Four single-dose rhSOD infants (33%) had neurodevelopmental abnormalities and two infants developed asthma. One multiple-dose rhSOD infant had evidence of neurodevelopmental abnormalities and one developed asthma. No other differences were found between the placebo and rhSOD groups. CONCLUSION: Preliminary data suggest that rhSOD is safe and not associated with any long-term adverse effects. Further results will depend on the results of multicenter trials of rhSOD in preterm infants.

Administration, Inhalation↗
PubMed1997

Intrathecal administration of recombinant human superoxide dismutase 1 in amyotrophic lateral sclerosis: a preliminary safety and pharmacokinetic study.

We undertook a safety and pharmacokinetic study of intrathecal (i.t.) recombinant human superoxide dismutase (rhSOD1). We administered rhSOD1 as an acute bolus in three sheep and 16 human subjects with amyotrophic lateral sclerosis (ALS). Two sheep received chronic i.t. infusion of rhSOD1 (one at 17.7 mg per day, the second at 38.0 mg per day) for six months. Two of the 16 subjects had familial ALS and mutations in the gene for Cu/Zn SOD1. They both received i.t. infusion of rhSOD1 (5 to 10 mg per day) for 3 to 6 months. Intrathecal rhSOD1 administration was safe. Bolus i.t. administration of 0.25 mg rhSOD1 in sheep revealed a mean elimination half-life of 0.4 (SD +/- 0.06) hours, clearance of 12.2 +/- 3.2 ml per hour, and volume of distribution of 7.3 +/- 0.9 ml. After chronic i.t. infusion, the initial alpha-phase half-life was estimated as 1.2 hours and the extended beta-phase half-life was 15.0 hours. The mean clearance rate was 25.9 ml per hour and the steady-state volume of distribution was 920.6 ml. Bolus i.t. administration of 20 micrograms of rhSOD1 in ALS subjects revealed a mean elimination half-life of 2.2 +/- 0.8 hours, clearance of 1.2 +/- 0.6 ml per hour, and volume of distribution of 3.5 +/- 0.4 ml. With chronic i.t. infusion of 5 mg per day, cerebrospinal SOD1 levels increased approximately fortyfold. We detected no benefit of this treatment in the two patients with familial ALS.

Adult↗
PubMed1997

Safety and pharmacokinetics of multiple doses of recombinant human CuZn superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome.

OBJECTIVES: To examine the safety and pharmacokinetics of multiple intratracheal (IT) doses of recombinant human CuZn superoxide dismutase (rhSOD) in premature infants with respiratory distress syndrome who are at risk for developing bronchopulmonary dysplasia (BPD). Methods. Thirty-three infants (700 to 1300 g) were randomized and blindly received saline, 2.5 mg/kg or 5 mg/kg rhSOD IT within 2 hours of surfactant administration. Infants were treated every 48 hours (as long as endotracheal intubation was required) up to 7 doses. Serial blood and urine studies, chest radiographs, neurosonograms, SOD concentration and activity measurements, and tracheal aspirate (TA) inflammatory markers were assessed throughout the 28-day study. RESULTS: SOD concentrations in serum (0.1 [0.05/0.15] microg/mL-geometric mean with lower/upper confidence intervals), tracheal aspirates (TA) (0.2 [0.1/0.3] microg/mL) and urine (0.3 [0.2/0.4] microg/mL) were similar at baseline in all 3 groups and did not change significantly in the placebo group. In the rhSOD treatment groups, SOD concentrations were increased on day 3 and did not change significantly thereafter over the 14-day dosing period (also measured on days 5, 7, and 13). SOD concentrations averaged 0.4 [0.3/0.5] microg/mL in serum, 0.8 [0.6/1.2] microg/mL in TA and 1.1 [1.0/1.3] microg/mL in urine for the low-dose group and 0.6 [0.5/0.7] microg/mL in serum, 1.1 [0.9/1.5] microg/mL in TA, and 2.2 [1.6/2.9] microg/mL in urine for the high-dose group over the 14-day dosing period. Enzyme activity directly correlated with SOD concentration and rhSOD was active even when excreted in urine. TA markers of acute lung injury (neutrophil chemotactic activity, albumin concentration) were lower in the rhSOD agroups compared with placebo. No significant differences in any clinical outcome variable were noted between groups. CONCLUSIONS: These data indicate that multiple IT doses of rhSOD increase the concentration and activity of the enzyme in serum, TA and urine, reduce TA lung injury markers and are well-tolerated. Further clinical trials examining the efficacy of rhSOD in the prevention of BPD are warranted.

Analysis of Variance↗
PubMed1996

Safety and pharmacokinetics of recombinant human superoxide dismutase administered intratracheally to premature neonates with respiratory distress syndrome.

OBJECTIVE: As a first step in the evaluation of recombinant human CuZn superoxide dismutase (rhSOD) in the prevention of neonatal lung injury, safety and pharmacokinetics of intratracheally (IT) administered rhSOD were studied. METHODS: Twenty-six preterm infants weighing 750 to 1250 g with respiratory distress syndrome were studied in three sequential groups (placebo, 0.5, and 5 mg/kg). Placebo or rhSOD was administered IT 30 minutes after the first surfactant dose. Serial blood and urine studies, rhSOD levels, tracheal aspirate fluid (TAF) markers of acute inflammation, radiographs, and ultrasounds were performed over the 28-day study period. RESULTS: Serum SOD concentrations were similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.1 to 0.2 microgram/mL). In the 0.5-mg/kg group, levels were highest at 12 hours (geometric mean 0.7, upper-lower limit 0.5 to 0.8 microgram/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were highest at 6 hours (geometric mean 3.0, upper-lower limit 2.3 to 4.0 micrograms/mL) and returned to baseline by day 4. Concentrations of SOD in TAF were also similar at baseline for all three groups (geometric mean 0.2, upper-lower limit 0.2 to 0.3 microgram/mL). There were no significant increases in the placebo group, but levels in the 0.5-mg/kg group were highest when first sampled at 24 hours (geometric mean 1.1, upper-lower limit 0.8 to 1.4 micrograms/mL) and returned to baseline by day 3. In the 5-mg/kg group, levels were also highest when sampled at 24 hours (geometric mean 1.4, upper-lower limit 0.9 to 2.1 micrograms/mL) and returned to baseline by day 4. Urine levels were highest at 12 hours in both the 0.5-mg/kg (geometric mean 1.3, upper-lower limit 1.0 to 1.7 micrograms/mL) and 5-mg/kg infants (geometric mean 6.4, upper-lower limit 3.9 to 10.4 micrograms/mL) and decreased significantly by day 2 to 3. rhSOD activity assays (serum, TAF, and urine) demonstrated that the enzyme still possessed significant activity. No adverse effects of rhSOD were found. TAF neutrophil chemotactic activity and albumin concentrations, important acute lung injury markers, were significantly lower in the high-dose rhSOD group compared with the other groups. CONCLUSIONS: Data suggest that a single IT dose of rhSOD results in significant increases in both concentration and activity of the antioxidant in serum, TAF, and urine for 2 to 3 days. The enzyme appears to be well tolerated, and TAF inflammatory markers are reduced after administration. This has important implications in rhSOD trials to prevent acute and chronic lung injury in preterm neonates.

Drug Monitoring↗
PubMed1992

A clinically relevant modification to existing inhaler therapy.

A modified formulation of inhaled salbutamol and a new inhaler device were studied in a group of 11 moderate-to-severe asthmatic patients. Changes in airway calibre (FEV1, Vmax30) were measured before and after inhalation of the new formulation, and compared with changes following inhalation of conventional salbutamol. A standard Rotahaler was used as a reference for the new inhaler. The study was conducted as a two-part randomized, double-blind cross-over trial. We found a significantly greater bronchodilatation of the larger airways using the modified drug in the Rotahaler. The new inhaler did not show any superiority over the Rotahaler, contrary to expectations from in vitro work. A slightly shorter model may better reflect the in vitro results. The study has implications for inhalation therapy in general.

Adult↗
PubMed1988

Effects of loratadine (SCH 29851) in suppression of histamine-induced skin wheals.

The efficacy and safety of single oral doses (10, 20, 40, and 80 mg) of loratadine (SCH 29851) in suppressing formation of histamine-induced wheals were assessed in a crossover study in 29 healthy male subjects. One hour prior to dosing and 1, 2, 3, 4, 6, 8, 12, 16, 24, 28, 32, 36, 40, and 48 hours after dosing, histamine and saline were injected intradermally into opposite arms. Measurements of resulting wheal areas showed loratadine suppressed wheal formation significantly better than placebo; suppression was dose related. The mean suppression over 48 hours was 16% in placebo-treated subjects and 35%, 45%, 51%, and 67% in the 10, 20, 40, and 80 mg loratadine-treated subjects, respectively. The onset of action occurred within the first hour. Duration of suppression was dose related, ranging from 12 hours with the lowest dose (10 mg) to 48 hours with the higher doses (40 and 80 mg). Incidence of sedation and other side effects were comparable among all doses of loratadine and placebo.

Adolescent↗
PubMed1986

Suppression of histamine-induced wheal response by loratadine (SCH 29851) over 28 days in man.

Five groups of 12 healthy volunteers each received in double-blind, randomized fashion oral b.i.d. doses of 10, 20, or 40 mg loratadine, 12 mg chlorpheniramine maleate (CTM), or placebo for 28 days. Histamine and saline were injected intradermally into opposite arms at baseline and at specified times following treatment on days 1, 3, 7, 14, 21, and 28. Notable suppression of adjusted wheal formation (histamine-induced minus saline-induced) occurred within two hours after the first dose of each active treatment on day 1. In general, throughout the treatment period, suppression of adjusted wheal formation by all doses of loratadine was significantly greater than by placebo. Suppression by 10 mg loratadine was comparable to CTM, and 20 and 40 mg loratadine were significantly greater than CTM. Suppression of wheal formation by loratadine during the treatment period and during five days posttreatment were dose related. The continued effectiveness of loratadine throughout the 28 days suggests that tolerance to loratadine did not develop in this study. Sedation occurred in 8 of 12 subjects receiving CTM, 1 of 12 receiving 10 mg loratadine, and 1 of 12 receiving placebo.

Adolescent↗
PubMed1985

Pharmacodynamics of intravenous labetalol and follow-up therapy with oral labetalol.

The effectiveness, safety, and pharmacodynamics of repeated doses of intravenous labetalol for rapid reduction of severe hypertension and of subsequent oral labetalol dosing were studied. Twelve patients with severe hypertension were admitted to the hospital after the withholding of antihypertensive therapy for 2 to 14 days. Thirty minutes after an injection of vehicle only, labetalol, 0.25 mg/kg body weight, was injected and followed by repeat injections of 0.5 mg/kg every 15 minutes until the supine diastolic blood pressure (BP) was reduced to less than 90 mm Hg or a total of 3.25 mg/kg had been administered. Twenty-four hours after the last injection, oral labetalol was started at an initial dosage of 100 or 200 mg b.i.d., then increased every 2 days until the standing diastolic BP was less than 90 mm Hg or a maximum daily dosage of 2400 mg was reached. The initial injection achieved mean falls in supine systolic/diastolic BPs of 11/7 mm Hg. Subsequent injections produced additional falls in a dose-related fashion; the mean falls after the last injection (total cumulative dose 2.7 mg/kg) were 40/20 mm Hg. The effect lasted for 12 hours or more in most patients and tended to be biphasic, with one peak at approximately 5 minutes and another much less pronounced peak at about 4 hours. There was no evidence of precipitous falls in BP. All patients were able to ambulate 6 hours after the last injection without symptoms of postural hypotension. Oral labetalol effectively and safely restored and maintained the BP reductions achieved with intravenous labetalol.

Administration, Oral↗