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Biomedical subjects

M H Silverman

Publications and source records attributed to M H Silverman.

10 recordsLinked to original sources
PubMed2004

Safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men.

AIMS: To assess the safety, tolerability and pharmacokinetics of subcutaneous A6, an 8-amino acid peptide with anti-angiogenic properties, in healthy men. METHODS: Double-blind, placebo-controlled, parallel-group, dose-rising, phase I study of single and repeated doses. In the single dose phase, successive groups of 5 subjects received A6 15, 35, 75, 150, 300 mg, or placebo, as subcutaneous injections in the upper thigh. In the repeat dose phase, 2 groups of 6 subjects received repeat doses of A6 35 mg and 75 mg, or placebo, and 1 group of 5 subjects received 150 mg, or placebo, 12-hourly for 6 days (11 doses in total). In each group, 4 subjects received active treatment, the remainder placebo. Pharmacokinetics of A6 were assessed up to 24 h after single doses, for 12 h after the first of the repeated doses, and up to 24 h after the last of the repeated doses. MATERIALS: A6 for subcutaneous injection in phosphate buffer, pH 5.6-6.0. Phosphate-buffered saline was used as placebo. RESULTS: All dose regimens of A6 were safe and well-tolerated, both systemically and locally. Time to peak plasma concentration was similar (0.5-2.1 h) in all dosage groups. Cmax and AUC(0-inf) were linearly proportional to dose. Mean Cmax ranged from 454-10,333 ng/ml and mean AUC(0-inf) from 1,690-43,371 ng x h/ml after the 15 and 300 mg single doses, respectively. Terminal t(1/2) was 1.4-1.8 h, and there was no evidence of unexpected drug accumulation. Urinary excretion of unchanged A6 was 94.6% (SD 20.7) after the 300 mg single dose (0-24 h collection), and 78.4% (SD 13.0) after the 150 mg repeated dose (0-12 h collection). A6 did not trigger production of anti-A6 IgG antibodies within 14 days of the first dose. CONCLUSION: Single doses of A6 up to 300 mg, and repeated doses up to 150 mg, were well-tolerated and safe in healthy young men. A6 was rapidly absorbed; it was eliminated, mainly unchanged, in urine. Plasma concentrations were dose-proportional. A6 did not trigger an early immunogenic response.

Adolescent↗
PubMed2004

Tolerability, pharmacokinetics and concentration-dependent hemodynamic effects of oral CF101, an A3 adenosine receptor agonist, in healthy young men.

OBJECTIVES: To assess safety, tolerability, pharmacokinetics and hemodynamic effects of oral CF 101, an A3 adenosine receptor (A3AR) agonist, in healthy men. METHODS: One single and 1 repeated dose, parallel-group, ascending dose, double-blind and placebo-controlled study in normal volunteers. In the single dose study, n = 15 subjects received 1, 5 or 10 mg oral CF101; in each group 1 subject received placebo, the remainder active CF101. In the repeat-dose study, n = 28 subjects received repeated 12-hourly oral doses of CF 101 (2, 3, 4 or 5 mg) for 7 days, in each group 2 subjects received placebo, the remainder active CF101. TEST MATERIALS: Single-dose study: CF101 in 30% Cremophor RH40. Multiple-dose sudy: CF101 in 0.5% methylcellulose suspension. Both studies: the corresponding vehicles were used as placebos. Galenicals were prepared remotely from the clinical study site to ensure double-blind nature of the study. RESULTS TOLERABILITY: Single doses up to 5 mg CF101 were safe and well-tolerated. However, the single dose of 10 mg CF101 was associated with flushing, tachycardia, nausea and vomiting, which were viewed as dose-limiting in normal volunteers. Single doses of CF101 (as well as the first of the multiple doses) were associated with increases in heart rate (8 - 24 beats/min after 5 mg and 18 - 55 beats/min after 10 mg). Multiple doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. However, the 5 mg multiple-dose group reported headache, drowsiness, hot flushes and dizziness on standing; this declined with dosing duration and was not dose-limiting in this study. Adverse events were commonest near t(max). RESULTS PHARMACOKINETICS: For oral CF101, the t(max) was always 1 - 2 h post-dose and t 1/2 about 9 h, in both the single- and multiple-dose studies. For a single 5 mg dose (mean +/- SD) C(max) = 81.6 +/- 23.6 ng/ml in the single dose study, and 63.6 +/- 22.0 ng/ml after the first of the multiple doses; AUC if was 904.0 +/- 221.9 ng.h/ml and 596.1 +/- 196.6 ng.h/ml for the 2 studies, respectively. After 7 days of multiple dosing there was little change, and AUC(0-24h) = 601.0 +/- 163.6 ng.h/ml. These pharmacokinetic parameters were linearly proportional to dose in the other treatment groups. RESULTS PHARMACODYNAMICS: Increases in heart rate were related to plasma concentration and evident only in the upper range of concentrations observed. There were no changes on ECG monitoring beyond sinus tachycardia, and, in particular, no evidence of PR prolongation in any subject (n = 43). In comparison with single doses, this response was almost absent after 7 days of dosing. Leucocytosis (increases up to about 1.5 x 10(9)/l after 5 and 10 mg) was similarly transient and reversible after multiple dosing. CONCLUSIONS: Single oral doses up to 5 mg CF101 and repeated doses up to 4 mg 12-hourly for 7 days were safe and well-tolerated. Multiple-dose CF101 pharmacokinetics were unchanged and predictable from single-dose estimates, and were linearly proportional to dose. Increases in heart rate and neutrophil count were reversible during multiple dosing and were not dose-limiting in the repeat dose study. CF101 warrants further study for its efficacy in treating human disease.

Adenosine↗
PubMed1993

Pilot trial of cyclosporine 1% ophthalmic ointment in the treatment of keratoconjunctivitis sicca.

This trial was a randomized, double-masked, crossover study during which patients with keratoconjunctivitis sicca underwent 6 weeks of treatment with either cyclosporine 1% ophthalmic ointment or placebo followed by 6 weeks of the alternative treatment. Washout periods using only unpreserved artificial tears preceded both treatment cycles. Twenty-five patients completed the first treatment period, but only eight met entry criteria for period II. Cyclosporine ointment was associated with initial mild to moderate redness, itching, and burning that returned to baseline levels within 1-2 weeks. Rose Bengal results and results of four subjective (patient diary) efficacy parameters favored cyclosporine: foreign body sensation, overall symptoms, hours of symptom control per day, and overall effectiveness. No systemic adverse events or laboratory abnormalities occurred. We conclude that (a) the crossover design is inappropriate for studying this disease; (b) mild to moderate itching, redness, and burning occur initially with cyclosporine administration, although tolerance quickly develops; (c) cyclosporine appears to benefit the ocular surface in keratoconjunctivitis sicca; and (d) further trials in this syndrome are warranted.

Adult↗
PubMed1991

Safety and tolerability of two percent cyclosporine (Sandimmune) ophthalmic ointment in normal volunteers.

Thirty-six healthy male volunteers were enrolled in two sequential double-masked, placebo-controlled trials with the objective of assessing the safety and local tolerability of 2% cyclosporine ophthalmic ointment. Subjects were randomly assigned to active or placebo groups and dosed once, twice, or thrice daily for 14 days. Safety and tolerability were assessed through patient interviews, ophthalmologic examinations, routine laboratory testing, and blood cyclosporine assays. Relative to placebo, cyclosporine ointment was associated with higher frequencies of ocular burning, tearing, redness, itching, and headache. These intolerances were dose-related and reported predominantly in the TID group; QD and BID cyclosporine ophthalmic ointment were better tolerated than the placebo control. Symptoms were usually mild, were reported only once beyond Day 2 in the QD-BID groups, and never required interruption of the study. Transitory, asymptomatic, and unexplained elevations of serum transaminases were seen in five subjects in the first study, but were not confirmed in the second and are not felt to be drug-related. Cyclosporine blood levels were uniformly below the limits of detection. We conclude that the tolerability profile of 2% cyclosporine ointment, dosed once or twice daily in normal volunteers, is acceptable and supportive of trials in patient populations.

Adult↗
PubMed1990

Randomized, controlled trial of a 10-day course of amifloxacin versus trimethoprim-sulfamethoxazole in the treatment of acute, uncomplicated urinary tract infection. Amifloxacin Multi-Center Trial Group.

We conducted a randomized controlled trial of orally administered amifloxacin versus trimethoprimsulfamethoxazole (TMP-SMX) as treatments of acute uncomplicated urinary tract infection in women. Amifloxacin at a dosage of 200 mg twice a day appeared as safe and effective as TMP-SMX, but amifloxacin at 400 mg twice a day tended to cause adverse events more frequently than did TMP-SMX.

Administration, Oral↗
PubMed1990

Preliminary study of the pharmacokinetics of oral amifloxacin in elderly subjects.

Amifloxacin pharmacokinetics after a single oral dose in healthy elderly subjects were determined. Five males and five females aged 65 to 79 years and having creatinine clearances of 39.3 to 87.2 ml/h per kg of body weight were given a 200-mg amifloxacin caplet following an overnight fast. Mean (standard deviation) pharmacokinetic parameters for amifloxacin were as follows: maximum observed concentration in plasma, 1.13 (0.48) and 1.95 (0.52) micrograms/ml; half-life, 5.37 (0.96) and 4.47 (0.87) h; total plasma clearance (unadjusted for fraction absorbed), 259 (53) and 199 (55) ml/h per kg; renal clearance, 113 (20) and 86 (26) ml/h per kg; Varea/F (Varea is volume of distribution; F is fraction absorbed), 2.05 (0.75) and 1.28 (0.39) liter/kg; and amifloxacin excreted in the urine, 42.5% (14.5%) and 42.8% (10.6%) for males and females, respectively. There were no statistically significant differences in pharmacokinetic parameters between sexes that could not be attributed to differences in body weight. Except for a modest 23% reduction in renal clearance and the suggestion of reduced bioavailability, mean values of pharmacokinetic parameters for elderly male subjects were similar to those previously determined for younger male volunteers. Therefore, a modification in amifloxacin dosage regimen based solely on age may not be necessary.

Adult↗
PubMed1990

Multiple-dose pharmacokinetics and safety of oral amifloxacin in healthy volunteers.

The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (q12h) and 400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was administered on day 11. Concentrations of amifloxacin in plasma and urine were measured on days 1, 5, and 11 by high-performance liquid chromatography. Steady-state amifloxacin concentrations were reached by day 5. Mean +/- standard deviation maximum observed amifloxacin concentrations in plasma were 2.52 +/- 1.12, 4.98 +/- 1.44, 5.40 +/- 2.02, 4.59 +/- 2.17, 6.53 +/- 2.44, and 8.01 +/- 3.00 micrograms/ml after the initial dose and 2.30 +/- 0.98, 5.41 +/- 0.74, 8.05 +/- 1.68, 6.87 +/- 2.81, 9.53 +/- 0.50, and 11.9 +/- 1.92 micrograms/ml on day 11 of the study for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. Amifloxacin was rapidly absorbed, as evidenced by the mean time to the maximum observed amifloxacin concentration of 0.98 h. Mean values for the terminal amifloxacin half-life in plasma ranged from 3.58 to 5.78 h. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 micrograms/ml for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Amifloxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointestinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically significant adverse reactions, including pruritus and transaminase elevations, occurred only at doses of 1,200 mg/day or above. Clinical and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinary tract infections.

Administration, Oral↗
PubMed1984

Polyarteritis nodosa associated with ulcerative colitis.

Three months after colectomy for severe ulcerative colitis, an 18-year-old male presented with a multisystem illness characterized by fever, arthralgias, hypertension, and declining renal function. A diagnosis of polyarteritis nodosa was made histologically and confirmed angiographically. Clinical and pathological findings suggest that the patient had 2 separate illnesses. Potential implications of this unique association are briefly discussed.

Adolescent↗
PubMed1978

The kidney in progressive systemic sclerosis: a prospective study.

Nine normotensive progressive systemic sclerosis patients with normal renal function underwent renal biopsy. Four specimens had prominent vascular abnormalities, two mild vascular abnormalities, and three were normal. Vascular deposits of C3 were present in all specimens. Plasma renin activity was elevated in three of four patients with prominent vascular abnormalities, one of two patients with mild vascular lesions, and none of two patients with normal biopsies. Plasma renin activity elevation in response to cold pressor testing in the four patients with prominent vascular lesions was 5.6 ng/ml.h compared to 0.55 ng/ml.h in those with mild or no lesions and 0.26 ng/ml.h in six control subjects. These data indicate that renal vascular lesions may be present in normotensive patients. Elevation or a substantial rise in plasma renin activity (1.8 ng/ml.h or greater) in response to cold pressor testing suggests preclinical renal involvement.

Adult↗