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Biomedical subjects

L T Friedhoff

Publications and source records attributed to L T Friedhoff.

32 records · Page 2Linked to original sources
PubMed1986

Quantitation of drug levels and platelet receptor blockade caused by a thromboxane antagonist.

SQ 28,668 is a structural analog of thromboxane A2. It inhibits the effects of thromboxane in vitro. Fifty-six healthy male subjects were given either placebo or three equal daily doses of SQ 28,668 ranging from 25 to 1200 mg. Plasma drug concentrations increased in a dose-dependent manner. The shape of the plasma drug concentration-time curve was consistent with enterohepatic recirculation. The effects of SQ 28,668 on ex vivo platelet aggregation suggested that SQ 28,668 is a specific competitive antagonist of thromboxane A2 with a platelet receptor dissociation constant (estimated by Schild analysis) of about 19 nmol/L. Approximately 94% occupation of thromboxane receptors by SQ 28,668 was required to produce a small but measurable increase of the template bleeding time. Dose-ranging studies of antithrombotic drugs are difficult and expensive. For this reason, a method was developed that allows estimation of the dose of a thromboxane receptor antagonist that would be expected to be therapeutically equivalent to a given dose of aspirin.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

Aztreonam penetration into synovial fluid and bone.

Eighteen patients with uncomplicated degenerative joint disease requiring joint replacement (hip or knee) were given a single 2-g intravenous dose of aztreonam over a 5-min period preoperatively. The mean concentration in synovial fluid of 83.0 +/- 9.2 micrograms/ml averaged 0.99 times the concomitant levels in serum. The mean concentration in cancellous bone of 16.0 +/- 4.3 micrograms/g averaged 0.20 times the concomitant levels in serum.

Adult↗
PubMed1986

Aztreonam concentration in abdominal tissues and bile.

Abdominal tissue, serum, and bile samples were obtained from 37 patients given a single, 2-g intravenous infusion of aztreonam immediately prior to an elective abdominal operation. Samples were obtained at 0 to 6 h after dosing. Mean concentrations in tissues and fluids and specimen/serum rations are reported. Levels in tissue and bile exceeded the reported MICs for 90% of most members of the family Enterobacteriaceae for up to 6 h.

Abdomen↗
PubMed1986

Aztreonam concentrations in human tissues obtained during thoracic and gynecologic surgery.

The concentrations of aztreonam in human tissues obtained during surgery were measured after a single 2-g intravenous dose. The average concentration in the skeletal muscle, atrial appendage, lung, sternum, pericardial fluid, endometrium, myometrium, fallopian tube, and ovary varied from 3 to 33 micrograms/g (or microgram/ml). These concentrations significantly exceed the MIC for 90% of strains for most members of the family Enterobacteriaceae.

Aged↗
PubMed1985

Penetration of aztreonam into human cerebrospinal fluid in the presence of meningeal inflammation.

Cerebrospinal fluid of aztreonam were measured in 11 patients with meningeal inflammation. Two to eight hours after a single 2 gm intravenous dose, CSF aztreonam levels ranged from 0.76 to 16.6 mg/l. The mean CSF concentration in four patients with viral meningitis was 1.28 mg/l, which was lower than the mean concentration of 7.2 mg/l in the five with bacterial, cryptococcal or carcinomatous meningitis. Two patients with infected subdural drains were also sampled serially and had CSF levels greater than 1 mg/l between 1 and 8 h post dose. Penetration of aztreonam into the CSF in the presence of meningeal inflammation appears adequate to warrant therapeutic trials in patients infected with susceptible organisms.

Adult↗
PubMed1985

Penetration of aztreonam into human bronchial secretions.

Nine intubated patients were given a single, 2-g intravenous dose of aztreonam over 5 min. Samples of serum and bronchial secretion were obtained 2, 4, and 8 h after administration and assayed for aztreonam content. The mean concentrations in bronchial secretion ranged from 1.9 to 5.2 micrograms/ml and tended to be highest at 4 h. The concentrations in bronchial secretion varied from patient to patient, but each patient had one or more bronchial secretion samples that contained at least 2.7 micrograms of drug per ml.

Adult↗
PubMed1984

Aztreonam concentrations in human prostatic tissue.

The concentrations of aztreonam in human prostatic tissue specimens obtained by transurethral resection were measured in nine patients after the intramuscular administration of a single 1-g dose. The average concentration of aztreonam was 7.8 microgram/g of prostate between 50 and 180 min after dosage. The average ratio of the drug concentration in prostate to that in serum was 0.25. The concentrations of aztreonam achieved were significantly higher than the MICs for most members of the family Enterobacteriaceae implicated in chronic prostatitis.

Adult↗
PubMed1983

The effect of ion channels on cell membrane motion.

Cell membranes possess ion channels and pumps which allow them to pass electrical currents. In this paper it is shown that the ion channels and pumps should induce electric fields in the area surrounding the membrane. The magnitude of this field is computed. It is shown that when the channels and pumps are separated by a sufficient distance, then the electric fields which they induce will cause the solution which surrounds the membrane to move. This movement of the fluid should cause motion of the membrane. Thus it is demonstrated that under certain conditions the conductance of ions across cell membranes will give rise to cell membrane motion. It is suggested that this phenomenon may play a role in processes such as chemotaxis, cell division, and pinocytosis.

Cell Membrane↗
PubMed1983

The membrane potential of human platelets.

The membrane potential of the human platelet was investigated using the membrane potential probes 3,3'-dipropyl-2,2'-thiadicarbocyanine iodide and tritiated triphenylmethylphosphonium bromide. The membrane potential in physiologic buffer was estimated to be 52-60 mV inside negative. The membrane was depolarized when extracellular potassium or hydrogen ion concentrations were increased. Changes in extracellular sodium, chloride, or calcium ion concentration had no measurable effect on membrane potential. Elevated extracellular potassium has been shown to increase platelet sensitivity to the aggregating agent, adenosine diphosphate. Our results show that changes in extracellular ion concentrations that depolarize platelets increase platelet sensitivity to aggregating agents. These results suggest that membrane potential changes may play a role in modulating the response of platelets to aggregating agents.

Benzothiazoles↗
PubMedDate not supplied

Single-dose pharmacokinetics of aztreonam in children with cystic fibrosis.

The single-dose pharmacokinetics of aztreonam was evaluated in 10 clinically stable subjects with cystic fibrosis. Each child received 30 mg aztreonam/kg intravenously over 2 to 3 minutes. Multiple timed blood samples were obtained over 8 hours for determination of aztreonam elimination kinetics; all urine excreted for 24 hours was collected in timed aliquots for the determination of aztreonam and its microbiologically inactive metabolite, SQ 26,992. Aztreonam pharmacokinetic parameters were determined by model-independent methods. Mean t1/2, steady-state volume distribution, and body clearance were 1.3 hr, 0.25 L/kg, and 127.2 ml/min/1.73m2, respectively. In 9 of the 10 subjects, two-compartment pharmacokinetic analysis was possible and compared favorably with model-independent parameter estimates. Twenty-four-hour urinary recovery of aztreonam was 76.3% of the administered dose; 2.6% was recovered as the metabolite SQ 26,992. The renal clearance of aztreonam averaged 92.5 ml/min/1.73m2. When these data are combined with in vitro susceptibility data for aztreonam against Pseudomonas aeruginosa isolated from the sputum of patients with cystic fibrosis, a dose of 200 mg aztreonam/kg/day divided six hourly would be predicted to maintain serum concentrations above the minimum inhibitory concentration (MIC) for these organisms for the majority of the dosing interval.

Adolescent↗
PubMedDate not supplied

The effects of donepezil in Alzheimer's disease - results from a multinational trial.

Donepezil has been shown to be well tolerated and to improve cognition and global function in patients with mild to moderately severe Alzheimer's disease (AD). The current trial was undertaken to investigate further the efficacy and safety of donepezil, in a multinational setting, in patients with mild to moderately severe AD. This 30-week, placebo-controlled, parallel-group study consisted of a 24-week, double-blind treatment phase followed by a 6-week, single-blind, placebo washout. Eight hundred and eighteen patients with mild to moderately severe AD were randomly allocated to treatment with single, daily doses of 5 or 10 mg donepezil, or placebo. The two primary efficacy measures were: a cognitive performance test, the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and a global evaluation, the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC plus). Secondary outcome measures included the Sum of the Boxes of the Clinical Dementia Rating Scale (CDR-SB), a modified Interview for Deterioration in Daily living activities in Dementia (IDDD) and a patient rated quality of life assessment. Statistically significant improvements in cognitive and global function were observed, as evaluated by ADAS-cog and CIBIC plus, respectively, in both the 5 and 10 mg/day donepezil groups, compared with placebo. Treatment-associated changes were also observed in functional skills, as shown by improved scores on the CDR-SB and the complex-tasks component of the IDDD. A dose-response effect was evident, with the 10 mg/day donepezil group demonstrating greater benefits in all outcome measures than the 5 mg/day group. Donepezil was well tolerated by this patient population and did not produce any clinically significant laboratory test abnormalities. The results of this study confirm that donepezil is effective and well tolerated in treating the symptoms of mild to moderately severe AD.

Aged↗
PubMedDate not supplied

The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US Multicentre, Randomized, Double-Blind, Placebo-Controlled Trial. The Donepezil Study Group.

This study evaluated the efficacy and safety of donepezil in patients with mild to moderately severe Alzheimer's disease, and examined the relationships between plasma donepezil concentration, red blood cell acetylcholinesterase (AChE) activity and clinical response. The trial was of a multicenter, double-blind, parallel-group design and patients were randomised to once-daily treatment with either donepezil (1, 3 or 5 mg) or placebo. The 12-week double-blind phase was followed by a 2-week single-blind placebo washout. 161 patients (55-85 years of age) entered the study and 141 completed treatment. Patients treated with donepezil showed dose-related improvements in the Alzheimer's Disease Assessment Scale-cognitive subscale score (ADAS-cog) and in MMSF scores. The improvements in ADAS-cog were statistically significantly greater with donepezil 5 mg/day than with placebo. There was a 50% reduction in the percentage of patients showing clinical decline with donepezil at 5 mg/day (11%) relative to placebo (20%). In addition, a statistically significant correlation between plasma concentrations of donepezil and AChE inhibition was demonstrated. A plateau of inhibition (76-84%) was reached at plasma donepezil concentrations > 50 ng/ml. The correlation between plasma drug concentrations and ADAS-cog (p = 0.014), MMSE (p = 0.023) and patient quality of life scores, assessed by the patient (p = 0.037) were also statistically significant, as was the correlation between AChE inhibition and change in ADAS-cog (p = 0.008). The incidence of treatment-emergent adverse events with all three dosages of donepezil (64-68%) was comparable to that observed with placebo (65%). Donepezil had no clinically significant effect on vital signs, haematology or clinical biochemistry tests. Importantly, donepezil was not associated with any hepatotoxicity, as observed with acridine-based cholinesterase inhibitors.

Acetylcholinesterase↗
PubMedDate not supplied

Serotonin induced platelet aggregation in systemic sclerosis.

We studied in vitro platelet aggregation response to serotonin in 19 patients with systemic sclerosis and 18 matched controls. Individuals with early systemic sclerosis had increased % platelet aggregation at 3 minutes over a wide range of serotonin concentrations when compared to individuals with late systemic sclerosis. Patients with generalized disease did not differ from those with limited disease. No significant differences in initial slope of platelet aggregation were detected in any patient subgroup. These data support previous studies suggesting platelet activation in systemic sclerosis and further suggest that future studies of platelet abnormalities in systemic sclerosis should consider the effects of disease duration.

Adult↗