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Biomedical subjects

W Stern

Publications and source records attributed to W Stern.

At least 19 recordsLinked to original sources
PubMed1995

Utility of pharmacodynamic measures for assessing the oral bioavailability of peptides. 1. Administration of recombinant salmon calcitonin in rats.

Salmon calcitonin (sCT) is a therapeutic peptide used in the treatment of Paget's Disease, postmenopausal osteoporosis, and hypercalcemia due to malignancy. In this study, recombinant sCT (rsCT) was administered intravenously (iv), subcutaneously (sc), and intraduodenally (id.) in rats to evaluate pharmacodynamic (PD) response as a measure of rsCT bioavailability (F) and to test the feasibility of delivering rsCT orally. rsCT pharmacokinetics were linear throughout the range of iv and sc doses studied. Following sc administration, F ranged from 11.2% to 23.1% and was linear. The absorption of rsCT after id. administration was low (0.022%); however, a significant lowering of serum calcium concentrations was observed. Serum calcium lowering was nonlinear and saturable after sc administration with the minimum dose required for maximum calcium lowering (Dmin/max) equal to 10.2 ng and a maximal response of 426.8 mg min/dL. Using Dmin/max as the reference dose, absolute Fs were recalculated using PD response after id. administration of 1 and 2 mg of rsCT and were 0.040% and 0.029%, respectively. Substantial overestimates of F were obtained when the reference dose was not properly selected. While the absorption of rsCT was low, the significant lowering of serum calcium levels suggests that oral delivery of sCT is feasible. The results of these studies also suggest that PD response is useful in assessing the oral bioavailability of peptides; however, when PD response is saturable, as is the case for rsCT, the reference dose should be carefully selected in order to avoid overestimates of F.

Administration, Oral↗
PubMed1995

[Dynamic 3D MR mammography using a rapid gradient-echo sequence].

Up to now, MR mammography is performed by two different methods: 2-D techniques with high temporal resolution and 3-D techniques with high spatial resolution. This article investigates whether a dynamic examination of the breast using a novel 3-D-gradient-echo sequence is feasible with sufficient spatial and temporal resolution. MR imaging was performed on a 1.0 Tesla imager using a gradient field strength of 15 mT/m. Phantom measurements were done to evaluate the correlation between signal intensity and contrast medium concentration for different sequences. Subsequently, 40 patients with 22 histologically verified lesions were examined using the double breast coil and a novel FLASH3D sequence (TR/TE/fa 9/3/50 degrees). Reading of the films in standardized documentation, multiplanar reconstruction (MPR), calculation and maximum intensity projection (MIP) of subtraction images as well as signal-to-time curve calculations in selected ROIs were performed for data evaluation. In the phantom measurements the FLASH3D-9/3/50 degrees sequence yielded the best correlation between signal intensity and Gd-DTPA concentration. The sequence provided good visualization even of small lesions. The 3-D postprocessing procedures facilitated the detection and localization of the lesions. Therefore, the new FLASH3D-9/3/50 degrees sequence enables a dynamic 3-D examination of the breast with a sufficient spatial and temporal resolution.

Adolescent↗
PubMed1994

A placebo-controlled evaluation of single, escalating doses of CL 284,846, a non-benzodiazepine hypnotic.

This report describes the first evaluation in humans of CL 284,846, a non-benzodiazepine compound with a preclinical profile indicative of sedative/hypnotic properties. Healthy, normal male volunteers were assigned randomly to receive single oral doses of 1, 5, 15, 30, or 60 mg of CL 284,846 or placebo on a double-blind basis. Observations were made over the subsequent 25 hours to determine the safety, pharmacokinetic profile, and psychometric effects of the test compound. CL 284,846 was well tolerated in the normal volunteers, causing no significant changes in vital signs, EEG, ECG, hematologic, or clinical chemistry laboratory parameters. Although few adverse events were noted at doses less than 60 mg, at the highest dose (60 mg), all volunteers reported transient neurologically related adverse events (e.g., impaired concentration, difficulty focusing, and impaired coordination), reflecting the central nervous system action of the compound. Although determination of hypnotic efficacy was not an objective in this Phase I study, daytime treatment with 60 mg of CL 284,846 was associated with greater reports of drowsiness and impaired performance on psychomotor tests. However, memory, as assessed by a word recall test, was not affected at any dose of the compound. Pharmacokinetic analyses revealed CL 284,846 to be absorbed and eliminated rapidly (Tmax = 0.9-1.5 hr, T 1/2 = 0.9-1.1 hr), with a dose-proportional AUC (area under cure). Plasma levels of CL 284,859, the primary desethylated metabolite of CL 284,846, were much lower in humans than in other species, indicating that the metabolism of CL 284,846 in humans may differ from that of rodents and dogs. Overall, CL 284,846 was well tolerated, and the authors recommend repeating dose safety and pharmacokinetic studies in healthy volunteers.

Acetamides↗
PubMed1993

Vitrectomy with silicone oil or perfluoropropane gas in eyes with severe proliferative vitreoretinopathy. Silicone Study Report 3.

Between 1985 and 1990, 340 eyes with rhegmatogenous retinal detachment (RRD) and severe (stage C3 or worse) proliferative vitreoretinopathy (PVR) were treated with vitrectomy and randomly selected to receive perfluoropropane gas or silicone oil; 183 eyes had undergone no prior vitrectomy (group 1), and 157 eyes had undergone prior vitrectomy with intraocular gas tamponade (group 2). No differences were found between eyes in the two groups in achieving visual acuity of 5/200 or better (44% vs. 39%), macular reattachment (78% vs. 77%), or complete retinal reattachment (67% for both groups). In group 1, 74 eyes achieved complete retinal reattachment after only one operation; 41 additional eyes achieved reattachment after a second surgical procedure. In group 2, these numbers were 74 and 26, respectively. Eyes treated successfully after more than one operation were less likely to regain a visual acuity of 5/200 or better than those successfully treated with one operation (P < 0.01). There was no difference in hypotony between groups, but keratopathy was more frequent in eyes in group 2 (P < 0.05). The results suggest that differences in outcomes between group 1 and group 2 eyes are not as great as previously believed.

Adult↗
PubMed1992

Use of an indwelling Doppler probe to study acute changes in umbilical vein waveforms in the fetal sheep.

A chronic sheep model for Doppler umbilical vascular analysis with indwelling probes was used for the investigation of umbilical vein velocity waveforms. Maternal aortic occlusions produced a delayed drop but never eliminated umbilical vein velocity. With umbilical cord occlusion, there was immediate umbilical vein waveform response. Sudden cord occlusion and release showed reactive venous overflow velocity at the beginning and end of occlusion. Total cord occlusion produced zero velocity, but within seconds, the flow velocity was seen despite persistent occlusion in 65% of the cases. A characteristic undulating venous waveform pattern synchronous with fetal heart rate in over half of the cases was often observed. Reduction of blood flow by uteroplacental insufficiency may be differentiated from umbilical cord occlusion.

Animals↗
PubMed1991

Accumulation of pepstatin in cultured endothelial cells and its effect on endothelial processing.

Aspartic acid proteases have been implicated in the processing of ET-1(1-39) to ET-1(1-21). To further understand the role of this class of enzymes in ET-1 synthesis, cultured vascular endothelial cells were incubated with pepstatin, and the accumulation of the inhibitor and its effect on the processing of ET-1(1-39) was examined. Pepstatin accumulated in the cells in a time-dependent manner, to a concentration (greater than 10(-7) M) sufficient to inhibit aspartic acid proteases. Pepstatin did not alter the ratio of ET-1(1-21) to ET-1(1-39), nor did it affect the rate of secretion of either peptide. When endothelial cells were incubated with phosphoramidon under identical conditions, the secretion of ET-1(1-21) was significantly reduced with a concomitant increase in the secretion of ET-1(1-39). These results suggest that the processing of ET-1(1-39) does not involve a pepstatin-sensitive aspartic acid protease, and that the enzyme responsible for generating ET-1(1-21) is sensitive to phosphoramidon.

Amino Acid Sequence↗
PubMed1991

Methods, statistical features, and baseline results of a standardized, multicentered ophthalmologic surgical trial: the Silicone Study.

This article describes the trial design and baseline results for the Silicone Study, a multicenter, randomized surgical trial designed to compare the effectiveness of silicone fluid versus long-acting gas in the treatment of proliferative vitreoretinopathy (PVR). Design features include (1) standardization of the surgical protocol to reduce intersurgeon variability, (2) formulation of a PVR clinical classification system relevant to modern vitreoretinal surgery, and (3) creation of a photographic protocol to document PVR pathology. Statistical issues affecting the analysis of the outcome data include (1) the addition of a second group of patients with more severely diseased eyes after the trial began, (2) the change to a different long-acting gas during the course of the trial, and (3) recurrent retinal detachments that require reoperations with the randomized treatment, and, in some instances, a crossover from the randomized to the alternate treatment. Demographic and baseline ocular characteristics are presented for the two groups under study.

Adult↗
PubMed1990

[Complications of central venous catheterization from an anatomical point of view].

For access to the central venous system numerous percutaneous methods and approaches exist. Questions are often raised concerning which approach is the safest. In 18 human cadavers, we punctured the internal jugular vein via an anterior and posterior approach and the subclavian vein via an infraclavicular route to determine which of these approaches is better with respect to success rate and frequency of puncture complications. The position of the needles was assessed by dissection. Successful venipunctures were achieved in 81% by the posterior approach, as opposed to 58% by the anterior approach and the infraclavicular route. The lowest frequency of complications was attained by the posterior approach (17%) too, whereas the anterior approach (33%) and the subclavian route (25%) had higher complication rates. The main complication of posterior and anterior approaches was inadvertent arterial puncture (9 vs. 19%). At the subclavian approach puncture of a 'wrong' vein was frequent (14%), and the complications included a case of pleura lesion. In conclusion the posterior approach to the internal jugular vein is superior to the other investigated approaches, and therefore, it can reasonably be proposed as a usual route for the insertion of a central venous catheter.

Aged↗
PubMed1989

The use of an indwelling Doppler probe to study acute changes in umbilical artery waveforms in the fetal sheep.

A chronic sheep model for Doppler umbilical vascular analysis was developed, in which indwelling Doppler probes were used. These were designed with a fixed angle of insonation and implanted directly on the umbilical cord to register umbilical artery velocity waveforms. The fetuses in eight pregnant ewes underwent maternal aortic and umbilical cord constrictions producing serial blood flow reductions. Occlusion of the umbilical cord and maternal aorta caused distinctly different waveforms. Cord occlusion produced an immediate response with an elevated systolic/diastolic ratio and disappearance of diastolic velocity. Maternal aortic occlusion produced a delayed response with drops in both systolic and diastolic velocity; diastolic velocity never reached zero. Although systolic/diastolic ratios are believed to reflect placental resistance, the maintenance of the systolic/diastolic ratio with diminution of systolic velocity suggests declining fetal cardiac output as an additional factor. It is possible to differentiate uteroplacental from umbilicoplacental insufficiency by Doppler methods. With technologic improvements Doppler ultrasonography may allow better analysis of acute stressful conditions during human labor.

Animals↗
PubMed1989

The validity and reliability of photographic documentation of proliferative vitreoretinopathy.

The Silicone Study is a multicentered, randomized surgical trial designed to compare the tamponade effectiveness of silicone oil versus long-acting gas in the treatment of proliferative vitreoretinopathy (PVR) by vitrectomy and associated techniques. Fundus photographs are taken to provide documentation of the anatomic status of eyes proposed for entry and are graded at an independent Reading Center. This article describes the protocol for photographic documentation of PVR as a continuum of increasing pathology, in which the pathology may only be present in the anterior retina, and the retina is usually highly elevated. In a validity and reliability study, agreement between photographic and clinical observation within one step was obtained for 88% of the eyes; intra- and inter-observer agreement within one step was 85 and 80%, respectively. Differences between the surgeon's grade and the Reading Center's were caused about equally by disagreement regarding extent of fixed folds and width of the funnel. Rarely did peripheral folds not visible in the photographs appear to be the sole explanation of the disagreement. Differences among readers were concerned mainly with differentiation of true full-thickness fixed folds from folds due to simple redundancy of the detached retina. These results demonstrate that complicated retinal detachment (RD) can be photographically documented and independently assessed.

Clinical Trials as Topic↗
PubMed1987

Geography, drinking water chemistry, pesticides and herbicides and the etiology of Parkinson's disease.

In 1984 we made the first observation of a correlation between early age exposure to rural environment (and drinking well water) and development of idiopathic Parkinson's disease (IPD). These findings were subsequently confirmed elsewhere (Barbeau, 1985;25 Tanner, 1985). Analysis of all early age onset IPD (EPD) cases born and raised in Saskatchewan revealed that 20 of 22 had exclusively rural exposure during the first 15 years of life. This distribution was significantly different from the general population (p = 0.0141). Further study of the EPD group included sampling and metal analysis of childhood sources of drinking water in 18 cases and 36 age and sex-matched controls. Water collected from the two groups was analyzed for 23 metals (including 7 elements implicated in the etiology of IPD). There was no difference in the metal composition of the water between the two groups. Finally, a review of herbicide and pesticide use in Saskatchewan agriculture was undertaken to determine if there was an increased incidence of EPD following utilization of any particular chemical. No increase was found in the incidence of EPD with the introduction of any pesticide or herbicide, including Paraquat, for agricultural use. We conclude that there is a strong correlation between early age rural environmental exposure and development of IPD. We believe well water is a likely vehicle for the causal agent, but neither water metal concentration nor any of the herbicides and pesticides used in Saskatchewan agriculture are related to the cause.

Adult↗
PubMed1986

Early onset Parkinson's disease in Saskatchewan--environmental considerations for etiology.

The cause of idiopathic Parkinson's Disease (PD) is not known but it is believed to be related to some environmental agent(s). Given a long preclinical interval and onset of symptomatology around age 60 years, it becomes impossible to identify and analyze all prior environmental factors satisfactorily. To circumvent these difficulties we evaluated the childhood environment in those PD patients whose symptoms began at age 40 years or earlier. Twenty-one such cases were born and raised in the province of Saskatchewan. Nineteen of these 21 patients spent the first 15 years of life exclusively in rural Saskatchewan. Detailed population analysis indicates a strong predisposition to early onset idiopathic Parkinson's Disease (EPD) in those raised in rural areas (p = 0.0154). All but one case utilized exclusively well water for the first 15 years of life--a trait significantly different from that expected in the provincial population. It is concluded that rural Saskatchewan environments contribute to EPD and that well water used in childhood should be considered as a potential vehicle for the etiological agent.

Age Factors↗
PubMed1986

Double-blind comparison of doxepin versus bupropion in outpatients with a major depressive disorder.

A double-blind controlled study comparing the effects of bupropion to doxepin in outpatients with primary depression was conducted to evaluate efficacy and safety differences between the two drugs. Following a 7-day placebo washout period, patients could be treated for up to 13 weeks on either treatment. Antidepressant response was assessed by the Hamilton Depression and Anxiety Scales, Clinical Global Severity and Improvement Ratings, and the Zung Self-Rating Depression Scale. Comparable efficacy between the compounds was found across the 13-week study. Doxepin differed from bupropion mainly on the sleep factor of the Hamilton Depression Scale, with doxepin improving sleep to a greater extent than bupropion. Doxepin produced a greater incidence of anticholinergic side effects, including dry mouth, constipation, sleepiness, and tiredness, in comparison to bupropion. Also, increased appetite and weight gain were consistent side effects of doxepin relative to bupropion.

Adult↗