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Biomedical subjects

A Hoffman

Publications and source records attributed to A Hoffman.

At least 91 records · Page 5Linked to original sources
PubMed1997

Modeling of drug release from erodible tablets.

A general mathematical model was developed to describe drug release from erodible tablets undergoing surface erosion. The model (which is based on the Hopfenberg equation) takes into account the three dimensions of a tablet dosage form. The model enables the characterization of the release kinetics by one or two erosion rate constants depending on the hydrodynamic conditions of the system. The model can be used to compare the release rates of the drug within different batches produced under different conditions. The model was utilized to evaluate some factors affecting the release rate from erodible tablets consisting of hydroxypropyl methylcellulose and amoxicillin. The release data of amoxicillin measured from the whole tablet followed the equation developed. Amoxicillin release data measured from the planar surface of the tablet appeared to follow zero-order kinetics as predicted by theory for drug release from an erodible device maintaining constant surface area with time.

Amoxicillin↗
PubMed1997

Managed care and the cystic fibrosis patient.

Since the first published report of mortality in cystic fibrosis in 1969, the median survival among cystic fibrosis patients has risen from 14 to 31 years. The reasons for this improved survival are complex and include earlier diagnosis; improved control of pulmonary infection; aggressive nutritional intervention; and enhanced monitoring of patients in peer-reviewed, accredited centers for cystic fibrosis care, teaching, and research. Emphasis on the importance of research on changing and improved treatment has been effectively communicated to patients and families. As a result, a group of highly educated medical consumers has been created. During the last decade, another focus of rapid change has appeared, that of cost containment in the medical profession, creating the field of managed care. Practicing medical professionals perceive the need for reduction in excessive spending in medicine and have taken a variety of approaches to balance better the value and cost of medical care while maintaining superb quality. Physicians and consumers continue to have concerns about the potential negative impact of managed care on a relatively rare, specialized, and chronic illness such as cystic fibrosis if managed care concepts are applied without proper understanding of the disease. A great concern is that managed care in cystic fibrosis may cause reversal of trends in improved quality and length of survival. The increased length of survival places an increasing demand on the already stressed system of health care financing. Understanding the changing area of managed care is therefore of paramount importance to clinicians involved in cystic fibrosis care. The Cystic Fibrosis Foundation has presented symposia on managed care at each of the last three annual meetings, including the North American Cystic Fibrosis Meeting, October 1996. The following issues were addressed by speakers and panel discussants, with portions excerpted for this review: trends in managed care, measures and guidelines useful in managed care, Medicaid managed care and cystic fibrosis, and practical aspects of using pathways in caring for patients with cystic fibrosis.

Critical Pathways↗
PubMed1997

Pharmacokinetic considerations of new insulin formulations and routes of administration.

There is a continuing search for improved insulin formulations in order to imitate as closely as possible the physiological pattern of insulin secretion, and thereby to minimise the complications of diabetes mellitus. The major advances achieved to date are in the area of human insulin analogue synthesis resulting from the introduction of recombinant DNA techniques, and in improved delivery systems that utilise noninvasive or minimally invasive modes of administration. To accommodate postprandial hyperglycaemia, monomeric insulin formulations have been developed, of which insulin lispro (the Lys-Pro analogue) is already approved for clinical use. These formulations have a rapid rate of absorption and, therefore, have to be administered at meal time (unlike the previous short-acting formulations). Their residence time is also about 2-fold shorter than regular human insulin; this minimises the risk of the excessive hypoglycaemic effect that characterises regular human insulin formulations. Certain proinsulin formulations with hepatoselective activity have been developed but were found to be poorly tolerated. The newer proinsulin molecules do not show hepato-selective properties. In order to generate basal insulin levels, peakless long-acting formulations have been developed, including: a soluble formulation (which upon subcutaneous administration, produces a 'depot-like' sustained release mechanism), albumin-bound insulin and cobalt-insulin hexamer formulations. To improve patient compliance the 'pen' device was developed for subcutaneous injections. Programmable infusion pumps were developed to avoid repetitive subcutaneous injections. Great efforts have been made in searching for noninvasive modes of insulin administration that will avoid the need for parenteral administration. These include: oral, colonic, rectal, nasal, ocular, buccal, pulmonary, uterine and transdermal routes of administration. Various enhancers have been tested to increase the bioavailability of each route. At present these alternative routes do not provide clinically relevant substitutes for the subcutaneous mode of administration. In conclusion, although the newer formulations provide certain advantages, there is still much to be done to further facilitate and improve insulin therapy.

Amino Acid Sequence↗
PubMed1997

The anticonvulsant effect of deprenyl on pentylenetetrazol-induced seizures in Lewis rats.

There is recent evidence that deprenyl may have anticonvulsant action in a rat kindling model of epilepsy as well as in a maximal electroshock model. We therefore investigated the effect of deprenyl on the brain sensitivity threshold to pentylenetetrazol (PTZ)-induced maximal seizures in Lewis rats, in a model that provides pharmacodynamic information free of pharmacokinetic interference. The novel finding of this investigation was the anticonvulsant effect of deprenyl following repetitive administration whereas a single deprenyl dose did not affect the PTZ concentrations required to induce maximal seizures. The data suggests that the mechanism of this effect is not associated with the dopaminergic activity of deprenyl since pretreatment with both bromocriptine (a dopamine D2 agonist) and haloperidol (dopamine antagonist) did not affect the seizure threshold, whereas levodopa caused a proconvulsant effect. It was also concluded that the mechanism is not related to changes in acetylcholine levels since prolonged pretreatment with deprenyl did not attenuate the brain sensitivity to pilocarpine-induced seizures. The fact that long term administration of deprenyl was needed to produce its anticonvulsant effect may indicate that the anticonvulsant effect of deprenyl may be due to changes in levels of certain endogenous compounds or down or up-regulation of relevant receptor/effector units.

Animals↗
PubMed1996

Bosentan improves renal regional blood flow in rats with experimental congestive heart failure.

The effects of the mixed endothelin receptor antagonist bosentan on renal regional haemodynamics were investigated in rats with aorto-caval fistula, an experimental model of congestive heart failure. A matched group of normal rats served as control. Injection of bosentan (10 mg/kg i.v.) to the rats with decompensated congestive heart failure produced an increase in cortical (+20%) and medullary (+12%) blood flow, and a decrease in vascular resistance in the cortex (-30%) and medulla (-23%), while reducing mean arterial pressure by approximately 10 mm Hg. In rats with compensated congestive heart failure and in normal animals, infusion of bosentan did not affect blood pressure and cortical perfusion. These findings indicate that 1) endothelin receptor blockade produces beneficial effects on renal haemodynamics in rats with experimental congestive heart failure and 2) endothelin-1 may be involved in the pathogenesis of renal hypoperfusion only in decompensated congestive heart failure.

Animals↗
PubMed1996

Possible role for endothelins in penile erection.

The effects of endothelins (endothelin-1 and endothelin-3) on penile erection were studied in vivo in the pithed rat. Penile erectile responses were evaluated by measurements of intracorporal pressure via a needle inserted into one corpus cavernosum. Injection of endothelins (0.1-10 micrograms/kg i.v.) was followed by a rapid rise in corporal pressure. The responses to endothelin-1 and endothelin-3 were equivalent at the lower doses, but at 10 micrograms/kg the response to endothelin-3 was greater than that to endothelin-1. NG-Nitro-L-arginine-methyl ester (20 mg/kg) but not indomethacin (10 mg/kg) antagonized the rise in corporal pressure caused by submaximal doses of endothelins. Electrical nerve stimulation-induced increase in corporal pressure was reduced after 5 micrograms/kg endothelin-1 but not after the same dose of endothelin-3. The results indicate that in corporal vasculature endothelin-3 has a predominantly vasodilator effect, while endothelin-1 has a vasodilator effect at lower doses and a vasoconstrictor effect at higher doses. The vasodilator action of endothelins is probably mediated by activation of endothelin ETB receptors and local release of nitric oxide. Thus, endothelins may participate in initiation and/or maintenance of penile erection.

Animals↗
PubMed1996

Crystal structure of a human TATA box-binding protein/TATA element complex.

The TATA box-binding protein (TBP) is required by all three eukaryotic RNA polymerases for correct initiation of transcription of ribosomal, messenger, small nuclear, and transfer RNAs. The cocrystal structure of the C-terminal/core region of human TBP complexed with the TATA element of the adenovirus major late promoter has been determined at 1.9 angstroms resolution. Structural and functional analyses of the protein-DNA complex are presented, with a detailed comparison to our 1.9-angstroms resolution structure of Arabidopsis thaliana TBP2 bound to the same TATA box.

Amino Acid Sequence↗
PubMed1996

Alterations in the promoter-specific imprinting of the insulin-like growth factor-II gene in Wilms' tumor.

The human IGF2 gene, which encodes a mitogenic peptide required for normal fetal development, is overexpressed in many types of tumors. IGF2 is transcribed from four promoters (P1-P4), and in most tissues, the gene is imprinted. In this study, we have analyzed IGF2 promoter usage and determined the allelic expression from each promoter in 19 ApaI- and 22 AluI-heterozygous Wilms' tumors. Loss of IGF2 imprinting (LOI) was observed in 8 ApaI-informative tumors. In these tumors, each parental allele was expressed in equal abundance, indicating that there was complete relaxation of IGF2 imprinting. In each LOI tumor, expression from promoter P1 as well as from the normally imprinted promoters P2-P4 was biallelic. In the 11 ApaI-informative tumors which maintained IGF2 imprinting (maintenance of imprinting), transcription from promoters P2-P4 was always monoallelic, while transcripts from P1 were derived from either one or both alleles. The lack of consistency of IGF2 imprinting of promoter P1 in maintenance of imprinting tumors was also observed in normal fetal tissues of 6 12 weeks gestation, suggesting a similarity in IGF2 regulation between Wilms' tumors and embryonic tissue development. These data suggest that the increased expression of IGF2 in Wilms' tumor may be caused either by biallelic gene expression in LOI tumors from promoters P2-P4 and/or by a reversion to an earlier stage of development which is characterized by increased synthesis of this fetal growth factor.

Alleles↗
PubMed1996

Clinical significance of hepatitis C viral RNA status and its correlation to antibodies to structural HCV antigens in anti-HCV reactive patients with normal liver tests.

Extensive serological testing and HCV RNA determination by RT-PCR was performed in serum, PBMCs, and liver tissue in thirteen anti-HCV reactive patients with persistently normal liver tests. Absolute concordance in the status of HCV RNA between serum, PBMCs, and liver was noted. Five patients were HCV RNA positive but only three had mild histological changes. Eight patients were HCV RNA negative in all three sites and had virtually normal liver histology. Patterns of reactivity in RIBA 2.0 strip immunoblot assay did not differentiate viremic from nonviremic patients. ELISA testing using multiple individual HCV recombinant antigens from the structural and non-structural regions of HCV demonstrated mean antibody titers to the structural antigens, in particular HCV E2 antibodies, to be significantly lower in HCV RNA negative patients. The status of HCV RNA in the serum appears to infer the status of HCV RNA in the liver and PBMCs in patients with persistently normal liver tests. Patients with persistently normal liver tests and undetectable HCV RNA have probably spontaneously cleared HCV infection.

Adult↗
PubMed1996

Probing self assembly in biological mixed colloids by SANS, deuteration, and molecular manipulation.

Small-angle neutron scattering was used to obtain information on the form and molecular arrangement of particles in mixed colloids of bile salts with phosphatidylcholine, and bile salts with monoolein. Both types of systems showed the same general characteristics. The particle form was highly dependent on total lipid concentration. At the highest concentrations the particles were globular mixed micelles with an overall size of 50A. As the concentration was reduced the mixed micelles elongated, becoming rodlike with diameter about 50A. The rods had a radial core-shell structure in which the phosphatidylcholine or monoolein fatty tails were arranged radially to form the core with the headgroups pointing outward to form the shell. The bile salts were at the interface between the shell and core with the hydrophilic parts facing outward as part of the shell. The lengths of the rods increased and became more polydispersed with dilution. At sufficiently low concentrations the mixed micelles transformed into single bilayer vesicles. These results give insight on the physiological function of bile and on the rules governing the self assembly of bile particles in the hepatic duct and the small intestine.

Bile Acids and Salts↗
PubMed1996

Neurological and psychological sequelae in transplant recipients after bridging with the bioartificial liver.

Prior to the advent of the bioartificial liver there was little hope to offer the families of comatose patients unless an organ could be found immediately, or xenografting was attempted. The elevated intracranial pressure that develops is more life-threatening than prolonged bleeding times. Over a 2-year period, nine patients were bridged to transplantation using the BAL to keep them neurologically intact prior to surgery. The goal is to maintain the ICP less than 20 mmHg in adults and between 10 and 15 mmHg in children, so that the cerebral perfusion pressure remains above 50 mmHg. The first patients, a 35-year-old woman, arrived in stage II coma. The second patient, a 10-year-old boy in stage IV coma, had decerebrate posturing and anisocoria. The third patient, an 18-year-old girl, had an ICP of 28 mmHg with decerebrate posturing and disconjugate gaze. The fourth patient, a 34-year-old male, had an ICP of > 38 mmHg. The fifth patient, a 24-year-old male, had fixed dilated pupils. The sixth patient, a 50-year-old woman, had readings to 52 mmHg. The seventh patient, a 48-year-old male, had postoperative numbness in his fingertips that remitted. The eighth patient, a 31-year-old female, had decerebrate posturing and an ICP of 64 mmHg transiently. The ninth patient, a 52-year-old woman, had decerebrate posturing with a peak ICP of 50 mmHg. All nine patients survived.

Adolescent↗
PubMed1996

Differential regulation of renal regional blood flow by endothelin-1.

The present study evaluated the effects and mechanisms of action of endothelin-1 (ET-1) on medullary and cortical blood flow (MBF and CBF, respectively). CBF and MBF were measured simultaneously by laser-Doppler flowmetry in anesthetized male Wistar rats. Bolus injection of ET-1 (1.0 nmol/kg iv) produced a sustained decrease in CBF (delta = -30%) and a transient increase in MBF (delta = +35%). The medullary vasodilation induced by ET-1 was observed with doses lower than that required to produce cortical vasoconstriction; was completely blocked by bosentan, a mixed ETA/B-receptor antagonist; and was mimicked by IRL-1620, a specific ETB-receptor agonist. In contrast, BQ-123, an ETA-receptor antagonist, failed to inhibit the ET-1-dependent medullary vasodilation but effectively blocked the cortical vasoconstriction induced by the peptide. Finally, inhibition of nitric oxide (NO) synthase completely abolished, whereas cylooxygenase inhibition attenuated, the effect of ET-1 on MBF. The data demonstrate that ET-1 exerts opposite effects on renal cortical and medullary circulation, i.e., ETA-receptor-mediated cortical vasoconstriction and ETB-mediated medullary vasodilation. Furthermore, the medullary vasodilation induced by ET-1 is dependent on the NO system and, to a lesser extent, on prostaglandin generation.

Animals↗