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Biomedical subjects

D B Campbell

Publications and source records attributed to D B Campbell.

At least 37 records · Page 2Linked to original sources
PubMed1997

Traumatic adult respiratory distress syndrome.

ARDS is the pulmonary manifestation of both direct and indirect insults to the lung. Trauma patients are at particular risk for ARDS from the direct effects of their injuries, as well as from complications that may occur during their hospital courses. ARDS prevention can be enhanced through diverse areas of medical focus. Public health issues addressing trauma prevention, improved understanding and treatment of trauma-related pathophysiology, as well as a better understanding of basic pathophysiology of this disease process will allow refinement and improvement of our management practices. Newer modes of mechanical ventilation may help us to avoid ventilator-induced exacerbation of lung injury. As we define the role of nonconventional therapies, such as anti-inflammatory and anticytokine therapies, our ability to actively interrupt and reverse the progression of the inflammatory cascade will be enhanced. As yet, ARDS continues to be a challenging disease process to both fully understand and successfully treat in our critically ill patients.

Humans↗
PubMed1997

The role of radiopharmacological imaging in streamlining the drug development process.

Radioimaging techniques have found a place in clinical diagnosis, but there has been a hesitancy to use this approach in drug development. This reluctance may have been due to the availability of ligands, the time and cost of synthesis and the number of centres and, although these perceived problems have been largely overcome, for many the benefits are not evident. The use in drug development is potentially large since tomography can measure drug levels, specific binding, blood flow and activity within the human body. In drug discovery, combinational chemistry and high throughput screening, the synthesis of candidate drugs with specific binding properties are dependent on understanding the disease and using appropriate in vitro or animal models. Using small animal tomographs, these can be validated using radioimaging. Pharmacokinetics and metabolic problems, such as the distribution of inhaled gases, drug targeting into tumours of the brain or specific gastrointestinal absorption sites can be investigated within the human rather than relying on animals. The high specific activity allows low doses to be administered to man with limited safety studies, permitting kinetic and metabolic studies to be undertaken early in development. Safety studies and ensuing toxicological endpoints in animals rely on histopathology for gross degenerative in physiological function. Where concern exists, radioimaging could detect early in situ changes in humans, for example hepatic toxicity, before they become hazardous. In clinical studies, the action of drugs can be measured directly at the effector site prior to undertaking longer studies, which is important for many diseases, but particularly for those such as Alzheimer's disease, where improvements may be slow or subtle.

Animals↗
PubMed1996

Extrapolation from animals to man. The integration of pharmacokinetics and pharmacodynamics.

This paper has focused on the difficulties of extrapolating toxicological or pharmacological data obtained from animals to those expected in man. For some drugs, under certain conditions, there may be no problem, but for many, this is clearly not the case. Differences in apparent activity are impossible to reconcile without "normalizing" the dose for differences in pharmacokinetics and metabolism. The increasing use of artificial intelligence and expert systems in drug investigations may provide a greater insight into why these differences may occur and allow prediction but, in the end, they must be tested in the experiments undertaken. The use of kinetic dynamic relationships in different species will certainly help in this regard and, wherever possible, should be included in experimental design to build up a database of experience since such information is sadly lacking. But we must interpret with caution the data produced by those that continue to extrapolate animal data to humans without some attempt to discuss in detail the validity of their assumptions.

Animals↗
PubMed1996

Responses to novelty stress in female F344 rats: effects of age and d-fenfluramine treatment.

To elucidate some of the mechanisms underlying the neuroendocrine and neurochemical changes associated with age in female rats, we administered the serotonin (5-HT) releaser and reuptake inhibitor, d-fenfluramine (d-FEN; 0.0 or 0.6 mg/kg/day, PO) for 30-38 days to young (4 month) and old (21 month) F-344 female rats. Animals were placed into a novel open field (OF) for 20 min before sacrifice. Control animals were sacrificed immediately upon removal from their home cage (HC). Old rats exhibited significantly (p < 0.05) less exploratory behavior and a smaller CORT response to OF than young animals. d-FEN treatment had no effect on plasma ACTH and CORT levels or exploratory behavior. The old HC rats had significantly (p < 0.05) higher plasma levels of prolactin (PRL) than the young HC rats. A stress induced increase in PRL secretion was observed in the old rats only, which was attenuated by d-FEN treatment. In the OF groups, both the young and old rats showed elevated medial frontal cortex (MFC) dopamine turnover (DOPAC/DA ratio), but only the young rats exhibited an elevation in norepinephrine (NE) turnover (MHPG/NE ratio). d-FEN treatment blocked the stress-induced increase in NE turnover in the young rats and the increase in DA turnover in the old rats. These data suggest that 5-HT activity could be involved in the age-related changes in the MFC catecholamine and PRL responses to stress in female rats.

Adrenocorticotropic Hormone↗
PubMed1996

Chromosomal localization of the neurological mouse mutations tottering (tg), Purkinje cell degeneration (pcd), and nervous (nr).

We have refined the map positions and identified molecular markers for three neurological mutations in the mouse, tottering (tg), Purkinje cell degeneration (pcd), and nervous (nr). These mutations were localized using simple sequence length polymorphisms between the mouse strain on which the mutation arose and the inbred strain onto which the mutation was bred. This approach to mutation mapping is generalizable to any mutant that has been backcrossed for several generations. The tg mutation was localized to the 1.1 cM region of chromosome 8 distal to simple sequence repeat (SSR) D8Mit103 and proximal to SSRs D8Mit79, D8Mit105, and D8Mit283. The pcd locus was mapped to the 5 cM interval of chromosome 13 between SSRs D13Mit139 and D13Mit67, and the nr locus was mapped between SSRs D8Mit155 and D8Mit18, a 5.6 cM region of chromosome 8. For each mutation, several SSRs distinguishing mutant from wild type chromosomes were identified within these regions. The definition of molecular markers distinguishing mutant from wild type alleles makes possible for the first time identification of tg, pcd, and nr mutants prior to behavioral manifestation of the mutant genotype. Thus, developmental studies of these mutants designed to describe or dissect the biochemical basis of the induction of the mutant phenotype are now feasible.

Alleles↗
PubMed1995

Are interspecies comparisons in the toxicity of centrally acting drugs valid without brain concentrations? A commentary.

Many pharmacological and toxicological studies of centrally acting drugs are undertaken in animals at doses expressed in mg.kg-1, and the results extrapolated to the clinical dose in man. Safety margins based on such no or lowest effect levels may have little relevance since they do not take into account differences in the kinetics and metabolism of the compounds. These deviations are accentuated when extremely high doses are used, and saturation of metabolism occurs.

Animals↗
PubMed1995

Mutations that affect ion channels change the sensitivity of Drosophila melanogaster to volatile anesthetics.

We have quantitated the response of D. melanogaster to general anesthetics with a device, the inebriometer, that assays the fly's geotactic and postural behavior. When alleles of several loci that encode or regulate subunits of ion channels were compared with control stocks, several ion channel mutants clearly increased the anesthetic sensitivity of Drosophila. The effects were specific in that: a) for several alleles, genetic tests indicated that the anesthesia phenotype was due to the ion channel mutation and not to extraneous genetic differences between the stocks; b) a given ion channel mutation often affected the response to one anesthetic but not another; and c) the behavior of decapitated flies in the inebriometer indicated that the anesthetic phenotype of several mutants did not merely reflect a global change in the fly's physiology. These results provide support for the idea that ion channels are on the pathway(s) influenced by anesthetics and that different anesthetics use different pathways. They also provide perspective on the behavior of previously isolated mutations (har) that decrease the sensitivity of Drosophila to anesthetics in the inebriometer.

Anesthetics, Inhalation↗
PubMed1994

Use of Drosophila mutants to distinguish among volatile general anesthetics.

The way general anesthetics cause their clinically useful effects on the nervous system is not known. Since the principal determinant of the potency of these agents is their solubility in oil, the role of chemical structure in affecting anesthetic targets has been obscured. In this work, we use an intense beam of light (Tinklenberg, J. A., Segal, I. S., Tianzhi, G. & Maze, M. (1991) Ann. N.Y. Acad. Sci. 625, 532-539) to assess the effect of general anesthetics on the capacity of fruit flies to sense a noxious stimulus and respond to it. By examining the effect of halothane-resistant (har) mutations on the potency of various volatile anesthetics in this assay, we establish similarities and differences between these agents that highlight the was chemical structure influences anesthetic action. In general, the potencies of anesthetics with different chemical structure are affected to different extents by one or more har mutations. However, three anesthetics of related structure (enflurane, isoflurane, and desflurane) show quantitatively indistinguishable alterations in potency in each of four genetic tests. These results not only identify important structural features of anesthetics but also place limits on the classical view that all anesthetics act at a common target.

Animals↗
PubMed1993

Neuroendocrine and neurochemical responses to novelty stress in young and old male F344 rats: effects of d-fenfluramine treatment.

To understand some of the mechanisms underlying the neuroendocrine and neurochemical changes associated with aging, we administered the serotonin [5-hydroxytryptamine (5-HT)] releaser and reuptake inhibitor d-fenfluramine (d-FEN; 0.0, 0.2, or 0.6 mg/kg/day, p.o) for 30-38 days to young (4 months) and old (22 months) F344 male rats. Rats were stressed by placement into a novel open field (OF) for 20 min before sacrifice. Control animals were sacrificed immediately upon removal from their home cage (HC). Old rats exhibited less (p < 0.05) exploratory behavior than young rats, which was not altered by treatment with d-FEN. Old HC rats also had higher (p < 0.05) basal plasma levels of adrenocorticotropic hormone (ACTH) and prolactin (PRL) than young HC rats. Old OF rats showed higher (p < 0.05) levels of ACTH and corticosterone (CORT) than young OF animals. A stress-induced increase in PRL secretion was not observed in old rats. Subchronic low-dose d-FEN normalized the enhanced ACTH and CORT responses of old animals to novelty. In addition to these endocrine changes, stress-induced increases in medial frontal cortex (MFC) dopamine (DA) and norepinephrine (NE) turnover also were observed. The increase in NE turnover was greater (p < 0.01) in old than in young rats. d-FEN treatment blocked the stress-induced increase in MFC NE but not MFC DA turnover in both young and old rats. These data support a role for 5-HT and/or NE in some age-related neuroendocrine perturbations and suggest that increased 5-HT neurotransmission can normalize the hyperactivation of the hypothalamo-pituitary-adrenal axis of old male rats.

Adrenocorticotropic Hormone↗
PubMed1992

Clinical trials of an intravenous oxygenator in patients with adult respiratory distress syndrome.

In patients with severe adult respiratory distress syndrome, mechanical ventilation may not be able to ensure gas exchange sufficient to sustain life. We report the use of an intravenous oxygenator (IVOX) in five patients who were suffering from severe adult respiratory distress syndrome as a result of aspiration, fat embolism, or pneumonia. IVOX was used in an attempt to provide supplemental transfer of CO2 and O2 and thereby reduce O2 toxicity and barotrauma. All patients were tracheally intubated, sedated, and chemically paralyzed and had a PaO2 < 60 mmHg when the lungs were ventilated with an FIO2 = 1.0 and a positive end expiratory pressure of > or = 5 cmH2O. The right common femoral vein was located surgically, and the patient was systemically anticoagulated with heparin. A hollow introducer tube was inserted into the right common femoral vein, and the furled IVOX was passed into the inferior vena cava and advanced until the tip was in the lower portion of the superior vena cava. IVOX use ranged from 2 h to 4 days. In this group of patients, IVOX gas exchange ranged from 21 to 87 ml x min-1 of CO2 and from 28 to 85 ml x min-1 of O2. One of the five patients survived and was discharged from the hospital. The IVOX transferred up to 28% of metabolic gas-exchange requirements. One patient with a small vena cava showed signs of caval obstruction. Three other patients demonstrated signs of a septic syndrome after the device was inserted.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Comparative biodisposition and metabolism of 14C-(+/-)-fenfluramine in mouse, rat, dog and man.

1. The comparative metabolism of fenfluramine was investigated in mouse, rat, dog and man following a single oral dose of 14C-(+/-)-fenfluramine hydrochloride (1 mg/kg), and also in rat after eight consecutive 12-h subcutaneous doses (24 mg/kg). 2. Main route of excretion of radioactivity in all species and at all doses was into urine (> 80%), with only minor amounts of radioactivity found in faeces. 3. From all species examined a total of 11 metabolites were observed in urine and plasma by t.l.c. and h.p.l.c. analysis and no metabolite was present in the plasma which was not present in urine. 4. All species dealkylate fenfluramine to the active metabolite norfenfluramine, to a relative greater or lesser extent, with plasma metabolic ratios (norfenfluramine/fenfluramine) showing inter-animal variation (rat >> dog >> mouse = man). 5. These differences are due to the efficient deamination of both compounds to polar inactive metabolites in man, with less dealkylation and lower plasma levels of norfenfluramine compared with the other species studied. 6. In conclusion, major species differences in the metabolism of (+/-)-fenfluramine, both qualitative and quantitative were observed, and no one species had a similar metabolic profile to that found in man.

Animals↗
PubMed1991

The mode of action and clinical pharmacology of gliclazide: a review.

Gliclazide is a sulphonylurea drug with an intermediate half-life of around 11 hours. It is extensively metabolised, and renal clearance accounts for only 4% of total drug clearance. The molecule contains an azabicyclo-octyl group which confers special properties on the basic sulphonylurea moiety. Gliclazide stimulates insulin secretion through the beta cell sulphonylurea receptor, and possibly through a direct effect on intracellular calcium transport. It specifically improves the abnormal first phase insulin release in type 2 diabetes, and also has an effect on the second phase. This pattern of insulin release is thought to explain the lower incidence of hypoglycaemic episodes and weight gain compared with some other sulphonylureas. There is also a reduction in hepatic glucose production and improvement in glucose clearance, without changes in insulin receptors. This suggests a possible post-receptor effect on insulin action, perhaps by stimulation of hepatic fructose-2,6-bisphosphatase and muscle glycogen synthase. Gliclazide reduces platelet adhesion, aggregation and hyperactivity and increases fibrinolysis. These actions, thought to be independent of its hypoglycaemic activity, may make gliclazide useful in halting the progression of diabetic microangiopathy.

Adult↗
PubMed1991

Effects of subchronic d-fenfluramine on splenic immune functions in young and old male and female Fischer 344 rats.

The present study was designed to demonstrate age- and sex-related differences in immune functions, and to determine whether subchronic elevations in serotonin (5-HT) availability in vivo would alter immune functions assessed subsequently in vitro. Male and female F344 rats (5 and 21 months of age) were administered the 5-HT releaser and reuptake inhibitor, d-fenfluramine (d-Fen), in their drinking water for 30-38 days then killed. The young animals received a higher dose (1.8 mg/kg/day) of d-Fen than the old rats (0.6 mg/kg/day) in order to compensate for age-related decreases in drug biotransformation and clearance. Brain and spleen d-Fen and metabolite concentrations, however, were considerably higher in the young than in the old rats. d-Fen treatment did not affect body weight or fluid intake. Although substantial sex differences in immune function were not discerned, age-related decreases were observed in absolute splenic cellularity, recombinant interleukin-2 (rIL-2) stimulated natural killer (NK) cytotoxicity, LPS stimulated B-cell mitogenesis, and in the level of Ox19 (CD5) positive cells. d-Fen caused an increase in absolute spleen weight and a decrease in absolute splenic cellularity only in the old rats of both sexes. Spleen cells from young male and old female rats receiving d-Fen had relatively more large granular lymphocytes and enhanced baseline and rIL-2 activated killing of YAC-1 cells than their vehicle matched or opposite sex counterparts. The drug also increased Con A-induced T-cell proliferation in young males and LPS induced B-cell proliferation in old females. d-Fen decreased Ox39 (CD25) levels by 19%, but did not affect any of the other phenotypes examined. The results suggest that 5-HT has a selective stimulatory effect on young male and old female NK activity, and that old female rats are more sensitive to the immunological effects of d-Fen than old male rats.

Adjuvants, Immunologic↗