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Biomedical subjects

D Grant

Publications and source records attributed to D Grant.

At least 109 records · Page 6Linked to original sources
PubMed1996

Evaluation of caffeine as a test drug for CYP1A2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations.

Caffeine is used to phenotype subjects in vivo for the cytochrome P450 isoforms CYP1A2 and CYP2E1, and for N-acetyltransferase type 2 (NAT2). However, how much of the variation in phenotyping parameters may be attributed to variations in CYP1A2 and CYP2E1 activities has not been determined. Therefore, this study intraindividually compared enzyme activities and/or content in liver samples with pharmacokinetic parameters of caffeine in vivo after administration of a test dose in 25 patients undergoing hepatectomy. Parameters measured in vitro were the high affinity components of caffeine 3-demethylation and phenacetin 0-deethylation, microsomal CYP1A2 and CYP2E1 immunoreactivity, and cytosolic sulfamethazine N-acetylation. Caffeine parameters in vivo included caffeine clearance from plasma and/or saliva, paraxanthine/caffeine ratios in plasma and saliva, plasma theophylline/caffeine ratio, and several metabolite ratios from spot urine sampled 6 h postdose. Correlations between parameters were determined using weighted linear regression analyses. Caffeine clearance and paraxanthine/caffeine ratios correlated most highly to intrinsic clearance of caffeine 3-demethylation and to CYP1A2 immunoreactivity (r= 0.584-0.82), whereas urinary CYP1A2 ratios correlated less strongly with CYP1A2 parameters in vitro. Assignment of acetylator phenotype by urinary NAT2 ratios was concordant with sulfamethazine-N-acetylation in vitro. In contrast to CYP1A2 parameters in vitro, CYP2E1 immunoreactivity was not related to the theophylline/caffeine plasma ratio. CYP1A2 activity, thus, is the major determinant of caffeine clearance and the paraxanthine/caffeine ratios in vivo, of which the saliva ratio 6 h postdose appears as the most advantageous parameter. The results confirm that phenotyping using caffeine provides valid estimates of CYP1A2 and NAT2 activity.

Aged↗
PubMed1996

Neoral in liver transplantation.

In conclusion, Neoral gives more consistent drug absorption, achieving better pharmacokinetic predictability. Among other advantages, this results in a close correlation between trough blood levels and drug exposure (AUC) so that trough blood levels can be used as a more meaningful monitoring parameter when using the new formulation. Studies have also now confirmed that absorption of Neoral is bile independent, making it more useful in the early postoperative period and in the setting of cholestasis and rejection. Furthermore, studies have now demonstrated that in patients who have problems absorbing Sandimmune such as patients with cystic fibrosis, pancreatitis, or Crohn's disease, conversion to Neoral results in correction of malabsorption of CyA. Issues that need to be addressed in the future will include long-term toxicity associated with maintaining high Cmax and AUC; whether the introduction of Neoral can result in steroid sparing; and whether the introduction of Neoral will result in a reduced incidence of acute and chronic rejection.

Administration, Oral↗
PubMed1995

US report on violence in the medical workplace may hold lessons for Canadian MDs.

Concern about the growing incidence of violence against health care professionals has prompted the Young Physicians Section of the American Medical Association to research and develop a publication designed to raise physicians' awareness. Violence in the Medical Workplace. Prevention Strategies provides some commonsense precautions that could minimize the possibility a physician will fall victim to violence at the hands of a patient.

Canada↗
PubMed1995

Expression of a high molecular weight form of insulin-like growth factor II in a Beckwith-Wiedemann syndrome associated adrenocortical adenoma.

Beckwith-Wiedemann syndrome is a rare condition (1/13,700 live births) occurring in both inherited and sporadic forms in the population. It is manifest as a fetal overgrowth syndrome, in which hypertrophy dominates the clinical picture. An additional complication is that these children are predisposed to a specific subset of childhood neoplasms, amongst which are Wilms' tumour and adrenocortical carcinoma. We report here the synthesis by an associated adrenal tumour of large quantities of a high molecular weight form of insulin-like growth factor II (IGF-II), associated with profound suppression of circulating IGFs in the patient's serum. As with other tumours of this type, the tumours showed loss of material on chromosome 11p.

Adenoma↗
PubMed1995

Allogeneic lymphocyte proliferation stimulated by small intestine-derived epithelial cells.

It has been more difficult to prevent intestinal allograft rejection than rejection of other solid organ transplants. Epithelial cells in the small intestine have the potential to actively participate in graft rejection because they constitutively express MHC class II antigens. The present study examined the ability of intestinal epithelial cells (IEC) to stimulate allogeneic T cells in vitro using one-way MLC. IEC from jejunum and ileum of ACI rats (RT1a) were used as the stimulator cells; purified T lymphocytes from Lewis rats (RT11) were used as the responder cells. Freshly isolated IEC were poor stimulators of naive allogeneic T lymphocytes. However, IEC induced a strong proliferation of primed allogeneic T lymphocytes, and this response could be blocked by anti-MHC class II mAb (OX-4). IEC stimulated a vigorous proliferation of naive T cells when co-cultured with (1) macrophages syngeneic with responder T lymphocytes, (2) supernatants of LPS-stimulated macrophages, or (3) a combination of IL-1 and IL-6. We conclude that MHC class II positive IEC require soluble costimulatory factors to fully activate naive allogeneic T cells. Immune stimulation by enterocytes may be one of the reasons why it is so difficult to prevent intestinal allograft rejection. Strategies that block interactions among IEC, macrophages, and lymphocytes may reduce the immunogenicity of small bowel transplants.

Animals↗
PubMed1995

Site and mechanism of antisense inhibition by C-5 propyne oligonucleotides.

Antisense gene inhibition occurs when an oligonucleotide (ON) has sufficient binding affinity such that it hybridizes its reverse complementary target RNA and prevents translation either by causing inactivation of the RNA (possibly by RNase H) or by interfering with a cellular process such as stalling a ribosome. The mechanisms underlying these processes were explored. Cellular antisense inhibition was evaluated in a microinjection assay using ON modifications which precluded or allowed in vitro RNase H cleavage of ON/RNA hybrids. RNase H-independent inhibition of protein synthesis could be achieved by targeting either the 5'-untranslated region or the 5'-splice junction of SV40 large T antigen using 2'-O-allyl phosphodiester ONs which contained C-5 propynylpyrimidines (C-5 propyne). Inhibition at both sites was 20-fold less active than inhibition using RNase H-competent C-5 propyne 2'-deoxy phosphorothioate ONs. In vitro analysis of association and dissociation of the two classes of ONs with complementary RNA showed that the C-5 propyne 2'-O-allyl phosphodiester ON bound to RNA as well as the C-5 propyne 2'-deoxy phosphorothioate ON. In vitro translation assays suggested that the two classes of ONs should yield equivalent antisense effects in the absence of RNase H. Next, ON/T antigen RNA hybrids were injected into the nuclei and cytoplasm of cells. Injection of C-5 propyne 2'-O-allyl phosphodiester ON/RNA hybrids resulted in expression of T antigen, implying that the ONs dissociated from the RNA in cells which likely accounted for their low potency. In contrast, when C-5 propyne 2'-deoxy phosphorothioate ON/T antigen RNA complexes were injected into the nucleus, the duplexes were stable enough to completely block T antigen translation, presumably by RNA inactivation. Thus, a dramatic finding is that C-5 propyne 2'-deoxy phosphorothioate ONs, once hybridized to RNA, are completely effective at preventing mRNA translation. The implication is that further increases in complex stability coupled with effective RNase H cleavage will not result in enhanced potency. We predict that the development of more effective ONs will only come from modifications which increase the rate of ON/RNA complex formation within the nucleus.

Alkynes↗
PubMed1995

Hypertrophic cardiomyopathy associated with tacrolimus in paediatric transplant patients.

Reported side-effects of tacrolimus, a potent immunosuppressive agent, have not included cardiotoxicity. We describe 5 consecutive paediatric transplant recipients (3 small bowel with or without liver and 2 liver) who received tacrolimus. 2 developed congestive heart failure and hypertrophic obstructive cardiomyopathy which resolved after changing to cyclosporin. In the other 3 patients the cardiomyopathy regressed or improved with a lower dose of tacrolimus or after stopping the drug.

Blood Pressure↗