Search PubMed⌕ Search

Biomedical subjects

J Giddings

Publications and source records attributed to J Giddings.

At least 19 recordsLinked to original sources
PubMed1999

Distribution of a 20-mer phosphorothioate oligonucleotide, CGP69846A (ISIS 5132), into airway leukocytes and epithelial cells following intratracheal delivery to brown-norway rats.

PURPOSE: To evaluate the pulmonary distribution of CGP69846A (ISIS 5132), a phosphorothioate oligonucleotide, following intra-tracheal (i.t.) instillation into Brown-Norway rats. METHODS: The pharmacokinetic profile of [3H]-CGP69846A was investigated following i.t. instillation into both naive and inflamed airways of Brown-Norway rats. The cellular distribution was determined using autoradiography, immunohistochemistry and flow cytometry/fluorescence microscopy, in inflamed airways. RESULTS: CGP69846A displayed a dose-dependent lung retention following i.t. administration which was unaffected by local inflammation. Autoradiography and immunohistochemistry showed distribution to alveolar macrophages, eosinophils, bronchial and tracheal epithelium and alveolar cells. Studies with [FITC]-CGP69846A demonstrated a preferential association of oligonucleotide with leukocytes in bronchial lavage fluid of: macrophages > eosinophils = neutrophils >> lymphocytes. CONCLUSIONS: The dose-dependency of lung retention together with cell-specific uptake suggests that the lung can be used as a local target for antisense molecules with potentially minimal systemic effects. Furthermore, the preferential targeting of macrophages and the airway epithelium by oligonucleotides may represent rational cellular targets for antisense therapeutics.

Animals↗
PubMed1999

Haemostatic and fibrinolytic responses to bone marrow transplantation.

Thrombin and plasmin activation markers were serially measured in 80 patients undergoing bone marrow transplantation (BMT). There were prothrombotic and fibrinolytic responses observed during autograft and allograft BMTs. Thrombin-antithrombin and prothrombin fragment F1+2 levels increased from day -7 to -3 (P<0.0001) from 3.7 to 7 ng/ml and 1.2 to 1.63 nmol/l, respectively. A rise in plasmin-antiplasmin levels occurred between days 4 and 14 (P< 0.0004), from 393 ng/ml on day -7 to a peak of 795 ng/ml on day 11. No correlation between reduced protein C levels post-BMT and a prothrombotic state was observed.

Adolescent↗
PubMed1998

Pulmonary bioavailability of a phosphorothioate oligonucleotide (CGP 64128A): comparison with other delivery routes.

PURPOSE: Phosphorothioate antisense oligodeoxynucleotides are promising therapeutic candidates. When given systemically in clinical trials they are administered via slow intravenous infusion to avoid their putative plasma concentration-dependent haemodynamic side-effects. In this study, we have evaluated alternative parenteral and non-parenteral administration routes which have the potential to enhance the therapeutic and commercial potential of these agents. METHODS: The delivery of CGP 64128A by intravenous, subcutaneous, intra-peritoneal, oral and intra-tracheal (pulmonary) routes was investigated in rats using radiolabelled compound and supported by more specific capillary gel electrophoretic analyses. RESULTS: Intravenously administered CGP 64128A exhibited the rapid blood clearance and distinctive tissue distribution which are typical for phosphorothioate oligodeoxynucleotides. Subcutaneous and intraperitoneal administration resulted in significant bioavailabilities (30.9% and 28.1% over 360 min, respectively) and reduced peak plasma levels when compared with intravenous dosing. Administration via the gastrointestinal tract gave negligible bioavailability (< 2%). Intra-tracheal administration resulted in significant but dose-dependent bioavailabilities of 3.2, 16.5 and 39.8% at 0.06, 0.6 and 6.0 mg/kg, respectively. CONCLUSIONS: Significant bioavailabilities of CGP 64128A were achieved following subcutaneous, intra-peritoneal and intra-tracheal administration. Pulmonary delivery represents a promising mode of non-parenteral dosing for antisense oligonucleotides. The dose-dependent increase in pulmonary bioavailability suggests that low doses may be retained in the lungs for local effects whereas higher doses may be suitable for the treatment of a broader spectrum of systemic diseases.

Administration, Oral↗
PubMed1998

Parenteral glutamine protects hepatic function during bone marrow transplantation.

Hepatic veno-occlusive disease (VOD) of the liver is a common complication following high-dose cytotoxic therapy for bone marrow transplantation (BMT). The major pathological changes are seen in centrilobular (zone 3) hepatocytes and adjacent endothelium. Glutathione (GSH) becomes depleted following chemotherapy and experimental evidence suggests reduced levels predispose to centrilobular hepatocyte and endothelial cell injury. Animal studies have shown that glutamine infusions can maintain GSH levels and protect against free radical injury. We have prospectively studied the effect of glutamine supplementation during BMT. Thirty-four patients undergoing BMT were randomised to receive either glycl-L-glutamine (n = 18) or an isonitrogenous mixture of non-essential amino acids (n = 16). Glutamine was shown to significantly preserve protein C (days +4 and +7, P < 0.05) and albumin levels (days 0 and +4, P < 0.02). Markers of thrombin and plasmin generation (thrombin-antithrombin, prothrombin fragment F1+2 and plasmin-antiplasmin levels) were not significantly changed between the two groups. These findings suggest that glutamine preserves hepatic function but does not alter thrombin or plasmin generation during BMT. Previous studies have shown reductions in protein C, albumin, factor X and factor VII levels post BMT. Falling protein C levels have been shown to be predictive of severe VOD. These data suggest a role for glutamine in the protection of hepatic function following BMT.

Adolescent↗
PubMed1998

A case of congenital mumps infection complicated with persistent pulmonary hypertension.

A low-birth-weight female baby was admitted with respiratory distress after birth. Her mother had been diagnosed with mumps 4 weeks and 5 days prior to delivery. Mumps IgM antibody was elevated in the neonate and mumps virus ribonucleic acid was detected in the umbilical cord blood by reverse transcription-polymerase chain reaction. The perinatal virus infection was complicated with persistent pulmonary hypertension of the newborn and pulmonary hemorrhage. Successful treatment included the use of high frequency oscillation ventilation together with the administration of artificial surfactant.

Antibodies, Viral↗
PubMed1996

Inhibition of growth of human tumor cell lines in nude mice by an antisense of oligonucleotide inhibitor of protein kinase C-alpha expression.

A 20-mer phosphorothioate oligodeoxynucleotide (ISIS 3521) designed to hybridize sequences in the 3'-untranslated region of human protein kinase C-alpha (PKC-alpha) mRNA has been shown to inhibit the expression of PKC-alpha in multiple human cell lines. In human bladder carcinoma (T-24) cells, inhibition of PKC-alpha was both concentration dependent and oligonucleotide sequence specific. ISIS 3521 had a IC50 of 50-100 nM for PKC-alpha mRNA reduction and was without effect on the expression of other members of the PKC family of genes (PKC-eta and zeta). Toxicity studies in mice revealed that the oligodeoxynucleotide was well tolerated at repeat doses of 100 mg/kg i.v. for up to 14 days, with no acute toxicity apparent. The oligodeoxynucleotide was found to also inhibit the growth of three different human tumor cell lines, the T-24 bladder, human lung carcinoma (A549), and Colo 205 colon carcinoma grown in nude mice. The inhibition was dose dependent with ID50 values for the growth inhibition between 0.06 and 0.6 mg/kg daily when given i.v., depending on the cell line examined. Three control phosphorothioate oligodeoxynucleotides not targeting human PKC-alpha were without effect on the growth of the tumors at doses as high as 6 mg/kg. Recovery of ISIS 3521 from tumor tissue and resolution by capillary gel electrophoresis revealed that 24 It after the final dose of oligodeoxynucleotide, intact, full-length 20-mer material was present as well as some apparent exonuclease degradation products (e.g., n-1 and n-2 mers). These studies demonstrate the in vivo antitumor effects of an antisense oligodeoxynucleotide targeting PKC-alpha and suggest that this compound may be of value as a chemotherapeutic agent in the treatment of human cancers.

Animals↗
PubMed1992

A non-occlusive model of arterial thrombus formation in the rat and its modification by inhibitors of platelet function, or thrombin activity.

A technically simple model of arterial thrombosis in the rat, induced by a crush injury to the dorsal aorta is described. The mechanical injury to the artery caused deep medial injury and the formation of a platelet-rich thrombus with associated fibrin formation which was assessed both radiometrically and morphometrically. No significant inclusion of erythrocytes was noted in the thrombus. Administration of the platelet inhibitors aspirin, BM 13505 (a thromboxane receptor antagonist) or CGS 12970 (a thromboxane synthase inhibitor) reduced the extent of platelet deposition on the injured vessel, but no decrease in fibrin(ogen) was observed. In contrast, infusion of prostacyclin resulted in reductions in both these components of the thrombus. In studies involving inhibition of thrombin activity, the direct thrombin inhibitor CGP 39393 (recombinant desulphatohirudin) inhibited both the platelet and fibrin(ogen) deposition. The indirect thrombin inhibitors were less effective; unfractionated heparin and low-molecular-weight heparin inhibited both platelet and fibrin(ogen) deposition but only at doses which rendered the blood uncoagulable, as evaluated by the activated partial thromboplastin time. Dermatan sulphate only inhibited platelet deposition. The results suggest that thrombin plays a key role in the initiation of thrombus formation in this experimental model. The agonist prostaglandins (PGG2, PGH2, and TXA2) would appear to have a supporting role in the platelet deposition onto the thrombotic surface but do not have a role to play with respect to fibrin(ogen) deposition.

Animals↗
PubMed1991

Phenotypic analysis of malignant lymphoma in simian immunodeficiency virus infection using anti-human antibodies.

Primates infected with simian immunodeficiency virus (SIV) develop a condition similar to the human acquired immunodeficiency syndrome (AIDS). The close resemblance between the simian acquired immunodeficiency syndrome (SAIDS) and the human disease has led to the widespread use of SIV-infected monkeys as an animal model in the study of acquired immunodeficiency. We have investigated the use of standard anti-human antibodies for the immunohistochemical analysis of formalin-fixed, paraffin-embedded tissues from monkeys with SAIDS. With the exception of antibodies UCHL1 (CD45RO), MT1 (CD43), 4KB5 (CD45RA), and Ber H2 (CD30), our routine (human) lymphoma panel of markers worked successfully on the animal tissues. Using the anti-human antibodies, we were able to analyse the phenotypes of two cases of malignant lymphoma arising in a study group of 26 SIV-infected rhesus monkeys. Both of the cases stained with the antibodies WR16 (CD45RA) and L26 (CD20), and the B-cell lineage of the lymphomas was confirmed by the detection of IgA lambda immunoglobulin expression in one case, and IgM heavy chain in the other. We therefore report the successful use of anti-human antibodies in the immunohistochemical analysis of lymphomas arising in non-human primates infected with SIV.

Animals↗
PubMed1991

Long-term diet modification and platelet activity.

Platelet activity was assessed in a sub-sample of 56 participants in the MRC Diet and Reinfarction Trial (DART). Men whose diets contained a high ratio of polyunsaturated to saturated fatty acids (a P:S ratio of greater than 0.5) showed reduced secondary platelet aggregation to adenosine diphosphate (ADP) in platelet-rich plasma (PRP), and diminished platelet aggregation to ADP in whole blood. A trend of reduced secondary platelet aggregation to ADP with increasing dietary eicosapentaenoic acid was noted, but this was not statistically significant. The results of this study and the MRC Diet and Reinfarction Trial suggest a mediatory role for platelet activity in the relationship between diet and ischaemic heart disease.

Adult↗
PubMed1990

An immunoradiometric assay for von Willebrand factor antigen to assess angiogenesis.

A method of determining the degree of vascularization of tissues would be of great value in dermatological research such as the investigation of neoangiogenesis in wounds and in the study of the vascular abnormality in psoriasis. We describe an adaptation of an immunoradiometric assay (IRMA) for von Willebrand factor antigen for this purpose. The results show that in endothelial cells in culture there was a good relationship between the number of cells and von Willebrand factor antigen measured by the IRMA. The relationships between the numbers of endothelial cells in biopsies of normal and healing wound skin as estimated by the histometric technique and the IRMA are less good (r = 0.45 and 0.32, respectively) but suggest that there is a positive and proportionate variation. There is a much stronger relationship (r = 0.79) between the biochemical and histometric methods in psoriatic skin.

Adolescent↗
PubMed1978

Mass and infrared spectra of diaryl and aryl alkyl sulfate diesters.

The synthesis and the infrared and mass spectra of diaryl and aryl alkyl sulfate diesters are described. The mass spectra of these two classes of compounds consistently showed an intense molecular ion and two or three additional intense, diagnostic ions. Their infrared spectra also gave information useful for characterizing and differentiating these two classes of compounds.

Benzene Derivatives↗