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Biomedical subjects

M Baker

Publications and source records attributed to M Baker.

At least 163 records · Page 9Linked to original sources
PubMed1994

A phase I study of curdlan sulfate--an HIV inhibitor. Tolerance, pharmacokinetics and effects on coagulation and on CD4 lymphocytes.

Curdlan sulfate (CRDS) is a semi-synthetic sulfated polysaccharide which has anti-HIV activity in vitro, and inhibits attachment of the virus to T-cells. After two weeks of exposure of virus and cells to CRDS, there is complete inhibition of virus replication. CRDS is also active against cytomegalovirus. The favorable toxicological profile of CRDS in animals suggested clinical trials. In this study, doses of 0.014, 0.14, 0.42, 1.42, 2.84 and 4.26 mg/Kg (hereinafter referred to as 1, 10, 30, 100, 200 and 300 mg/body, respectively, for convenience) were administered to three HIV-positive patients at each dose level for four hours intravenously. Activated partial thromboplastin times (APTT) were measured hourly. Unexpectedly, single doses of CRDS produced marked, dose-related, increases in CD4 lymphocytes in HIV-infected patients. There were no clinical side effects seen at any dose tested. All laboratory parameters were normal except for prolongation of APTT in the 200 and 300 mg dose group. Two patients in the 300 mg dose group had a doubling of the APTT during the four hour infusion, which was the termination point of the trial according to the protocol. The half-life of CRDS was estimated to be 2 to 3 hours from the APTT data and from the blood level assays (not shown). CRDS was well tolerated in the study with the APTT levels being a convenient monitoring basis for dosing. Marked increases in CD4 levels were seen at higher doses, which, if confirmed and extended, may have therapeutic implications. CRDS is considered safe for multiple dosing with monitoring of APTT.

Adult↗
PubMed1994

Measuring swainsonine in serum of cancer patients: phase I clinical trial.

Swainsonine, an indolizidine alkaloid and competitive inhibitor of Golgi alpha-mannosidase II (EC 3.2.1.114), reduces tumor growth and stimulates immune function in mice. On the basis of these observations, a phase I clinical trial was initiated to determine whether swainsonine could be administered safely to cancer patients. We describe a method for extraction, acetylation, and quantification of swainsonine in human serum samples. Methyl alpha-D-mannopyranoside and methyl beta-D-galactopyranoside were added to serum samples as internal standards and, after sequential extraction of lipids and proteins with chloroform and acetonitrile, respectively, samples were acetylated with acetic anhydride and 4-dimethylaminopyridine and separated by gas-liquid chromatography. The identity of swainsonine and the internal standards after their extraction from serum and acetylation was confirmed by gas chromatography/mass spectrometry. Swainsonine was recovered at an efficiency of 90%, relative to internal standards, and calibration graphs were rectilinear from 3 to 18 mg/L with a detection limit of approximately 0.1 mg/L. The CV for multiple samples was < or = 6.7%. In patients receiving swainsonine (50-550 micrograms/kg per day) continuously for 5 days by intravenous infusion, serum concentrations of the drug reached 3-11.8 mg/L, 100 to 400 times greater than the 50% inhibitory concentration for Golgi alpha-mannosidase II and lysosomal alpha-mannosidases. Accurate measurements of swainsonine in biological fluids with this method should facilitate further clinical studies with the drug.

Acetylation↗
PubMed1993

Mechanism of intragastric tetramethylammonium protection against 40% ethanol injury in rat stomach.

The effect of tetramethylammonium (TMA), a ganglionic stimulant, on gastric mucosal injury induced by 40% ethanol was examined. In studies I-III, rats were treated with intragastric vehicle or TMA (1 or 10 mg/kg). In study I, 1 hr after the treatment, 40% ethanol was given intragastrically. The length of the linear corpus mucosal lesions was measured unbiasedly with a caliper after another hour. In study II, mean blood pressure was assessed before and after the treatment. In study III, 1 hr after the treatment, gastric mucus and juice volumes, and titratable acid were measured. In study IV, 40% ethanol (10 ml/kg) was administered intragastrically immediately after 0.2 or 1.4 ml of intragastric vehicle treatment. One hour later, gastric lesions score was assessed as in study I. Results show that (1) intragastric TMA dose-dependently protected against 40% ethanol-induced gastric injury; (2) neither dose of intragastric TMA increased mean blood pressure; (3) there was a dose-related increase in gastric mucus secretion for TMA 1 and 10 mg/kg, and a significant increase in gastric juice volume only for TMA 10 mg/kg; and (4) the rats treated with 1.4 ml of vehicle plus 40% ethanol had significantly less injury than those treated with 0.2 ml of vehicle plus 40% ethanol. We conclude that the protective effect of intragastric TMA can be explained by its dose-related effect in enhancing gastric mucus secretion for TMA 1 and 10 mg/kg and the significantly greater increase in gastric juice volume for TMA 10 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1993

Involvement of alpha 2-adrenoceptors in mechanism of intragastric nicotine protection against ethanol injury in rat stomach.

To elucidate the role of alpha- and beta-adrenoceptors in the mechanism of intragastric nicotine protection against ethanol-induced gastric mucosal injury, the following studies were performed. At 0.5-hr prior to the injury study, rats were pretreated with: subcutaneous control, prazosin (0.5 mg/kg) or yohimbine (5 mg/kg) to block alpha 1- or alpha 2-adrenoceptors; or intraperitoneal control, metoprolol (2 mg/kg) or butoxamine (4 mg/kg) to block beta 1- or beta 2-adrenoceptors, respectively. At 1-hr intervals, rats received intragastric vehicle or nicotine (4 mg/kg) and 40% ethanol (10 ml/kg). Total lengths of the linear gastric corpus mucosal lesions were measured by an unbiased observer using a caliper. In a separate study, 0.5-hr after subcutaneous control or yohimbine (5 mg/kg), rats were treated with intragastric vehicle or nicotine (4 mg/kg). One hour later, gastric mucus volume, gastric juice volume and pH, and titratable acid in the gastric juice were measured. In the rat stomach, the intragastric nicotine protection against 40% ethanol-induced mucosal injury was not blocked by selective alpha 1-(prazosin), beta 1-(metoprolol), or beta 2-(butoxamine) adrenoceptor antagonists. The protection was significantly reduced although not completely abolished by selective alpha 2-(yohimbine) adrenoceptor antagonist. Yohimbine also significantly reduced basal and nicotine-stimulated increase in gastric mucus volume. These data suggest that alpha 2-adrenoceptors are involved in the protective effect of intragastric nicotine against 40% ethanol-induced gastric mucosal injury possibly by a mucus-dependent mechanism.

Adrenergic alpha-Antagonists↗
PubMed1993

Management of major biliary complications after laparoscopic cholecystectomy.

OBJECTIVE: A total of 50 major bile duct injuries after laparoscopic cholecystectomy were managed by the Duke University Hepatobiliary Service from 1990-1992. The management of these complex cases is reviewed. SUMMARY BACKGROUND DATA: Laparoscopic cholecystectomy is the preferred method for removing the gallbladder. Bile duct injury is the most feared complication of the new procedure. METHODS: Review of videotapes, pathology, and management of the original operations were reviewed retrospectively, and the injuries categorized. Major biliary injury was defined as a recognized disruption of any part of the major extrahepatic biliary system. Biliary leakage was defined as a clinically significant biliary fistula in the absence of major biliary injury, i.e., with an intact extrahepatic biliary system. RESULTS: Thirty-eight injuries were major biliary ductal injuries and 12 patients had simple biliary leakage. Twenty-four patients had the classic type injury or some variant of the classic injury. A standard treatment approach was developed which consisted of ERCP for diagnosis, preoperative PTC with the placement of stents, CT drainage immediately after the PTC for drainage of biliary ascites, and usually Roux-en-Y hepaticojejunostomy with placement of O-rings for future biliary access if necessary. Major ductal injuries were high in the biliary system involving multiple ducts in 31 of the 38 patients. Re-operation was required in 5 of the 38 patients with particularly complex problems. CONCLUSIONS: Successful management of bile duct injury after laparoscopic cholecystectomy requires careful understanding of the mechanisms, considerable preoperative assessment by experts, and a multidisciplinary approach.

Anastomosis, Roux-en-Y↗
PubMed1993

Two types of 4-aminopyridine-sensitive potassium current in rabbit Schwann cells.

1. Delayed rectifier K+ currents were studied in Schwann cells cultured from neonatal rabbit sciatic nerves with the whole-cell patch-clamp technique. 2. Depolarizing voltage steps (40 ms duration) activated two types of K+ current: type I, whose apparent activation threshold was about -60 mV (half-maximal conductance at -40 +/- 1 mV, n = 10); and type II, whose apparent activation threshold was about -25 mV (half-maximal conductance at + 11 +/- 1 mV, n = 9). 3. Type I current was blocked by alpha-dendrotoxin (alpha-DTX) with an apparent equilibrium dissociation constant (KD) of 1.3 nM, whereas the type II current was unaffected by exposure to 500 nM toxin. The action of alpha-DTX on the type I current was reversible. 4. Most cells exhibited both types of current, but occasionally some cells displayed just type I or just type II. 5. Type I current activated rapidly and then showed a much slower fade, which became more noticeable with larger depolarizations. Activation of type II current was slower than that of type I and depended less steeply on voltage. The time constants of activation for type I and type II currents were derived with a Hodgkin-Huxley formalism (based on second-power activation and deactivation kinetics). The longest activation time constant for type II gating was more than twice the corresponding time constant for type I; however, the time constants determined from tail current decays at potentials more negative than -60 mV were shorter for the type II currents than for the type I currents. 6. Both type I and type II currents were sensitive to micromolar concentrations of 4-aminopyridine (4-AP). The KD for 4-AP blockade of type II current was 630 microM (pH 7.2, membrane potential (Em) = -10 mV), which is about 6 times higher than the corresponding value for 4-AP blockade of type I current at negative membrane potentials. The differential sensitivity of the type I and type II currents to 4-AP may account for the apparent voltage dependence of 4-AP block of delayed rectifier K+ currents. 7. In addition to types I and II, a third type of outward K+ current (type III) was generated in most cells at positive membrane potentials. This latter current was insensitive to millimolar concentrations of 4-AP. 8. Similarities between Schwann cell and neuronal potassium channels are discussed.

4-Aminopyridine↗
PubMed1993

Role of aberrant sialylation of chronic myeloid leukemia granulocytes on binding and signal transduction by chemotactic peptides and colony stimulating factors.

Chronic myelogenous leukemia (CML) granulocytes exhibit a number of characteristics attributable to immature granulocytes, including marked increases in cell surface sialylation of glycoproteins which may be due, at least in part, to an increased activity of cytidine 5'-monophosphate-N-acetylneuraminic acid:Ga1 beta 1-3Ga1NAc alpha(2-3)-sialyltransferase (EC 2.4.99.4), and perhaps to altered activity of other glycosyltransferases and sialidases. This aberrant sialylation of CML granulocytes contributes to the decreased binding of the synthetic chemotactic peptide, formyl Met Leu Phe (fMLP), to the surface of CML granulocytes which leads to a rapid, transient increase in cytosolic free calcium ([Ca2+]i), an integral step in the biochemical cascade leading to cell activation. To determine if the decrease in binding of fMLP to CML granulocytes translates into a functional deficit, we measured fMLP-induced increases in [Ca2+]i. Compared to normal granulocytes, fMLP-induced increases in [Ca2+]i were markedly decreased in CML granulocytes. After sialidase treatment, a significant augmentation in fMLP-induced increases in [Ca2+]i was noted in CML granulocytes, indicating that the decreased signalling may be a consequence of aberrant sialylation. To determine if the effects of aberrant sialylation also alters the binding of endogenous polypeptide mediators, we determined the effect of desialylation of CML and normal granulocytes on binding of the colony stimulating factor for granulocytes and monocytes (GM-CSF), which plays a role in differentiation and proliferation of myeloid-lineage cells. As with fMLP binding, we also showed that the binding of GM-CSF to CML granulocytes, but not normal granulocytes, was markedly increased after sialidase treatment. Similarly, binding of GM-CSF to undifferentiated HL-60 cells was markedly increased after sialidase treatment. Therefore, we have demonstrated that aberrant sialylation of CML granulocytes not only alters the binding of fMLP and GM-CSF to their receptor(s), but may also alter signal transduction. Thus, aberrant glycosylation of CML granulocytes may reduce the binding of hematopoietic growth factors, which in turn may be responsible for the immature phenotype of CML granulocytes.

Calcium↗
PubMed1993

Samarium-153-EDTMP biodistribution and dosimetry estimation.

Fifty-two patients were treated with single doses of 153Sm-EDTMP in a Phase I escalating dose protocol for palliation of bone pain from metastatic prostate carcinoma. Samarium-153 (T1/2 46.3 hr), maximum beta-particle energies 810 keV (20%), 710 keV (30%), 640 keV (50%), gamma photon 103 keV (28%), was complexed to the tetraphosphonate chelate, EDTMP. Five groups of patients were treated at doses of 1.0, 1.5, 2.0, 2.5, and 3.0 mCi/kg to evaluate toxicity from treatment. Patients were screened prior to treatment and followed after treatment with 99mTc-MDP bone scans. Biodistribution data on this group of patients were acquired and showed rapid uptake of 153Sm-EDTMP into bone with complete clearance of nonskeletal radiotoxicity by 6-8 hr. Also included are complete sets of dosimetry estimations on an additional seven patients who received 0.5 mCi/kg 153Sm-EDTMP Ca++ as part of a multiple dose therapy trial. Estimated radiation absorbed doses to bone surfaces averaged 25,000 mrad/mCi (6686 Gy/MBq), and urinary bladder doses averaged 3600 mrad/mCi (964 Gy/MBq).

Bone Neoplasms↗
PubMed1993

Phase I study of a continuous infusion of high-dose ara-C in conjunction with a fixed dose of 2'-deoxycytidine (IND 28108) in patients with refractory leukemia: an interim report.

A total of 16 patients with refractory leukemia have been entered on a phase I study employing escalating doses of a 96 h continuous infusion of high-dose cytosine arabinoside (ara-C) administered in conjunction with a 120 h infusion of a fixed dose (22 g/m2 per day) of 2'-deoxycytidine (IND 28108) as a host-protective agent. Extramedullary toxicities, even at the highest ara-C dose level (e.g. 14 g/m2 per day) were mild (e.g. CALGB grade I or II), and consisted of diarrhea, fluid retention, somnolence, hepatic dysfunction, and febrile episodes. Neutropenia and thrombocytopenia were noted in all patients, but no serious infections or bleeding episodes were encountered. Steady state plasma ara-C concentrations of 20-60 microM were observed in patients treated at the 14 g/m2 dose, and were associated with plasma ara-U concentrations approaching 1 mM. Although no complete remissions were obtained at the ara-C dose levels tested to date, three partial remissions were noted, and the large majority of patients experienced a clearing of peripheral blood blasts. In addition, several patients who failed to achieve objective responses exhibited atypically benign clinical courses following completion of therapy. These findings demonstrate that 2'-deoxycytidine protects humans from otherwise lethal doses of high-dose ara-C administered by continuous infusion, and substantially ameliorates the hematologic and non-hematologic toxicity of such regimens without completely abrogating antileukemic activity. Determination of the ultimate efficacy of this strategy will require identification of an ara-C maximum tolerated dose and evaluation of the antileukemic potential of this regimen in prospective phase 11 trials.

Adult↗
PubMed1992

On the block of outward potassium current in rabbit Schwann cells by internal sodium ions.

Currents through delayed rectifier-type K+ channels in Schwann cells cultured from rabbit sciatic nerve were studied with patch-clamp techniques. When the internal and external solutions contained physiological concentrations of sodium, the amplitude of these outward currents declined as the cell was depolarized to potentials above about +40 mV, despite the increased driving force. This reduction in the amplitude of outward K+ currents was observed in many cells before the subtraction of leakage currents; it was also observed for ensemble currents recorded in outside-out patches. It was therefore not the result of a leak-subtraction artefact nor of inadequate voltage-clamp control. Several lines of evidence also suggested that it was not the result of the extracellular accumulation of K+. By contrast, when the Na+ ion concentration of the internal solution was nominally zero, the reduction in the amplitude of outward K+ currents at positive membrane potentials was not observed. The apparent amplitude of single-channel currents through two types of K+ channel was reduced by 30 mM internal Na+, apparently as the result of a rapid 'flickery' block. The results suggest that channel block by internal Na+ is largely responsible for the negative slope conductance seen in current-voltage plots of whole-cell K+ currents at positive membrane potentials. In addition, our analysis of single-channel currents suggests that the current-voltage curve for a delayed rectifier channel in rabbit Schwann cells (in the absence of internal Na+) is roughly linear with internal and external K+ concentrations of 140 mM and 5.6 mM, respectively.

Animals↗
PubMed1992

How well are we protecting our children? An immunisation coverage survey in Hawke's Bay.

AIMS: In July 1991, an immunisation coverage survey was conducted to assess the proportion of two year old children who have been vaccinated in the Hawke's Bay. METHODS: Parents from a representative sample of 100 households with children between the ages of two and four years of age were interviewed regarding household characteristics and parental attitudes towards immunisation. Immunisation histories were abstracted from each child's Health and Development Record Book or, if this was not available or was incomplete, from records retained by the general practitioner(s) responsible for administering immunisations to the child. RESULTS: Coverage levels among two year olds exceeded 85% for all postneonatal vaccinations scheduled for the first year of life; however, levels among two year olds were lower than 85% for all vaccinations scheduled to be received after the first birthday. Overall, only 61% (95% confidence interval (CI) = 50.7, 70.6) of the children were fully vaccinated by the age of two years. Children living in a household where the principal source of income was from benefits were almost 60% less likely to have been fully immunised at two years of age (odds ratio (OR) = 0.42, 95% CI = 0.18, 0.97), as were Maori children (OR = 0.43, 95% CI = 0.18, 1.06). CONCLUSIONS: These results emphasise the need for enhanced education about the importance of completing the full series of recommended vaccinations and of on-time vaccination, as well as for checking childrens' vaccination histories at every contact with the healthcare system and, where necessary, administering past-due immunisations.

Adult↗
PubMed1992

Effects of the peroxisome proliferators ciprofibrate and perfluorodecanoic acid on hepatic cellular antioxidants and lipid peroxidation in rats.

The purpose of this study was to determine if hepatic cellular antioxidants and indices of oxidative damage are altered by administration of the peroxisome proliferators ciprofibrate and perfluorodecanoic acid (PFDA). Rats were fed 0.01% ciprofibrate in the diet or were injected with PFDA (0.5 or 5.0 mg/kg, i.p.) every 4 weeks for 6, 14, 30, 54, and 78 weeks. Peroxisomal fatty acyl-CoA oxidase and catalase activities were increased by both ciprofibrate and PFDA throughout the study. Neither ciprofibrate nor PFDA increased the levels of malonaldehyde or conjugated dienes, but ciprofibrate decreased these indices at early time points. Ciprofibrate decreased the following cellular antioxidants or antioxidant enzymes: vitamin C, vitamin D, DT-diaphorase, glutathione peroxidase, glutathione-S-transferase, and glutathione reductase; superoxide dismutase and glutathione were not affected. PFDA decreased DT-diaphorase and increased superoxide dismutase, but did not affect other cellular antioxidants. This study shows that administration of the peroxisome proliferators ciprofibrate and PFDA did not increase indices of lipid peroxidation, but that cellular antioxidant defenses were inhibited for a prolonged period of time by the peroxisome proliferator ciprofibrate.

Acyl-CoA Oxidase↗