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Biomedical subjects

R Carlin

Publications and source records attributed to R Carlin.

At least 19 recordsLinked to original sources
PubMed2006

Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome.

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy. In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.

Acute Disease↗
PubMed1986

Binding of L-[3H]glutamate to fresh or frozen synaptic membrane and postsynaptic density fractions isolated from cerebral cortex and cerebellum of fresh or frozen canine brain.

Synaptic membrane (SPM) and postsynaptic density (PSD) fractions isolated from cerebral cortex (CTX) and cerebellum (CL) of canine brain, either fresh or frozen and isolated from either fresh or frozen tissue, were found to contain L-[3H]glutamate binding sites. It was found that there was a concentration of L-glutamate binding sites in CTX-PSD and CL-PSD over the respective membrane fractions, and the Bmax value of CL-PSD (92.0 pmol/mg protein) was about three times that of CTX-PSD (28.9 pmol/mg). The results, together with those of others, suggest that the thin CL-PSD are probably derived from the excitatory synapses in the molecular layer. The ion dependency of L-glutamate binding to canine CTX-SPM fraction was found to be similar to that reported for a rat brain SPM fraction: (a) Cl- increased the number of L-glutamate binding sites and the effect was enhanced by Ca2+; Ca2+ alone had no significant effect; (b) the Cl-/Ca2+-sensitive binding sites were abolished by 2-amino-4-phosphonobutyrate (APB) or freezing and thawing; (c) the effect of Na+ ion was biphasic; low concentration of Na+ (less than 5 mM) decreased Cl-/Ca2+-dependent L-glutamate binding sites, whereas at higher concentrations of Na+ the binding of glutamate was found to increase either in the presence or absence of Ca2+ and Cl-. In addition, the K+ ion (50 mM) was found to decrease the Na+-independent and Cl-/Ca2+-independent binding of L-glutamate to fresh CTX-SPM by 18%, but it decreased the Na+-dependent and Cl-/Ca2+-independent L-glutamate binding by 93%; in the presence of Cl-/Ca2+, the K+ ion decreased the Na+-dependent binding by 78%. Freezing and thawing of CTX-SPM resulted in a 50% loss of the Na+-dependent L-glutamate binding sites assayed in the absence of Ca2+ and Cl-. The CL-SPM fraction showed similar ion dependency of L-glutamate binding except for the absence of Na+-dependent glutamate binding sites. The CTX-PSD fraction contained neither Na+-dependent nor APB (or Cl-/Ca2+)-sensitive L-glutamate binding sites and its L-glutamate binding was unaffected by freezing and thawing, in agreement with the reported findings using rat brain PSD preparation. L-Glutamate binding to CTX-SPM or CTX-PSD fraction was not affected by pretreatment with 10 mM L-glutamate, nor by simultaneous incubations with calmodulin.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminobutyrates↗
PubMed1985

Existence of a Ca2+-dependent K+ channel in synaptic membrane and postsynaptic density fractions isolated from canine cerebral cortex and cerebellum, as determined by apamin binding.

Apamin, a 18-amino acid neurotoxin isolated from bee venom, is a specific blocker of one class of the Ca2+-dependent K+ channels. The monoiodo derivative of the toxin with high specific radioactivity (1600 Ci/mmol) has been used to study its binding to synaptic membrane (SM) and postsynaptic density (PSD) fractions isolated from cerebral cortex (CTX) and cerebellum (CL) of canine brains. The Bmax (30.2 fmol/mg protein) for CTX-PSD is about twice that for CTX-SM (17.3 fmol/mg protein), suggesting a concentration of the apamin receptor protein in CTX-PSD over CTX-SM fractions. The lower value of Bmax for CL-PSD (12.3 fmol/mg protein), and the higher Kd value (51 pM) than for CTX-SM (33 pM), CTX-PSD (24 pM), and CL-SM (39 pM), may reflect the disruptive effect of Triton X-100 on these thin structures. The values of Bmax and Kd for CTX-SM are similar to those (22.0 fmol/mg protein and 33 pM) for rat CTX-SM. Both Ca2+ and Na+ inhibit apamin binding to CTX-PSD with K0.5 values of 14 and 31 mM, respectively, while the optimum concentration of KCl for activation is 5 mM. All these values are similar to those found for rat synaptosomes. Covalent labeling of the apamin binding protein, using the non-cleavable cross-linker, disuccinimidyl suberate, reveals an apamin binding polypeptide of 27 kdaltons under reducing and denaturing conditions in both the CTX-SM and CTX-PSD preparations, similar to that (28 kdaltons) reported for rat CTX-SM fractions. Prior phosphorylation of isolated CTX-PSD had no effect on apamin binding, nor did apamin binding influence subsequent phosphorylation of CTX-PSD. Calmodulin, an intrinsic PSD protein, may not play a role in apamin binding to PSD, since addition of calmodulin, or removal of the calmodulin by EGTA treatment, resulted in no change in the binding capacity of the PSD. The apamin binding protein seems to be bound quite firmly in the CTX-PSD fraction since treatments with 0.5% deoxycholate, 1% N-lauroyl sarcosinate, 4 M guanidine-HCl, pH 7.0, 0.5 M KCl and 1.0 M KCl, could only remove the apamin-receptor complexes from CTX-PSD by 40, 55, 52, 12 and 15%, respectively. These results contrast with the findings that the two detergents mentioned solubilize 80-93% of the receptor from synaptosomal or synaptic membrane fractions, indicating that a good deal of the receptor in these fractions is membrane-bound and not connected to the PSD.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Mortality, morbidity and long-term results in surgically treated hyperthyroid patients. Review of 597 cases.

An analysis is presented of 597 cases of Graves' disease or toxic multinodular goitre surgically treated in 1956-1980. The mortality rate was only 0.2%. The incidence of postoperative haemorrhage was 0.2%, damage to the recurrent laryngeal nerve 3.2%, postoperative thyrotoxic crisis 1.7%, acute hypoparathyroidism 2.2% and acute postoperative respiratory failure due to tracheomalacia 0.5%. Early complications were significantly more common among the patients with Grave's disease than in the multinodular goitre group. Thyroid function was re-evaluated in 116 patients after a mean postoperative interval of 9 years. Hyperthyroidism had recurred in ten of them and six were hypothyroid (8.6 and 5.2%). The evolution of the thyroid functional status was not significantly related to the pathology or to the sex or age of the patients.

Adolescent↗
PubMed1983

[Clinico-epidemiological study of patients with phlebolymphatic diseases admitted to the hospitals of the Piedmont region 1976-1979. I. Analysis of all phlebolymphatic diseases].

In conjunction with the University Calculation Centre and the Piedmont Region, a computerised study was made of all patients (31,514 cases) admitted to Piedmont hospitals for phlebopathy and peripheral lymphopathy, including pulmonary embolism, in the period 1976-79. An account is given of the method used, the material, and the statistical technique. An 18.9% prevalence of women was noted. Occupation, age category, type of pathology, and treatment adopted were assessed for phlebopathies in toto and for each type. The data for each public health unit, divided by age category, were correlated with the general cases for the Region and those for each unit. In this way, it was possible to determine the incidence of phlebopathies in each unit and over the Region as a whole in relation to age. A map of the Region showing areas of higher, lower, and not significantly different from the regional mean hospitalisation (i.e. phlebopathy) was prepared. The significance of the different incidences in the several units is discussed in relation to their populations, geographical location, raye of migration, and types of occupational activity.

Adult↗
PubMed1983

[Clinico-epidemiological study of patients with phlebolymphatic diseases admitted to the hospitals of the Piedmont region 1976-1979. II. Analysis of lymphatic diseases and pulmonary embolism].

The second part of this research project looks at two very different pathologies. Pulmonary embolisms are usually emergency admissions, while lymphopathies, and this may well be an incorrect term, usually receive outpatient treatment and are only hospitalised in cases of serious incapacitation. Whereas lymphopathies were so few as to prevent any conclusions being drawn, regional admissions of pulmonary embolism occur every 28 hours and 44 minutes i.e. about 1 case per day. No particular relation between the distribution of pulmonary embolism and geographical area, level of industrialisation or migration was discovered. On the contrary there are few areas with higher figures than the expected regional average and these may be attributed to better medical organisation. Finally it should be emphasised that while cases of pulmonary embolism increase with age, the rise is less substantial than might have been expected.

Adult↗
PubMed1983

[Clinico-epidemiologic study of patients with phlebolymphatic diseases admitted to the hospitals of the Piedmont region 1976-1979. III. Analysis of varicose disease].

With the aid of the University and Piedmont Region Computer Centre all cases of varicose admitted to Piedmontese hospitals between 1976 and 1979 were examined. One admission every 1 hour 35 minutes is the regional average. In terms of age there is a numerical prevalence (8526 cases) of the under forty-fives, while in percentage terms, admissions appear to increase in proportion to age. Admissions in age groups to all the individual clinics were correlated with a view to the evaluation of any variations from the regional average, without incidentally confirming these figures. Detailed statistical analysis was employed to correlate the study.

Adult↗
PubMed1983

[Clinico-epidemiological study of patients with phlebolymphatic diseases admitted to the hospitals of the Piedmont region 1976-1979. IV. Analysis of thrombophlebitis].

In the 1976-79 period, 8040 cases of thrombophlebitis, equivalent to 0.17% of the population, were admitted to Piedmontese hospitals, an average of 1 admission every 4 hours and 3 minutes. The present study revealed a numerical and percentage increase with increasing age. The figures per age group from each individual clinic revealed two large areas in the East and South West of the Region where phlebitis cases were numerically lower than the regional average. In other areas figures were higher than estimated, while still others produced statistically insignificant figures. An interpretation of these results is attempted.

Adult↗
PubMed1977

Partition of xenon and iodoantipyrine among erythrocytes, plasma, and myocardium.

A new method was developed for determining directly the distribution of 133Xe between red cells and plasma in vitro without an air-fluid interface; the partitioning of 133Xe and 133-i-iodantipyrine between blood and myocardium was investigated in the dog in situ. The red cell-plasma partition coefficient for 133Xe (lambdacpX, unit: ml/ml) at 37 degrees C was 2.27 +/- 0.07 (mean +/- SD) for human blood and 3.31 +/- 0.06 for dog blood. The red cell-plasma partition coefficient for 131I-iodantipyrine (lambdacpI, ml/ml) was 0.75 +/- 0.04 for human blood and 0.97 +/- 0.03 for dog blood. lambdacpX and lambdacpI did not change significantly after the intravenous administration of sodium pentobarbital (30 mg/kg) into the dog. lambdacpX of dog blood varied inversely with temperature, whereas lambdacpI showed very little change with temperature. The blood-left ventricle partition coefficient for 133Xe (lambda'btX, corrected for trapped blood) varied directly with directly with red cell volume fraction (H): lambda'btX = 1.32 + 2.00 H. Blood-left ventricle partition coefficient for 131I-iodoanitpyrine did not vary significantly with H. The results support the concept of a three-compartment partition of the indicator among erythrocytes, plasma, and myocardium. The mean values (+/- SD) of the hematocrit-independent plasma-tissue partition coefficient in the left ventricle for 133Xe and 131I-iodoantipyrine were 1.08 +/- 0.16 and 1.54 +/- 0.20 g/ml, respectively.

Anesthesia, Intravenous↗
PubMed1977

Effect of hematocrit on the washout of xenon and iodantipyrine from dog myocardium.

The rates of washout of 133Xe and 131I-iodoantipyrine from the myocardium into the coronary sinus blood were determined over a wide range of hematocrits after simultaneous injection of the isotopes into the left anterior descending coronary artery of dogs. The ratio of the monoexponential disappearance constants (kX/kI), which is a measure of the ratio of the dynamic blood-tissue partition coefficients (lambdabIX/lambdabtI), increases linearly with hematocrit. This dynamic lambdabt ratio has almost the same relationship to hematocrit as the static lambdabt ratio. By the use of appropriate hemotocrit-specific lambdabt values, we found that simultaneous blood flows calculated from the two indicators with different disappearance constants showed excellent agreement. If this hematocrit-dependent alteration in indicator partitioning is neglected, blood flow measurement in the dog with 133Xe washout may introduce an error of approximately 1.15% per unit hematocrit deviation from the normal value (taken as 45%), whereas blood flow measurements with 131I-iodanatipyrine washout had negligible errors.

Animals↗
PubMed1977

Inhaled nitrous oxide and cathepsin D activity in the lung.

Acute exposures of lungs to nitrous oxide in anesthetic concentration results in an initial lowered free activity of cathepsin D. Chronic exposures with either continuous or interrupted anesthetic exposure increases the free activity of this enzyme.

Anesthesia, Inhalation↗