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Biomedical subjects

D Chang

Publications and source records attributed to D Chang.

At least 307 records · Page 17Linked to original sources

Effect of synthetic substance P on monoaminergic mechanisms in brain.

Synthetic substance P has been discovered to stimulate significantly the formation of dopa in the limbic, striatum, hemisphere and diencephalon regions of the brain and the lower brain stem. There was no effect upon 5-hydroxytryptophan formation or on tryptophan or tyrosine levels. After inhibition of monoamine synthesis by N'-(DL-SERYL)-N2-(2, 3, 4-trihydroxybenzyl)hydrazine, substance P significantly accelerated the disappearance of dopamine, noradrenaline and 5-hydroxytryptamine. Substance P appears to stimulate monoaminergic neurons in the brain and to serve as an excitatory transmitter in nerve terminals impinging upon dopaminergic cell bodies. A similar stimulation of noradrenaline and 5-hydroxytryptamine indicate a similar transmitter role for noradrenergic and serotonergic neurons. These data strengthen questions about the possible clinical influence of substance P in disease states involving monoaminergic mechanisms including Parkinsonism and schizophrenia.

Animals↗

Synthesis and activities of neurotensin, and its acid and amide analogs: possible natural occurrence of [Gln4]-neurotensin.

It was considered, a priori, that the isolation of the tridecapeptide, neurotensin, might have inadvertently sllowed the hydrolysis of either the [Gln4]- or the [Leu13-NH2]-moieties. Neurotensin and its three acid and amide analogs, i.e., [Gln4]-neurotensin, neurotensin-NH2, and [Gln4]-neurotensin-NH2 were synthesized. Neurotensin and [Gln4]-neurotensin were indistinguishable by the hypotensive assay, hyperglycemic assay, contraction of the ileum, and radioimmunoassay. Neurotensin-NH2 and [Gln4]-neurotensin-NH2 showed less than 1% of these neurotensin activities. Present information does not elucidate whether the glutamic acid residue in position 4 of neurotensin in situ is present as Glu4 or as Gln4. At high levels, neurotensin released the luteinizing hormone, follicle stimulating hormone, and thyrotropin; [Gln4]-neurotensin-NH2 released thyrotropin, and [Gln4]-neurotensin released luteinizing hormone and follicle stimulating hormone, but these activities do not appear biologically significant.

Animals↗

Chemistry of cholera toxin: the subunit structure.

The toxin of Vibrio cholerae was separated into two subunits by gel filtration on Sephadex G-75 in 5% formic acid. The subunits were designated A and B. Amino acid analysis indicated that subunit B corresponded to choleragenoid. Renatured subunit B was found to be antigenically identical to the whole molecule, whereas renatured subunit A was not. On reduction and S-carboxymethylation with [2-14C] iodoacetate in 8 m urea, subunit A separated into two polypeptides of unequal sizes, A1 and A2, with equal amounts of radioactivity. Subunit B, on the other hand, remained a single molecular species. Molecular weights of the polypeptides A1, A2, and B were estimated by polyacrylamide gel electrophoresis in sodium dodecyl sulfate-urea buffer, in conjunction with amino acid analysis, to be 20,000, 7,500, and 9,500 daltons, respectively. The carboxyl terminal sequence of subunit B was found to be -Met-Ala-Asn. After treatment of toxin with cyanogen bromide, the peptide Ala-Asn could be isolated and quantitated. From this data the number of B polypeptides in a molecule of toxin was estimated as six.

Amino Acids↗

Cardiovascular and metabolic actions of neurotensin and (Gln4)-Neurotensin.

The actions of the tridecapeptides neurotensin and (Gln4)-neurotensin have been studied on the heart and on the blood flow in subcutaneous adipose tissue, skin and small intestine of anesthetized dogs. In addition, their possible actions have been investigated on blood glucose concentration and lipolysis in subcutaneous adipose tissue. The two peptides were found to be approximately equipotent. Intravenous infusion of 20-120 ng X kg-1 X min-1 produced slight hypotension, an initial vasodilatation in the small intestine and a delayed vasoconstriction in denervated subcutaneous adipose tissue and to a lesser extent in the skin and small intestine. At this infusion rate, neurotensin and (Gln4)-neurotensin did not elicit vasodilatation in the skin or adipose tissue and had no effect on heart rate. The delayed vasoconstriction in adipose tissue was not inhibited by local alpha-receptor blockade. Both neurotensin and (Gln4)-neurotensin increased glucose concentration in the upper dose range. No effects on lipolysis were observed, either in vivo or in vitro. These experiments show that neurotensin and (Gln4)-neurotensin have both vasodilator and vasoconstrictor actions in the peripheral vasculature but seem to be without cardiac actions. They also increase blood glucose concentration. It remains to be shown whether these actions are direct or whether some are indirectly mediated.

Adipose Tissue↗

Amino acid sequence of rabbit muscle aldolase and the structure of the active center.

Elucidation of the amino acid sequence of fructose-1,6-bis-phosphate aldolase from rabbit muscle has made it possible to assign the positions of the functional groups known to play specific roles in the catalytic activity, and also to locate the buried, exposed, and active site cysteine residues. The results indicate that the middle portion of the polypeptide chain, including Cys-134, Cys-149, Cys-177, and Cys-l99, is buried in the native structure, with regions containing Cys-72, Lys-107, Lys-227, Cys-336, His-359, and the COOH-terminal residue (Tyr-361) folded into the active center of the enzyme, at or near the surface of the enzyme molecule.

Amino Acid Sequence↗

In vitro potentiation of the activity of synthetic ovine corticotropin-releasing factor by arginine vasopressin.

The ability of arginine vasopressin (AVP) to potentiate the actions of synthetic ovine corticotropin-releasing factor (CRF) was examined using anterior pituitary fragments. Marked potentiation of ACTH release was observed upon incubating the fragments with a combination of 2 nM AVP and 1 nM CRF. Potentiation of CRF-induced ACTH release was also observed when the fragments were incubated with a combination of 1 nM AVP and 0.5 nM CRF. These results suggest that AVP may play a role in the release of ACTH from the adenohypophysis.

Adrenocorticotropic Hormone↗

Immunocytochemical localization of CRF in the ovine hypothalamus.

A population of neuronal cell bodies and their fiber pathways have been elucidated within the ovine hypothalamus. The immunoreactive neurons were located in the anterior and dorsal hypothalamus interspersed throughout the paraventricular nucleus. These perikarya were only observed when an antiserum that was generated against the C-terminal of CRF was employed. A dense fiber projection traversed the medial-basal hypothalamus and ended within the palisade-contact zone of the median eminence and neural stem. Fibers were revealed by antisera generated against both the N-terminal and the C-terminal of CRF. Antisera pre-absorbed with synthetic CRF failed to yield immunoreactivity.

Animals↗

Characterization and localization of atriopeptin in rat atrium.

An antiserum specific for atriopeptin was used to characterize and localize atriopeptin-like immunoreactive material in rat atrium by radioimmunoassay and immunohistochemical techniques. The antiserum recognizes atriopeptin I, atriopeptin III, and alpha-human atrial natriuretic polypeptide, but does not recognize met-enkephalin, cholecystokinin, dynorphin A, bradykinin, substance P, or beta-endorphin. A high content of atriopeptin was found in crude extracts of rat atria, as compared to ventricles, and the atriopeptin-like immunoreactive material was found to be located exclusively in granules within atrial cardiocytes. Fractionation of the immunoreactive material by gel filtration and reverse-phase HPLC revealed the presence of multiple atriopeptins.

Animals↗

Alpha-human atrial natriuretic polypeptide (alpha-hANP) in normal volunteers and patients with heart failure or hypertension.

The presence of alpha-hANP immunoreactive material in human heart and plasma was investigated with a specific and sensitive radioimmunoassay and immunohistochemical method. It was found that alpha-hANP immunoreactive staining of specific atrial granules was located around the nucleus of atrial cardiocytes. No immunoreactive staining was found in the ventricle. The content of immunoreactive hANP was 0.5 pmol/mg protein in the atria and 0.11 +/- 0.01 pmol/ml in the plasma of 26 normal volunteers. In 16 patients with congestive heart failure and 26 patients with essential hypertension, the plasma level of immunoreactive alpha-hANP was significantly lower than that in normal humans. The above evidence indicate that alpha-hANP is a putative hormone secreted by human atrium. A relative shortage of alpha-hANP in the circulatory system may be involved in the mechanism of heart failure and hypertension.

Atrial Natriuretic Factor↗

Radiofrequency hyperthermia in the palliative treatment of mucinous carcinomatosis of appendiceal origin: optimizing and monitoring heat delivery in western patients.

Mucinous peritoneal carcinomatosis from a primary gastrointestinal malignancy is a lethal condition that has few treatment options with the use of surgery, chemotherapy or radiation therapy. Recent advances in hyperthermia technology and in knowledge of the natural history of this disease has suggested the possible utility of hyperthermia in the application of aggressive local-regional therapy. Radiofrequency (RF) hyperthermia to the whole abdomen, to the hemithorax, or to an isolated mucinous tumour deposit obstructing the gastrointestinal tract was used in patients with disseminated mucinous adenocarcinoma of appendiceal origin. There were 228 hyperthermia treatments in 21 patients, with a median of 10 treatments per patient. The maximum number of treatments was 26, and minimum was one. For the first six hyperthermia treatments, escalating doses of deep hyperthermia (41-45 degrees C) was monitored with multiple sensor internal temperature probes and a single sensor subcutaneous temperature probe. After reaching a maximal hyperthermia treatment, this was maintained for all subsequent treatments. Initially, the maximal temperature allowed in tumour and subcutaneous tissue was 43 degrees C. After 50 hyperthermia treatments, this was changed to 45 degrees C. If disease stabilization or response was insufficient and maximal tolerable hyperthermia had been established, the frequency of treatment was increased from every 4 weeks to every 2 weeks, and escalating doses of mitomycin C at 8 mg/m2 were added to the regimen. Mitomycin C was infused during the hyperthermia treatment. For the first 165 treatments, patients were monitored just before and 10 days after hyperthermia with a complete blood count and a full battery of laboratory tests including amylase and lipase. Response was monitored by carcinoembryonic antigen assays on a monthly basis and CT scans on a 6 monthly basis. None of the 21 patients included in this study died, required intensive care, or required major surgical interventions as a result of hyperthermia treatments. One potentially life-endangering event was profound bradycardia and hypotension observed in a 76-year-old male receiving hyperthermia treatment to his right hemithorax. Two patients developed an enterocutaneous fistula (a frequent spontaneous event in this group of patients) while under treatment. No abnormal laboratory tests were observed in the first 165 hyperthermia treatments. Heat damage to normal tissue was limited to skin blisters in three patients and induration of the subcutaneous tissues in 10 patients. Skin pain on an analogue scale of 0-10 was scored by patients as a mean of 3.6 (range 0-8) before skin analgesia was routinely utilized. With anesthetic gel, the skin discomfort was greatly reduced. Prolonged abdominal pain for 4-20 days following treatment which required narcotic analgesia was seen in four patients. A complication rate of 62% was caused by the long-term indwelling temperature probe sheaths. Infection was observed in four patients, small bowel fistula in one, and dislodgement of the temperature probe sheath requiring repeat CT was necessary in seven patients. After maximal escalation of RF power in seven patients (33%), deep hyperthermia compatible with thermal destruction of tumour (> or = 43 degrees C for 45 min) was recorded in all subsequent treatments. In eight patients (38%), heat generation compatible with chemotherapy augmentation (41.5-43 degrees C) was consistently recorded. In six patients, non-therapeutic temperatures were recorded. There was no correlation of maximal tumour temperature, maximal subcutaneous tissue temperature and maximal RF power. With the use of skin anaesthetic there was no correlation of tumour temperature and the thickness of the subcutaneous layer of the skin. Progression was seen in 14 patients, and 11 of these patients died. No patients who showed disease stabilization have died with a minimum of 2 year follow-up. (ABSTRACT TRUNCATED)

Adenocarcinoma, Mucinous↗

Long-term results of cytoreductive surgery for advanced and recurrent epithelial ovarian cancers and papillary serous carcinoma of the peritoneum.

The aim of this study was to review the long-term results of cytoreductive surgery in the treatment of advanced primary and recurrent epithelial ovarian cancers and papillary serous carcinoma of the peritoneum. Our goal was to identify clinical factors by which to select patients likely to benefit from a comprehensive management plan. Clinical data of 28 females who underwent surgery were retrieved from a prospective database. Major cytoreductive procedures were possible in 25 patients. Heated intraoperative or early postoperative intraperitoneal chemotherapy was also used where appropriate. The median follow-up after cytoreduction was 26.9 months. The overall median survival after cytoreduction was 45.8 months. The prognostic indicators associated with a statistically significant impact on survival were the prior surgery score (P < 0.001), the completeness of cytoreduction score (CC; P = 0.037), and response to chemotherapy prior to surgery (P = 0.012). Our findings suggest that cytoreductive surgery can be effective when combined with perioperative intraperitoneal chemotherapy. Results can be improved by excluding cases where CC seems unlikely. Extensive prior surgery without the protection of adjunctive intraperitoneal chemotherapy is associated with a poor prognosis. This may be due to disruption of anatomical planes leading to deep abdominal and pelvic dissemination intractable to further treatment.

Adult↗

Long-term results of cytoreductive surgery for advanced and recurrent epithelial ovarian cancers and papillary serous carcinoma of the peritoneum.

The aim of this study was to review the long-term results of cytoreductive surgery in the treatment of advanced primary and recurrent epithelial ovarian cancers and papillary serous carcinoma of the peritoneum. Our goal was to identify clinical factors by which to select patients likely to benefit from a comprehensive management plan. Clinical data of 28 females who underwent surgery were retrieved from a prospective database. Major cytoreductive procedures were possible in 25 patients. Heated intraoperative or early postoperative intraperitoneal chemotherapy was also used where appropriate. The median follow-up after cytoreduction was 26.9 months. The overall median survival after cytoreduction was 45.8 months. The prognostic indicators associated with a statistically significant impact on survival were the Prior Surgery Score (P < 0.001), the Completeness of Cytoreduction Score (P = 0.037) and response to chemotherapy prior to surgery (P = 0.012). Our findings suggest that cytoreductive surgery can be effective when combined with perioperative intraperitoneal chemotherapy. Results can be improved by excluding cases where completeness of cytoreduction seems unlikely. Extensive prior surgery without the protection of adjunctive intraperitoneal chemotherapy is associated with a poor prognosis. This may be due to disruption of anatomic planes leading to deep abdominal and pelvic dissemination intractable to further treatment.

Adult↗

Heated intraoperative intraperitoneal mitomycin C and early postoperative intraperitoneal 5-fluorouracil: pharmacokinetic studies.

PURPOSE: The purpose of this study was to report the pharmacokinetics of heated intraoperative intraperitoneal mitomycin C (MMC) and to analyze the impact of heat, extent of peritoneal resections, and effect of intraoperative hyperthermic chemotherapy on the pharmacological properties of the peritoneal plasma barrier. METHODS: Sixty patients with peritoneal carcinomatosis were included in a phase I/II study combining cytoreductive surgery with 2 h of heated intraperitoneal mitomycin C in an intraoperative lavage technique and one cycle of early postoperative 5-fluorouracil (5-FU) given on postoperative days 1-5. Three pharmacokinetic analyses were performed: (1) pharmacokinetics of heated intraoperative intraperitoneal MMC was determined for 18 patients by sampling peritoneal fluid, plasma, and urine during the 2-h procedure; (2) impact of peritoneal resections on MMC pharmacokinetics was assessed by comparing a group of patients who underwent < or = 1 peritonectomy procedure (minimal surgery) to a group of patients who underwent > or = 2 peritonectomy procedures (extensive surgery), and (3) effects of heated intraoperative intraperitoneal chemotherapy on the pharmacokinetics of early postoperative intraperitoneal 5-FU by comparing a group of patients treated with heated intraoperative intraperitoneal MMC to a control group who did not receive heated intraoperative intraperitoneal chemotherapy. RESULTS: The mean dose of heated intraoperative intraperitoneal MMC per patient was 22.5+/-7.1 mg (12.9+/-3.8 mg/m2). Drug absorption from perfusate was 14.3+/-2.7 mg. The mean aeras under the curve (AUC) for perfusate and plasma were, respectively, 340+/-138 and 15+/-4 microg/ml x min. The mean AUC peritoneal fluid/plasma ratio was 23.5+/-5.8. Patients who underwent extensive peritoneal resections exhibited a significantly (p = 0.037; Wilcoxon rank test) increased peak plasma concentration of MMC, a significantly (p = 0.029) increased AUC of plasma concentrations and a significantly (p = 0.034) decreased peritoneal fluid/plasma AUC ratio. Pharmacokinetic studies of early postoperative intraperitoneal 5-FU showed no significant difference in plasma AUC, perfusate AUC and AUC ratio between patients who received and those who did not receive heated intraoperative intraperitoneal MMC. CONCLUSIONS: Heated intraoperative intraperitoneal chemotherapy achieves high peritoneal concentrations of MMC with limited systemic absorption. Systemic drug absorption during heated intraoperative intraperitoneal chemotherapy is increased when extensive peritoneal resections are performed, but such slight increases are unlikely to change the risk of systemic drug toxicities. Heated intraoperative intraperitoneal chemotherapy does not alter the pharmacokinetics of early postoperative intraperitoneal 5-FU.

Antibiotics, Antineoplastic↗