Blood concentrations of acetaldehyde during chlorpropamide-alcohol flush.

To test the suggestion that chlorpropamide-alcohol flushing (CPAF) resembles the disulfiram effect and might be mediated by acetaldehyde, the initial metabolite of alcohol, blood concentrations of acetaldehyde were measured after a drink of alcohol in controls and diabetics positive and negative for CPAF. The CPAF-positive diabetics had significantly greater blood acetaldehyde concentrations after alcohol than the CPAF-negative diabetics both with a single dose of chlorpropamide and after two weeks'' chlorpropamide treatment. Concentrations in the CPAF-positive group after chlorpropamide were also significantly greater than after a placebo tablet. There was also a clear separation in the increase in facial temperature after two weeks of chlorpropamide between the CPAF-positive and CPAF-negative groups (although there was some overlap after a single tablet). There was no difference in plasma chlorpropamide or alcohol concentrations between CPAF-positive and CPAF-negative diabetics. These findings show that CPAF is distinct from alcohol flushing and that the acetaldehyde concentration in the blood provides an objective measure of CPAF. The difference between flushing and non-flushing diabetics cannot be accounted for by differences in blood concentrations of chlorpropamide or alcohol.     

Chlorpropamide-alcohol flushing,aldehyde dehydrogenase activity,and diabetic complications.

Many diabetics who take chlorpropamide (a sulphonylurea compound) experience facial flushing after drinking even small amounts of alcohol. These flushers have a noticeably lower prevalence of late complications of diabetes (microangiopathy, macroangiopathy, and neuropathy) than non-flushers. This flush reaction is accompanied by increased blood acetaldehyde concentrations, suggesting an inhibition of aldehyde dehydrogenase activity. In the present study the activity of this enzyme in erythrocytes was assessed in the absence of chlorpropamide. Erythrocyte homogenates obtained from flushers and non-flushers were incubated with acetaldehyde and the rate of metabolism studies. Flushers eliminated acetaldehyde more slowly at a low range of concentrations (0--30 mumol/l), suggesting a difference in aldehyde dehydrogenase activity. Further studies are needed to clarify the role of this enzyme in the pathogenesis of diabetic complications.     

Chlorpropamide-alcohol flushing: a dominantly inherited trait associated with diabetes.

A simple test was devised to identify people susceptible to chlorpropamide-alcohol flushing (CPAF). Subjects were given a placebo tablet, followed by sherry 12 and 36 hours later. They then received a chlorpropamide tablet and sherry again after 12 and 36 hours. This single-dose challenge test was given to non-insulin-dependent diabetics, insulin-dependent diabetics, and normal subjects. CPAF was common in the non-insulin-dependent diabetics but rare in the other groups. When the test was used in identical twins and families of affected subjects CPAF appeared to be a dominantly inherited trait. We conclude that facial flushing after alcohol in people taking chlorpropamide is related to non-insulin-dependent diabetes, especially when there is a strong family history of diabetes, but not to insulin-dependent diabetes. It is a dominantly inherited trait.     

Chlorpropamide alcohol flush and circulating met-enkephalin: a positive link.

Chlorpropamide-alcohol flushing may be due to sensitivity to endogenous opiates. To investigate this possibility the plasma met-enkephalin and beta-endorphin responses to sherry with and without chlorpropamide were studied in six patients with non-insulin dependent diabetes and in six normal subjects. After chlorpropamide all patients showed a rise in met-enkephalin concentrations from a basal level of 50 +/- 7.2 ng/l to a peak of 75 +/- 8.1 ng/l (p less than 0.001). In contrast, before chlorpropamide treatment was started met-enkephalin values did not change after alcohol. No significant changes in beta-endorphin values were observed. In six normal subjects pretreated with chlorpropamide the met-enkephalin concentration also rose from a basal level of 72 +/- 15 ng/l to a peak of 103 +/- 9.4 ng/l (p less than 0.002). Again, the met-enkephalin rise was not observed after placebo. Neither beta-endorphin concentrations nor facial temperature changed significantly. These data suggest that endogenous opiates may be implicated in CPAF. Furthermore, this is the first study in which a significant change in circulating met-enkephalin values has occurred.     

Potent tetrapeptide enkephalins

Small peptides with opiate-like activity have generally had structures closely resembling that of the opioid pentapeptide enkephalin: Tyr-Gly-Gly-Phe-Met-COOH. Single deletions of any one of the amino acids has been demonstrated to reduce opiate activity drastically. In this work we show that the potency losses resulting from the removal of glycine³ can be fully attenuated by substitution of D-alanine in position two and derivatization of the acid to the amide. This tetrapeptide (Tyr-DAla-Phe-Met-NH₂) has narcotic activity similar to the parent pentapeptide in the guinea pig ileum and mouse tail-flick tests. This enhanced potency, relative to the unaltered tetrapeptide, is theorized to arise from increased resistance to enzymatic destruction. the data presented show that a five amino acid sequence is not mandatory for the expression of opiate activity in enkephalin analogs.     

Synthesis and biological activity of some glucose-enkephalin conjugates

Two O-glucopeptides, H-Tyr(beta-D-Glc)-Gly-Gly-Phe-OH(10) and H-Tyr(beta-D-Glc)-Gly-Gly-Phe-Leu-OH (11), having the amino acid sequence of enkephalin, were synthesized to determine the influence of the carbohydrate molecule on the biological activity and conformation of these opioid peptides. The synthesis were carried out in a stepwise and/or direct manner by fusing the activated O-glucosylpseudourea intermediate with suitably protected amino acid or peptide derivatives, followed by hydrogenolytic removal of protecting groups. The pure compounds were tested for opiate-like activity by using the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations.     

Hormones with adrenocorticotropic and opiate-like activities from the carp (Cyprinus carpio) pituitary

Carp (Cyprinus carpio) pituitary acetone powder was extracted with a mixture of water, hydrochloric acid and acetone. An acid acetone powder was formed by adding the pituitary extract into a large volume of chilled acetone and subsequently recovering the precipitate. The powder was subjected to ion exchange chromatography on CM cellulose. Fractions adsorbed on the ion exchanger exhibited ACTH-like activity as evidenced in the ability to stimulate lipolysis in isolated hamster adipocytes and corticosterone production in isolated rat adrenal decapsular cells and also in cross-reactivity in an ACTH-specific radioimmunoassay. A portion of the ACTH-like bioactivity and immunoactivity was unadsorbed on the ion exchanger. Opiate-like activity in opiate receptor binding assay, employing [3H]D-ala2-D-leu5 enkephalin or [3H]naloxone as ligand, also resided in fractions adsorbed on CM cellulose. The data indicate a separation of ACTH-like and opiate-like activities, and the presence of opiate-like molecules with different affinities of binding to mu and delta opiate receptors.     

Alterations of plasma opioid activity in human diabetics

Plasma opioid levels were determined in 9 obese non-diabetic subjects, their 8 age matched controls, and in 29 diabetic patients; 10 maintained on diet alone, 6 on an oral hypoglycemic agent (chlorpropamide) and 13 treated with insulin. Five age matched controls for the diabetic groups were also studied for comparison. β-endorphin and met-enkephalin levels were measured by radioimmunoassay. Enkephalin-like activity was measured by a receptor assay. Among the study groups, diabetic patients receiving insulin showed a 64% elevation of plasma β-endorphins and diabetic patients on chlorpropamide showed a 121% increase in enkephalin-like activity. There were no statistically significant differences in the plasma met-enkephalin values in the treatment groups though levels were decreased (p<0.05) in diabetics vs non-diabetics. The pathophysiological importance of these alterations remains to be elucidated.     

小儿喘息性疾病喘息反复发作的病原学及危险因素分析

摘要目的：分析小儿喘息性疾病病原学及与喘息发作有关的因素。方法：227例患儿来我院儿科住院的患儿,在有喘息发作及无喘息发作时均取分泌物进行细菌和病毒检测,并对可能与喘息发作有关的因素做统计分析。结果：喘息发作时细菌感染91例（40．1％）,病毒感染110例（48．5％）,无喘息时72例（31．7％）检出细菌感染,59例（26％）检出病毒感染,喘息发作时细菌和病毒感染检出率均显著高于无喘息时（P〈0．05）。单因素分析过敏史、细菌感染、病毒感染、被动吸烟史、家族史和季节等暴露因素在喘息次数超过和低于4次患儿之间存在差异（P〈O．05）。多因素非条件Logistic回归分析显示病毒感染（OR=2．839）、细菌感染（OR=2．434）、过敏史（OR=4．412）和家族史（OR=2．158）为喘息性疾病患儿喘息发作次数增多的主要危险因素。结论：病毒和细菌感染为小儿喘息性疾病的主要致病原,病毒和细菌感染、有过敏史与家族史是喘息反复发作的危险因素。     

Preparation and opioid activities of N-methylated analogs of [D-Ala2,Leu5]enkephalin

Analogs of opioid pentapeptide [D-Ala2,Leu5]enkephalin were prepared using two kinds of N-methylation reactions, namely quaternization and amide-methylation. Quaternization reaction with CH3I-KHCO3 in methanol was applied to the deprotected N-terminal group of the pentapeptide derivatives affording trimethylammonium group-containing analogs. [Me3+Tyr1,D-Ala2,Leu5]enkephalin and its amide were found to show opioid activity on guinea pig ileium assay only slightly lower than the parent unmethylated peptides. Application of amide-methylation reaction using CH3I-Ag2O in DMF to the protected pentapeptide yielded a pentamethyl derivative in which all of the five N atoms were methylated. Deprotection of the derivative gave pentamethyl analogs of [D-Ala2,Leu5]enkephalin, which showed no significant activity on the guinea pig ileum assay and opiate-receptor binding assay.     

滇产胡椒属植物醇提物抗血小板活性研究

采用Born氏比浊法观察了12种滇产胡椒属植物的乙醇提取物对血小板活化因子(PAF)、花生四烯酸(AA)和二磷酸腺苷(ADP)引起血小板活化聚集的影响.结果表明,这12种醇提物均明显抑制PAF诱导的血小板聚集,其中部分醇提物对AA和ADP引起的聚集亦有显著拮抗作用.结果提示,该12种滇产胡椒属植物醇提物具有较高的抗血小板活性     

Chlorpropamide-alcohol flushing and large-vessel disease in non-insulin-dependent diabetes.

A total of 220 non-insulin-dependent diabetics aged over 45 (139 with a history of chlorpropamide-alcohol flushing and 81 without such a history) were examined for the prevalence of large-vessel disease. Large-vessel disease was significantly more common in the group without a history of flushing (41% v 24% of the two groups respectively; p < 0.05). A history of myocardial infarction was found in 14 (17%) of the patients without flushing but in only 10 (7%) patients with flushing. Similar differences were detected in the prevalences of angina, intermittent claudication, and absent foot pulses. There were, however, no significant differences in the prevalence of cerebrovascular disease or hypertension between the two groups. These results suggest that patients with non-insulin-dependent diabetes who flush in response to chlorpropamide and alcohol are significantly less likely to develop large-vessel disease than those who do not. Hence such flushing is probably related to the pathogenesis not only of small-vessel but also of large-vessel disease.     

Effects of hydrocortisone and aminophylline on plasma leukotriene C4 levels in patients during an asthmatic attack

To study the role of leukotriene C4(LTC4) and the effect of hydrocortisone and aminophylline on plasma LTC4 levels in patients with asthmatic attacks, we measured LTC4 in plasma of 18 asthmatics during a wheezing attack and of 7 normal subjects. Blood samples were obtained before and after treatment with aminophylline and/or hydrocortisone injections. We extracted LTC4 using a Sep-Pak C18 cartridge for the measurement of LTC4 by radioimmunoassay. The plasma levels of immunoreactive LTC4 (i-LTC4) of the normal subjects were 142 +/- 25 pg/ml (n = 7), while those of nonatopic type asthmatic patients with wheezing attacks were 208 +/- 68 pg/ml (n = 15) (p less than 0.01). Before and after treatment with both hydrocortisone succinate (100 mg) and aminophylline (250 mg), 6 asthmatic patients with wheezing attacks had a mean plasma level of i-LTC4 181 +/- 24 and 132 +/- 18 pg/ml (p less than 0.01), respectively. On the other hand, the treatment with aminophylline 250 mg alone increased the i-LTC4 levels from 178 +/- 19 pg/mg to 213 +/- 16 pg/mg (n = 6)(p less than 0.05), while treatment with hydrocortisone succinate 100 mg decreased the i-LTC4 level 0.05 from 284 +/- 99 pg/ml to 249 +/- 85 pg/ml (n = 4)(p less than 0.05). In conclusion, the present study shows that the i-LTC4 level in venous blood of patients with asthmatic attacks is decreased significantly by treatment with hydrocortisone succinate.     

Bronchial Reactions to Western Red Cedar (Thuja Plicata)

The clinical features and the results of investigations (including immunological tests) of three patients with asthma due to western red cedar are described. Bronchial provocation tests with extract of this wood produced immediate asthmatic reaction in one patient, late asthmatic and peripheral reactions in another and late asthmatic reaction alone in the third. While mild immediate skin reactions were detected in two patients, no late skin reactions were observed. Serum precipitins to this extract were not detected. An attempt was made to identify the responsible allergen in the red cedar extract.     

CLINICAL EXPERIENCE WITH CHLORPROPAMIDE

Seventy-eight patients with mild diabetes were treated with chlorpropamide in doses up to 1 gm. daily. Eight showed primary failure to respond and two showed an initial but not a sustained response. Patients whose diabetes was of recent onset and who had not been treated with insulin or a sulfonylurea, required smaller doses than the remainder except for a group of patients who had been diabetic for more than 15 years.The average dose for the 64 patients who took chlorpropamide for more than three months was 0.46 gm. per day. Serious side effects were uncommon and disappeared when the drug was stopped. One patient became jaundiced, one had a rash, and one showed granulocytopenia. Changes in liver function tests were seen in 17 out of 56 patients treated for more than three months and were correlated with the dosage of the drug and the duration of treatment.     

An electrospray/inductively coupled plasma dual-source time-of-flight mass spectrometer for rapid metallomic and speciation analysis. Part 1. Molecular channel characterization

A new time-of-flight mass spectrometer has been developed that uses an electrospray source and an inductively coupled plasma to extract molecular, atomic, and isotopic information simultaneously from a single sample. This paper will focus on characterization of the ESI channel. Sensitivities are reported for hexadecyltrimethylammonium, tetrahexylammonium, tetraoctylammonium, myoglobin, insulin, cyanocobalamin, leucine enkephalin, and alcohol dehydrogenase. Skimmer-nozzle collisionally induced dissociation is explored for adduct removal and analyte fragmentation on the ESI channel for tetraoctylammonium ion and leucine enkephalin. Long-term and short-term spray stability is also examined.     

Cerebellar stimulation for spastic cerebral palsy--double-blind quantitative study

Thirty spastic cerebral palsy (CP) patients were involved in a double-blind quantitative study to determine the effectiveness of chronic cerebellar stimulation, (CCS) and 19 patients completed the testing. Of the 12 patients undergoing the five motor performance tests, 8 (66%) showed improvements with the stimulation. Of the 16 patients tested for active motion in seven bilateral joints, 10 (63%) showed increases with CCS. Profiles of six mood states were tested in 15 patients, and CCS produced an overall 15% improvement.     

Opiate-like peptides with primary structure different from that of enkephalins

Some new opiate-like peptides originating from opioid peptide precursors, dinorphine, histone H2b, major myeline protein, natriuretic atriopeptide and from the immunomodulating protein splenin whose primary structure differs essentially from that of enkephalins are described. Being intracysternally injected to mice, all the peptides under study caused a naloxone-sensitive analgetic effect as could be judged from the tail pinch tests. The effects of some opiate-like peptides were much stronger than that of leu-enkephalin. According to their primary structure, the opiate-like peptides can randomly be allocated into two families. Dipeptide Lys-Arg and free arginine also possess a marked analgetic activity which is abolished by naloxone. It seems likely that the epiate-like activity of the peptides under study is due to the similarity of their secondary and ternary structure to that of enkephalins of to their involvement in the regulation of opioid peptide metabolism.     

Familial ADH-responsive diabetes insipidus: response to thiazides and chlorpropamide

Twenty cases of familial ADH-responsive diabetes insipidus were identified within five generations, and eight patients were studied by one of two established dehydration protocols. In each case there was partial to total failure of response to the initial administration of ADH which was slowly corrected by continued administration. This initial failure can lead to misinterpretation of the dehydration test unless the medullary solute washout effect is taken into account in chronically polyuric patients.Treatment consisted of thiazides and/or chlorpropamide. All cases responded well.The response to chlorpropamide suggests that the failure of ADH production is not complete in these patients, and that the major defect is a failure of ADH release in response to normal stimuli. Chlorpropamide may act by either facilitating ADH release or by synergistically interacting with available ADH at the tubular level.     

Inflammatory response in induced sputum mononuclear cells from patients with acute exacerbation of asthma

Examination of sputum provides a direct method to investigate airway inflammation non-invasively in particular Th1 (IL-2, IFN-gamma) and Th2 (IL-4, IL-10) cytokine production. IL-2, IL-4, IL-10 and IFN-gamma cytokine were studied in induced sputum mononuclear cells of asthmatic patients. Sputum induction was performed on 10 patients and 10 normal controls. Basal and mitogen-stimulated cytokine production was determined in induced sputum T-cell culture. Supernatants were collected and assayed not only with specific ELISA but also with polymerase chain reaction (PCR) techniques. Data showed a significantly higher production of IL-10 by both the ELISA and the RT-PCR techniques in asthmatic patients compared with sputum mononuclear cells from healthy controls. IL-4 production was detected at a low level using the ELISA method in asthmatic patients. The RT-PCR analysis detected a significantly IL-4-mRNA expression in all asthmatic patients, compared with controls. Results of IL-10 and IL-4 mRNA expression were reproducible. We did not find any alteration in the expression of the type 1 derived cytokines (IL-2 and IFN-gamma) in asthmatic patients or in healthy controls. Our study showed a tendency of induced sputum mononuclear cells to express a Th2-like cytokine pattern in acute exacerbation of asthmatic patients, where IL-10 and IL-4 are synthesized in larger amounts. The combination of sputum induction as a non-invasive tool to explore the lung and the identification of disease-associated cytokine expression and of specific cytokine mRNA should help elucidate mechanisms of the immunologically mediated inflammatory responses in asthma.