Pseudomembranous Enterocolitis: Resurgence Related to Newer Antibiotic Therapy

Six patients with pseudomembranous entercolitis were seen at one institution over a six-month period. Clindamycin therapy preceded the diagnosis in all six patients and possibly caused the disease in five cases. Common clinical features included diarrhea, abdominal pain, fever, leukocytosis, radiographic findings of large bowel dilatation with mucosal thickening and a characteristic sigmoidoscopic or gross pathologic demonstration of discrete yellow-white plaques on an otherwise normal mucosa. Complications included toxic megacolon and sigmoid colon perforation. Two of the six patients died. The literature since 1970 is tabulated to clarify the clinical and pathological features of pseudomembranous enterocolitis associated with newer antibiotic therapy. Lincomycin and clindamycin are strongly implicated in the recent resurgence of this formerly rare variety of colitis.     

Inhibition of human neutrophil oxidative burst by pyrazolone derivatives

The risk of agranulocytosis associated with the use of pyrazolone drugs at therapeutical doses and for short periods of time has been considered to be very low. However, little or no attention at all has been devoted to the possible hindrance of neutrophil burst and scavenging of neutrophil-generated reactive oxygen species (ROS) by these compounds. Such an effect could be beneficial in the case of overactivation of neutrophils but could also be highly detrimental if the number of circulating neutrophils is already decreased. Thus, the aim of the present study was to evaluate the putative inhibitory effect of the pyrazolones dipyrone, aminopyrine, isopropylantipyrine, and antipyrine against human neutrophil burst and their scavenging activity against O2.-, H2O2, HO., ROO., and HOCl. The obtained results showed that dipyrone and aminopyrine prevent phorbol-12-myristate-13-acetate-induced neutrophil burst with high efficiency, while isopropylantipyrine had little effect and antipyrine had no effect at all. Dipyrone and aminopyrine were highly potent scavengers of HO. and HOCl, while, in accordance with the neutrophil burst results, isopropylantipyrine had little effect and antipyrine had no effect at all against these two ROS. None of the studied pyrazolones was capable of scavenging O2.- or H2O2, while dipyrone was shown to be the most reactive against ROO..     

The syndrome of pneumococcemia,disseminated intravascular coagulation and asplenia.

A 58-year-old man who survived an episode of fulminant pneumococcal septicemia with disseminated intravascular coagulation had undergone splenectomy 23 years previously. In the literature there are 25 reported cases of fulminant septicemia and disseminated intravascular coagulation associated with asplenia in adults (excluding cases in which corticosteroid or immunosuppressive therapy was given). The pneumococcus was responsible for all of these cases as well. The mortality in this series was more than 90%, and death occurred within 24 hours of presentation at hospital in almost 70% of the fatal cases and was associated with high-density bacteremia and adrenal hemorrhage. Gram-staining of the buffy coat of the peripheral blood or the exudate from purpuric skin lesions was carried out in only 6 of the 26 cases but yielded positive results in all but 1. It is concluded that a diagnosis of septicemia in asplenic adults can be established within a short time of presentation on the basis of statistical probability and the results of Gram-staining of the peripheral blood and exudate from the skin lesions. Prevention appears to be the cornerstone of management because of the variable interval from splenectomy to the onset of the syndrome and the high mortality.     

Quinine-induced agranulocytosis: toxic effect of quinine bisulphate on bone marrow cultures in vitro.

In a case of quinine-induced agranulocytosis marrow culture studies confirmed the inhibitory effect on the patient''s cells of equivalent therapeutic plasma concentrations of quinine. Similar concentrations had no effect on normal marrow cells. Quinidine, the stereoisomer of quinine, had no effect on either cells from the patient or normal cells. The results encourage the use of in-vitro bone marrow cultures for identifying drugs responsible for agranulocytosis.     

Does uremic enterocolitis exist? A morphological and functional investigation of rat intestine in chronic renal insufficiency

In rats a severe but compensated chronic renal insufficiency was induced by stepwise 9/10 nephrectomy. Despite this severe chronic renal insufficiency we observed no relevant pathological changes in the intestinal mucosa. In particular, we found no evidence of mucosal erosions, ulceration or pseudomembranous colitis, findings which are traditionally thought to be characteristic of the uremic state. This was also true of those animals dying prematurely from uremia. Thus serious doubts arise about the existence of "uremic enterocolitis", doubts which also proved justified after a critical review of the literature on human pathology.     

Hepatotoxicity from antithyroid drugs

We review the cases of hepatic injury from propylthiouracil, methimazole and carbimazole in the English language literature and compare them to cases of agranulocytosis in a recent review. The data on hepatotoxicity confirm the findings for agranulocytosis that low-dose methimazole is safer than propylthiouracil and that methimazole toxicity is more common over 40 years old. In contrast, propylthiouracil hepatotoxicity often occurs in younger patients. Most cases of hepatic injury occur in the first few months of drug therapy as with agranulocytosis. The reason that methimazole typically causes cholestatic hepatitis while propylthiouracil causes cytotoxic hepatitis remains unknown.     

Partial inhibition of hepatic microsomal aminopyrine N-demethylase by caffeine in partially purified cytochrome P450

Cytochrome P-450 substrate interactions were studied with cytochrome P-450 partially purified from livers of untreated, phenobarbital-treated, benzo[a]pyrene-treated and caffeine-treated rats. Partial inhibition of aminopyrine N-demethylase in presence of in vitro caffeine observed with intact microsomes was further investigated in a reconstituted system composed of partially purified cytochrome c reductase. Caffeine addition (in vitro) to partially purified cytochrome P-450 altered the hexobarbital, aniline and ethylisocyanide induced spectral change, and decreased NADPH oxidation in presence of substrates aminopyrine and acetanilide. NADPH oxidation was found to be increased in presence of aminopyrine and unaltered in presence of acetanilide in reconstituted system having partially purified cytochrome P-450 from caffeine-treated rats. Our studies suggest that caffeine acts as a true modifier of cytochrome P-450 and is possibly responsible for the formation of abortive complexes with aminopyrine.     

Idiosyncratic NSAID drug induced oxidative stress

Many idiosyncratic non-steroidal anti-inflammatory drugs (NSAIDs) cause GI, liver and bone marrow toxicity in some patients which results in GI bleeding/ulceration/fulminant hepatic failure/hepatitis or agranulocytosis/aplastic anemia. The toxic mechanisms proposed have been reviewed. Evidence is presented showing that idiosyncratic NSAID drugs form prooxidant radicals when metabolised by peroxidases known to be present in these tissues. Thus GSH, NADH and/or ascorbate were cooxidised by catalytic amounts of NSAIDs and hydrogen peroxide in the presence of peroxidase. During GSH and NADH cooxidation, oxygen uptake and activation occurred. Furthermore the formation of NSAID oxidation products was prevented during the cooxidation indicating that the cooxidation involved redox cycling of the first formed NSAID radical product. The order of prooxidant catalytic effectiveness of fenamate and arylacetic acid NSAIDs was mefenamic acid>tolfenamic acid>flufenamic acid, meclofenamic acid or diclofenac. Diphenylamine, a common moiety to all of these NSAIDs was a more active prooxidant for NADH and ascorbate cooxidation than these NSAIDs which suggests that oxidation of the NSAID diphenylamine moiety to a cation and/or nitroxide radical was responsible for the NSAID prooxidant activity. The order of catalytic effectiveness found for sulfonamide derivatives was sulfaphenazole>sulfisoxazolez.Gt;dapsone>sulfanilic acid>procainamide>sulfamethoxazole>sulfadiazine>sulfadimethoxine whereas sulfanilamide, sulfapyridine or nimesulide had no prooxidant activity. Although indomethacin had little prooxidant activity, its major in vivo metabolite, N-deschlorobenzoyl indomethacin had significant prooxidant activity. Aminoantipyrine the major in vivo metabolite of aminopyrine or dipyrone was also more prooxidant than the parent drugs. It is hypothesized that the NSAID radicals and/or the resulting oxidative stress initiates the cytotoxic processes leading to idiosyncratic toxicity.     

Predicting drug-induced agranulocytosis: characterizing neutrophil-generated metabolites of a model compound,DMP 406, and assessing the relevance of an in vitro apoptosis assay for identifying drugs that may cause agranulocytosis

DMP 406 is a clozapine analogue developed by Dupont-Pharma for the treatment of schizophrenia. Unfortunately it caused agranulocytosis in dogs during preclinical studies. Clozapine also causes agranulocytosis and this is believed to be due to a reactive nitrenium ion metabolite produced by neutrophils. We studied the oxidation of DMP 406 by activated neutrophils and found that the major reactive species that is produced is not a nitrenium ion but rather an imine. This metabolite is similar to the reactive metabolite that has been proposed to be responsible for mianserin-induced agranulocytosis. Therefore we also studied the oxidation of mianserin by activated neutrophils and found that, although the major species is an iminium ion, it also bears a lactam moiety in the piperazine ring resulting from further oxidation. We usually find that HOCl is a good model system for the production of reactive metabolites of drugs that are formed by activated neutrophils, but in the case of both DMP 406 and mianserin, the products produced were significantly different than those formed by activated neutrophils. In contrast, the combination of horseradish peroxidase and hydrogen peroxide (HRP/H(2)O(2)) formed a very similar pattern of products, and this system was used to produce sufficient quantities of metabolites to allow for identification. The reactive metabolites of both DMP 406 and mianserin reacted with a range of nucleophiles, but in many cases the reaction was reversible. The best nucleophile for trapping these reactive metabolites was cyanide. It has been demonstrated that the products of clozapine oxidation by HRP/H(2)O(2), presumably the nitrenium ion, induced apoptosis in neutrophils at therapeutic concentrations of clozapine. It has been suggested that this process is involved in the mechanism of clozapine-induced agranulocytosis. We tested DMP 406 and mianserin in this system to see if the ability of a reactive metabolite of a drug to cause apoptosis could predict the ability of that drug to cause agranulocytosis. We used clozapine as a positive control and we also tested olanzapine, a drug that forms a reactive metabolite similar to that of clozapine but is given at a lower dose and does not cause agranulocytosis. We found that DMP 406 did not increase apoptosis at concentrations below 50 microM, and although mianserin did increase apoptosis at 10 microM this is above the therapeutic concentration. Olanzapine caused an increase in apoptosis at the same concentration as clozapine (1 microM), but because its therapeutic concentration is lower, this concentration was above the pharmacological range. There was no increase in apoptosis with any drug in the absence of HRP/H(2)O(2). These results indicate that this assay is unable to reliably predict the ability of different types of drugs to cause agranulocytosis. This is not a surprising result given that different drugs may induce agranulocytosis by different mechanisms.     

人艰难梭菌感染的致病机制与防治策略研究进展

艰难梭菌是一种非常重要的医院感染病原菌,其感染占抗菌素相关腹泻的10．25％,占抗菌素相关肠炎的50．75％,占抗菌素相关伪膜炎的90．100％。而且越来越多的证据表明艰难梭菌的感染与其它疾病,如活性关节炎、婴儿突发性死亡、溶血性尿毒症、坏死性肠炎、希施斯普龙病等有关。更糟糕的是艰难梭菌存在着复发性感染,15—20％的病人在成功治愈后会复发。近年来,随着强毒株的出现,艰难梭菌的感染率和发病率逐年上升,病情也越来越严重,由艰难梭菌感染引起的死亡率也成倍增加。到目前为止,艰难梭菌发病率升高的原因及其致病机制还有待进一步研究。由于艰难梭菌是一种孢子产生菌,对大部分抗菌素都有抗性,目前用于艰难梭菌防治的主要抗菌素甲硝唑和万古霉素的治疗效果也在不断下降,所以正确认识艰难梭菌的感染与流行,进一步了解其致病机制,寻找新的替代疗法已是迫在眉睫。本文对艰难梭菌感染和流行的病因进行了较为全面的分析,对其致病机制进行了深入的总结,并探讨了艰难梭菌防治的最新策略和方法,将有利于更好的认识和研究艰难梭菌,为艰难梭菌的防治提供新思路。     

Antibiotic therapy of abscess of the lung and bronchiectasis

A clinical evaluation of phenylbutazone and Butapyrin(R) (a mixture of phenylbutazone and aminopyrine) was made in 409 patients who had a variety of rheumatic diseases. Preliminary European claims were substantiated.In gout a specific favorable effect was brought about by phenylbutazone alone. Effects equivalent to the previously reported favorable response to Butapyrin (Irgapyrin) were observed when its constituent phenylbutazone was used alone. The drug had a suppressive effect in a high percentage of patients with rheumatoid arthritis, ankylosing spondylitis, arthritis with psoriasis and mixed arthritis (rheumatoid arthritis plus osteoarthritis). Favorable effect in peritendinitis of the shoulders, osteoporosis of the spine and acute lumbosacral strain also was noted. Toxicity resulted in discontinuance of medication in 10 per cent of patients with each drug. Manifestations of toxicity generally included fluid retention, nausea and rash, but there were several instances of transitory leukopenia and anemia. There was one instance of agranulocytosis with Butapyrin but none with phenylbutazone.dagger Aggravation of peptic ulcer occurred in ten patients with hemorrhage in two. Generally the toxicity was of a low order as compared with that of other drugs having an antirheumatic effect.     

Fatty acid cellular metabolism and lactone production by the yeast Pichia guilliermondii

Methyl ricinoleate conversion into γ-decalactone by fungi is already widely used by the aromatic industry. It offers an interesting alternative to chemical synthesis by permitting acquisition of a natural label. Peroxisomal β-oxidation has been described as the probable transformation mechanism. This paper provides information about this metabolism and shows the importance of the step catalysed by carnitine octanoyltransferase. After culture of the yeast Pichia guilliermondii on a medium containing methyl ricinoleate as sole carbon source, we confirmed that mitochondrial β-oxidation could not be responsible for the biotransformation. We also observed the effect of chlorpromazine, an inhibitor of carnitine octanoyltransferase, on peroxisomal β-oxidation and therefore on lactone production, and on lipid accumulation by the yeasts. The presence of chlorpromazine caused a reduction in aromatic specific production yield. This reduction was inversely proportional to the amount of chlorpromazine present in the medium. A considerable accumulation of methyl ricinoleate derivatives was also observed. We therefore concluded that the metabolism responsible for the bioconversion was peroxisomal β-oxidation. The effects of chlorpromazine suggested that the entry of fatty acids into the peroxisomes took place in a carnitine-dependent manner. This step might be a limiting step in the metabolism. Received: 26 June 1995/Received revision: 16 November 1995/Accepted: 4 December 1995     

金黄色葡萄球菌溶血素的研究进展

金黄色葡萄球菌简称金葡菌,是一类革兰阳性需氧或兼性厌氧菌,可导致化脓性感染、肺炎、伪膜性肠炎、心包炎等局部感染,以及败血症、脓毒血症等全身感染。金黄色葡萄球菌的致病力强弱主要取决其产生的毒素和侵袭性酶,其中溶血素已经成为该细菌的一个重要致病因子。本文对金黄色葡萄球菌溶血素的分子特征、作用机制、免疫预防及临床应用方面的研究进展进行综述。     

82例极低/超低出生体重儿败血症的临床分析

目的:分析极低/超低出生体重儿败血症的临床特征、病原菌及药物敏感情况,为其早期诊断及治疗提供参考。方法:对2014年1月1日至2017年12月31日阜阳市人民医院新生儿重症监护病房(NICU)确诊的82例早产极低/超低出生体重儿败血症的临床表现、实验室检查、病原菌及药敏情况进行回顾性分析。结果:极低/超低出生体重儿败血症以早发型(≤7天)为主,晚发型以院内感染为主,临床表现缺乏特异性,实验室检查中白细胞、血小板出现减低,C反应蛋白和降钙素原增高。病原菌以革兰阴性菌为主,其次为革兰阳性菌和真菌。药敏结果显示革兰阴性菌对三代头孢、氨苄西林类抗生素100%耐药,对加他唑巴坦的抗生素耐药率较低,对碳氢酶烯类抗生素敏感。革兰阳性菌对β-内酰胺类、大环内酯类、氨基糖甙类及克林霉素等耐药率较高,对万古霉素、利奈唑烷敏感。82例败血症患儿中,死亡6例,死亡率为7.3%。结论:早产极低/超低出生体重儿败血症缺乏特异性临床表现,且发病率高,应密切观察患儿临床表现及动态监测其C反应蛋白、血小板等的变化,同时及时完善细菌培养及药敏试验,有效合理使用抗生素,以减少多重耐药菌株产生,改善患儿预后。     

PHENYLBUTAZONE (BUTAZOLIDIN) AND BUTAPYRIN?—A Study of Clinical Effects in Arthritis and Gout

A clinical evaluation of phenylbutazone and Butapyrin® (a mixture of phenylbutazone and aminopyrine) was made in 409 patients who had a variety of rheumatic diseases. Preliminary European claims were substantiated.In gout a specific favorable effect was brought about by phenylbutazone alone.Effects equivalent to the previously reported favorable response to Butapyrin (Irgapyrin) were observed when its constituent phenylbutazone was used alone. The drug had a suppressive effect in a high percentage of patients with rheumatoid arthritis, ankylosing spondylitis, arthritis with psoriasis and mixed arthritis (rheumatoid arthritis plus osteoarthritis). Favorable effect in peritendinitis of the shoulders, osteoporosis of the spine and acute lumbosacral strain also was noted.Toxicity resulted in discontinuance of medication in 10 per cent of patients with each drug. Manifestations of toxicity generally included fluid retention, nausea and rash, but there were several instances of transitory leukopenia and anemia. There was one instance of agranulocytosis with Butapyrin but none with phenylbutazone.^† Aggravation of peptic ulcer occurred in ten patients with hemorrhage in two. Generally the toxicity was of a low order as compared with that of other drugs having an antirheumatic effect.     

Ischemic bowel disease

The clinical, radiologic and pathologic features of 25 cases of ischemic bowel disease are presented. The majority of patients presented with the triad of abdominal pain, diarrhea and vomiting. In 13 patients the diarrhea was associated with the passage of bright red blood per rectum. There were 10 cases of infarction, 11 of enterocolitis and 4 had resulted in stricture formation. In five cases of enterocolitis the lesion was transient; symptoms improved with conservative medical management and the radiologic findings returned to normal. Barium enema examination yielded abnormal findings in the majority of the cases in which it was performed. Plain films of the abdomen, however, were not helpful. The actual mortality in this group of patients was 44%, 80% in those with infarction of the bowel and 20% in the other two groups.     

Microsomal electron transport reactions. II. The use of reduced triphosphopyridine nucleotide and-or reduced diphosphopyridine nucleotide for the oxidative N-demethylation of aminopyrine and other drug substrates

The ratio of formaldehyde formed to TPNH oxidized during aminopyrine oxidative demethylation as catalyzed by rabbit liver microsomes was found to be about 0.5. This is less than the expected 1:1 ratio for a mixed function oxidase reaction and may reflect the oxidation of TPNH by other reactions. Similar results were obtained when measuring the oxidative demethylation of codeine and ethylmorphine. In all cases the addition of DPNH significantly increased the yield of formaldehyde formed in the presence of TPNH. The stimulatory effect of DPNH was a linear function of the DPNH concentration added until the initial concentrations of DPNH and TPNH were equal. Increasing the DPNH concentration above a DPNH:TPNH ratio of 1:1 had no further effect upon the final concentration of formaldehyde formed. This observation, as well as the inhibition of DPNH-supported aminopyrine metabolism by TPN⁺, argue against the role of a transhydrogenase mechanism for the DPNH effect. The rate of DPNH oxidation catalyzed by liver microsome was also observed to increase markedly in the presence of TPNH.     

Risk of agranulocytosis and aplastic anaemia in relation to use of antithyroid drugs. International Agranulocytosis and Aplastic Anaemia Study.

The relation of the use of antithyroid drugs to the risk of developing agranulocytosis and aplastic anaemia was evaluated in a population based case-control study with patients from Israel and seven regions in Europe. Data were obtained from cases and hospital controls by interview. Use of antithyroid drugs in the week before the onset of illness was compared in 262 patients with agranulocytosis and 1771 controls. Forty five patients (17%) and five controls (0.3%) had used antithyroid drugs. The relative risk was estimated to be 102 (95% confidence interval 38 to 275) taking into account confounding by other factors, including the use of other drugs. The excess risk for use of antithyroid drugs in any one week was estimated to be 6.3 cases of agranulocytosis per million users. Use of antithyroid drugs in a five month period ending one month before admission to hospital was compared in 135 patients with aplastic anaemia and 2145 controls. Four patients (3%) and five controls (0.2%) had taken drugs; the estimate of relative risk was 9.2 (95% confidence interval 1.8 to 47) after control for confounding. The estimate of excess risk of agranulocytosis with the use of antithyroid drugs was lower than found previously. Although the excess risk for aplastic anaemia was not calculated, these data suggest that it is very low.     

The pharmacokinetic interaction of diethyl ether with aminopyrine in the rat

Our studies in rats clearly demonstrate a significant depression of aminopyrine metabolism in vivo by ether anesthesia. The depression of aminopyrine elimination was shown both by measurements of plasma aminopyrine clearance and by depression of the [14C]aminopyrine breath test. No apparent effect of ether was seen on aminopyrine volume of distribution. The effect of ether was prolonged, as judged by its persistence in the aminopyrine breath test for 3 hr after stopping ether anesthesia. In addition, when ether was administered in combination with a single dose of ethanol, aminopyrine clearance was inhibited significantly more than with ethanol alone. These data not only have a bearing on proper methodologic design of drug clearance studies but also may relate to the effects of some anesthetics on hepatic function.     

Exploring off-targets and off-systems for adverse drug reactions via chemical-protein interactome--clozapine-induced agranulocytosis as a case study

In the era of personalized medical practice, understanding the genetic basis of patient-specific adverse drug reaction (ADR) is a major challenge. Clozapine provides effective treatments for schizophrenia but its usage is limited because of life-threatening agranulocytosis. A recent high impact study showed the necessity of moving clozapine to a first line drug, thus identifying the biomarkers for drug-induced agranulocytosis has become important. Here we report a methodology termed as antithesis chemical-protein interactome (CPI), which utilizes the docking method to mimic the differences in the drug-protein interactions across a panel of human proteins. Using this method, we identified HSPA1A, a known susceptibility gene for CIA, to be the off-target of clozapine. Furthermore, the mRNA expression of HSPA1A-related genes (off-target associated systems) was also found to be differentially expressed in clozapine treated leukemia cell line. Apart from identifying the CIA causal genes we identified several novel candidate genes which could be responsible for agranulocytosis. Proteins related to reactive oxygen clearance system, such as oxidoreductases and glutathione metabolite enzymes, were significantly enriched in the antithesis CPI. This methodology conducted a multi-dimensional analysis of drugs' perturbation to the biological system, investigating both the off-targets and the associated off-systems to explore the molecular basis of an adverse event or the new uses for old drugs.