THE EFFECT OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS ON FAECAL FLORA AND BACTERIAL ANTIBODY LEVELS IN RHEUMATOID ARTHRITIS

The faecal flora and bacterial antibody levels of 22 patientswith active rheumatoid arthritis (RA) were compared with thoseof 26 patients with osteoarthritis (OA) undergoing comparabletreatment with non-steroidal anti-inflammatory drugs (NSAIDs),and a further 22 patients with OA who were not receiving NSAIDs.Faecal counts of Clostridium perfringens were significantlyhigher in the RA patient group and in those OA patients receivingNSAIDs, compared with those OA patients not taking NSAIDs (P=0.032,P=0.0004 respectively). Total aerobic and anaerobic counts were,however, identical in all three groups. Levels of serum IgA antibody to the alpha toxin of Cl. perfringenswere higher in the RA group and in the OA group taking NSAIDsthan in OA patients not taking NSAIDs (P=0.011, P=0.055). SerumIgG antibody to alpha toxin was higher in the RA group thanin OA patients both on and off NSAIDs (P=0.019, P=0.0072) andalso a group of normal controls (P=0.032). These results suggest that the increased faecal counts of Cl.perfringens together with the associated increased antibodylevels seen in this and previous studies are more likely toresult from NSAID therapy used to treat the disease than froma disease specific changk in bowel flora. KEY WORDS: Rheumatoid arthritis, Cl. perfringens, NSAIDs     

THE USE OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN PAEDIATRIC RHEUMATIC DISEASES

The use of NSAIDs for arthritis differs in children from adultsin their indications, uses and pharmacokinetics, and fewer areavailable. Children with arthritis are assessed differently,as they complain less of pain. Salicylates, indomethacin andibuprofen are used for the fever of systemic JCA. For controlof joint symptoms, diclofenac, ibuprofen, tolmetin and naproxenare equal in their efficacy and tolerance: salicylates and indomethacinare no more effective but more toxic. Children tolerate NSAIDswell. Gastrointestinal symptoms appear to be less common thanin adults, but the evidence regarding endoscopic changes isconflicting. Renal toxicity is rare. Tolmetin can cause pseudoproteinuriaand naproxen pseudoporphyria. The liver in systemic JCA is vulnerableto drug toxicity. A therapeutic trial of an NSAID should continuefor 8 weeks. Interactions with methotrexate and carbonic anhydraseinhibitors for glaucoma complicating iridocyclitis may occur. KEY WORDS: Children, JCA, Juvenile rheumatoid arthritis, Drug therapy, Side effects     

INTERACTIONS BETWEEN NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND ANTIHYPERTENSIVES AND DIURETICS

Non-steroidal anti-inflammatory drugs (NSAIDs) may increase blood pressure and antagonise the effects of antihypertensive agents, they can cause salt and water retention and an increase in extracellular volume. NSAIDs also cause a decrease in prostaglandin synthesis in blood vessel walls which removes a direct vasodilatory influence and also increases the vascular response to vasoconstrictor stimuli. The hypotensive effects of frusemide and captopril are due in part to their stimulation of prostaglandin synthesis. Hence the antagonism of the hypotensive effect of these agents is probably due to NSAID-induced inhibition of prostaglandin synthesis. However, the interactions of NSAIDs with the other antihypertensive agents may not be related to inhibition of antihypertensive-induced release of prostaglandin but to independent and opposing actions of the NSAIDs on the various physiological mechanisms which regulate blood pressure. Clinicians should remain alert to these potential drug interactions. (Aust NZ J Med 1986; 16: 537–546.)     

EVENING PRIMROSE OIL IN PATIENTS WITH RHEUMATOID ARTHRITIS AND SIDE-EFFECTS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Forty patients with rheumatoid arthritis and upper gastrointestinallesions due to non-steroidal anti-inflammatory drugs entereda prospective 6-month double-blind placebo controlled studyof dietary supplementation with gamma-linolenic acid 540 mg/day.Nineteen patients received active therapy (as evening primroseoil 6g/day) and 21 received placebo (olive oil 6g/day). No patientstopped non-steroidal anti-inflammatory therapy but three patientsin each group reduced their dose. Other results showed a significantreduction in morning stiffness with gamma-linolenic acid at3 months and reduction in pain and articular index at 6 monthswith olive oil. Whilst gamma-linolenic acid may produce mildimprovement in rheumatoid arthritis, olive oil may itself havehitherto unrecognized benefits. KEY WORDS: Rheumatoid arthritis, Inflammation, Evening primrose oil, NSAIDs, Peptic ulcer, Gastritis     

GASTRO-DUODENAL DAMAGE DUE TO NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN CHILDREN

Thirteen juvenile chronic arthritis patients with abdominalsymptoms related to non-steroidal anti-inflammatory drug therapywere endoscoped before and after a 6-week course of either misoprostolor ranitidine therapy. Major presenting symptoms were generalizedabdominal pain and nausea. Symptoms did not correlate well withendoscopic findings which revealed no evidence of ulcerationand minimal erosive damage. Five patients had mild erythemaor gastritis. Bleeding lesions were confined to small numbersof petechiae. Following treatment with either misoprostol orranitidine, patients improved symptomatically without a correspondingimprovement on endoscopic and histological examination of stomachand duodenum. Both treatments were well tolerated. KEY WORDS: JCA, Non-steroidal anti-inflammatory agents, Gastroscopy, Duodenoscopy     

IN VIVO AND IN VITRO STUDIES ON THE EFFECT OF METOCLOPRAMIDE ON ALDOSTERONE SECRETION

Metoclopramide, a dopamine antagonist drug, elevated plasma aldosterone and prolactin levels without significantly affecting plasma renin activity, ACTH or potassium. Studies with isolated perfused rat zona glomerulosa cells showed that metoclopramide could directly stimulate aldosterone release and that this action was blocked by dopamine. These results suggest that dopamine may play an important inhibitory role in the control of aldosterone secretion.     

THE EFFECT OF FENCLOFENAC ON THYROID FUNCTION TESTS IN VIVO AND IN VITRO

Clinically euthyroid patients on long term maintenance therapy with the non-steroidal anti-inflammatory drug fenclofenac (Flenac) show an unusual and abnormal pattern of serum thyroid function tests. In all twelve patients studied, total T4 concentrations were grossly subnormal (mean 28.4±9.9 (SD) nmol/1 and total T3 levels low-normal (mean 1.4 ± 0.3 (SD) nmol/1), whereas rT3 (mean 0.36 ± 0.06 (SD) nmol/1) and basal TSH levels (mean 1.9 ± 0.5 (SD) mu/1) were within their respective normal ranges. Free T4 levels were low normal (mean 11.0 ± 1.0 (SD) pmol/1) while TSH, T4 and T3 responses to intravenous TRH were similar to those found in euthyroid subjects. These effects appear to be due predominantly to in vivo inhibition of binding of thyroid hormones to carrier proteins in serum, rather than in vitro drug interference in the radioimmunoassays employed. Fenclofenac does, however, interfere in those laboratory methods employing serum proteins as binding agents. Thus the Thyopac 4 method for serum total T4 grossly over-estimates T4 levels, while thyroid hormone binding capacity (Thyopac 3) is low. Since fenclofenac is one of the most potent drugs interfering with routine indices of thyroid status, it is suggested that suspected thyroid dysfunction is excluded before commencing therapy with the drug.     

THE EFFECT OF ANTITHYROID DRUGS ON B AND T CELL ACTIVITY IN VITRO

This study examined the abilities of methimazole, propylthiouracil (PTU) and propranolol to exert an immunosuppressive effect in vitro. Incubation of peripheral blood lymphocytes (PBL) with propranolol showed the drug to have no effect on either B- or T-cell activity. Methimazole or PTU at concentrations of greater than or equal to 10(-5)M resulted in significantly lower amounts of IgG and IgM being released into the culture medium. Both drugs were also found to have a direct effect on T-cell function as they caused the percentage of total and suppressor cells to increase towards normal levels. The three drugs were all found to have some free radical scavenging ability. These ranked PTU greater than methimazole greater than propranolol. These in-vitro findings would suggest that both methimazole and PTU have some direct effect on the immune system. It would seem more likely however that these effects are mediated via interleukin 2 rather than by their ability to act as free radical scavengers.     

EFFECT OF A NON-STEROIDAL ANTI-INFLAMMATORY DRUG, NAPROXEN, ON FAECAL MICROBIAL FLORA

Faecal Clostridium perfringens counts have been observed tobe elevated in RA patients. The use of NSAIDs has been suggestedas being responsible for this increase. To clarify the potentialof NSAIDs to change faecal flora, 10 male volunteers were givennaproxen 500 mg twice daily for 2 weeks in a randomized, placebo-controlledand double-blind study, and 10 other volunteers were given aplacebo in tablets of identical appearance. Stool samples were collected and subjected to direct stool samplegas—liquid chromatography of bacterial fatty acids. Themethod has proved to be practical and sensitive in detectingoverall changes in faecal flora. The samples were also culturedfor Cl. perfringens. No significant change of faecal flora wasobserved by either method. The results show that naproxen given in doses and over a periodin excess of the levels reported to increase intestinal permeability,does not change intestinal flora. KEY WORDS: Clostridium perfringens, Faecal flora, Fatty acids, Gas chromatography, Naproxen, Non-steroidal anti-inflammatory drugs     

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS, HIATUS HERNIA, AND HELICOBACTER PYLORI, IN PATIENTS WITH OESOPHAGEAL ULCERATION

The frequency of oesophageal ulceration in 55 patients undergoingendoscopy for dyspeptic symptoms and who had recently used NSAIDswas studied, and compared with 86 patients seen in the sameclinic who had not recently used these drugs. Oesophageal ulcerationwas significantly more common in those who had used NSAIDs (P= 0.012), and also showed a highly significant association withthe presence of a hiatus hernia (P<0.001). No associationwas found between the presence of gastric Helicobacter pyloriand either oesophageal ulceration or histological oesophagitis.Patients receiving NSAIDs, especially those with a hiatus hernia,are at risk of oesophageal ulceration and presumably subsequentstricture formation. This should be borne in mind when prescribingthese agents. KEY WORDS: Anti-inflammatory drugs, Non-steroidal, Oesophagus, Oesophagitis, Oesophageal ulcer, Peptic ulcer, Stricture, Helicobacter pylori, Hiatus hernia     

INTERACTION OF CLONIDINE AND GHRH ON GH SECRETION IN VIVO AND IN VITRO

To investigate the mechanism by which clonidine stimulates GH-secretion in vivo and in vitro, we studied its interaction with GHRH. In vivo: eight or six normal male subjects were submitted to five protocols: (1) 150 micrograms clonidine orally followed by 50 micrograms GHRH 1-44 i.v. 2 h later, (2) 50 micrograms GHRH 1-44 i.v. followed by 150 micrograms clonidine orally 2 h later, (3) 150 micrograms clonidine orally followed by GHRH i.v. 30 min later, (4) 300 micrograms clonidine orally followed by 50 micrograms GHRH i.v. 3 h later and (5) 50 micrograms GHRH i.v. followed by 300 micrograms clonidine orally 90 min later. In vitro: Rat anterior pituitary cells were coincubated with clonidine (10(-11), 10(-9), 10(-7) and 10(-5) M) and GHRH (0.005, 0.05, 10 nM) for 4 h. Results: 150 micrograms clonidine alone does not stimulate GH-secretion. Furthermore, the GH-increase was not significantly different when GHRH bolus was given before, after or together with clonidine. When 300 micrograms clonidine was given before GHRH GH-levels were significantly higher (max 28.6 +/- 8.0 mU/l) at 90 min, compared to when clonidine was given after GHRH (max 7.8 +/- 3.6 mU/l). The GHRH bolus after clonidine led to a significantly lower GH-increase (max 31.6 +/- 17.0 mU/l) compared to the GHRH-induced GH-increase (max 47.2 +/- 13.0 mU/l) before clonidine. In vitro, clonidine had no stimulatory effect on GHRH-stimulated GH secretion. These findings are compatible with clonidine leading to stimulation of GH by inducing endogenous GHRH release.     

抗包虫药物的实验研究——Ⅲ.甲苯达唑和阿苯达唑体外抗细粒棘球蚴原头节的作用

在20％小牛血清-RPMI 1640中培养的细粒棘球蚴原头节经甲苯达唑或阿苯达唑20μg/ml作用3～5d后,其死亡率分别为42.4～64.2％和40.6％。用囊液培养原头节时,两种药物的效果更差。甲苯达唑或阿苯达唑与低浓度的吡喹酮合并应用时,原头节的死亡率较两药单用的明显增加。小鼠1次口服甲苯达唑或阿苯达唑1g/Kg后4h,其血清具有较强的抗原头节作用。     

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS: HOW DO THEY DAMAGE THE GUT?

NSAIDs are widely prescribed for the treatment of musculoskeletaldisorders. The gastrointestinal tract, predominantly the stomach,bears the brunt of their side-effects. The basis of this toxicityis certainly multifactorial, with a wide range of local effectsand mucosal defences being implicated. This review will highlight:(1) the epidemiology of NSAID-induced gastrointestinal toxicity;(2) their effects on prostaglandins, and the phenomenon of cytoprotection;(3) effects on neutrophil function; (4) effects on mucosal bloodflow; (5) responses of the mucosa to damage (restitution, adaptation,and regenerative repair); (6) the relevance of growth factors;(7) interactions with Helicobacter pylori in ulcerogenesis,and finally (8) the effects of NSAIDs on the small intestineand colon. KEY WORDS: Non-steroidal anti-inflammatory drugs, Gastrointestinal tract, Toxicity, Gastropathy, Repair, Adaptation, Healing, Cytoprotection, Blood flow, Neutrophil, Helicobacter pylori, Growth factors     

左旋吡喹酮、右旋吡喹酮和消旋吡喹酮的体外与体内抗不同发育期日本血吸虫的作用

目的：测定消旋吡喹酮（Ｐｒａ）、左旋吡喹酮（Ｌ－Ｐｒａ）和右旋吡喹酮（Ｄ－Ｐｒａ）对不同发育期日本血吸虫的作用。方法：用含２０％小牛血清的ＰＲＭＩ１６４０培养不同发育期的血吸虫，测定上述三种药物的体外抗血吸虫作用。体内试验系于小鼠感染血吸虫尾蚴后不同时间灌服（ｉｇ）Ｐｒａ、Ｌ－Ｐｒａ或Ｄ－Ｐｒａ，根据残留平均虫数评估药效。结果：依据药物引起虫的皮层损害程度，虫龄为２８ｄ（ｄ２８）和３５ｄ（ｄ３５）的成虫对Ｌ－Ｐｒａ最敏感，而１４ｄ（ｄ１４）童虫则最不敏感。在药物浓度为０．１－１μｇ／ｍｌ时，Ｌ－Ｐｒａ的抗血吸虫作用较Ｐｒａ的为强，即使Ｌ－Ｐｒａ的浓度减至Ｐｒａ最低有效药浓度的１／２亦有效。在体外，上述浓度的Ｄ－Ｐｒａ对不同发育期血吸虫无明显作用。感染小鼠ｉｇ单剂量的Ｌ－Ｐｒａ，Ｐｒａ或Ｄ－Ｐｒａ３００ｍｇ／ｋｇ或５００ｍｇ／ｋｇ，仅前２种药物对３ｈ（ｄｏ）、２１ｄ（ｄ２１）童虫和ｄ２８及ｄ３５成虫有较明显的疗效，而对３ｄ（ｄ３）、７ｄ（ｄ７）和ｄ１４童虫的疗效甚差或无效。与Ｌ－Ｐｒａ和Ｐｒａ相比，Ｄ－Ｐｒａ仅对ｄ３５成虫有较差的疗效。感染ｄ３５血吸虫成虫的小鼠用Ｌ－Ｐｒａ１５０ｍｇ／ｋｇｉｇ治疗，其疗效与用Pra 300mg/kg 治疗的相仿。D-Pra 的总剂量增至L -Pra 的2—6 倍时亦仅示很差的疗效。结论: 在消旋Pra 中,L-Pra 是抗血吸虫的活性成分。     

三氯苯达唑体内外杀灭卫氏并殖吸虫的效果和虫体蛋白质、糖原及DNA含量测定

目的　探讨三氯苯达唑在家犬体内及体外培养中对卫氏并殖吸虫的杀虫效果 ,并取得大量死虫。探讨该药对虫体蛋白质、糖原及DNA含量的影响 ,为研究该药的杀虫机理奠定基础。方法　用卫氏并殖吸虫囊蚴感染家犬 ,至粪检查到虫卵后 ,用三氯苯达唑口服治疗观察疗效。将从对照犬获得的活虫培养于BME培养液内 ,观察体外杀虫效果。用Lowry法测定虫体蛋白质含量 ;用Johnson法测定还原糖含量 ;用二苯胺显色法测定DNA含量。结果　治疗犬于服药后 3天及 5天解剖 ,均可获得大量死虫 ,杀虫率达 10 0 %。在体外培养中 ,加入药物后虫体的平均存活时间为 2 39天 ,与对照组有显著差异。体内杀虫所取得的死虫较对照组的活虫 ,虫体显著缩小 ,重量减轻 ;体外培养中杀死的虫体 ,体积无明显缩小 ,但重量显著减轻。经测定体内外杀虫组与对照组之间 ,虫体蛋白质含量及DNA含量均有非常显著的减少 ;而虫体糖原的含量 ,体内杀虫组有非常显著的减少 ,而体外杀虫组则无显著差异。结论　三氯苯达唑在体内外对卫氏并殖吸虫有良好的杀虫效果。药物主要作用于虫体的蛋白质及核酸的合成或代谢 ,而对虫体糖原的合成与代谢影响不大。     

COMPARISON OF THE ANALGESIC EFFECT OF TEN NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

The analgesic effect of 10 anti-inflammatory drugs was comparedusing a single-blind method in 90 patients with rheumatoid arthritis.Each patient received two different drugs, for three days eachand each drug was evaluated in 18 patients. After the trial,the patients considered which of the drugs they preferred. The greatest relief from pain was achieved by diclofenac, indomethacin,naproxen and tolfenamic acid, each of these being preferredby the majority of patients and being significantly (p>0.01)better than the least effective drugs ketoprofen and proquazone.Acetylsalicylic acid, azapropazone, carprofen and ibuprofenwere considered intermediate in efficacy. KEY WORDS: Rheumatoid arthritis, Nonsteroidal drugs     

单克隆抗体抗贾第虫作用的研究

应用体外纯培养的贾第虫滋养体免疫ＢＡＬＢ／ｃ小鼠和常规杂交瘤细胞技术，制备特异的抗贾第虫单克隆抗体（１Ｅ２，１Ｇ５），以其与贾第虫滋养体相互作用，均发现具有明显的抗贾第虫效果，生长抑制率分别为３５％和６３．４％；将此单抗加入正常培养液中，其含量与抑制率呈现明显的剂量反应关系，相关系数分别为０．９７６４和０．８９８７；单抗经滋养体吸收后，对贾第虫的生长抑制作用消失；经补体灭活前后的豚鼠血清对单抗的抑制作用无影响。