The effect of indomethacin and other anti-inflammatory drugs on the renin-angiotensin system

The administration of two different doses of indomethacin, 9 and 18 mg/kg, to two different groups of rabbits was followed 6 h later by a significant decrease in plasma renin activity, and these levels were not increased by hemorrhage. The administration of 2 mg/kg of indomethacin did not alter the basal levels of plasma renin activity, but it was effective in diminishing the peripheral increase of renin produced by hemorrhage. Similar effects were obtained in other groups of rabbits treated with 9 mg/kg of meclofenamate or 18 mg or aspirin. The lowering effect of indomethacin on plasma renin activity is not specifically related to hemorrhage because it also prevented the increase in plasma renin activity elicited by 5 mg/kg of furosemide. Further studies showed that indomethacin did not exert any significant effect in vivo on the plasma level of renin substrate or on the generation of angiotensin from normal plasma by exogenous renin. And indomethacin did not interfere with the binding capacity of anti-angiotensin I for angiotensin I in the radioimmunoassay reaction or with the in vitro formation of angiotensin from hog renin-nephrectomized rabbit plasma reaction. The results thus indicate that the lowering effect of indomethacin on plasma renin activity is due to the interference with renal renin release. That this effect may be related to the blockade of prostaglandin synthesis is suggested by the similar effect exhibited by other blockers of prostaglandin synthesis.     

Effects of non-steroidal anti-inflammatory drugs on the luminol and lucigenin amplified chemiluminescence of human neutrophils

A panel of non-steroidal anti-inflammatory drugs commonly used for therapeutic purposes was assessed for their effects on the respiratory burst of isolated human polymorphonuclear neutrophils. Cells were stimulated with opsonised yeast and the production of reactive oxygen species was measured by amplified chemiluminescence with luminol and lucigenin which are two luminogenic agents measuring different cellular events. A special attention was devoted to the establishment of dose-effect curves and calculation of ED50. Some of the drugs tested (acemetacine, diclofenac, flufenamic acid and niflumic acid) were able to decrease both luminol and lucigenin chemiluminescence in a dose-dependent manner reflecting an inhibitory effect on the respiratory burst. The most potent derivative was flufenamic acid (ED50 8 and 78 microM, respectively, with luminol and lucigenin), followed by diclofenac (21 and 98 microM), niflumic acid (97 and 227 microM) and acemetacine (585 and 427 microM). In contrast, several other drugs (flurbiprofen, ibuprofen, ketoprofen, piroxicam) stimulated both luminol and lucigenin chemiluminescence, suggesting a pro-oxidant activity. Acetylsalicylic acid (up to 1250 microM) was a modest inhibitor (maximum 25% inhibition) showing no dose-dependent effect and tolmetin (up to 125 microM) had no significant effect in both systems. The results were in agreement using both luminogenic agents, except for indomethacin, naproxen and tenoxicam which showed different kinds of effects. The unspecific and complex nature of the measurement systems used did not allow to give a complete mechanistic interpretation of the results, but the comparison with literature data gave some pertinent explanations for both anti- and pro-oxidant effects.     

The use of non-steroidal anti-inflammatory drugs for the relief of pain in laboratory rodents and rabbits

The data concerning the use of non-steroidal anti-inflammatory drugs (NSAIDs) and evidence for their efficacy in laboratory rats and mice are reviewed. This information is then extrapolated to clinical situations and dose rates that take account of ulcerogenic side effects are recommended. NSAIDs have the potential to be a very useful group of analgesics and should always be considered when attempting to provide pain relief in laboratory animals.     

Effect of non-steroidal anti-inflammatory drugs on the anticonvulsive activity of valproate and diphenylhydantoin against maximal electroshock-induced seizures in mice

OBJECTIVE: To collect the ratings of American rheumatologists regarding relative short-term and long-term effectiveness of disease-modifying antirheumatic drug (DMARD) therapy in the treatment of rheumatoid arthritis and to compare these data with results of a meta-analysis of randomized, controlled clinical trials (RCTs) of these drugs. METHODS: A survey was mailed to 3,200 United States rheumatologists who were members of the American College of Rheumatology during the summer of 1996. The survey was completed by 645 rheumatologists. RESULTS: Methotrexate (MTX) was rated as substantially more effective than any other DMARD after both 1 year and 4 years of therapy. At 1 year, more than 90% of rheumatologists rated MTX as "good or excellent," compared with 35% giving a similar rating to intramuscular (IM) gold, the second-ranked DMARD. At 4 years, MTX was rated as "good or excellent" by 65%, compared with 53% for combinations, 30% for prednisone, and 11% for hydroxychloroquine, the second-ranked single DMARD. These ratings reflect results of long-term observational studies, but differ considerably from a meta-analysis of results of short-term RCTs, in which the efficacy of MTX, sulfasalazine, penicillamine, and IM gold were indistinguishable. CONCLUSION: The ratings of US rheumatologists regarding effectiveness of DMARD therapies are in agreement with observational data, but differ substantially from results of RCTs. These findings suggest that observational studies may yield useful and important information about treatment results, which are complementary to, but not available from, the RCT model. Regulatory agencies should consider long-term observational studies as a part of the evaluation of drugs.     

In vivo selectivity of nonsteroidal anti-inflammatory drugs on COX-1-COX-2 and gastrointestinal ulcers, in rats]

BACKGROUND: General anaesthesia affects lung volume and pulmonary gas exchange. What role is played by mechanical stimulation by the endotracheal tube? METHODS: We investigated the effects of intubation on arterial oxygenation and lung volume in rats. RESULTS: Endotracheal intubation caused an increase in PA-aO2 and volume of trapped gas in the lung. This was accompanied by a reduction in neuropeptides and calcitonin gene-related peptide (CGRP) in trachea, bronchi and lung, and in vasoactive intestinal peptide (VIP) in the trachea. The increase in PA-aO2 and volume of trapped gas due to intubation was not altered in the animals given capsaicin, in which neuropeptide levels were reduced. CONCLUSIONS: These data suggest that the decrease in CGRP and VIP content in the airway tissues may be one of the consequences, but not the cause, of impaired gas exchange by endotracheal intubation. The increase in volume of trapped gas in the lung is apparently not mediated by activation of capsaicin-sensitive sensory nerves.     

The effect of cholestyramine on the pharmacokinetics of meloxicam, a new non-steroidal anti-inflammatory drug (NSAID), in man

The influence of multiple oral doses of cholestyramine on the single dose pharmacokinetics of meloxicam has been studied in 12 healthy male volunteers. Each subject received on two occasions a single IV injection of meloxicam 30 mg. The cholestyramine group received the material suspended in water 3 times a day. Compared to controls, cholestyramine accelerated the elimination of meloxicam. The mean terminal phase elimination half-life was reduced from 19.5 h to 12.7 h due to an increase in clearance of the drug (0.426 vs 0.636 l.h-1). Also, as a consequence of increased clearance in the presence of cholestyramine, the mean residence time of the drug in the body was significantly decreased (39%) P < 0.01. However, the volume of distribution for meloxicam was largely unaffected by cholestyramine which suggests that meloxicam undergoes gut recirculation. These changes are of the same magnitude as those previously reported for the structurally related piroxicam and are much smaller than those observed for tenoxicam.     

Oxaprozin and piroxicam, nonsteroidal antiinflammatory drugs with long half-lives: effect of protein-binding differences on steady-state pharmacokinetics

The development of recombinant-met human granulocyte-colony stimulating factor (r-metHuG-CSF) for clinical use has had a major influence on the treatment of many diseases. This impact has perhaps been greatest for treatment of severe chronic neutropenia (SCN) conditions for which there were no predictably effective treatment before the availability of these growth factors, particularly r-metHuG-CSF (Filgrastim, Amgen Inc, Thousand Oaks, CA; or Lenograstim, Rhone-Poulenc Rorer, Milan, Italy). Based on careful studies in many countries it is now known that more than 95% of these patients will respond promptly to r-metHuG-CSF treatment with normalization of the blood neutrophil levels and reduction in the occurrence of both major and minor consequences of their severe neutropenia. The availability of this treatment will undoubtedly lead to much additional research on the mechanisms governing neutrophil production and the basic mechanisms that can cause neutropenia among patients who have SCN. Among patients who have SCN those who are diagnosed to have severe congenital neutropenia (Kostmann's syndrome) or Shwachman-Diamond syndrome are at risk of developing myelodysplasia and/or acute myelogenous leukemia. The role of r-metHuG-CSF in facilitating the risk remains to be determined. Thus, it is important that long-term evaluation of the safety and efficacy of treatment of SCN and cooperation in research on these rare conditions proceed under the auspices of an international registry monitoring the clinical outcome of patients with severe congenital neutropenia.     

A clinical evaluation of non-steroidal anti-inflammatory drugs (NSAIDS) as adjuncts in the management of periodontal disease

Several effectors and mediators of inflammation have been identified as principle factors in periodontal disease progression. It has been reported that topical and systemic application of flurbiprofen (non-steroidal anti-inflammatory drug) reduced the rate of alveolar bone loss as well as signs of gingival inflammation. Twenty rapidly progressive as well as juvenile periodontitis patients were included in the present study. Results of the present study showed a significant reduction in pocket depth & gingival index in the experimental group over the control group. Radiographs revealed more bone fill in the experimental group over the control group.     

Assessment of the antiexudative and antiproliferative activities of non-steroidal anti-inflammatory drugs in inflammatory models developed in rats by subcutaneous implantation of bacterial cell walls from the dental plaque

Previous studies have shown that linearized SV40-based shuttle vectors transfected into mammalian cells are efficiently recircularized by an error-prone end-joining pathway. To determine whether and with what specificity free radical-mediated double-strand breaks are rejoined by this pathway, a structural mimic of such a break was introduced at a specific site in an SV40-based shuttle vector, by ligating purified 3'-phosphoglycolate-terminated oligonucleotides into 3' recessed ends generated in the linearized vector. These terminally blocked linear vectors were efficiently repaired and replicated when transfected into simian CV-1 cells. Sequencing across the repair joints in progeny plasmid indicated that, for a blunt-ended vector, the most frequent mechanism of rejoining was splicing at a terminal 4-base homology; however, a significant fraction of the joints retained all bases from both ends of the break, consistent with a mechanism involving simple 3'-phosphoglycolate removal, followed by blunt-end ligation. For the analogous 3'-hydroxyl terminated break, the fraction of simple blunt-end ligations was considerably higher. For a phosphoglycolate-terminated vector with cohesive ends the most frequent repair mechanism was simple ligation of the annealed cohesive ends, presumably preceded by phosphoglycolate removal. For all these substrates, the remaining repair joints showed small or large deletions from one or both of the ends, usually with apparent annealing at short (1-4-base) homologies. The results suggest that while breaks with 3'-phosphoglycolates can be repaired, these blocked termini represent a significant barrier to DNA end-joining, and can significantly alter its specificity. The presence of cohesive ends appears to improve markedly the fidelity of rejoining for terminally blocked double-strand breaks.     

Inhibitory effects of centrally administered somatostatin on the adrenal zona glomerulosa in male rats

Segmental zoster paresis (SZP) is the focal, asymmetrical neurogenic weakness which may occur in a limb affected by cutaneous zoster. We have summarized the features of this syndrome, based on a retrospective review of 8 personal and 96 published cases. Limb SZP becomes apparent in at least 3-5% of patients with cutaneous zoster, who are usually over the age of sixty and weak proximally (C5,6,7 or L2,3,4 innervated muscles). Functional motor recovery occurs in about 75% of cases, generally by 1-2 years. Limb weakness is probably due to a lesion of the ventral nerve root, in close proximity to the initiating dorsal ganglionitis. The electrodiagnostic findings, scarce in the literature, typically consist of absent compound sensory nerve action potentials in the involved limb, with less frequent reduction or loss of compound muscle action potentials. Fibrillations and positive sharp waves become detectable within 1-4 months in limb and related paraspinal muscles, decreasing or disappearing later. In addition to this radiculopathy, peripheral nerves may also occasionally become involved, manifest as mononeuropathies of the median, ulnar, long thoracic, recurrent laryngeal, and phrenic nerves. The zoster infection or consequent inflammatory response appears able to affect motor axons distally as well as proximally.     

Inhibitory effect of prostaglandin F2 alpha on oxytocin release and on milk ejection in lactating rats

Eleven Southdown male lambs averaging 19.8 kg were randomly allotted to two groups and fed diets containing 7.7% (low-N) or 15.8% (high-N) crude protein. All of the supplemental nitrogen in the high-N diet was supplied as urea. Intake of the low-N and high-N diets averaged 372.3 g and 340.5 g/day, respectively. Findings at the end of the thirty-day trial were: (1) mean body weights unchanged for the two groups; (2) plasma urea nitrogen three-fold higher in the high-N (19.07 mg/100 ml) than the low-N (6.57) animals; (3) similar hepatic activity levels of three urea cycle enzymes (ornithine transcarbamylase, argininosuccinase, arginase) in the two groups, and (4) similar liver weights and liver protein concentration. The absence of adaptive change in enzyme levels suggests the hypothesis that addition of non-protein nitrogen to maintenance diets may cause ammonia intoxication by exceeding the liver's reserve capacity for urea synthesis.     

Reactivation of ulcerative rectocolitis with the use of non-steroidal anti-inflammatory drugs. Report of a case and review of the literature

The case of a patient with ulcerative colitis and isolated sacro-ileitis is presented. She suffered reactivation of the intestinal disease with diclofenac. The patient was allergic to sulfasalazine and was using fish oil fatty acid. The possible mechanisms of reactivation of the inflammatory bowel disease with non-steroidal anti-inflammatory drugs are discussed. It is suggested when necessary the utilization of non-steroidal anti-inflammatory drugs that inhibits the lipoxygenase in these patients.     

Inhibitory effect of progesterone on androgen-induced lordosis in ovariectomized rats

The role of family history as a risk factor of coronary heart disease was explored in the first-degree relatives of 121 female and 586 male survivors of a recent acute myocardial infarction and in those of 130 control women. It was significantly more common for female patients than male patients to have first-degree relatives with coronary artery disease before the age of 65 (76% vs 62%, P = 0.0026). For the sisters of the female patients the cumulative risk of coronary heart disease by the age of 65 years was almost twice that of the sisters of the male patients (25.9% vs 15.8%, P = 0.0123). The risk for the brothers of the females did not significantly differ from that of the brothers of the male patients, but it was 3.5 times that of the brothers of the controls. Thus, while a history of coronary heart disease in first-degree relatives is a risk factor for the disease, the risk is greater in women than in men.     

Comparison of indomethacin and nimesulide, a selective cyclooxygenase-2 inhibitor, on key pathophysiologic steps in the pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in the rat

OBJECTIVE: To examine the differences between independent and behavior-dependent stressful life events and chronic adversities in child psychiatric patients, community controls, and children with asthma. METHOD: The Psychosocial Assessment of Childhood Experiences was used to assess recent severe events (life events with high long-term threat) and major adversities (long-term experiences with high negative impact on child) in children attending a psychiatric clinic (n = 99), community controls (n = 26), and children with chronic asthma (n = 94). RESULTS: In the previous year, the psychiatric patients had, on average, experienced significantly more independent and behavior-dependent severe events and major adversities than either the controls or the asthmatic patients. The differences were most pronounced in relation to behavior-dependent high-threat life events and long-term-experiences. Among the psychiatric patients, one third of all severe events and one quarter of all major adversities were dependent on the child's behavior. The corresponding proportions in the controls and children with asthma were between one fifth and one twelfth. CONCLUSIONS: Psychiatrically disturbed children have an increased risk of experiencing behavior-dependent life events and long-term adversities compared with their peers in the community at large and compared with children suffering from a chronic physical illness such as asthma. Future studies need to examine the possible contributions of such experiences to the development and maintenance of psychiatric and physical illness in children.     

Quantitative stereological studies of a ''selection'' protocol of hepatocarcinogenesis following initiation in neonatal male and female rats

Understanding the reasons for infertility and the development of new techniques for its treatment is one of the fields within medicine which has undergone a dramatic development during the last two decades. In the past, gynecologists seemed more successful in the treatment of female problems than urologists and andrologists on the male side, while in the last couple of years this scenario has changed due to the development of both operative procedures to harvest spermatozoa from the epididymis and the testis and the ability to micro-inject single spermatozoa (ICSI) or even spermatides directly into metaphase II oocytes. It should, however, be emphasized that the successful development of in vitro fertilization (IVF) and other assisted reproduction technologies (ART), could not have taken place without the development of diagnostic innovations, such as immunoassays of hormones, high resolution ultrasound and various endoscopic techniques. Today, treatment of the infertile couple is less of a medico-technical problem and more a socio-economic dilemma. This communication is an attempt to summarize the more prominent steps in reproductive medicine during the last decades and one more general conclusion of global relevance which can be drawn, is that less money must be spent on diagnosis and more resources transferred to treatment options.     

Effect of a non-steroidal anti-inflammatory drug on tissue levels of immunoreactive prostaglandin E2, immunoreactive leukotriene, and pain after periodontal surgery

The aim of this study was to measure tissue levels of immunoreactive prostaglandin E2 (iPGE2), immunoreactive leukotriene B4 (iLTB4), and pain after periodontal surgery and to evaluate the effect of the non-steroidal anti-inflammatory drug (NSAID), ibuprofen, on these levels. Two contralateral quadrants in each of nine patients were selected to undergo separate surgical procedures, one with ibuprofen (800 mg 1 hour presurgery and 400 mg postsurgery) and one with a placebo. Intra-operatively, a custom-made microdialysis probe, with a 3,000 dalton molecular weight cut-off, was inserted beneath the soft tissue flap and a dialysate collected every 20 minutes for 4 hours after surgery. Pain perception was measured at the same time intervals using two pain scales. Dialysate samples were assayed using two enzyme immunoassays. Mean tissue levels of iPGE2 in the placebo group increased from 74 nM at 40 minutes to a peak of 261 nM at 200 minutes. Mean tissue levels of iLTB4 in the placebo group fluctuated between 0.2 and 0.6 nM. Pain levels in this group increased continuously with time, peaking at 4 hours. Mean tissue levels of iPGE2 in the ibuprofen group were significantly suppressed, exhibiting more than a 95% reduction. This was accompanied by a significant reduction in pain. Ibuprofen had no detectable effect on tissue levels of iLTB4. These data indicate that iPGE2 and iLTB4 are present at relatively high concentrations in the periodontal tissues after surgery. Since these concentrations exceed the Kd values for binding to their respective receptors, PGE2 and LTB4 may be associated with the development of postsurgical pain and inflammation. These data also indicate that ibuprofen can successfully inhibit iPGE2 production in the periodontal tissues and in this way may help reduce postoperative pain and inflammation.     

Involvement of dopamine D2 receptors in the effect of cocaine on sexual behaviour and stretching-yawning of male rats

The effect of cocaine (7.5, 15 and 30 mg/kg) administered in acute or subchronic mode, on the mating behaviour of sexually active male rats varied in a dose- and mode-dependent manner. Regardless of mode of treatment, 30 mg/kg markedly impaired the rats copulatory ability and impairment continued for a week after suspension of subchronic treatment. An acute dose of 15 mg/kg reduced intromission frequency, while in subchronic mode it also reduced ejaculation latency. Mount frequency was increased by 7.5 and 15 mg/kg, but only on first injection. In the case of sexually-naive male rats, acute administration of cocaine (3-30 mg/kg) stimulated penile erections at 7.5 mg/kg and motor hyperactivity at all doses. (-) Eticlopride (0.025 and 0.05 mg/kg), a DA D2 antagonist, counteracted cocaine-induced motor hyperactivity but not penile erection, which it enhanced. (-) Eticlopride at the same doses also antagonized cocaine potentiation of lisuride (0.2 mg/kg)-induced behavioural effects. When male rats treated with subchronic cocaine (15 mg/kg) were injected with the DA D2 agonist SND 919 (0.1 mg/kg), they displayed a more marked stretching-yawning behaviour than control animals receiving SND 919 at the same dose. The involvement of DA D2 receptors in cocaine-induced effects is suggested.     

Inhibitory effect of linoleic acid on chain elongation and desaturation of 18:2 c,t isomers in lactating and neonatal rats

OBJECTIVE: To evaluate community pharmacists' interpersonal skills, ability to make appropriate assessment of a patient' s drug-related problems, and ability to propose an appropriate therapeutic plan. DESIGN: A disguised shopper design was used. Four different case scenarios were designed, with input from a five-member community/primary care pharmacist advisory committee. Two different cases were assigned to each of two shoppers. One hundred and one pharmacies were shopped twice, totaling 202 shopping experiences. A three-member evaluation committee made up of clinical faculty members in ambulatory care and internal medicine assessed the appropriateness of the recommendations. SETTING: The study was conducted in 101 randomly selected community pharmacies in the Pittsburgh area, including both chain and independent pharmacies. MAIN OUTCOME MEASURES: Main outcome measures included the quality of the pharmacists' interpersonal skills, patient assessment skills, and recommendations. RESULTS: The majority of pharmacists demonstrated acceptable to good interpersonal skills. Overall, 31.7% of the recommendations were appropriate, while 39.1% were poor (i.e., recommendations that would likely worsen the patient's condition or potentially harm the patient). In 33.2% of the cases, recommendations were made without prior assessment of the patient's problems. CONCLUSIONS: A lack of clinical knowledge and skills should be considered as a barrier that must be overcome if the provision of pharmaceutical care is to become a reality in community practice.     

The effect of deferoxamine on ciprofibrate-induced hepatocarcinogenesis in the rat

A 74-year-old woman was hospitalised for pleuro-pneumonia of the right base. The chest x-ray showed the presence of a right paratracheal opacity which persisted during the course of the infectious episode. A computed tomographic scan of the thorax showed a voluminous anterior mediastinal mass which compressed the trachea without invading it. Surgical excision enabled the ablation of a tumour which was haemorrhagic and the histological examination established a diagnosis of cystic parathyroid adenoma. At anytime did the patient present either clinical symptoms or biochemical signs suggesting primary hyperparathyroidism.     

Inhibitory effect of selenium on biliary secretion of methyl mercury in rats

The inhibitory effect of sodium selenite on biliary secretion of methyl mercury was examined in rats. The biliary secretion of methyl mercury in rat treated with 1 mumol/kg of methyl mercury was significantly decreased by administration of selenite at doses of 0.05 mumol/kg or higher. In rats given 10 mumol/kg of methyl mercury, marked depression of biliary secretion of mercury was observed when selenite was injected at a dose of 0.2 mumol/kg. On the other hand, secretion of substantial amounts of selenium was observed when biliary secretion of mercury was depressed. When the concentration of selenium in the bile was higher than 5 nmol/ml, biliary secretion of mercury was markedly depressed independently of the dose of methyl mercury administered (1 mumol/kg or 10 mumol/kg). These results suggest that the degree of inhibitory effect of selenite may be determined by the selenium concentration in the liver or the bile after treatment with selenite rather than the molar ratio of the dose of methyl mercury and selenite. We concluded that the decrease in biliary secretion of methyl mercury induced by selenite may result from inhibition of pathway for secretion of methyl mercury from liver to bile rather than the direct formation of a complex between methyl mercury and selenium. Methyl mercury has been considered to be secreted from liver to bile as a complex with glutathione (GSH). However, administration of selenite did not affect biliary secretion of GSH or hepatic glutathione S-transferase activity. Moreover, gel filtration of liver cytosol demonstrated that the distribution pattern of hepatic methyl mercury between macromolecules and GSH was not significantly changed by administration of selenite. These results suggest that selenite does not affect complex formation of methyl mercury with GSH at least in the liver. Selenite might specifically inhibit the activity of the canalicular transporter(s) which transport complexes of methyl mercury and GSH from the liver to bile.