Segmental effects on motor function following different intrathecal receptor agonists and antagonists in rabbits

BACKGROUND: The occurrence of motor impairment after intrathecal drug administration is infrequently reported in the literature and the methods of determining motor function vary. METHODS: Motor function was examined in rabbits after a wide dose range of a variety of intrathecally administered opioid agonists, alpha-adrenergic agonists, non-competitive NMDA antagonists, a benzodiazepine agonist, a sigma agonist, paracetamol, isotonic and acidified saline. The opioids, sigma agonist and NMDA antagonists were additionally examined following pretreatment with naloxone. The opioid antagonists naltrindole and MR2266 (delta- and kappa-opioid receptor antagonists, respectively) were administered before the delta agonist and the kappa agonist. The alpha 2-adrenergic antagonist yohimbine was given before administration of dexmedetomidine and xylazine. Motor function was evaluated by a five-point scale of motor impairment ranging from normal function to total paralysis of the hindlegs. RESULTS: DPDPE (delta agonist), paracetamol, naloxone, naltrindole, yohimbine, isotonic and acidified saline did not affect motor function. MR2266 produced minor motor impairment. The alpha-adrenergic agonist dexmedetomidine reduced motor function slightly and dose independently. The remaining compounds affected motor function in a dose-dependent fashion. High doses of morphine produced hypersensitivity and myoclonus. An irreversible paralysis of the hindlegs was observed following intrathecal administration of the sigma agonist SKF10047 in high doses. Naloxone and MR2266 attenuated the effects of U50488H (kappa agonist). CONCLUSION: The present results reveal a dose-dependent reduction in motor function after intrathecal administration of some of the investigated compounds. The mechanisms behind these effects appear to be multifactorial.     

Organic mood syndrome associated with detoxification from methadone maintenance

OBJECTIVE: The authors delineate the clinical characteristics of mood state changes that occur in stable opioid-dependent patients undergoing therapeutic detoxification from methadone maintenance treatment. METHOD: Twenty-four patients participated in a blinded protocol for gradual methadone dose reduction that included weekly assessments of affective state using the Profile of Mood States (POMS) as well as weekly assessments of signs and symptoms of opioid withdrawal. Data obtained before methadone dose reduction and during the 2-week period of maximal dysphoric symptoms were compared. Changes in affective and opioid withdrawal measures were compared in patients who differed in their success in completing the detoxification regimen. RESULTS: Sustained increases in POMS scores of greater than 20 points were observed in 12 of the 24 patients during the course of detoxification. The emergence of symptoms of dysphoria was accompanied by insomnia, loss of appetite, and somatic complaints consistent with symptoms of opioid withdrawal but only minimal levels of objective signs of withdrawal. Greater changes from baseline in mood state and opioid withdrawal measures occurred in patients who were unable to complete the detoxification regimen. CONCLUSIONS: The development of an organic mood syndrome is a common occurrence in patients undergoing slow detoxification from methadone maintenance treatment and is associated with a poor outcome.     

Does intrathecal morphine in the treatment of cancer pain induce the development of tolerance?

OBJECTIVE: This retrospective study was designed to investigate whether chronic lumbar intrathecal administration of morphine leads to the development of opioid tolerance in patients suffering from intractable cancer pain. METHODS: Between 1978 and 1995, 159 patients with refractory cancer pain were treated with intrathecal morphine in our Multidisciplinary Pain Center. The treatment consisted of preservative-free morphine administered through an access port as a single bolus. In this series of patients (n = 159), the daily doses of intrathecal morphine were determined as a function of duration of follow-up. RESULTS: The mean follow-up period was 95 days (range, 5-909 d), the mean starting daily dose of intrathecal morphine was 2.69 mg (range, 1-7.5 mg), and the mean terminal dose was 7.82 mg (range, 1-80 mg). The results demonstrated that only a moderate increase in daily dose of intrathecal morphine was required during the course of treatment (a two- to threefold increase for a 3-mo period). Furthermore, the dose increment was similar for patients followed up for more or less than 60 days. This increase did not result in any central opioid-related side effects, and the pain was managed satisfactorily. CONCLUSION: The requirement for a moderate increase in intrathecal opioid doses reflects the development of tolerance but did not limit the patients' ability to obtain adequate analgesia during the course of their painful disease.     

Effects of N-methyl-D-aspartate receptor antagonists on discriminative stimulus effects of naloxone in morphine-dependent rats using the Y-maze drug discrimination paradigm

The present study assessed the ability of various site-selective N-methyl-D-aspartate (NMDA) receptor antagonists to affect the discriminative stimulus properties of naloxone in morphine-dependent rats. Adult male Wistar rats were trained to discriminate 0.1 mg/kg of s.c. naloxone from saline using a Y-maze shock-avoidance procedure. Naloxone-appropriate responding was exhibited as a function of naloxone dose (0.01-1.0 mg/kg, ED50 = 0.03 mg/kg) and was also observed when morphine treatment temporarily was discontinued (8-96 hr, peak at 24 hr). Discriminative stimulus effects of naloxone (0.1-3.0 mg/kg) were antagonized by morphine (10-100 mg/kg). Ligands of peripheral opioid receptors failed to either substitute for naloxone (methylnaloxone, 0.1-3.0 mg/kg) or attenuate naloxone's stimulus effects (loperamide, 1-30 mg/kg). In rats treated with the training dose of naloxone, administration of dizocilpine (0.03-0.3 mg/kg) and D-CPPene (1-10 mg/kg) decreased levels of naloxone-appropriate responding, whereas memantine (1-30 mg/kg), ACEA-1021 (10 and 50 mg/kg) and eliprodil (3-30 mg/kg) seemed to have little or no effects. Meanwhile, all NMDA receptor antagonists produced a decrease in the occurrence of two or more of the following opioid withdrawal signs: weight loss, forelimb tremor, ptosis, diarrhea and "wet-dog"-like shaking. Additionally, dizocilpine (0.1 mg/kg), D-CPPene (5.6 mg/kg) and ACEA-1021 (50 mg/kg) but not memantine (10 mg/kg) or eliprodil (30 mg/kg) significantly reduced the naloxone-appropriate escape area selection when administered during the period of suspended morphine treatment 24 hr after the last morphine injection. Thus, NMDA receptor antagonists appear to inhibit the discriminative stimulus effects of both naloxone-precipitated and spontaneous morphine withdrawal, and this ability depends on the type of antagonist applied.     

Severe opioid toxicity and somatization of psychosocial distress in a cancer patient with a background of chemical dependence

A case of severe opioid toxicity is described in a 52-year-old cancer patient. The patient presented with classical clinical features of central hyperexcitability associated with opioid toxicity: delirium, myoclonus, hallucinations, hyperalgesia, and a possible seizure. This patient had a background of severe psychosocial distress and somatization in addition to a history of benzodiazepine dependence and alcohol abuse. The occurrence of opioid toxicity in this patient highlights the risks of a unidimensional approach to cancer pain, which ignores the non-organic components of pain, such as psychosocial distress, which will not respond to escalating doses of opioid medication.     

Age, pain intensity, and opioid dose in patients with advanced cancer

BACKGROUND: Elderly patients are more likely to be affected by the acute and chronic toxicities of opioids, but an association between age and long term opioid consumption has not been established clearly in patients with advanced cancer. METHODS: The computerized records of 197 cancer patients admitted to a palliative care unit in Edmonton, Alberta, Canada were examined. The authors examined: demographics (age, gender, and location of primary tumor), pain characteristics (presence of neuropathic pain and incidental pain), mean daily pain intensity (MDPI), and daily opioid consumption measured as (parenteral) morphine equivalent daily dose (MEDD). MDPI and MEDD were assessed on Days 2 and 7 after admission, on the day of maximum opioid consumption, and on the day of maximum pain intensity during admission. Average values for MDPI and MEDD were calculated between Days 2 and 7. RESULTS: When age was treated as a categoric variable (< 65 years, 65-74 years, and 75+ years), statistically significant differences in MEDD were observed for age for all estimates except those for Day 7, with older patients requiring a lower equianalgesic dose. No major differences were observed for pain intensity and for the presence of incidental or neuropathic pain across the different age groups. In the multivariate analysis, the reduction in MEDD ranged between 27-71 mg when patients age > or = 75 years were compared with younger adults. A MEDD increase that ranged between 82-137 mg was associated with the presence of neuropathic pain. CONCLUSIONS: The current study suggests that elderly cancer patients may experience a similar level of pain intensity but require a lower amount of opioid analgesia than younger adults. However, because elderly patients are more likely to be affected by the acute and chronic toxicities of opioids, opioids should be initially administered at a lower dose and titrated cautiously in these patients.     

The role of smoothing techniques in the interpretation of results from genomic scans using sib-pair data

BACKGROUND: Budesonide, a corticosteroid with high topical anti-inflammatory activity and low systemic activity, has been shown to prolong time to relapse in Crohn's disease. In the present study, the efficacy of budesonide in an oral pH-modified-release formulation was evaluated for maintenance treatment in patients with steroid-dependent ulcerative colitis. METHODS: Fourteen patients with steroid-dependent ulcerative colitis in the reduction phase of conventional glucocorticosteroids (c-GCS) following a severe attack, were treated with budesonide 3 mg t.d.s. for 6 months. The primary investigation parameters were changes in the clinical activity index (CAI) and in the daily dose of c-GCS. RESULTS: In 11 cases the CAI improved significantly and treatment with c-GCS could be terminated. Three patients experienced relapse and needed further c-GCS treatment. The average daily dose of c-GCS and the average value of the CAI before treatment with budesonide were significantly higher in the relapse group than in the remission group. CONCLUSIONS: In patients with c-GCS-dependent ulcerative colitis, a dose of 9 mg budesonide daily in an oral pH-modified-release formulation was well tolerated, significantly decreased the CAI, and rendered c-GCS unnecessary in the majority of cases.     

Diprivan: sedation for difficult intubation

No study has compared anaesthetic protocols appropriate for the sedation for fiberoptic tracheal intubation. Extrapolation of results of randomised studies comparing sedation techniques for diagnostic bronchoscopy under local anaesthesia enables the following conclusions: 1. Possible hypnotic agents for this procedure are benzodiazepines, barbiturates and propofol. Fentanyl improves the conditions for bronchoscopy. 2. Sedation using propofol is a well established technique. The induction dose, given as a bolus injection is 1 mg.kg-1, followed by continuous maintenance infusion of 1 mg.kg.h-1. 3. Irrespective of the sedation protocol used, there is always respiratory depression which justifies the need for preoxygenation, continuous oxygenation and Spo2 monitoring. Reversal of benzodiazepine and opioid effects may temporarily protect against respiratory depression.     

Transcription factor NF-kappaB regulation of renal fibrosis during ureteral obstruction

BACKGROUND: Oxycodone is metabolized in the liver by means of O-demethylation to form oxymorphone in a reaction catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). This enzyme is expressed as 2 phenotypes (extensive and poor metabolizers). Several drugs are metabolized by CYP2D6, and clinically relevant drug interactions may occur. The aim of this study was to evaluate the role of oxymorphone in mediating the opioid effects of oxycodone by means of blocking CYP2D6 with quinidine. METHODS: Ten healthy extensive metabolizers were administered 20 mg controlled-release oxycodone after premedication with placebo or 200 mg quinidine in this randomized, double-blind crossover study. A dose of 100 mg quinidine was administered 6 hours later. Plasma opioid concentrations, subjective pharmacodynamic ratings, and psychomotor function were assessed for 24 hours after drug administration. RESULTS: No oxymorphone was detected at any time after quinidine premedication in 8 of 10 subjects. Plasma oxycodone (difference not significant) and noroxycodone (P < .01) concentrations were greater after quinidine pretreatment. Prevention of the production of oxymorphone by quinidine did not affect the psychomotor or subjective drug effects of oxycodone. No difference in number of adverse effects was observed after the 2 pretreatments. CONCLUSIONS: A significant reduction in plasma oxymorphone levels did not substantially alter the pharmacodynamic effects of oxycodone. Analgesia was not evaluated because pain was not present.     

Study of the efficacy of the new antischistosomal drug 10-[2-(diethylamino)ethyl]-9-acridanone-(thiazolidin-2-ylidene) hydrazone against an Egyptian strain of S. mansoni in mice

The efficacy of 3 doses (10, 15 and 20 mg/kg) of the new antischistosomal drug Ro 15-5458 (10-[2-(diethylamino)ethyl]-9-acridanone-(thiazolidin-2-ylidene)hy drazone, CAS 092928-47-7) against an Egyptian strain of S. mansoni was studied in mice. The effect of duration of infection on the response of mice to treatment with 20 mg/kg was evaluated at 7 and 12 weeks after infection. The criteria used for the assessment of drug efficacy were: worn count and distribution in the liver and portomesenteric system, oogram changes in the small intestine, estimation of the number of ova/g stood, liver and intestine and histopathological examination of mice liver. Data revealed a dose dependent decrease in number of adult worms and number of ova/g stool, liver and intestine. A reduction of 83.6, 89.4 and 94.9% in mean number of schistosomes compared to control was recorded following treatment with 10, 15 and 20 mg/ kg of the drug, respectively. Oogram changes were more remarkable following treatment with 20 mg/kg as evidenced by complete disappearance of all immature stages. Treatment with Ro 15-5458 in a dose of 20 mg/kg resulted in complete disappearance of couples and 100% shift or worms to the live. Examination of mice liver 2 weeks post treatment revealed on changes in pathology following treatment with 10 mg/kg compared to control. Treatment with 20 mg/kg gave better results comparable to 15 mg/kg, a decreased number and size of granulomas with minimal areas of necrosis was observed. Parasitological cure was effectively achieved when treatment was initiated 7 or 12 weeks post infection. However, histopathological data revealed that the earlier the treatment the better the results.     

The diagnosis of malignant pleural mesothelioma]

OBJECTIVE: To investigate the existence of an opioid stimulatory tone on growth hormone (GH) secretion in the human male. DESIGN: Seven healthy male volunteers, aged 19-30, were studied in the Endocrine Unit of the University of Sassari. GH-releasing hormone (GHRH), 100 micrograms as an intravenous (IV) bolus, as administered with and without preadministration of IV naloxone, 2 mg as a bolus followed by a constant infusion of 2 mg/h. Blood samples were taken for 120 minutes after GHRH administration. RESULTS: Naloxone significantly blunted the GH response to GHRH, measured either as mean peak value (at times 30 to 90) or as integrated concentrations. CONCLUSIONS: Naloxone is able to decrease the effect of a maximal dose of GHRH, thus suggesting the existence of an opioid stimulatory tone on GH secretion.     

Induction with levomethadyl acetate: safety and efficacy

BACKGROUND: Levomethadyl acetate hydrochloride (known as LAAM) is a mu-opioid agonist approved for the treatment of opioid dependence. Clinical trials comparing LAAM and methadone have reported lower patient retention rates during LAAM induction; however, this may reflect dose and schedule differences. Few studies have systematically examined LAAM dose induction. This study compared induction with 3 different LAAM dosage levels. METHODS: In a randomized, double-blind trial, male and female opioid-dependent patients (N = 180) were assigned to 1 of 3 LAAM doses. The low-dose (25 mg) induction was constant from the onset of treatment, the medium-dose (50 mg) induction lasted 7 days, and the high-dose (100 mg) induction lasted 17 days. Safety and efficacy were assessed on retention, urinalysis and self-reported drug use, symptoms, and patient ratings of medication adequacy. RESULTS: The high-dose group had significantly fewer illicit opioid-positive urine samples in weeks 3 and 4 as compared with the low-dose group. The high-dose group had significantly lower self-reported heroin craving in weeks 2 and 3. All groups demonstrated significant decreases in illicit drug use, withdrawal symptoms, and depression. There were no between-group differences in retention; however, there was a trend (P = .08) for lower retention and a greater number of agonist adverse effects were observed in the high-dose group. Overall, LAAM doses were well tolerated by most patients. CONCLUSION: Induction with low and medium LAAM doses can be safely and effectively achieved within 7 days. Induction with higher LAAM doses can be safely achieved within 17 days, but may result in greater rates of patient dropout and opioid agonist adverse effects. Therefore, higher doses should be approached more slowly.     

Ontogeny of noradrenergic effects on ultrasonic vocalizations in rat pups.

The ontogeny of noradrenergic effects and the interaction of opioid and noradrenergic systems on vocalizations in rat pups from Day 10 to Day 18 were evaluated. Day 10 pups given clonidine (0.05 or 0.5 mg/kg) ip showed a sustained high level of calling throughout a 25-min isolation period that was reversed with yohimbine (0.1 mg/kg). Day 15 pups showed identical profiles with a lower baseline rate. Day 17 pups' calls were differentially affected according to dose; Day 18 pups reduced vocalizing with clonidine. In addition, it was found that at all ages when clonidine increased calling during isolation, the pups vocalized in the nest as well. Naltrexone, an opioid antagonist, lost its effectiveness to increase vocalizations after Day 15 unless it was given subsequent to clonidine. These results suggest that pups' vocalizations are differentially affected by noradrenergic and opioid stimulation or inhibition with developmental changes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioid antagonist profile of SC nor-binaltorphimine in the formalin paw assay

The antinociceptive effects of mu and kappa agonists were examined after the systemic administration of the opioid antagonists nor-binaltorphimine (nor-BNI) and naloxone in the late response or tonic nociceptive phase of the mouse formalin assay. Initially, SC morphine (ED50, 0.97 mg/kg), racemic U-50488H (ED50, 0.79 mg/kg), (-)U-50488 (ED50, 0.41 mg/kg), and another agonist PD 117,302 (ED50, 0.28 mg/kg) were found to produce graded increases in the level of antinociception as measured by this procedure; naloxone, administered immediately before morphine and U-50488H, antagonized their antinociceptive actions. The effects of morphine and U-50488H then were evaluated 10 min to 96 h after the administration of nor-BNI. Subcutaneous nor-BNI at 30.0 mg/kg, but not at 3.0 or 10.0 mg/kg, attenuated the antinociceptive effects of morphine and U-50488H when the interval separating nor-BNI and the agonists was kept constant at 1 h. Time-course analysis of the effects of combinations of nor-BNI with morphine led to irregular findings: 10.0 mg/kg of nor-BNI lessened the effects of morphine (2.0 mg/kg) if the dosing interval was 10 min, whereas 30.0 mg/kg of nor-BNI attenuated the effects of morphine (2.0 mg/kg) if the dosing interval was 1 or 4 h; 10.0 mg/kg of nor-BNI also diminished the antinociceptive effects of U-50488H (1.7 mg/kg) only if the interval spacing the two drugs was 24 h. In comparison, a threefold higher dose of nor-BNI (30.0 mg/kg) reduced the effects of U-50488H (1.7 mg/kg) if the interval was 1 h or more. In these latter experiments, the antagonist effects of SC nor-BNI (30.0 mg/kg) were evident up to 96 h posttreatment. These results show that the mu opioid antagonist activity of nor-BNI is variable and that the kappa opioid antagonist selectivity of nor-BNI is a function of dose and treatment interval and is long-lasting even after systemic administration.     

Specific reductions of striatal prodynorphin and D1 dopamine receptor messenger RNAs during cocaine abstinence

It is well established that the opioid neuropeptide and dopamine systems are altered following the use of cocaine. However very little information is available about their possible involvement during cocaine abstinence. In the present study, the mRNA expression of the dopamine receptors, D1 and D2, and the opioid peptides, prodynorphin and proenkephalin, were analyzed in the rat striatum using in situ hybridization histochemistry. Saline or cocaine (30 mg/kg, i.p.) were administered to rats once daily for 1 or 10 days. To examine cocaine abstinence, animals were treated for 10 days as described followed by a 10-day drug free period. Acute and intermittent cocaine administration elevated the prodynorphin mRNA expression in the dorsal striatum, consistent with previous reports, while the abstinent phase resulted in a significant reduction of prodynorphin mRNA levels in the ventrorostral striatum. The D1-receptor mRNA was decreased in the caudorostral striatum during cocaine withdrawal, a finding opposite to the increase observed following a single injection of the drug. Proenkephalin and the D2-receptor mRNAs were not altered during cocaine abstinence, though proenkephalin was elevated following acute but not repeated cocaine administration. These results show long-term suppression on prodynorphin and D1-receptor systems in specific striatal populations localized mainly in rostral areas during withdrawal from cocaine.     

Chronic caffeine and the anticonvulsant potency of antiepileptic drugs against maximal electroshock

The anticonvulsant activities of intraperitoneally (IP) given carbamazepine (CBZ) or diphenylhydantoin (DPH), expressed as their respective ED50 values in mg/kg, were assessed after caffeine (CAFF) treatment against maximal electroshock-induced seizures in mice. CAFF was administered IP either in a single dose or every 12 h for 3 (subchronic CAFF) and 14 days (chronic CAFF). Moreover, the protective activity of the antiepileptics was determined in mice which, following chronic CAFF, received a challenge dose of CAFF after either 24 or 72 h since CAFF withdrawal. A significant reduction of the protective efficacy of CBZ was observed after chronic CAFF treatment (in a dose of 11.55 mg/kg), while a single dose and a 3-day treatment did not alter the action of CBZ. In case of CAFF (23.1 mg/kg), a significant elevation of CBZ's ED50 value was noted after 3- and 14-day treatments with CAFF. In contrast, chronic CAFF (23.1-46.2 mg/kg) decreased the anticonvulsive activity of DPH to the same extent as did acute CAFF. Moreover the ED50 values for both, CBZ and DPH, evaluated 24 h after a 14-day treatment with CAFF (in doses of 23.1 and 46.2 mg/kg, respectively), were significantly elevated compared to respective control groups. A strong impairment of the anticon-vulsant action of CBZ and DPH was observed when a challenge dose of CAFF was injected following either 24 or 72 h injection-free time. Pharmacokinetic interactions do not seem to explain the obtained results in terms of total plasma levels of the antiepileptics after chronic treatment with CAFF. Our results may suggest that epileptic patients should avoid CAFF-containing beverages and medicines.     

Antioxidant vitamins and age-related eye disease

OBJECTIVE: To study specific serotonin (5-hydroxytryptamine [5-HT]) receptor subtype antagonists in an animal model of posthypoxic myoclonus. BACKGROUND: Although serotonergic system dysfunction is implicated in posthypoxic myoclonus, anatomic specificity and linkage to receptor subtypes are not delineated. METHODS: The authors performed a pharmacologic study to identify specific serotonin receptor subtype antagonists effective in inhibiting myoclonus in posthypoxic rats. Sprague-Dawley rats underwent cardiac arrest for 8 minutes and were resuscitated. On the day of pharmacologic testing, animals were rated every 10 minutes at -30 minutes to time 0 (drug injection) and from +60 to +150 minutes. Using a blinded methodology, animals were injected with normal saline, vehicle, or one of seven serotonin antagonists given at a dose that maintains serotonin receptor subtype specificity: WAY100135 (5-HT1A), methiothepin mesylate (5-HT1B/1D/2), mesulergine hydrochloride (5-HT2A/2B), GR 127935 (5-HT1D), SR 46349 (5-HT2), ondansetron (5-HT3), or GR 125487 (5-HT4). Drugs that produced a significant decrease in myoclonus compared with the control were studied in a dose-response study with six doses across a range from the original dose studied to 10% of that dose. RESULTS: Two drugs were significantly different from placebo: methiothepin mesylate and mesulergine hydrochloride. GR 127935 showed a trend toward reducing myoclonus. Dose-response studies showed that all doses of methiothepin mesylate and the three highest doses of mesulergine hydrochloride inhibited myoclonus effectively. CONCLUSIONS: 5-HT1B, 5-HT2A/2B, and possibly 5-HT1D receptor subtypes likely play a role in posthypoxic myoclonus. More specific 5-HT antagonists that affect these receptor subtypes are candidates for future testing in this model and in Lance-Adams syndrome.     

Inhibition of tumor necrosis factor and subsequent endotoxin shock by pirfenidone

Tumor necrosis factor-alpha (TNF) is an extremely potent cytokine which is involved in the pathogenesis of a number of diseases. Interruption of its synthesis can result in a reduction of inflammation and subsequent pathology. A new experimental drug pirfenidone (5-methyl-L-phenyl-2-(1H)-pyridone, trade name: Deskar) has been reported to have beneficial effects for the treatment of certain fibrotic diseases. The present study describes the inhibition of TNF in vitro as well as the inhibition of circulating TNF in vivo by pirfenidone. Isolated, thioglycollate-induced peritoneal macrophages (Mphi) from C57BL/6 mice were exposed to either lipopolysaccharide (LPS) or mannosylated bovine serum albumin then incubated with 0.1-0.9 mg/ml of pirfenidone. This substance inhibited the production of TNF in a dose-dependent manner as measured by ELISA. One i.p. injection of either 100 or 200 mg/kg pirfenidone inhibited the induction of circulating TNF following a single i.v. injection of LPS. Endotoxin shock was induced in mice using an i.p. injection of galactosamine and LPS. The higher dose of pirfenidone (200 mg/kg) completely inhibited shock and subsequent mortality. Lower doses of pirfenidone or administration either prior to or post challenge only partially inhibited symptoms. These results indicate that pirfenidone is able to inhibit both TNF induction and subsequent endotoxin shock. Additional studies are warranted to establish this drug as a potential treatment for diseases where TNF plays a major role.