The Journal of pharmacy and pharmacology
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J. Pharm. Pharmacol. · Feb 2004
Comparative StudyEffect of MX-68 on airway inflammation and hyperresponsiveness in mice and guinea-pigs.
MX-68 is a newly synthesized antifolate, which is a derivative of methotrexate (MTX). In this paper, the effect of MX-68 on allergic airway responses in mice and guinea-pigs was studied. In the first experiment, antigen-induced airway inflammation and airway hyperresponsiveness (AHR) to acetylcholine in mice were examined and compared with the effects of classical antifolate methotrexate and prednisolone. ⋯ In the guinea-pig model for bronchial asthma, biphasic increases in airway resistance (immediate asthmatic response, IAR, and late asthmatic response, LAR), as well as accumulated inflammatory cells in BALF, were observed after repeated antigen challenge. These asthmatic responses and inflammatory signs were significantly decreased by administration of MX-68. These results suggest that MX-68 obviously has an anti-inflammatory effect in an animal model of asthma and would be useful clinically for the treatment of bronchial asthma.
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The hepatic disposition and biliary excretion of amphotericin B were investigated in the isolated perfused rat liver (IPRL). Bolus dose of 50 microg, 99 microg and 198 microg amphotericin B in lipoprotein-free perfusate and 198 microg amphotericin B in perfusate with 1 microM high-density lipoprotein (HDL) or 1 microM low-density lipoprotein (LDL) were examined in the IPRL. Amphotericin B concentration in perfusate was measured using a validated HPLC assay. ⋯ No metabolites were detected in perfusate, bile and liver samples. The hepatic disposition of amphotericin B was not affected by the presence of HDL and LDL in the perfusate. In conclusion, the hepatic disposition of amphotericin B demonstrates restrictive elimination and is concentration-dependent, consistent with carrier-mediated uptake, and lipoproteins do not influence amphotericin B hepatobiliary disposition.
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J. Pharm. Pharmacol. · Oct 2003
Clinical TrialIntratumoural chemotherapy with 5-fluorouracil for palliation of bronchial cancer in patients with severe airway obstruction.
Patients with tracheal or major airway obstruction owing to inoperable carcinomas are at risk of developing respiratory failure or postobstructive pneumonia. In such cases, there is an urgency to restore the airway. Bronchoscopic interventional procedures for palliation of malignant airway obstruction are becoming more common in clinical practice. ⋯ The therapy was well tolerated, with no systemic side-effects or any serious complications. The results of this study suggest that in patients with life-threatening airway obstruction, intratumoural injection of anticancer drugs should be regarded as an important new therapeutic approach and an integral part of interventional bronchoscopic management. This study further encourages more general consideration of intratumoural drug injection as a minimally invasive therapeutic method for the treatment of lung cancer and various inoperable cancers.
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J. Pharm. Pharmacol. · Jul 2003
Regional transport and metabolism of ropivacaine and its CYP3A4 metabolite PPX in human intestine.
The major aim of this study was to investigate the CYP3A4 metabolism and polarized transport of ropivacaine and its metabolite 2',6'-pipecoloxylidide (PPX) in tissue specimens from the human small and large intestine. Ropivacaine has been shown to be effective in the treatment of ulcerative colitis in human colon. This study was conducted using a modified Ussing-chamber technique with specimens from jejunum, ileum and colon collected from 11 patients. ⋯ P-glycoprotein was probably not involved in the metabolite extrusion. No other metabolite than PPX was found. This in-vitro study with human intestinal tissues provides new mechanistic insights into regional transport and metabolism of drugs.
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J. Pharm. Pharmacol. · May 2003
Gastrointestinal mucosal injury following repeated daily oral administration of conventional formulations of indometacin and other non-steroidal anti-inflammatory drugs to pigs: a model for human gastrointestinal disease.
Non-steroidal anti-inflammatory drugs (NSAIDs) vary in their propensity to cause damage in different regions of the gastrointestinal (GI) tract in laboratory animals and humans. This may depend on the type of drug formulation as well as the intrinsic pharmacological properties of the drugs. The purpose of this study was to determine the effects of NSAIDs, with cyclooxygenase 1 and 2 inhibitory activity but with different potency as inhibitors of prostaglandin production, when given orally as tablet/capsule formulations of NSAIDs for 10 days to pigs, a species that has close resemblance in structure and function of the tract to that in humans. ⋯ The mucosal concentrations of indometacin in the gastric and intestinal mucosa correlated with mucosal injury. These findings show that: (i) NSAIDs vary in their propensity to produce mucosal injury in different regions of the GI tract according to their pharmacological properties and formulation; (ii) mucosal injury from some NSAIDs may not directly relate to blood loss at low doses of NSAIDs and this may depend on inhibition of platelet aggregation; and (iii) the occurrence of caecal ulcers uniquely observed with indometacin treatment may be relevant to the development of intestinal pathology (e.g. diaphragm-like structures) seen occasionally in humans. These results suggest that the pig model employed in the present studies may be useful for investigations of GI damage from NSAID tablets/capsules, especially in regions that are generally inaccessible to routine endoscopic investigations in humans (e.g. the proximal regions of the large intestine).