Biomedical subjects

Alan Cowan

Publications and source records attributed to Alan Cowan.

27 records · Page 2Linked to original sources

PubMed2003

Antinociceptive synergy, additivity, and subadditivity with combinations of oral glucosamine plus nonopioid analgesics in mice.

Glucosamine (2-amino-2-deoxy-d-glucose) and glucosamine-containing products have been reported to have efficacy in the treatment of various musculoskeletal disorders. Glucosamine's efficacy, including reduction of pain, is attributed to disease-modifying properties, specifically to cartilage-rebuilding associated with modulation of interleukin-1-induced activation of chondrocytes and to inhibition of proinflammatory effects of the nuclear factor-kappaB pathway. However, glucosamine has not been shown to have direct analgesic activity. We report here that commercial glucosamine (90.4% glucosamine sulfate + 9.6% excipients) administered as the sole agent (up to 500 mg/kg p.o.) was inactive in the mouse abdominal irritant test but that certain combinations of glucosamine with nonopioid analgesics at the oral doses and ratios tested resulted in a synergistic (ibuprofen and ketoprofen), additive (diclofenac, indomethacin, naproxen, and piroxicam), or subadditive (aspirin and acetaminophen) antinociceptive interaction. In the specific case of ibuprofen, the racemate (standard ibuprofen) produced dose-related antinociception with ED50 = 26.1 +/- 3.4 mg/kg. Combinations containing racemic ibuprofen and glucosamine in greater than 1:1 ratio (glucosamine/ibuprofen) were synergistic in the test (e.g., ED50 = 11.0 +/- 2.1 for the 9:1 ratio; p < 0.01, analysis of variance). Combinations containing glucosamine and ibuprofen (2:1 and 9:1) yielded plasma levels of ibuprofen that were no different from administration of ibuprofen alone. The possibility that combinations containing certain fixed ratios of glucosamine and certain nonsteroidal anti-inflammatory drugs (NSAIDs) might enhance pain relief in patients with pain or might achieve acceptable levels of pain relief with lower doses of NSAIDs (reduced adverse effects) is presently being pursued in clinical trials.

Acetaminophen↗

PubMed2003

Buprenorphine: new pharmacological aspects.

Buprenorphine is an opioid analgesic, derived from thebaine. Buprenorphine was initially classified as a "mixed agonist-antagonist analgesic" or a narcotic antagonist analgesic. The work of Martin et al (1976) on the animal model of the chronic spinal dog substantiated the substance's action as partial agonist at the mu-opioid receptor. These findings were underscored by the substance's general pharmacological profile. Further, buprenorphine was one of the first narcotic analgesics to be assessed for its abuse liability in humans. The lower abuse liability of the drug in humans soon turned it into a widely used therapeutic agent in patients with opioid dependence. Interest in buprenorphine spanning more than 30 years has been attributed to its unique pharmacological characteristics, including moderate intrinsic activity, high affinity to and slow dissociation from mu-opioid receptors. Early pharmacological studies demonstrated buprenorphine's strong binding to opioid receptors, and an inverted U-shaped dose-response curve in rodents. In the rat paw formalin test, although buprenorphine demonstrated a bell-shaped dose-response curve against an acute noxious stimulus, it showed a classic sigmoidal curve in the later phase of the assay. In most preclinical antinociceptive tests, buprenorphine was shown to be fully efficacious, with an antinociceptive potency 25 to 40 times higher than morphine. A ceiling effect for respiratory depression (but not for analgesia) has been demonstrated in humans. Current studies are focusing on norbuprenorphine, an N-dealkylated metabolite of buprenorphine. Norbuprenorphine is a likely contributor to the overall pharmacology of buprenorphine; in the mouse writhing test, norbuprenorphine provides antinociceptive efficacy similar to buprenorphine, with analgesic activity shown to be dose-dependent.

Analgesics, Opioid↗

PubMed2002

Antipruritic and antihyperalgesic actions of loperamide and analogs.

Loperamide and three of its analogs were evaluated for their ability to inhibit binding to cloned human opioid receptor subtypes and to produce antipruritus and antinociception following local s.c. administration to rodents. All four compounds were fully efficacious agonists with affinities of 2 to 4 nM for the cloned human mu opioid receptor. Local s.c. injection of loperamide, ADL 01-0001 or ADL 01-0002 at the same site as the introduction of the pruritogenic compound 48/80 resulted in antipruritic activity in a mouse model of itch. Similarly, i.paw or i.pl. administration of compounds ADL 01-0001, ADL 01-0002 and ADL 01-0003 to inflamed paws caused potent antinociception, inhibiting late phase formalin-induced flinching, Freund's adjuvant-induced mechanical hyperalgesia and tape stripping-induced mechanical hyperalgesia. Loperamide and its analogs were efficacious in animal models of itch and inflammatory pain, and may have potential therapeutic utility as antipruritic and antihyperalgesic agents.

Analgesics↗

PubMed2002

Single millimeter wave treatment does not impair gastrointestinal transit in mice.

Millimeter wave treatment (MWT) is based on those biological effects that develop following skin exposure to low power electromagnetic waves. This method of treatment is in wide clinical use in several Eastern European countries for treatment of a variety of conditions, including pain syndromes. However, most treatment modes of MWT were developed empirically, and certain indications and contraindications for the use of MWT remain to be established. In our previous blind experiments we have shown that the hypoalgesic effect of MWT may be quantitatively evaluated, and most probably mediated by the neural system in general, and the system of endogenous opioids in particular. Taking in consideration a well-known ability of opioids to cause gastrointestinal disturbances, which could limit clinical application of MWT, the main aim of the present study was to investigate whether a single MWT, that can produce opioid-related hypoalgesia, may also retard gut transit and colorectal passage in mice. The charcoal meal test was used to quantitatively evaluate upper gastrointestinal transit, and the glass bead test was employed to examine colonic propulsion in mice. MWT was applied to the nose area of mice. The MWT characteristics were: frequency = 61.22 GHz; incident power density = 15 mW/cm(2); and duration = 15 min. The results obtained have shown that MWT does not significantly change small intestinal or colonic transit in mice, and thus suppression of gastrointestinal motility should not be a setback in the clinical use of MWT.

Analgesia↗

PubMed2002

Abrupt or precipitated withdrawal from morphine induces immunosuppression.

The present studies tested the effect of withdrawal from morphine by two different paradigms, abrupt withdrawal (AW) or precipitated withdrawal (PW), on the capacity of murine spleen cells to mount an in vitro antibody response. Mice were made dependent by chronic treatment using s.c. implanted morphine slow-release pellets. Splenocytes were harvested at various time points after withdrawal and the number of antibody-forming cells determined using a plaque-forming cell (PFC) assay. The results indicate that induction of abstinence from morphine in dependent mice by either paradigm caused marked immunosuppression between 24 and 48 h post-withdrawal. However, the kinetics of onset and recovery from immunosuppression were different in AW and PW.

Analgesics, Opioid↗

PubMed2002

Characterization of the pharmacokinetics of buprenorphine and norbuprenorphine in rats after intravenous bolus administration of buprenorphine.

The purpose of this project was to characterize the dose-dependent pharmacokinetics of buprenorphine (BN) and norbuprenorphine (NBN), the primary metabolite, after intravenous administration of different doses of BN to rats. Adult male Sprague-Dawley rats were divided into six groups and received a single intravenous bolus dose of 0.1, 0.3, 1, 3, 10 or 30 mg/kg of BN. A separate study was performed where BN and NBN were simultaneously administered intravenously (1 mg/kg+1 mg/kg). Plasma samples were obtained by centrifugation of the blood and analyzed for BN and NBN using a sensitive and selective gas chromatographic-mass spectrometric (GC-MS) bio-analytical method. Noncompartmental and compartmental methods were used to perform pharmacokinetic data analysis. BN declined triexponentially with a dose-dependent increase in its volume of distribution, V(ss) (8.37-18.2 l/kg) and clearance CL (2.70-6.10 l/h per kg). The pharmacokinetics of NBN were linear and biexponential. Coadministration of BN and NBN resulted in a significant increase in the volume of distribution and clearance of BN. The present results suggest that the nonlinear disposition in the clearance and volume of distribution of BN can be attributed, in part, to the increasing concentration of the metabolite.

Analgesics, Opioid↗

PubMed1996

The Analgesic Interaction of Misoprostol with Nonsteroidal Anti-Inflammatory Drugs.

The purpose of this project was to evaluate the analgesic efficacy of misoprostol when combined with ibuprofen or diclofenac Na. Animal experiments using the inflamed rat paw formalin model suggested that misoprostol potentiates the analgesic effect of some NSAIDs (nonsteroidal anti-inflammatory drugs) including diclofenac Na but not propionic acid derivatives or opiates. The dental pain model was used to evaluate the clinical relevance of this interaction. Patients received a single oral dose of study medication following surgical removal of impacted teeth. Patients were medicated for moderate to severe postsurgical pain and then filled in an analgesic diary for a 6-h observation period. Several blood samples were taken over the observation period. In addition, microdialysis samples were taken directly from the extraction socket and were analyzed for immunoreactive prostaglandin E(2) levels. The studies were single-dose, parallel group and double-blind assays. In the first study, 70 patients received an oral dose of either placebo (n = 13), misoprostol 200 &mgr;g (n = 18), ibuprofen 200 mg (n = 19), or the combination of misoprostol + ibuprofen (n = 20). Misoprostol alone demonstrated a small analgesic effect compared to placebo. Both the ibuprofen and combination groups were substantially more effective than placebo but not different from each other. The combination group had higher ibuprofen blood levels during the first 45 min but had a lower C(max) and longer time to T(max). The second study evaluated oral doses of placebo (n = 11), misoprostol 200 &mgr;g (n = 21), diclofenac Na 50 mg (n = 18), and the combination of misoprostol + diclofenac Na (n = 20). Relative to placebo, misoprostol performance was similar to the first study. When the results of the two studies were combined, there was a small, but statistically significant, analgesic effect for misoprostol. Diclofenac Na was superior to both placebo and to misoprostol alone. The combination was the most effective treatment, and for hours 4--6 it was significantly better than diclofenac Na alone. Analysis of the blood samples showed an earlier and higher peak effect for the diclofenac Na group compared to the combination, and the combination again had a lower C(max). The microdialysis probe assays demonstrated that misoprostol depressed PGE(2) levels at the peripheral site of trauma over the first 2 h after surgery. These pilot studies used small samples, and the results only suggest trend effects. Both studies demonstrated that misoprostol 200 &mgr;g, a prostaglandin analog, does have an analgesic effect. When combined with ibuprofen, there was no potentiation of analgesia. In contrast, the combination of misoprostol + diclofenac Na demonstrated an enhanced peak effect, total effect for pain intensity difference and pain relief (sum pain intensity difference [SPID] and total pain relief [TOTPAR]), and

Journal Article↗

PubMed1991

Neurokinin and NMDA antagonists (but not a kainic acid antagonist) are antinociceptive in the mouse formalin model.

While much evidence implicates substance P (SP), an endogenous neurokinin (NK), as a primary sensory transmitter of acute pain in mammalian spinal cord, its role in continuous (tonic) pain is less clear. Although glutamate is co-localized with SP in dorsal root ganglion neurons, its role in nociceptive processing is uncertain. While antagonists of NKs and excitatory amino acids (EAAs) have been found to be antinociceptive in some acute assays, they have not been tested against tonic pain. We hypothesize that: (1) NKs and EAAs contribute to signaling of tonic chemogenic nociception; and (2) interaction between NK and EAA systems is important in determining the perceived intensity of a continuous noxious stimulus. We therefore evaluated two NK antagonists ([D-Pro2,D-Trp7,9] SP (DPDT-SP, 0.26-6.6 nmoles, non-specific) and [D-Pro4, D-Trp7,9,10,Phe11]-SP(4-11) (DPDTP-octa, 1.6-12.3 nmoles, somewhat NK-1 selective], as well as DL-2-amino-5-phosphonovalerate (DL-AP5, NMDA antagonist, 0.05-1 nmole) and urethane (a kainic acid (KA) antagonist at 2.5 mumoles) for antinociceptive activity in the mouse formalin model. Administered intrathecally (i.t.), DL-AP5 and both NK antagonists were significantly antinociceptive while urethane (2.5 mumoles) and naloxone (2.7 nmoles) were inactive. A50 values for mean % analgesia, nmoles/mouse i.t. (95% CLs) were: DPDT-SP, 1.1 (0.79-1.6); DPDTP-octa, 3.9 (2.4-6.1); DL-AP5, 0.29 (0.16-0.71). The antinociception associated with 1.3 nmoles of DPDT-SP was not reversed by co-administering 2.7 nmoles of naloxone. Co-administration of 0.1 nmoles of DL-AP5 with either 1.3 nmoles of DPDT-SP or 3.3 nmoles of DPDTP-octa did not lead to additive antinociception.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗

PubMed1990

The rat paw formalin test: comparison of noxious agents.

A comparison was made of the spontaneous nociceptive behaviors elicited by s.c. injection into the rat hind paw of the following 8 irritants: acetic acid, carrageenan, formalin, kaolin, platelet-activating factor, mustard oil (given topically), serotonin, and yeast. Two distinct quantifiable behaviors indicative of pain were identified: flinching/shaking of the paw and hindquarters and licking/biting of the injected paw. These behaviors were prolonged and intense after formalin and acetic acid. Formalin-induced flinching was biphasic across time, a finding potentially useful for the study of both acute and tonic pain. Of the remaining test agents, only yeast caused significant spontaneous behavioral activity, which was of low intensity but long duration. Different time-courses for nociceptive behavior and development of edema were demonstrated for formalin, acetic acid and yeast. It is therefore unlikely that these endpoints are causally related. Overall, the present data strongly support the use of formalin as a noxious stimulus in tonic pain research.

Acetates↗