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Biomedical subjects

R B Raffa

Publications and source records attributed to R B Raffa.

At least 19 recordsLinked to original sources
PubMed2006

Metabolism of two analgesic agents, tramadol-n-oxide and tramadol, in specific pathogen-free and axenic mice.

The in vivo metabolism of both tramadol-N-oxide (TNO) and tramadol was investigated in urine pools obtained from 0-24 h after a single 300 mg kg-1 oral dose administration of each compound to specific pathogen-free and axenic mice. Unchanged TNO (< or =42% of the initial drug sample), tramadol, and 23 metabolites from TNO-treated mice and unchanged tramadol (< or =15% of the sample) plus 20 metabolites from tramadol-treated mice were profiled, quantified and tentatively identified on the basis of atmospheric pressure ionization mass spectrometry (API-MS) and tandem mass spectrometry (MS/MS) data. Of the tramadol metabolites, five (M1-5) have been previously identified in mice. Of the tramadol and TNO metabolites, six (M18-23) are new metabolites. The tramadol and TNO metabolites were formed via the following seven metabolic pathways: N-oxide reduction (TNO), O/N-demethylation, cyclohexyloxidation, oxidative N-dealkylation, dehydration (TNO), N-oxidation (tramadol), and glucuronidation. Pathways 1-3 appear to be predominant steps forming four major O/N-desmethyl and hydroxycyclohexyl metabolites, and in conjunction with pathway 7, formed six minor glucuronides. Both tramadol-N-oxide and tramadol are extensively metabolized in mice, and no significant qualitative or quantitative differences in metabolism were observed between specific pathogen-free and axenic mice with the exception of a greater amount of unchanged TNO in axenic mice than in specific pathogen-free mice, more M2 in specific pathogen-free mice than in axenic mice in the TNO-dosed mice, and visa versa for M2 of tramadol-dosed mice.

Analgesics, Opioid↗
PubMed2003

Disruption of a drug-induced choice behavior by UV light.

A considerable body of evidence suggests that UV light disrupts ligand binding in vitro. In vivo, UV light effects have been reported to disrupt simple behaviors such as spontaneous locomotor activity. However, there are no reports of UV light blocking a more complex drug-altered behavior. We now report that: (1) cocaine dose-relatedly reversed planarians' usual selection of dark over light (from 19.4+/-4.4% to 73.3+/-6.7%) (this effect was not due to an increase in locomotor activity, since cocaine only minimally increases locomotor activity at the highest dose tested); and (2) the cocaine-induced alteration of behavioral choice was attenuated significantly (P<0.05) by UV light (366 nm and 254 nm). The results demonstrate alteration of a relatively complex choice behavior by UV light.

Animals↗
PubMed2002

Differential tramadol and O-desmethyl metabolite levels in brain vs. plasma of mice and rats administered tramadol hydrochloride orally.

OBJECTIVE: To investigate a possible differential brain uptake of tramadol vs. its major metabolite (O-desmethyl tramadol; M1) in mice and rats. METHODS: An extraction and measurement technique (gas chromatograph equipped with a nitrogen phosphorus detector) was used to measure plasma and brain levels of tramadol and M1 at intervals 10-300 min after oral dosing of tramadol hydrochloride to mice and rats. RESULTS: For all doses of tramadol administered (5, 10, 20, or 40 mg/kg), tramadol and M1 plasma levels were greatest 10 min after dosing: in mice, peak tramadol plasma levels were 47.75-736.72 ng/mL and peak M1 levels were 75.30-1084.92 ng/mL; in rats, peak tramadol plasma levels were 185.03-455.81 ng/mL and peak M1 levels were 106.74-455.70 ng/mL. Tramadol brain levels were also greatest 10 min after dosing. In mice, peak tramadol brain levels were 226.42-1847.46 ng/g. Peak M1 levels (72.17-572.97 ng/g) occurred 20-60 min after dosing. In rats, peak tramadol brain levels were 258.50-1777.37 ng/g and peak M1 levels were 80.35-289.60 ng/g. In mice, the ratio of tramadol/M1 in plasma was 0.5-1.0 throughout the measurements, whereas the ratio in brain was about 10 at 10 min and about 2 from 20 to 50 min. In rats, the ratio of tramadol/M1 in plasma was 0.5-1.5, whereas the ratio in brain was about 15 at 10 min and about 4-7 thereafter. CONCLUSION: In mice and rats, there appears to be preferential brain vs. plasma distribution of tramadol over M1.

Administration, Oral↗
PubMed2002

Potential novel targets for Alzheimer pharmacotherapy: I. Secretases.

The prevailing major theory of Alzheimer's disease (AD) is that insoluble amyloid beta-peptide (Abeta) found in the cerebral plaques characteristic of the disease is causative or is at least a contributing factor. According to this theory, inhibition of aberrant Abeta production should prevent or at least limit the extent of AD pathophysiology. As three 'secretase' enzymes (alpha, beta and gamma) catalyse the proteolytic cleavage of amyloid precursor protein (APP) (the precursor protein of Abeta), one or more secretases have become targets for potential novel AD pharmacotherapy. Secretase inhibitors have been designed and are in various stages of development. The clinical trials of these compounds will, if positive, result in drugs with dramatically better clinical efficacy or, if negative, will force a reassessment of the theory about the role of Abeta in AD.

Alzheimer Disease↗
PubMed2001

Gas chromatographic method using nitrogen-phosphorus detection for the measurement of tramadol and its O-desmethyl metabolite in plasma and brain tissue of mice and rats.

A method that allows the measurement of plasma and brain levels of the centrally-acting analgesic tramadol and its major metabolite (O-desmethyl tramadol) in mice and rats was developed using gas chromatography equipped with nitrogen-phosphorus detection (GC-NPD). Plasma samples were extracted with methyl tert.-butyl ether (MTBE) and were injected directly into the GC system. Brain tissue homogenates were precipitated with methanol, the resulting supernatant was dried then acidified with hydrochloric acid. The aqueous solution was washed with MTBE twice, alkalinized, and extracted with MTBE. The MTBE layer was dried, reconstituted and injected into the GC system. The GC assay used a DB-1 capillary column with an oven temperature ramp (135 to 179 degrees C at 4 degrees C/min). Dextromethorphan was used as the internal standard. The calibration curves for tramadol and O-desmethyl tramadol in plasma and brain tissue were linear in the range of 10 to 10000 ng/ml (plasma) and ng/g (brain). Assay accuracy and precision of back calculated standards were within +/- 15%.

Analgesics, Opioid↗
PubMed2001

Cocaine withdrawal in Planaria.

Cocaine-exposed planarians displayed abstinence-induced withdrawal behavior when placed into cocaine-free, but not cocaine-containing, water. The effect, manifested and quantified using a new spontaneous locomotor velocity metric, was dose-dependently related to cocaine exposure (8x10(-9) to 8x10(-5) M). Ultraviolet light (254 nm=7.83x10(-19) J), which was previously shown to interfere with drug-receptor interactions in Planaria, enhanced the abstinence-induced decreased locomotor velocity.

Animals↗
PubMed2001

Alpha(2) adrenoceptor agonists as potential analgesic agents. 3. Imidazolylmethylthiophenes.

A series of imidazolylmethylthiophenes has been prepared and evaluated as ligands for the alpha(2) adrenoceptor. These compounds were tested in two animal models that are predictive of analgesic activity in humans. The 3-thienyl compounds were generally the most potent, particularly those with substitution in the 4-position. A subset of the most active compounds was further evaluated for adverse cardiovascular effects in the anesthetized rat model. In addition to excellent binding at the alpha(2D) adrenoceptor, the 4-bromo analogues 20e and 21e were very active in the rat abdominal irritant test (RAIT) with ED(50) doses of 0.38 and 0.31 mg/kg, respectively. We constructed a pharmacophore model based on the biological activity of the present series, dexmedetomidine (1), and conformationally restrained analogues 3 and 4.

Adrenergic alpha-Agonists↗
PubMed2001

Unexpected and pronounced antinociceptive synergy between spinal acetaminophen (paracetamol) and phentolamine.

Acetaminophen was administered to mice by spinal (intrathecal, i.t.) injection alone or with phentolamine (11.3 microg = 0.03 micromol). Acetaminophen produced dose-related antinociception in the abdominal irritant test with an ED(50) value of 137.2 microg (0.9 micromol) Phentolamine had no effect. For combined administration, the potency of acetaminophen was significantly increased (ED50=24.4 vs. 137.2 microg), indicative of multiplicative interaction and strong synergism. These results reveal the significant and surprising interaction of spinal cord adrenoceptors or ion channel subtypes with acetaminophen-induced antinociception.

Acetaminophen↗
PubMed2001

Antihistamines as analgesics.

Histamine activates pain-transmitting nerve fibres, releases pain-related neuropeptides, and is painful when injected into the skin. Histamine agonists mimic these effects, suggesting that histamine plays a role in mediating the signal transduction of tissue damage or other painful stimulus. Certain 'antihistamines' (histamine H1 receptor antagonists) and other antihistaminics are 'analgesic' in preclinical or clinical models. Potential sites of action of these agents include the brain and spinal cord and a specific histamine receptor subtype might be involved (three subtypes have been identified). However, it is possible that other mechanisms account for the analgesic effect.

Analgesia↗
PubMed2001

Pharmacology of oral combination analgesics: rational therapy for pain.

No single analgesic agent is perfect and no single analgesic can treat all types of pain. Yet each agent has distinct advantages and disadvantages compared to the others. Hence, clinical outcomes might be improved under certain conditions with the use of a combination of analgesics, rather than reliance on a single agent. A combination is most effective when the individual agents act through different analgesic mechanisms and act synergistically. By activating multiple pain-inhibitory pathways, combination analgesics can provide more effective pain relief for a broader spectrum of pain, and might also reduce adverse drug reactions. This overview highlights the therapeutic potential of combining analgesic medications with different mechanisms of action, particularly a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen with an opioid or tramadol.

Administration, Oral↗
PubMed2001

Metabolism of the analgesic drug, tramadol hydrochloride, in rat and dog.

1. Metabolism of the analgesic agent, tramadol hydrochloride, was investigated after a single oral administration of 14C-tramadol to four rats (50)mgkg(-1) and two dogs (20)mg kg(-1). 2. Recovery of total radioactivity in rat and dog urine samples over 24 h was 73 and 65% of the radioactive dose, respectively. 3. Unchanged tramadol and a total of 24 metabolites, consisting of 16 Phase I metabolites and eight conjugates (seven glucuromides, one sulphate), were isolated and tentatively identified, which accounted for > 52% of the dose in urine of both species. 4. Of the metabolites, five (M1-5) were previously identified. 5. The metabolites were formed via the following six metabolic pathways: O-demethylation, N-demethylation, cyclohexyl oxidation, oxidative N-dealkylation, dehydration and conjugation. 6. Pathways 1-3 appear to be major steps, forming seven O-desmethyl/N-desmethyl and hydroxy-cyclohexyl metabolites in major quantities. 7. Pathways 1-3 in conjunction with pathway 6 produced four glucuronides along with four minor conjugates. 8. In addition, the in vitro metabolism of tramadol was conducted using rat hepatic S9 fraction in the presence of an NADPH-generating system. Unchanged tramadol (30% of the sample) plus nine metabolites, M1-7, tramadol-N-oxide (M31) and OH-cyclohexyl-M1 (M32), were profiled and tentatively identified based on MS and MS/MS data.

Analgesics, Opioid↗
PubMed2000

Energy-dependent UV light-induced disruption of (-)sulpiride antagonism of dopamine.

The dopamine D2 receptor antagonist sulpiride decreases the spontaneous locomotor activity of Planaria in an enantiomeric-selective and dose-dependent manner. We now report that (-)sulpiride (0.1 microM)-induced decrease of planarian locomotor activity is significantly (P<0.05) attenuated by low-energy (366 nm) ultraviolet (UV) light and to a greater extent by high-energy (254 nm) UV light. The phenomenon offers a novel approach for studying dopamine D2 receptor transduction processes in a simple in vivo model.

Animals↗
PubMed2000

Is there a basis for novel pharmacotherapy of autism?

No medication has yet been shown to consistently alter the symptoms or the course of autism in the majority of patients. The present pharmacotherapy is mainly palliative and sometimes effective in attenuating specific behaviors. The search for better treatment involves examination of the underlying pathophysiology, the genetic or environmental etiology (including possible iatrogenic causes), and assessment of the clinically-generated evidence of efficacy, including serendipitous or unexplained findings. Subtle neuroanatomic and neurochemical changes are being explored and there are anecdotal reports or limited clinical trials that suggest some therapy might be possible. Secretin is a surprising recent addition to the list of candidates. The pharmacologic mechanism by which these agents might provide such effect is not clear, but hypotheses are beginning to emerge. In addition, the prevention of some uncertain number of autism cases is being investigated by examination of certain vaccinations as putative causative or contributory factors. These topics are reviewed in this article, which has the additional purpose of stimulating novel drug discovery efforts for this enigmatic disorder.

Amino Acid Sequence↗
PubMed2000

Actions of Ginkgo Biloba related to potential utility for the treatment of conditions involving cerebral hypoxia.

Neuronal hypoxia results from a variety of cerebrovascular accidents or 'normal' age-associated anatomic changes. The consequences vary from mild deficits in neurologic function to massive neuropathology. Present pharmacotherapeutic therapy is not ideal. Two apparently disparate approaches to the search for better treatment or prevention-one involving reassessment of herbal remedies as 'alternative' medicine and the other one involving the desirability of increased structural diversity in HTS (high-throughput screening) libraries and as combinatorial chemistry templates-have converged in a rekindling of interest and a reevaluation of the pharmacologic properties of substances such as extract from the leaves of Ginkgo biloba Linne (form. Salisburia adiantifolia Sm.). There are reports of positive results from a small number of controlled clinical trials (albeit with small numbers of patients) sufficient to suggest that 'Ginkgo' might have therapeutic benefit in some situations or subset of patients. The pharmacologic mechanism by which Ginkgo might be able to provide the observed effect is not clear. However, it is believed that the flavonoid and terpenoid components of Ginkgo extract might produce beneficial therapeutic effects through mechanisms acting separately or in concert, such as the antagonism of PAF (platelet activating factor), antioxidant and metabolic actions, and effects on neurotransmitters. These mechanisms are reviewed in this article.

Ginkgo biloba↗