A comparative analysis of monoaminergic involvement in the spinal antinociceptive action of DAMPGO and DPDPE.
Male; Animals; Rats; Injections; Enkephalins/*pharmacology; Naloxone/pharmacology; Anesthetics/*pharmacology; Biogenic Monoamines/*physiology; Pain/*metabolism; Spinal Cord/drug effects/metabolism/*physiopathology; Dose-Response Relationship; Drug; Inbred Strains; Receptors; Enkephalin; Ala(2)-MePhe(4)-Gly(5)-; Spinal; 5)-; D-Penicillamine (2; Opioid/drug effects/*physiology; Enkephalins; Intraspinal; Amines – Physiology; Anesthetics – Pharmacodynamics; Cell Surface – Drug Effects; Cell Surface – Physiology; Enkephalins – Pharmacodynamics; Naloxone – Pharmacodynamics; Pain – Metabolism; Spinal Cord – Drug Effects; Spinal Cord – Metabolism; Spinal Cord – Physiopathology
The antinociceptive properties of intrathecally (i.t.) administered [D-Ala2,
Spanos L J; Stafinsky J L; Crisp T
Pain
1989
1989-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0304-3959(89)90046-8" target="_blank" rel="noreferrer noopener">10.1016/0304-3959(89)90046-8</a>
A lack of supersensitivity to opioid receptor agonists following chronic spinal opioid receptor antagonist administration in the rat.
5)-; Ala(2)-MePhe(4)-Gly(5)-; Animals; D-Penicillamine (2; Dose-Response Relationship; Drug; Enkephalin; Enkephalins/*pharmacology; Male; Naltrexone/analogs & derivatives/pharmacology; Narcotic Antagonists/*pharmacology; Opioid/*drug effects; Rats; Receptors; Somatostatin/analogs & derivatives/pharmacology; Species Specificity; Spinal Cord/*drug effects; Sprague-Dawley
1. Male Sprague-Dawley rats were chronically tested with intrathecal (i.t.) receptor selective opioid antagonists to determine if antinociceptive supersensitivity developed to selective i.t. opioid receptor agonists. 2. A subcutaneously implanted osmotic minipump was used to deliver the mu-opioid receptor antagonist CTOP (0.3 nmol) or the delta-opioid receptor antagonist naltrindole (5.5 nmol) for 7 days. 3. Following a 24 hr washout period, rats received a single i.t. dose (ED50) of either DAMPGO (for CTOP-treated animals) or DPDPE (for naltrindole-treated animals) and the antinociceptive effects of the agents were tested on the tail-flick test. 4. Our findings revealed that chronic spinal treatment with selective opioid receptor antagonists did not induce an antinociceptive supersensitivity to selective opioid receptor agonists. 5. Perhaps this lack of supersensitivity is reflective of difficulties inherent to opioid receptor antagonists that do not possess negative intrinsic activity.
Keck B J; Stafinsky J L; Uram M; Crisp T
General pharmacology
1995
1995-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0306-3623(94)00154-f" target="_blank" rel="noreferrer noopener">10.1016/0306-3623(94)00154-f</a>
A novel binding assay identifies high affinity ligands to the rosiglitazone binding site of mitoNEET.
Binding Sites/drug effects; Dose-Response Relationship; Drug; Ligands; Mitochondrial Proteins/*antagonists & inhibitors/metabolism; Molecular Structure; Recombinant Proteins/antagonists & inhibitors/metabolism; Rosiglitazone; Stereoisomerism; Structure-Activity Relationship; Thiazolidinediones/chemical synthesis/chemistry/*pharmacology
A novel outer mitochondrial membrane protein containing [2Fe-2S] clusters, mitoNEET was first identified through its binding to the anti-diabetic drug pioglitazone. Pioglitazone belongs to a family of drugs that are peroxisome proliferator-activated receptor (PPAR) gamma agonists, collectively known as glitazones. With the lack of pharmacological tools available to fully elucidate mitoNEET's function, we developed a binding assay to probe the glitazone binding site with the aim of developing selective and high affinity compounds. We used multiple thiazolidine-2,4-dione (TZD), 2-thioxothiazolidin-4-one (TTD), and
Geldenhuys Werner J; Funk Max O; Awale Prabha S; Lin Li; Carroll Richard T
Bioorganic & medicinal chemistry letters
2011
2011-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.bmcl.2011.06.111" target="_blank" rel="noreferrer noopener">10.1016/j.bmcl.2011.06.111</a>
A Rare Case of Tubulointerstitial Nephritis and Uveitis Syndrome Treated with a Multi-Specialty Approach.
Female; Humans; Young Adult; Follow-Up Studies; Biopsy; Glucocorticoids/administration & dosage; Kidney/*diagnostic imaging; Prednisolone/administration & dosage/*analogs & derivatives; Prednisone/*administration & dosage; Recurrence; Uveitis/diagnosis/*drug therapy; Diagnosis; Dose-Response Relationship; Drug; Differential; Drug Therapy; Combination; Interstitial/diagnosis/*drug therapy; Nephritis
BACKGROUND It is important for an ophthalmologist and nephrologist to look for hidden causes of uveitis and nephritis, respectively. Delay in diagnosis leads to increased morbidity and failure to systemically manage the patient results in future recurrence of disease. It is likely that TINU remains underdiagnosed and could potentially account for some of the cases of idiopathic uveitis, especially when greater than 50% of uveitis cases have no identifiable cause. Fewer than 300 cases of tubulointerstitial nephritis and uveitis (TINU) syndrome have been reported. In TINU syndrome, inflammation affects the renal tubules, interstitial tissue, and uveal tract. Its pathogenesis remains poorly understood. CASE REPORT We report a rare case of TINU syndrome in a 23-year-old female who was treated using a multispecialty approach. Her primary care physician diagnosed her with proteinuria and acute kidney injury and referred her to the nephrologist, who later referred her to the ophthalmologist. A left kidney biopsy confirmed acute interstitial nephritis. Following the discovery of a "pink eye", the patient was referred to ophthalmology and diagnosed with anterior uveitis, confirming TINU syndrome. Without the additional findings of uveitis, the diagnosis would have been missed. Resolution was obtained through steroid therapy. CONCLUSIONS Correctly diagnosing TINU syndrome requires a multispecialty approach and may not be obvious upon initial presentation. Therefore, the ophthalmologist needs to consider TINU in the differential diagnosis for a patient with bilateral uveitis and evaluate a urinalysis for proteinuria as part of the work up.
Purt Boonkit; Hiremath Siri; Smith Sarah; Erzurum Sergul; Sarac Erdal
The American journal of case reports
2016
2016-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.12659/ajcr.900701" target="_blank" rel="noreferrer noopener">10.12659/ajcr.900701</a>
A standardized extract of Butea monosperma (Lam.) flowers suppresses the
*Butea; Aged; Autophagy; Autophagy/drug effects/physiology; Butea monosperma (Lam.); Chondrocytes/drug effects/*metabolism; Dose-Response Relationship; Drug; Flowers; Gene Expression; Humans; Interleukin-1beta/*pharmacology; Interleukin-6/*biosynthesis/genetics; Matrix Metalloproteinase 13/biosynthesis/genetics; Matrix Metalloproteinase 3/biosynthesis/genetics; Matrix Metalloproteinase 9/biosynthesis/genetics; Matrix Metalloproteinases/*biosynthesis/genetics; Middle Aged; mTOR; Nutraceuticals; Osteoarthritis; Osteoarthritis/*metabolism; Plant Extracts/isolation & purification/pharmacology
BACKGROUND/OBJECTIVE: Osteoarthritis (OA) is a leading cause of joint dysfunction, disability and poor quality of life in the affected population. The underlying mechanism of joint dysfunction involves increased oxidative stress, inflammation, high levels of cartilage extracellular matrix degrading proteases and decline in autophagy-a mechanism of cellular defense. There is no disease modifying therapies currently available for OA. Different parts of the Butea monosperma (Lam.) plant have widely been used in the traditional Indian Ayurvedic medicine system for the treatment of various human diseases including inflammatory conditions. Here we studied the chondroprotective effect of hydromethanolic extract of Butea monosperma (Lam.) flowers (BME) standardized to the concentration of Butein on human OA chondrocytes stimulated with IL-1beta. METHODS: The hydromethanolic extract of Butea monosperma (Lam.) (BME) was prepared with 70% methanol-water mixer using Soxhlet. Chondrocytes viability after BME treatment was measured by MTT assay. Gene expression levels were determined by quantitative polymerase chain reaction (qPCR) using TaqMan assays and immunoblotting with specific antibodies. Autophagy activation was determined by measuring the levels of microtubule associated protein 1 light chain 3-II (LC3-II) by immunoblotting and visualization of autophagosomes by transmission electron and confocal microscopy. RESULTS: BME was non-toxic to the OA chondrocytes at the doses employed and suppressed the IL-1beta induced expression of inerleukin-6 (IL-6) and matrix metalloprotease-3 (MMP-3), MMP-9 and MMP-13. BME enhanced autophagy in chondrocytes as determined by measuring the levels of
Ansari Mohammad Y; Khan Nazir M; Haqqi Tariq M
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
2017
2017-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.biopha.2017.09.140" target="_blank" rel="noreferrer noopener">10.1016/j.biopha.2017.09.140</a>
A subtherapeutic international normalized ratio despite increasing doses of warfarin: could this be malabsorption?
*Drug Resistance; Administration; Adult; Anticoagulants/administration & dosage/metabolism/pharmacokinetics/therapeutic use; Area Under Curve; Biological Availability; Dose-Response Relationship; Drug; Female; Humans; Injections; Intestinal Absorption/*physiology; Intravenous; Kidney Transplantation; Oral; Warfarin/*administration & dosage/*metabolism/pharmacokinetics/therapeutic use
OBJECTIVE: To describe a case of warfarin resistance apparently caused by malabsorption and to review the literature regarding warfarin resistance. CASE SUMMARY: A 28-year-old renal transplant patient with systemic lupus erythematosus was admitted for upper extremity thrombophlebitis. Resistance to oral warfarin was demonstrated. Potential causes were investigated. The trapezoidal rule was used to compare the area under the curve for intravenous versus oral dosing of warfarin. The usual bioavailability of warfarin should be 100%. In this patient, warfarin bioavailability after oral dosing was 1.5%. Three potential causes, malabsorption (FF), enzymatic degradation (FG), and first-pass extraction in the portal circulation (FH), are discussed. CONCLUSION: This case demonstrates resistance to warfarin presumably caused by malabsorption.
Lara L F; Delgado L L; Frazee L A; Haupt K M; Rutecki G W
The American journal of the medical sciences
2000
2000-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0002-9629(15)40823-7" target="_blank" rel="noreferrer noopener">10.1016/s0002-9629(15)40823-7</a>
Activation of metabotropic glutamate receptor 1 dimers requires glutamate binding in both subunits.
Blotting; Calcium Channels/drug effects/metabolism; DNA/biosynthesis/genetics; Dose-Response Relationship; Drug; Fluorescent Antibody Technique; Genes; Glutamic Acid/*metabolism; Humans; Membrane Potentials/drug effects; Metabotropic Glutamate/genetics/*metabolism; myc/genetics; Patch-Clamp Techniques; Plasmids/genetics; Receptors; Signal Transduction/drug effects; Superior Cervical Ganglion/cytology/drug effects/metabolism; Sympathetic Nervous System/cytology/drug effects/metabolism; Western
Group I metabotropic glutamate receptors (mGluRs) form stable, disulfide-linked homodimers. Lack of a verifiably monomeric mGluR1 mutant has led to difficulty in assessing the role of dimerization in the molecular mechanism of mGluR1 activation. The related GABA(B) receptor exhibits striking intradimer cross talk (ligand binding at one subunit effectively produces G protein activation at the other), but it is unclear whether group I mGluRs exhibit analogous cross talk. Signaling of heterologously expressed mGluR1 was examined in isolated rat sympathetic neurons by measuring glutamate-mediated inhibition of native calcium currents. To examine mGluR1 activity when only one dimer subunit has access to glutamate ligand, wildtype mGluR1 was coexpressed with mGluR1 Y74A, a mutant with impaired glutamate binding, and the activity of the heterodimer (mutant/wild type) was examined. The mGluR1 Y74A mutant alone had a dose-response curve that was shifted by about 2 orders of magnitude. The half-maximal dose of glutamate shifted from 1.3 (wild-type mGluR1) to about 450 (mGluR1 Y74A) microM. However, the maximal effect was similar. Wild-type mGluR1 was expressed with excess Y74A mGluR1 to generate a receptor population consisting largely of mutant homodimers and mutant/wild-type heterodimers but without detectable wild-type homodimers. Under these conditions, no glutamate-mediated calcium current inhibition was observed below approximately 300 microM glutamate, although wild-type mGluR1 protein was detectable with immunofluorescence. These data suggest that mutant/wild-type heterodimeric receptors are inactive at ligand concentrations favoring glutamate association with receptor dimers at only one subunit.
Kammermeier Paul J; Yun June
The Journal of pharmacology and experimental therapeutics
2005
2005-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1124/jpet.104.073155" target="_blank" rel="noreferrer noopener">10.1124/jpet.104.073155</a>
Acute and subchronic effects of methylenedioxymethamphetamine [(+/-)MDMA] on locomotion and serotonin syndrome behavior in the rat.
Male; Time Factors; Animals; Rats; Behavior; Motor Activity/*drug effects; Amphetamines/*pharmacology; Designer Drugs/*pharmacology; Dose-Response Relationship; Drug; Inbred Strains; Receptors; 3; Animal/*drug effects; N-Methyl-3; 4-methylenedioxyamphetamine; 4-Methylenedioxyamphetamine/analogs & derivatives/*pharmacology; Serotonin/*drug effects
Specific behaviors comprising the serotonin syndrome (low body posture, forepaw treading, headweaving) and the autonomic signs of piloerection and salivation were determined and analyzed with locomotor activity in response to MDMA at three doses (2.5, 5.0, and 7.5 mg/kg). All behaviors were dose-responsive. Serotonin syndrome behaviors increased in both intensity and duration of response with increasing doses. In contrast, locomotion varied only in intensity. Subchronic injections, in the same group of animals, permitted an analysis of acute vs. subchronic effects on these same behaviors. Both the serotonin syndrome and locomotor behaviors were augmented on subsequent testing, indicating that, (+/-)MDMA, like amphetamine, is capable of producing behavioral sensitization.
Spanos L J; Yamamoto B K
Pharmacology, biochemistry, and behavior
1989
1989-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(89)90044-0" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(89)90044-0</a>
Acute exercise attenuates phenylephrine-induced contraction of rabbit isolated aortic rings.
Animals; Rabbits; In Vitro Techniques; Phenylephrine/*pharmacology; Aorta/physiology; Muscle Contraction/*drug effects; Dose-Response Relationship; Drug; Muscle; Receptors; Animal; Smooth; Adrenergic; *Physical Conditioning; alpha/physiology; Vascular/*drug effects/physiology
Factors associated with a single bout of dynamic exercise (increased circulating catecholamines, increased body temperature, and decreased pH) are known to attenuate the vascular response to alpha-adrenergic receptor activation. Therefore, we postulate that an acute bout of dynamic exercise may decrease the vascular response to catecholamines. To test this hypothesis, we evaluated contractile responsiveness to phenylephrine (PE) in aortae of two groups of New Zealand white rabbits, a control group (no exercise) and an exercise group (treadmill running, 24m.min-1; 16 +/- 2.0 min). Aortic rings were prepared from age-matched control (N = 6) and exercise rabbits (N = 5) and mounted for isometric tension recording (in Krebs-Henseleit-bicarbonate solution, 37 degrees C, 1.5 g passive tension). After equilibration (2 h) a cumulative concentration-response curve to PE (10(-7) M-10(-2) M) was obtained. The results demonstrate that a single bout of dynamic exercise attenuates (P \textless 0.05) the maximal contractile tension (2,457 +/- 120 vs 3,620 +/- 321 mg tension.mg-1 ring wt), gain (602 +/- 31 vs 878 +/- 87 mg.M-1 PE), and rate of contraction (6.2 +/- 0.3 vs 4.7 +/- 0.3 mg tension.s-1). In addition, contraction threshold was significantly increased in exercise (2.6 +/- 0.4 x 10(-6) M) vs control aortae (1.03 +/- 0.4 x 10(-6) M). A single bout of dynamic exercise did not alter the contractile response to 70 mM KCl (3,555 +/- 270 vs 3,083 +/- 233 mg tension.mg-1 ring weight). These data suggest that an acute bout of dynamic exercise significantly attenuates alpha-adrenergic receptor-mediated contraction of vascular smooth muscle.
Howard M G; DiCarlo S E; Stallone J N
Medicine and science in sports and exercise
1992
1992-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1249/00005768-199210000-00006" target="_blank" rel="noreferrer noopener">10.1249/00005768-199210000-00006</a>
Acute exercise enhances nitric oxide modulation of vascular response to phenylephrine.
*Physical Exertion; Animals; Arginine/analogs & derivatives/pharmacology; Blood Flow Velocity; Blood Pressure/drug effects; Blood Vessels/*drug effects; Dose-Response Relationship; Drug; Female; Heart Rate/drug effects; Iliac Artery/drug effects/physiology; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide/antagonists & inhibitors/*physiology; Phenylephrine/*pharmacology; Rats; Sprague-Dawley; Time Factors; Vasoconstriction/drug effects/physiology
The influence of the release of endothelium-derived nitric oxide (NO) on the vasoconstrictor response to phenylephrine (PE) was evaluated before and after a single bout of dynamic exercise. Each rat ran on a motor-driven treadmill at
Patil R D; DiCarlo S E; Collins H L
The American journal of physiology
1993
1993-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.1993.265.4.H1184" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.1993.265.4.H1184</a>
Advantages and disadvantages of a rapid method to train drug discrimination.
Male; Animals; Rats; Drug Tolerance; Methods; Discrimination Learning/*drug effects; Amphetamines/*pharmacology; Dose-Response Relationship; Drug; 3; N-Methyl-3; 4-methylenedioxyamphetamine; 4-Methylenedioxyamphetamine/analogs & derivatives/*pharmacology
In an effort to reduce the often extensive period of time needed to train rats to discriminate between a drugged and nondrugged state, a fast training regimen was employed with 1.5 mg/kg 3,4-methylenedioxymethamphetamine (MDMA) used as the training drug in ten rats. This protocol consisted of one to three training sessions per day and it was compared to the more conventional method of once-per-day training in an equal number of rats. Results indicate that the fast-trained rats learned the discrimination in significantly fewer sessions than the slowly-trained rats. However, the subsequent dose-response experiments indicate that when the fast-trained rats are tested with various doses of MDMA, without prior vehicle treatment, their sensitivity to the drug is less than that of the slowly-trained rats. When a vehicle session is presented prior to drug dose-response testing, both groups perform similarly. It appears that the preceding vehicle sessions function as a reference point for the fast-trained rats and, although the more rapid training regimen allows for faster learning, these treatment regimens should be employed with caution when subsequent dose-response tests and generalization tests with other drugs are conducted.
Schechter M D
Pharmacology, biochemistry, and behavior
1988
1988-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(88)90340-1" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(88)90340-1</a>
Age-related changes in the spinal antinociceptive effects of DAGO, DPDPE and beta-endorphin in the rat.
Male; Animals; Rats; Analysis of Variance; Aging/*physiology; Injections; Analgesics/*pharmacology; Pain/*physiopathology; beta-Endorphin/administration & dosage/*pharmacology; Enkephalins/administration & dosage/*pharmacology; Spine/drug effects/growth & development/*physiology; Dose-Response Relationship; Drug; Enkephalin; Inbred F344; Ala(2)-MePhe(4)-Gly(5)-; Spinal; 5)-; D-Penicillamine (2
These studies were designed to investigate how the aging process alters the spinal antinociceptive efficacy of mu (mu), delta (delta) and epsilon (epsilon) opioid receptor agonists administered intrathecally (i.t.) in rats. Various doses of the mu agonist DAGO, the delta agonist DPDPE or the putative epsilon beta-endorphin were injected i.t. in young (5-6-month-old), mature (15-16-month-old) and aged (25-26-month-old) Fischer 344 rats. Antinociception was measured using the rat tail-flick analgesiometric assay. The data demonstrated a decline in spinal opioid-induced antinociception as a function of age. For instance, the i.t. dose of DPDPE or beta-endorphin needed to produce antinociception in the 25-26-month-old rats was higher than that needed to elevate tail-flick latency in the young and mature animals. We also noted that the i.t. doses of the opioid agonists needed to produce 'antinociception' in the aged cohort were within a range of spinal doses that produced motor impairment. Apparently, the aging process alters the ability of opioid receptors to mediate antinociception. Perhaps an age-related decrease in the number and/or affinity of opioid receptor sites in the rat spinal cord accounts for these observations.
Crisp T; Stafinsky J L; Hoskins D L; Perni V C; Uram M; Gordon T L
Brain research
1994
1994-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
An open-label dose escalation study to evaluate the safety of administration of nonviral stromal cell-derived factor-1 plasmid to treat symptomatic ischemic heart failure.
*Plasmids; Aged; Brain/blood; Chemokine CXCL12/*genetics/metabolism; Cohort Studies; Dose-Response Relationship; Drug; Echocardiography; Exercise Tolerance; Female; Follow-Up Studies; Genetic Therapy/*adverse effects/*methods; Heart Failure/metabolism/pathology/*therapy; Humans; Male; Middle Aged; Myocardium/metabolism/pathology; Natriuretic Peptide; Peptide Fragments/blood; Positron-Emission Tomography; Quality of Life; Treatment Outcome
RATIONALE: Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1:chemokine receptor type 4 axis. JVS-100 is a DNA plasmid encoding human stromal cell-derived factor-1. OBJECTIVE: We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters. METHODS AND RESULTS: Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction
Penn Marc S; Mendelsohn Farrell O; Schaer Gary L; Sherman Warren; Farr Maryjane; Pastore Joseph; Rouy Didier; Clemens Ruth; Aras Rahul; Losordo Douglas W
Circulation research
2013
2013-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/CIRCRESAHA.111.300440" target="_blank" rel="noreferrer noopener">10.1161/CIRCRESAHA.111.300440</a>
Anti-Inflammatory Mechanism Involved in Pomegranate-Mediated Prevention of Breast Cancer: the Role of NF-kappaB and Nrf2 Signaling Pathways.
Female; Animals; Anti-Inflammatory Agents/*pharmacology; Rats; Gene Expression Regulation; Signal Transduction; Apoptosis/drug effects; anti-inflammatory effects; Anticarcinogenic Agents/pharmacology; breast tumor; COX-2; Cyclooxygenase 2/genetics/metabolism; DMBA; HSP90; HSP90 Heat-Shock Proteins/genetics/metabolism; I-kappa B Kinase/genetics/metabolism; NF-E2-Related Factor 2/genetics/*metabolism; NF-kappa B/genetics/*metabolism; NF-kappaB; Nrf2; Plant Preparations/*pharmacology; Punica granatum; Punicaceae/*chemistry; Pomegranate; Chemoprevention; Dose-Response Relationship; Drug; Neoplastic; Mammary Neoplasms; 10-Dimethyl-1; 9; Neoplastic/drug effects; Cell Transformation; 2-benzanthracene/toxicity; Experimental/*prevention & control; Animal Studies; Breast Neoplasms; Inflammation Mediators; Physical Education and Training; Neoplasms – Prevention and Control
Pomegranate (Punica granatum L.), a nutrient-rich unique fruit, has been used for centuries for the prevention and treatment of various inflammation-driven diseases. Based on our previous study, a characterized pomegranate emulsion (PE) exhibited a striking inhibition of dimethylbenz(a)anthracene (DMBA)-initiated rat mammary tumorigenesis via antiproliferative and apoptosis-inducing mechanisms. The objective of the present work is to investigate the anti-inflammatory mechanism of action of PE during DMBA rat mammary carcinogenesis by evaluating the expression of cyclooxygenase-2 (COX-2), heat shock protein 90 (HSP90), nuclear factor-kappaB (NF-kappaB) and nuclear factor erythroid 2p45 (NF-E2)-related factor 2 (Nrf2). Mammary tumor samples were harvested from our previous chemopreventive study in which PE (0.2-5.0 g/kg) was found to reduce mammary tumorigenesis in a dose-dependent manner. The expressions of COX-2, HSP90, NF-kappaB, inhibitory kappaBalpha (IkappaBalpha) and Nrf2 were detected by immunohistochemical techniques. PE decreased the expression of COX-2 and HSP90, prevented the degradation of IkappaBalpha, hindered the translocation of
Mandal Animesh; Bhatia Deepak; Bishayee Anupam
Nutrients
2017
2017-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3390/nu9050436" target="_blank" rel="noreferrer noopener">10.3390/nu9050436</a>
Antiepileptics inhibit cortical N-methyl-D-aspartate-evoked [3H]norepinephrine efflux.
Animals; Anticonvulsants/*pharmacology; Dose-Response Relationship; Drug; Female; Male; N-Methylaspartate/*antagonists & inhibitors; Norepinephrine/*metabolism; Rats
The antiepileptic drugs phenytoin, valproic acid and phenobarbital were examined for their ability to inhibit N-methyl-D-aspartate (NMDA)-stimulated [3H]norepinephrine efflux from rat brain cortical slices. All three drugs inhibited efflux at varying concentrations. Valproic acid was the most potent and inhibited efflux at 0.01 mg/ml. Phenytoin and phenobarbital inhibited efflux at 0.1 mg/ml. These results indicate that some antiepileptic drugs are capable of inhibiting NMDA receptor function in the therapeutic range.
Brown L M; Lee Y P; Teyler T J
European journal of pharmacology
1994
1994-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0014-2999(94)90472-3" target="_blank" rel="noreferrer noopener">10.1016/0014-2999(94)90472-3</a>
Antitumor activities of extracts from selected desert plants against HepG2 human hepatocellular carcinoma cells.
Humans; Time Factors; Hep G2 Cells; Desert Climate; Inhibitory Concentration 50; Liver Neoplasms/*drug therapy/pathology; Plant Extracts/administration & dosage/*pharmacology; Tetrazolium Salts/chemistry; Thiazoles/chemistry; Carcinoma; Dose-Response Relationship; Drug; Plants; Antineoplastic Agents; Aerial; Hepatocellular/*drug therapy/pathology; Medicinal/chemistry; Phytogenic/administration & dosage/*pharmacology; Plant Components
CONTEXT: Phytochemicals are produced by desert plants to protect themselves against stressful environments. They have been shown to be useful in preventing and fighting adverse pathophysiological conditions and complex diseases, including cancer. Although many desert plants have been investigated for their antitumor properties, a large number of them still remain to be explored for possible therapeutic applications in oncologic diseases. OBJECTIVE: To screen the antitumor effects of selected desert plants, namely Achillea fragrantissima (Forssk.) Sch. Bip. (Compositae), Ochradenus baccatus Delile (Resedaceae), Origanum dayi Post (Lamiaceae), Phlomis platystegia Post (Lamiaceae) and Varthemia iphionoides Boiss (Compositae), against an in vitro tumor model utilizing HepG2 human hepatocellular carcinoma cells. MATERIALS AND METHODS: The aqueous extracts of aerial parts of the aforementioned plants were prepared and used for the in vitro experiments. The HepG2 cells were exposed to varying concentrations (0-4 mg/mL) of each plant extract for 24 or 48 h and the cytotoxicity was measured by the MTT assay. RESULTS: Following 24 h exposure, O. dayi extract exhibited a substantial antiproliferative effect in HepG2 cells (IC50 = 1.0 mg/mL) followed by O. baccatus (IC50 = 1.5 mg/mL). All plant extracts displayed cytotoxicity following 48 h exposure. Nevertheless, a substantial effect was observed with O. dayi (IC50 = 0.35 mg/mL) or O. baccatus (IC50 = 0.83 mg/mL). CONCLUSION: The aqueous extracts from aerial parts of O. dayi and O. baccatus possess antitumor effects against human liver cancer cells. These desert plants represent valuable resources for the development of potential anticancer agents.
Thoppil Roslin J; Harlev Eli; Mandal Animesh; Nevo Eviatar; Bishayee Anupam
Pharmaceutical biology
2013
2013-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.3109/13880209.2012.749922" target="_blank" rel="noreferrer noopener">10.3109/13880209.2012.749922</a>
Antitumor efficacy and tolerability of systemically administered gallium acetylacetonate-loaded gelucire-stabilized nanoparticles.
*Lethal Dose 50; Adenocarcinoma/*drug therapy/pathology; Animals; Antineoplastic Agents/administration & dosage/pharmacokinetics/toxicity; Cell Line; Dose-Response Relationship; Drug; Drug Stability; Drug Tolerance; Gallium/*administration & dosage/pharmacokinetics/*toxicity; Humans; Metabolic Clearance Rate; Mice; Nanocapsules/*administration & dosage/chemistry/*toxicity; Nude; Organ Specificity; Tissue Distribution; Treatment Outcome; Triglycerides/chemistry; Tumor
The widespread clinical success with most gallium compounds in cancer therapy is markedly hampered by lack of tumor specific accumulation, poor tumor permeability and undesirable toxicity to healthy tissues. The aim of this work was to investigate for the first time antitumor mechanism of a new gallium compound (gallium acetylacetonate; GaAcAc) while assessing effectiveness of gelucire-stabilized nanoparticles (NPs) for potential application in gallium-based lung cancer therapy. NPs loaded with GaAcAc (Ga-NPs) were prepared using mixtures of cetyl alcohol with Gelucire 44/14 (Ga-NP-1) or Gelucire 53/13 (Ga-NP-2) as matrix materials. Of special note from this work is the direct evidence of involvement of microtubule disruption in antitumor effects of GaAcAc on human lung adenocarcinoma (A549). In-vivo tolerability studies were based on plasma ALT, creatinine levels and histopathological examination of tissues. The superior in-vivo antitumor efficacy of Ga-NPs over GaAcAc was depicted in marked reduction of tumor weight and tumor volume as well as histological assessment of excised tumors. Compared to free GaAcAc, Ga-NPs showed a 3-fold increase in tumor-to-blood gallium concentrations with minimized overall exposure to healthy tissues. Overall, enhancement of antitumor effects of GaAcAc by gelucire-stabilized NPs coupled with reduced exposure of healthy tissues to gallium would likely ensure desired therapeutic outcomes and safety of gallium-based cancer treatment.
Wehrung Daniel; Bi Lipeng; Geldenhuys Werner J; Oyewumi Moses O
Journal of biomedical nanotechnology
2013
2013-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1166/jbn.2013.1598" target="_blank" rel="noreferrer noopener">10.1166/jbn.2013.1598</a>
Attenuation of drinking sweetened water following calcium channel blockade.
Animals; Calcium Channel Blockers/*pharmacology; Cocaine/pharmacology; Dihydropyridines/pharmacology; Dose-Response Relationship; Drinking Behavior/*drug effects; Drug; Female; Inbred Strains; Injections; Intraventricular; Isradipine; Male; Rats; Reward; Taste/*drug effects
Recent reports cite results that both cocaine-induced conditioned place preference and activity stimulation are attenuated by pretreatment with the calcium channel blocker isradipine (ISR) in rats. By blocking voltage-dependent
Calcagnetti D J; Schechter M D
Brain research bulletin
1992
1992-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0361-9230(92)90219-n" target="_blank" rel="noreferrer noopener">10.1016/0361-9230(92)90219-n</a>
Behavioral effects of N-ethyl-3,4-methylenedioxyamphetamine (MDE; "EVE").
Male; Time Factors; Animals; United States; Rats; Discrimination (Psychology); Amphetamines/*pharmacology; Dose-Response Relationship; Drug; Inbred Strains; 3; N-Methyl-3; 4-methylenedioxyamphetamine; 4-Methylenedioxyamphetamine/analogs & derivatives/*pharmacology; Legislation
Eight male rats were trained to discriminate 2.0 mg/kg
Boja J W; Schechter M D
Pharmacology, biochemistry, and behavior
1987
1987-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(87)90206-1" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(87)90206-1</a>
Biphasic effects of ethanol tested with drug discrimination in HAD and LAD rats.
Alcohol Drinking/genetics/*psychology; Animals; Discrimination (Psychology)/*drug effects; Discrimination Learning/drug effects; Dose-Response Relationship; Drug; Ethanol/*pharmacology; Inbred Strains; Male; Pentobarbital/pharmacology; Rats; Serotonin Antagonists/pharmacology; Sleep/drug effects; Time Factors; Tropanes/pharmacology
Seventh-generation selectively bred high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats were trained to make differential responses for ethanol (0.75 g/kg, IP) and saline vehicle, following postadministration intervals (PI) of 2 min (HAD-2 and LAD-2 animals) and 30 min (HAD-30 and LAD-30 animals). ED50 values of 0.395 and 0.352 g/kg, respectively, for HAD-2 and LAD-2 animals and 0.269 and 0.314 g/kg, respectively, for HAD-30 and LAD-30 animals reflect the absence of any phenotypic difference for the discriminative stimulus effects of ethanol. HAD-2 animals were more responsive than LAD-2 animals to the stimulating effects of ethanol as measured by total response rates during training sessions. The differential ethanol response generalized to pentobarbital in all four groups but not to morphine, an alternative CNS depressant. The specific antagonist of 5-hydroxytryptamine3 receptors,
Krimmer E C
Pharmacology, biochemistry, and behavior
1992
1992-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(92)90508-d" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(92)90508-d</a>
Calcium channel blockade attenuates angiotensin II-induced drinking in rats.
Amino Acid Sequence; Angiotensin II/*antagonists & inhibitors/pharmacology; Animals; Calcium Channel Blockers/administration & dosage/*pharmacology; Dimethyl Sulfoxide/pharmacology; Dose-Response Relationship; Drinking Behavior/*drug effects; Drug; Injections; Intraventricular; Isradipine/pharmacology; Male; Molecular Sequence Data; Rats; Sprague-Dawley
Lateral ventricular administration of angiotensin II (ANG II) produces potent dipsogenic effects in water-sated rats. ANG II seems to require functional voltage-gated calcium channels on neurons throughout circumventricular brain sites to exert its effects. Although there are at least three types of calcium channels, only L-type calcium channel-blocking drugs have been reported to decrease drinking. (4-(4-Benzofurazanyl)-1-4-dihydro-2,6-dimethyl-3,5-pyridine-dic arb oxylic acid methyl 1-methyl-ethyl ester) [PN 200-110; isradipine (ISR)], a selective L-type calcium channel blocker, has been shown to attenuate significantly the intake of sweetened water in water-sated rats following either peripheral or ICV administration, but ISR does not affect plain-water intake in water-deprived rats. The present experiment was designed to determine whether ISR would attenuate ANG II-induced drinking that is not either motivated by palatability or dependent on deprivation. Rats, each fitted with chronic indwelling ventricular cannulae, were pretreated with ISR (0.3, 3.0, and 30 micrograms/rat; ICV). ANG II (40 ng/rat; ICV) was administered 10 min later and rats were allowed free access to water for 15 min. Injections of ANG II plus saline and ANG II plus the ISR vehicle (dimethyl sulfoxide) did not attenuate ANG II-induced polydipsia, whereas ANG II+ISR (0.3 and 3.0 micrograms) attenuated ANG II-induced drinking to 62 and 22% of control, respectively. Results with the 30-micrograms dose were not different from the 3.0 dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Calcagnetti D J; Schechter M D
Brain research bulletin
1993
1905-6
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0361-9230(93)90087-r" target="_blank" rel="noreferrer noopener">10.1016/0361-9230(93)90087-r</a>
CGS 10746B is able to attenuate the effects of amphetamine: further evidence for dopaminergic mediation.
Male; Animals; Rats; Dopamine/*physiology; Discrimination (Psychology)/*drug effects; Antipsychotic Agents/*pharmacology; Thiazepines/*pharmacology; Apomorphine/pharmacology; Cocaine/pharmacology; Alkaloids/pharmacology; Dextroamphetamine/antagonists & inhibitors/*pharmacology; Dose-Response Relationship; Drug; Conditioning; Operant/drug effects
Previous results indicate that agents which either decreases synthesis or block postsynaptic dopamine receptors will attenuate the discriminative stimulus produced by d-amphetamine. CGS 10746B has been reported to decrease dopamine release without changing its metabolism or occupying its receptors. In the present study, rats successfully trained to discriminate intraperitoneally administered (0.8 mg/kg) d-amphetamine in a two-lever, food-motivated operant task were observed to be unable to discriminate amphetamine when pretreated with 30 mg/kg CGS 10746B. This antagonism was shown to be dose-responsive and constitutes a third mechanism, i.e., dopamine release inhibition, that evidences the dopaminergic mediation of amphetamine in the discriminative paradigm. When both cathinone (0.8 mg/kg) and cocaine (10.0 mg/kg) were administered to the amphetamine-trained rats they each were recognized as amphetamine and are, thus, considered to generalize to the amphetamine discriminative stimulus. Coadministration of CGS 10746B and cathinone totally antagonized this generalization, whereas pretreatment with CGS 10746B prior to cocaine significantly reduced cocaine's effects. These results implicate dopamine mechanisms in the discriminative stimulus properties of the psychostimulants amphetamine, cathinone and cocaine.
Schechter M D; Boja J W
Pharmacology, biochemistry, and behavior
1988
1988-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(88)90145-1" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(88)90145-1</a>
Chemopreventive doses of resveratrol do not produce cardiotoxicity in a rodent model of hepatocellular carcinoma.
*Chemoprevention; Analysis of Variance; Animal; Animal Studies; Animal/drug effects; Animals; Antioxidants; Behavior; Blotting; Carcinoma; Cardiotoxicity; Cardiotoxins/*toxicity; Chemoprevention; Data Analysis Software; Descriptive Statistics; Disease Models; Doppler; Dose-Response Relationship; Drug; Echocardiography; Feeding Behavior/drug effects; Female; Fisher's Exact Test; Funding Source; Heart – Drug Effects; Heart/drug effects/physiopathology; Hepatocellular – Prevention and Control; Hepatocellular/*drug therapy/pathology/physiopathology; Hepatocytes/drug effects/pathology; Humans; Liver Neoplasms/*drug therapy/pathology/physiopathology; Liver/drug effects/pathology/physiopathology; Polyphenols – Therapeutic Use; Rats; Resveratrol; Sprague-Dawley; Stilbenes/*therapeutic use; Systole/drug effects; Western
Hepatocellular carcinoma (HCC), one of the most lethal cancers, results in more than one million fatalities worldwide every year. In view of the limited therapeutic alternatives and poor prognosis of liver cancer, preventive control approaches, notably chemoprevention, have been considered to be the best strategy in lowering the present prevalence of the disease. Resveratrol, a naturally occurring antioxidant and antiinflammatory agent found in grapes and red wine, inhibits carcinogenesis with a pleiotropic mode of action. Recently, we have reported that dietary resveratrol significantly prevents chemically-induced liver tumorigenesis in rats. One of the mechanisms of resveratrol-mediated chemoprevention of hepatocarcinogenesis could be related to its antiinflammatory action through hepatic cyclooxygenase (COX-2) inhibition. Although several COX-2 inhibitors are known to exert chemopreventive efficacy, not all are considered ideal candidates for chemoprevention due to the risk of adverse cardiovascular events. Accordingly, the objective of the present study was to evaluate the role of resveratrol on cardiac performance during experimental hepatocarcinogenesis initiated with diethylnitrosamine and promoted by phenobarbital. Rats had free access to diet supplemented with resveratrol four weeks before the carcinogen injection and 14 weeks thereafter. The cardiotoxicity of resveratrol was assessed by monitoring the cardiac function using transthoracic echocardiography as well as Western blot analysis of cardiac tissue. Long-term dietary administration of resveratrol dose-dependently suppressed hepatic tumor multiplicity, the principal endpoint for evaluating the chemopreventive potential of a candidate agent. The chemopreventive effects of resveratrol were also reflected in histopathological assessment of hepatic tissues. Resveratrol did not exhibit any cardiotoxicity but rather improved the cardiac function in a dose-responsive fashion. Our results indicate that resveratrol-mediated chemoprevention of rat liver carcinogenesis is devoid of any adverse cardiovascular events. Resveratrol may be developed as a chemopreventive as well as therapeutic drug for human HCC.
Luther Daniel J; Ohanyan Vahagn; Shamhart Patricia E; Hodnichak Cheryl M; Sisakian Hamayak; Booth Tristan D; Meszaros J Gary; Bishayee Anupam
Investigational new drugs
2011
2011-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s10637-009-9332-7" target="_blank" rel="noreferrer noopener">10.1007/s10637-009-9332-7</a>
Clinical impact of temporary therapy interruptions on anticoagulation control in patients treated with warfarin.
Female; Male; Aged; Prospective Studies; International Normalized Ratio; Drug Administration Schedule; Preoperative Care; Postoperative Care; Human; Middle Age; Retrospective Design; Dose-Response Relationship; Drug; Treatment Outcomes; Drug Monitoring; Anticoagulants – Therapeutic Use; Anticoagulants – Administration and Dosage; Atrial Fibrillation – Drug Therapy; Blood Coagulation Disorders – Drug Therapy; Coronary Thrombosis – Drug Therapy; Euthanasia; Passive; Venous Thromboembolism – Drug Therapy; Warfarin – Administration and Dosage; Warfarin – Therapeutic Use
This retrospective cohort study was completed to describe the impact of short-term therapy interruptions on anticoagulation control in patients receiving warfarin. Patients seen in a pharmacist-managed anticoagulation clinic were included if they were on a stable warfarin dose and then underwent a planned interruption in therapy. Patients were excluded if phytonadione was administered before the interruption or if medications known to interact with warfarin were altered during the interruption. Data were analyzed for 2 groups: (1) patients with a single interruption in therapy (group 1) and (2) patients with a single interruption in therapy plus patients with an extended interruption in therapy (group 2). The primary endpoint was the change in weekly maintenance warfarin dose from preinterruption to postinterruption. Evaluation of 199 patients resulted in 31 interruptions in group 1 and 34 interruptions in group 2. A change in dose was required in 58% of patients in group 1 and 56% of patients in group 2. The mean absolute change in dose was 2.03 ± 2.79 mg (P \textless 0.003) in group 1 and 1.96 ± 2.72 mg (P \textless 0.002) in group 2. For the majority of patients, the dose change represented \textless10% of their preinterruption weekly dose. Of patients requiring a dose change, 50% required an increase in dose. In conclusion, close follow-up is warranted after a warfarin therapy interruption as dose adjustments will likely be needed to regain anticoagulation control and the direction of this dose change cannot be predicted.
Boros Melanie L; Rybarczyk Amy M; Gallegos Patrick J; Zimmerman Jacob P
American Journal of Therapeutics
2013
2013-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1097/MJT.0b013e31824ea644" target="_blank" rel="noreferrer noopener">10.1097/MJT.0b013e31824ea644</a>
Cocaethylene produces discriminative stimulus properties in the rat: effect of cocaine and ethanol coadministration.
Animals; Cocaine/*analogs & derivatives/pharmacokinetics/*pharmacology; Discrimination (Psychology)/*drug effects; Dose-Response Relationship; Drug; Ethanol/pharmacokinetics/*pharmacology; Male; Rats; Reinforcement Schedule; Sprague-Dawley
Experimentally naive Sprague-Dawley male rats were trained to discriminate the interoceptive stimulus cues produced by either 10.0 mg/kg cocaine or 10.0 mg/kg cocaethylene from their saline vehicles. Although it required more sessions to train the cocaethylene rats, once they were trained to criterion performance the ED50 value for cocaethylene (2.89 mg/kg) was very similar to that of cocaine (3.04 mg/kg). Coadministration of a 300-mg/kg dose of ethanol that produced saline-like responding in cocaethylene-trained rats with 2.5 mg/kg cocaine allowed for 88.9% of first lever selections being made on the cocaethylene-appropriate lever. Time-course evidence using coadministered (1.25-mg/kg) cocaine and (300-mg/kg) ethanol indicated that the formation of cocaethylene was highest, as indicated by discriminative performance, at 15 min and progressively decreased as the postinjection interval was increased to 30, 60, and 120 min. The results are discussed in light of rapid formation of cocaethylene from cotreatment with ethanol and cocaine in the mouse, rat, and human subject. The suggestion is made as to the prevalent, and growing, use of this drug combination in the human population of cocaine abusers.
Schechter M D
Pharmacology, biochemistry, and behavior
1995
1995-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(94)00378-v" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(94)00378-v</a>
Cocaethylene-induced lethality in mice is potentiated by alcohol.
Animals; Cocaine/*analogs & derivatives/poisoning; Dose-Response Relationship; Drug; Drug Synergism; Ethanol/*pharmacology; Female; Inbred Strains; Lethal Dose 50; Male; Mice
Mice of the heterogeneously bred HS line were concurrently administered intraperitoneal injections of either 95, 75, 60, or 48 mg/kg cocaethylene or 48, 38, or 30 mg/kg cocaethylene in conjunction with the non-lethal dose of 6.0 g/kg (20% w/v) alcohol. Results indicate that alcohol administration significantly potentiated cocaethylene-induced lethality. This observation suggests that alcohol is capable of enhancing the lethal effects of cocaethylene. Results are discussed in terms of observations of sudden death in humans who abuse cocaine and alcohol.
Meehan S M; Schechter M D
Alcohol (Fayetteville, N.Y.)
1995
1995-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0741-8329(95)00022-j" target="_blank" rel="noreferrer noopener">10.1016/0741-8329(95)00022-j</a>
Cocaine discrimination is attenuated by isradipine and CGS 10746B.
Animals; Antipsychotic Agents/*pharmacology; Calcium Channel Blockers/*pharmacology; Cocaine/antagonists & inhibitors/*pharmacology; Conditioning; Discrimination (Psychology)/*drug effects; Dose-Response Relationship; Drug; Ibogaine/pharmacology; Isradipine/*pharmacology; Male; Operant/drug effects; Rats; Serotonin Antagonists/pharmacology; Sprague-Dawley; Thiazepines/*pharmacology; Tropanes/pharmacology
The discriminative stimulus properties of cocaine are thought to be mediated by dopaminergic mechanisms that may be modulated by calcium ion influx and/or interact with 5-hydroxytryptamine3 (5-HT3) receptors. To test these possibilities, rats were trained to discriminate between the stimulus properties of 10.0 mg/kg cocaine and its vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance when tested with lower cocaine doses. An analysis of the dose-response curve indicated an ED50 value of 3.04 mg/kg. Pretreatment with the presynaptic dopamine release-inhibiting agent CGS 10746B (20-40 mg/kg) resulted in a dose-related decrease in cocaine discrimination with the highest dose significantly attenuating cocaine discrimination. Pretreatment with 10-30 mg/kg isradipine, a calcium channel blocker, also resulted in a dose-related decrease in cocaine discriminative performance. In contrast to these positive results, pretreatment with the 5-HT3 receptor antagonist MDL 72222 (3.5-7.0 mg/kg), or the same doses of ibogaine, did not significantly affect cocaine discrimination. The results suggest that cocaine controls differential responding in a discriminative stimulus task by mechanisms that involve presynaptic release of dopamine, which may be regulated by neuronal calcium influx through L-type calcium channels.
Schechter M D
Pharmacology, biochemistry, and behavior
1993
1993-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(93)90183-t" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(93)90183-t</a>
Comparison of anorectic drugs in rats trained to discriminate between satiation and deprivation.
Male; Animals; Rats; Analysis of Variance; Discrimination Learning/*drug effects; Amphetamine/*pharmacology; *Food Deprivation; Fenfluramine/*analogs & derivatives/*pharmacology; Norfenfluramine/*pharmacology; Satiation/*drug effects; Dose-Response Relationship; Drug; Inbred Strains
Eight male rats were trained to discriminate between the internal states produced by food deprivation of 3 hours (satiation) and that produced by food deprivation of 27 hours duration (deprivation). One lever, in a two-lever operant chamber, had to be pressed to receive reinforcement in the satiation state, whereas pressing the other lever was required when the rat was in the deprivation state. Once the rats were trained, increasing the number of hours of food deprivation, from 1 to 48 hours, resulted in more deprivation-appropriate lever responses in the two-lever operant task. Administration of doses of fenfluramine (0.5-1.5 mg.kg), its active metabolite norfenfluramine (0.25-1.0 mg/kg) or d-amphetamine (0.5-1.5 mg/kg) produced a dose-responsive decrease in deprivation-appropriate responses when each drug/dose was injected (i.p.) 15 min prior to deprivation (27 hours) testing. Norfenfluramine was 1.5 times more potent than fenfluramine which was 1.5 times more potent than amphetamine.
Schechter M D
Life sciences
1990
1905-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0024-3205(90)90561-5" target="_blank" rel="noreferrer noopener">10.1016/0024-3205(90)90561-5</a>
Comparison of the behavioral effects of ibogaine from three sources: mediation of discriminative activity.
*Discrimination (Psychology); Animal/*drug effects; Animals; Behavior; Dose-Response Relationship; Drug; Ibogaine/*pharmacology; Male; Rats; Serotonin Receptor Agonists/pharmacology; Sprague-Dawley
Ibogaine is an alkaloid employed for its hallucinatory properties in West Central Africa which has been the subject of alleged efficacy as an aid in the interruption and treatment of chemical dependency. The major sources of the Schedule I agent are: Sigma Chemical Co., the National Institute on Drug Abuse and as NDA International Inc.'s Endabuse. The intent of the present study was to, for the first time, train rats to discriminate the interoceptive stimuli produced by (10 mg/kg, intraperitoneally administered) ibogaine. Once trained, these rats were used to investigate the dose-response effects to ibogaine from each of the three suppliers. In addition, stimulus generalization to the dopamine antagonist CGS 10476B, as well as to the serotonergically active compounds fenfluramine, TFMPP (1-(m-trifluoromethylphenyl)piperazine, DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), MDMA (3,4-methylenedioxymethamphetamine), quipazine and LSD, was tested. The results indicate that ibogaine is readily discriminable from its vehicle and that ibogaine from each of the three supplies produced statistically similar discrimination with ED50 values ranging from 2.5 to 3.4 mg/kg. In addition, various doses of the novel drugs tested produced, at best, intermediate ibogaine-appropriate responding and, thus, no drug tested can be considered to generalize to ibogaine-like stimuli. Discussion concerns the multiple actions of ibogaine that have been cited in the scientific literature. The similarity in potency of ibogaine from three potential suppliers should allow for pre-clinical work using any of these research samples to be comparable.
Schechter M D; Gordon T L
European journal of pharmacology
1993
1993-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0014-2999(93)90664-4" target="_blank" rel="noreferrer noopener">10.1016/0014-2999(93)90664-4</a>
Conditioned place aversion produced by dopamine release inhibition.
Analysis of Variance; Animal; Animals; Antipsychotic Agents/administration & dosage/*pharmacology; Aversive Therapy; Conditioning (Psychology); Disease Models; Dopamine Antagonists/administration & dosage/*pharmacology; Dose-Response Relationship; Drug; Injections; Intraperitoneal; Male; Motor Activity/*drug effects; Random Allocation; Rats; Sprague-Dawley; Thiazepines/administration & dosage/*pharmacology
CGS 10746B, a dopamine release inhibitor with properties similar to the atypical antipsychotic clozapine, was assessed as to its behavioral properties using spontaneous locomotor activity and the conditioned place preference test. Rats conditioned with interperitoneally administered doses of 1.25, 2.5, 5.0, 10.0, 20.0 or 30.0 mg/kg CGS 10746B showed a conditioned place aversion, whereas only doses of 5.0 mg/kg or greater suppressed locomotor activity. Results are discussed in terms of dopaminergic mediation of conditioned place preference and spontaneous locomotor activity and methodological concerns involved in employing the conditioned place preference test with drugs that produce opposing affective cues.
Schechter M D; Meechan S M
European journal of pharmacology
1994
1994-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0014-2999(94)90329-8" target="_blank" rel="noreferrer noopener">10.1016/0014-2999(94)90329-8</a>
Conditioned place preference produced by the psychostimulant cathinone.
Alkaloids/administration & dosage/*pharmacology; Animals; Central Nervous System Stimulants/administration & dosage/*pharmacology; Choice Behavior/drug effects; Conditioning (Psychology)/drug effects; Dose-Response Relationship; Drug; Habituation; Male; Motor Activity/*drug effects; Psychophysiologic; Rats; Sprague-Dawley
Previous work has indicated that the psychostimulant cathinone produces a location preference in the conditioned place preference task. The present study expanded upon this earlier work by examining the dose-response nature of cathinone-induced conditioned place preference, as well as testing its effect upon spontaneous locomotor activity. At doses ranging from 0.2 to 1.6 mg/kg, cathinone produced a conditioned place preference at all but the lowest dose, and the highest dose but not the lowest dose increased locomotor activity. Results are discussed in terms of dopaminergic mediation of conditioned place preference and the relationship between conditioned place preference and locomotion being subserved by the same neuronal system.
Schechter M D; Meehan S M
European journal of pharmacology
1993
1993-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0014-2999(93)90739-5" target="_blank" rel="noreferrer noopener">10.1016/0014-2999(93)90739-5</a>
Differences in response to the aversive properties and activity effects of low dose ethanol in LAS and HAS selectively bred rats.
Animals; Avoidance Learning/*drug effects; Conditioning; Dose-Response Relationship; Drug; Ethanol/*pharmacology; Motor Activity/drug effects; Operant/drug effects; Rats; Sleep/drug effects; Species Specificity
Rats selectively bred for high alcohol sleep times (HAS) and those that are less affected (LAS) by hypnotic doses (3.0-3.6 g/kg) of ethanol were tested for differential responses to the aversive effects of 1.0 g/kg ethanol in a conditioned place preference task. Likewise, the effects of 0.3-1.0 g/kg ethanol on spontaneous locomotor activity over a 30-min period, as well as the loss of righting reflex with a higher ethanol dose (3.0 g/kg), were determined in these animals. The LAS rats reacted more aversively to 1.0 g/kg during conditioned place aversion testing than the HAS animals and also had a shorter mean sleeping time following 3.0 g/kg ethanol. Furthermore, dose-related depression of spontaneous motor activity was seen in the HAS animals and not in the LAS animals over a 30-min period using doses of 0.3, 0.6, or 1.0 g/kg (10% w/v) ethanol. Taken together, the results indicate that the intoxicating sequelae of high ethanol doses, such as ataxia and sedation, may not be correlated with the aversive effects of low ethanol doses.
Schechter M D; Krimmer E C
Psychopharmacology
1992
1905-6
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/bf02245271" target="_blank" rel="noreferrer noopener">10.1007/bf02245271</a>
Differential training sequence effect upon psychostimulant discrimination.
Alkaloids/pharmacology; Animals; Appetite Depressants/pharmacology; Central Nervous System Stimulants/*pharmacology; Discrimination Learning/*drug effects; Dose-Response Relationship; Drug; Food; Male; Phenylpropanolamine/pharmacology; Psychotropic Drugs/pharmacology; Rats; Reinforcement Schedule; Sprague-Dawley
1. Previous studies indicate that rats trained to discriminate either cathinone or cathine from its vehicle have a diminished discriminative performance when tested 24 hours after a drug administration when compared to tests conducted after a vehicle administration. The phenomenon of rapid tolerance may occur to produce a lessened interceptive cue on the test day following administration of the drug. It would, therefore, be probable that when rats are trained with consecutive cathinone or cathine administrations they would perform less well than if they were trained with these drugs never given in consecutive training sessions. 2. To test this hypothesis, rats were trained with 0.8 mg/kg
Schechter M D
Progress in neuro-psychopharmacology & biological psychiatry
1993
1993-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0278-5846(93)90051-s" target="_blank" rel="noreferrer noopener">10.1016/0278-5846(93)90051-s</a>
Direct microinjection of cathinone into the rat brain produces discriminative stimuli.
*Brain/anatomy & histology; Alkaloids/administration & dosage/*pharmacology; Animals; Discrimination (Psychology)/*drug effects; Discrimination Learning/drug effects; Dose-Response Relationship; Drug; Inbred Strains; Injections; Intraventricular; Male; Microinjections; Nucleus Accumbens/anatomy & histology; Psychotropic Drugs/*pharmacology; Rats
Rats were trained to discriminate IP administration of 800 micrograms/kg cathinone using a food-motivated, two-lever discrimination procedure. Following training, 800 micrograms/kg cathinone discrimination was produced (generalized) by lower cathinone doses in a dose-responsive manner after IP administration; an ED50 value of 330 micrograms/kg was calculated. Subsequently, guide cannulae were implanted into the lateral ventricle and bilaterally into the nucleus accumbens. After recovery, injections were made via cannulae that extended 0.5 mm past the tip of the guide cannulae. ICV administration of 256 micrograms cathinone/rat produced discriminative responding on the cathinone-appropriate lever to the same degree as did the peripherally administered training dose of cathinone. Decreasing ICV doses produced decreased discriminative performance and allowed the calculation of an ED50 value of 90.5 micrograms. Likewise, administration of 64 micrograms cathinone/nucleus accumbens (for a total of 128 micrograms/rat) substituted for the IP training dose of cathinone. These results evidence the central mediation of the cathinone-induced discriminative stimulus cue and show that administration of cathinone into the nucleus accumbens is sufficient to produce these stimuli. Thus, these data suggest that receptors in the nucleus accumbens are important for the discrimination of this psychostimulant.
Schechter M D; Schechter J B; Calcagnetti D J
Pharmacology, biochemistry, and behavior
1992
1992-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0091-3057(92)90007-3" target="_blank" rel="noreferrer noopener">10.1016/0091-3057(92)90007-3</a>
Discrete versus cumulative dosing in dose-response discrimination studies.
4-methylenedioxyamphetamine/*pharmacology; Animals; Chemical; Cocaine/*pharmacology; Discrimination Learning/*drug effects; Dose-Response Relationship; Drug; Drug Administration Schedule; Drug Evaluation; Male; N-Methyl-3; Preclinical; Rats; Sprague-Dawley; Stimulation
This study describes the results of a 'side-by-side' comparison of two measurement techniques and two dosing regimens in a discrimination study using rats trained to either 10 mg/kg cocaine or 2 mg/kg 3,4-methylenedioxymethamphetamine (MDMA). The measurements employed were either quantal or quantitative; the former an all-or-none correct lever selection measure and the latter a measure of all responses made at the time that the criterion for selection was met. The dosing regimens were either a discrete single injection of lower doses than used in training or a cumulative dose administration sequence, in an ascending order, during one session on two separate occasions. Results indicate that the cumulative dose-response relationships, as indicated by both the slope of the curve or the generated ED50 value, for the discrete and cumulative dose response curves do not significantly differ. In addition, both the quantal and quantitative measurements yield almost identical ED50 values, thus allowing for accurate comparability of drug-discrimination data using different techniques. The present experimentation employed two drugs known to produce heightened response rates which would not allow for behavioral suppression at the highest doses used either in discrete or cumulative regimens. The pharmacokinetics of the two drugs employed in the discrimination tests are considered and discussed in light of the advantages and disadvantages of each of the two methods employed.
Schechter M D
European journal of pharmacology
1997
1997-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0014-2999(97)85404-0" target="_blank" rel="noreferrer noopener">10.1016/s0014-2999(97)85404-0</a>
Discrimination of cocaethylene in rats trained to discriminate between its components.
Animals; Cocaine/*analogs & derivatives/*pharmacology; Discrimination Learning/*drug effects; Dose-Response Relationship; Drug; Ethanol/*pharmacology; Male; Rats
Two groups of eight male Normalized/National Institutes of Health (N/Nih) rats were used in a food-motivated, 2-lever drug discrimination task with one group being trained to discriminate between 10 mg/kg cocaine vs. 1 g/kg ethanol, whereas the second group was trained to discriminate the metabolic product of these two agents, i.e., cocaethylene (10 mg/kg) vs. its saline vehicle. All drugs were administered intraperitoneally and training/testing was conducted 15 min post-injection. Once both groups of animals attained criterion performance, they were each tested in sessions, interspersed with maintenance sessions, with numerous doses of both cocaine and cocaethylene; this resulted in a typical dose-response relationship in each group but indicated that the cocaine-ethanol trained animals were more sensitive to the lower doses of cocaine (as indicated by a decreased ED50 value, i.e., 1.74 mg/kg) when compared to previously trained cocaine-saline animals (ED50 4.22 mg/kg) and, that in both groups, cocaine was significantly more potent than was cocaethylene. Although numerous laboratories have trained drug vs. drug in the drug discrimination paradigm, this is the first study to train animals to discriminate between two drugs which, although having different discriminative properties, form a third psychoactive compound when co-administered. The sensitivity of drug-drug testing vs. drug-saline testing is discussed, as well as the use of these two agents in human abuse.
Schechter M D
European journal of pharmacology
1997
1997-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0014-2999(96)00876-x" target="_blank" rel="noreferrer noopener">10.1016/s0014-2999(96)00876-x</a>
Discriminative characteristics of high and low cocaine administration: effect of other psychostimulants.
Amphetamine/pharmacology; Animals; Central Nervous System Stimulants/pharmacology; Cocaine/*pharmacology; Conditioning; Discrimination Learning/*drug effects; Dopamine Agents/*pharmacology; Dose-Response Relationship; Drug; Drug Evaluation; Generalization; Male; Methamphetamine/pharmacology; Operant/*drug effects; Preclinical; Propiophenones/pharmacology; Psychotropic Drugs/*pharmacology; Rats; Response/*drug effects
Two groups of N/Nih male rats were trained to discriminate saline vehicle from either 2.0 mg/kg (n = 10) or 10.0 mg/kg (n = 10) cocaine in a food-motivated, two-lever operant paradigm. The rats trained at the low-dose cocaine took a significantly longer training period to reach criterion performance than did the high-dose cocaine group. In addition, the ED50 value for the 2.0 mg/kg cocaine-trained animals (0.465 mg/kg) was significantly lower than the ED50 value (2.105 mg/kg) for those animals trained at the 10.0 mg/kg dose of cocaine. This correlation of ED50 values for stimulus generalization decreasing with reduction in training dose was in contrast to the time-course of the two groups when tested from 15 to 240 min post-injection; this experimentation indicated that there was a non-significant difference in half-life for the 2.0 mg/kg (t1/2: 97.1 min) vs. that of the 10.0 mg/kg cocaine-trained group (t1/2: 83.4 min). Generalization tests with other purportedly dopaminergically-active drugs of abuse including 0.05-0.8 mg/kg d-amphetamine, 0.125-1.5 mg/kg methamphetamine and 0.125-1.0 mg/kg methcathinone indicated that the highest doses of each produced generalization and, with the exception of methcathinone, the ED50 values were significantly lower in the low-cocaine trained group. The stimulus properties of cocaine, as they generalize to amphetamine, methamphetamine and methcathinone, can be explained by effects upon central dopaminergic neurons and may be qualitatively different in low-and high-dose trained rats.
Schechter M D
Pharmacology, biochemistry, and behavior
1997
1997-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0091-3057(96)00301-2" target="_blank" rel="noreferrer noopener">10.1016/s0091-3057(96)00301-2</a>
Discriminative effects of cocaethylene in rats trained to discriminate cocaine or ethanol.
Animals; Cocaine/*analogs & derivatives/*pharmacology; Discrimination Learning/*drug effects; Dose-Response Relationship; Drug; Drug Interactions; Ethanol/*pharmacology; Inbred Strains; Male; Rats
Two groups of rats were trained to discriminate between the stimulus properties of either intraperitoneally administered 10.0 mg/kg cocaine or 60 mg/kg ethanol and its vehicle in a two-lever operant chamber. Once trained, both groups exhibited a dose-related decrease in discriminative performance when tested with lower doses. A dose of 10 mg/kg cocaine, as well as doses of 10-30 mg/kg cocaethylene, in the ethanol-trained animals produced no greater than 38.9% responding on the ethanol-appropriate lever. Combinations of the approximate ethanol ED50 dose with either 10 mg/kg cocaine or 20 mg/kg cocaethylene did not increase ethanol lever responding. In contrast, in the cocaine-trained animals, administration of cocaethylene produced dose-responsive cocaine-like discrimination with 30 mg/kg producing 88.9% responding on the cocaine-appropriate lever. In addition, 600 mg/kg ethanol co-administered with a (2.5 mg/kg) dose of cocaine that was poorly discriminated produced 85% of responses on the cocaine-appropriate lever. The peak effect of cocaine and cocaethylene were observed to occur in 15-30 min post-administration with cocaine choice behavior decreasing at a faster rate than seen for cocaethylene discrimination. Results are discussed in light of ethanol and cocaine producing a heightened, as well as prolonged, euphoria in humans.
Schechter M D
Life sciences
1994
1905-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0024-3205(94)00638-5" target="_blank" rel="noreferrer noopener">10.1016/0024-3205(94)00638-5</a>
Discriminative stimulus effect of phenylephrine.
Male; Animals; Rats; Cues; Adrenergic alpha-Antagonists/pharmacology; Discrimination (Psychology)/*drug effects; Reinforcement Schedule; Phenylephrine/*pharmacology; Adrenergic alpha-Agonists/pharmacology; Dose-Response Relationship; Drug; Inbred Strains; Receptors; Generalization; Stimulus/drug effects; Adrenergic; alpha/drug effects
Rats were trained to discriminate phenylephrine in a two-lever, food-motivated operant task by increasing the i.p. administered training dose from 0.8 to 2 mg/kg. Stable discrimination to 2 mg/kg phenylephrine was established and testing of 0.5-2.5 mg/kg was shown to be dose-responsive and allowed for a calculated ED50 value of 0.87 mg/kg. Administration of methoxamine (0.5-6 mg/kg), another alpha 1-adrenoceptor agonist, produced a dose-responsive generalization, whereas only the lowest (0.04 mg/kg) and highest (0.12 mg/kg) doses of the alpha
Schechter M D
Archives internationales de pharmacodynamie et de therapie
1991
1991-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Discriminative stimulus properties of CGS 10746B: similarity to dopamine D1 receptor antagonists.
Amphetamines/pharmacology; Animals; Antipsychotic Agents/*pharmacology; Cholinergic Agents/pharmacology; Clozapine/pharmacology; Cues; Discrimination (Psychology)/*drug effects; Discrimination Learning/drug effects; Dopamine D1/*antagonists & inhibitors; Dose-Response Relationship; Drug; Generalization; Male; Rats; Receptors; Response/drug effects; Serotonin Agents/pharmacology; Serotonin Receptor Agonists/pharmacology; Sprague-Dawley; Thiazepines/*pharmacology
CGS 10746B is an imidazole-derivative related to the atypical antipsychotic clozapine which produces a decrease in dopamine release without altering dopamine metabolism or occupying D2 receptors. Rats were trained on an appetitively-motivated, two-choice, operant task to discriminate 20.0 mg/kg CGS 10746B from its vehicle. CGS 10746B was highly discriminable, producing rapid acquisition of the discrimination, and its effects were dose-responsive allowing generation of an ED50 value of 6.16 mg/kg. Substitution tests were conducted with other typical and atypical antipsychotic compounds: haloperidol, chlorpromazine, clozapine and SCH 23390. Additional tests examined generalization from the CGS 10746B stimulus properties to the calcium channel blocker isradipine, as well as to the anticholinergics atropine, scopolamine and methylscopolamine, as well as to the serotonergic agonist DOI. Clozapine and SCH 23390 were the only substances to substitute for the CGS 10746B stimulus cue. Results are discussed in terms of potential D1 receptor selectivity of CGS 10746B.
Meehan S M; Schechter M D
Behavioural brain research
1996
1996-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/0166-4328(95)00167-0" target="_blank" rel="noreferrer noopener">10.1016/0166-4328(95)00167-0</a>