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1.
Rationale
The transition from infrequent and controlled cocaine use to dependence may involve enduring changes in neurobiology as a consequence of persistent drug use.Objective
The present study utilized an intravenous drug self-administration protocol of increasing cocaine access to evaluate potential changes in dopamine function in vivo, including changes in sensitivity to psychostimulants.Materials and methods
Drug-naïve rhesus monkeys were provided limited access (1 h) to cocaine self-administration for 60 days followed by 60 days under an extended access condition (4 h). Basal levels of striatal extracellular dopamine and its metabolites, as well as the effectiveness of cocaine and amphetamine to elevate dopamine, were determined with in vivo microdialysis before the initiation of cocaine self-administration and during limited and extended access. The effect of cocaine and amphetamine on the acoustic startle response was also examined to assess complementary behavioral changes as a function of drug history.Results
Extended access to cocaine self-administration lead to increased daily intake compared to limited access conditions but did not result in escalated intake over time. However, cocaine- and amphetamine-induced increases in striatal dopamine were diminished as a function of cocaine self-administration history. Surprisingly, there was no effect of drug-taking history on sensitivity to psychostimulant-induced enhancement of startle amplitude.Conclusions
The present experiments provide evidence of a hypofunctional dopamine system that is not associated with an escalation in drug intake or reflected in measures of acoustic startle.2.
Rationale
It has been hypothesized that sensitization of the neurochemical effects within the mesolimbic dopamine (DA) system might account for specific aspects of the addiction process. We have recently developed a self-administration procedure which produces increases in responding reinforced by cocaine on a progressive ratio (PR) schedule. This may reflect an increased motivation to self-administer cocaine, one hallmark of addiction.Objectives
The goal of this experiment was to investigate behavioral and neurochemical changes associated with increased cocaine self-administration on a PR schedule.Materials and methods
Rats self-administered cocaine over 14 days under a PR schedule. Cocaine-stimulated locomotor activity was evaluated before as well as 1 or 14 days after self-administration training. Cocaine-induced DA changes in the core and shell of the nucleus accumbens in the same animals were also examined.Results
Subjects showed increased responding over time, to about 200% of baseline. Cocaine-induced locomotor activation was decreased at both withdrawal times compared to naïve animals. Microdialysis showed no differences after self-administration in the nucleus accumbens core dopamine response at either time point. There was, however, a significant decrease in the dopamine response to cocaine in the shell of the nucleus accumbens.Conclusion
The present results demonstrate that a progressive increase in breakpoints on a PR schedule can be established in rats at a time when the ability of cocaine to increase extracellular DA levels and stimulate locomotor activity is reduced. Therefore, sensitization of the mesolimbic DA system does not account for the observed change in drug-taking behavior.3.
Rationale
Topiramate is an anticonvulsant drug which has been evaluated as a therapeutic option for the treatment of cocaine addiction during the last decade.Objectives
The purpose of this study was to evaluate the effects of topiramate on the reinforcing actions of cocaine. To this aim, the topiramate-mediated regulation of acquisition and extinction phases of the cocaine conditioned place preference (CPP) was assessed in young-adult mice using three experimental designs.Methods
Topiramate (50 mg/kg, p.o.) was given as follows: (1) during cocaine (1 and 25 mg/kg, i.p.) conditioning sessions (4 days) and cocaine (25 mg/kg) post-conditioning session; (2) 2 weeks before and during cocaine conditioning (25 mg/kg); and (3) during extinction of CPP induced by cocaine (25 mg/kg). In the first experimental design, changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene expressions were measured in the ventral tegmental area (VTA).Results
Topiramate significantly increased cocaine-induced CPP and delayed or failed to produce extinction after the first cocaine reinstatement extinction in the first and second experiments. Furthermore, treatment with topiramate after place conditioning blocked the extinction of cocaine-induced CPP. TH and DAT gene expression in the VTA was significantly lower both with topiramate alone and in combination with cocaine compared with animals receiving only cocaine.Conclusions
These findings suggest that topiramate increases the rewarding properties of cocaine, at least in part, by regulating dopaminergic signaling in the mesolimbic circuit. Consequently, the results of this study do not support the use of topiramate for the treatment of problems related to cocaine dependence.Highlights
? Topiramate increases the rewarding properties of cocaine in CPP? Topiramate alters dopaminergic signaling in the mesolimbic circuit? Topiramate delays the extinction of cocaine-induced CPP? TH and DAT gene expression in the VTA decreases with topiramate and/or with cocaine? Results show that it should limit the use of topiramate in cocaine-dependent subjects4.
Sara Faccidomo Michael C. Salling Christina Galunas Clyde W. Hodge 《Psychopharmacology》2015,232(18):3417-3430
Rationale
Extracellular-signal regulated protein kinase (ERK1/2) is activated by ethanol in reward-related brain regions. Accordingly, systemic inhibition of ERK1/2 potentiates ethanol reinforcement. However, the brain region(s) that mediate this effect are unknown.Objective
This study aims to pharmacologically inhibit ERK1/2 in the medial prefrontal cortex (PFC), nucleus accumbens (NAC), and amygdala (AMY) prior to ethanol or sucrose self-administration, and evaluate effects of operant ethanol self-administration on ERK1/2 phosphorylation (pERK1/2).Methods
Male C57BL/6J mice were trained to lever press on a fixed-ratio-4 schedule of 9 % ethanol?+?2 % sucrose (ethanol) or 2 % sucrose (sucrose) reinforcement. Mice were sacrificed immediately after the 30th self-administration session and pERK1/2 immunoreactivity was quantified in targeted brain regions. Additional groups of mice were injected with SL 327 (0–1.7 μg/side) in PFC, NAC, or AMY prior to self-administration.Results
pERK1/2 immunoreactivity was significantly increased by operant ethanol (g/kg?=?1.21 g/kg; BAC?=?54.9 mg/dl) in the PFC, NAC (core and shell), and AMY (central nucleus) as compared to sucrose. Microinjection of SL 327 (1.7 μg) into the PFC selectively increased ethanol self-administration. Intra-NAC injection of SL 327 had no effect on ethanol- but suppressed sucrose-reinforced responding. Intra-AMY microinjection of SL 327 had no effect on either ethanol- or sucrose-reinforced responding. Locomotor activity was unaffected under all conditions.Conclusions
Operant ethanol self-administration increases pERK1/2 activation in the PFC, NAC, and AMY. However, ERK1/2 activity only in the PFC mechanistically regulates ethanol self-administration. These data suggest that ethanol-induced activation of ERK1/2 in the PFC is a critical pharmacological effect that mediates the reinforcing properties of the drug.5.
Rationale
Chronic cocaine produces changes in the dopamine (DA)/D1/cAMP/protein kinase A (PKA)-regulated signaling pathway that may underlie the development of addiction.Objective
Given sex differences in the progression to cocaine addiction, we examined the possibility that the PKA pathway is differentially activated by cocaine in male and female rats.Materials and methods
Rats were given 24-h access to cocaine (1.5 mg/kg) or saline for 7 days under a discrete trial procedure (four trials per hour). Rats were then retested on responding for cocaine under a progressive-ratio schedule after either 0 (no-delay retest) or 10 (10-day-delay retest) days of abstinence. Markers of PKA-regulated signaling in the striatum and nucleus accumbens were evaluated by Western blotting, including phosphorylation of DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr 34 and glutamate receptor 1 (GluR1) at Ser 845.Results
Compared to males, females had higher levels of DARPP-32 phosphorylated at the PKA site in the striatum. Increased phosphorylation of DARPP-32 at the PKA site was also seen in the nucleus accumbens of females compared to males, particularly among controls and rats tested after a 10-day abstinence period. DARPP-32 phosphorylation was also increased as a consequence of cocaine when tested after a 0-day abstinence period in male rats but not female rats.Conclusion
These findings indicate sex differences in PKA-regulated signaling in drug-naïve controls. Furthermore, these data suggest that regulation of PKA signaling by cocaine is differentially influenced in male and female rats as a consequence of cocaine exposure and cocaine abstinence period.6.
Ming-Che Ho Chianfang G. Cherng Yen-Ping N. Tsai Chih-Yuan Chiang Jia-Ying Chuang Shu-Fang Kao Lung Yu 《Psychopharmacology》2009,205(1):141-149
Rationale and objective
Whether monoamine oxidase inhibitors (MAOIs) can be used to suppress the reinforcing effect of cocaine remains unknown. This study was undertaken to examine effects of a long-term dosing regimen with selective MAOIs on cocaine and food reward.Materials and methods
Since single dose of clorgyline (2 mg/kg), deprenyl (1 mg/kg), and pargyline (10 mg/kg) did not acutely affect mouse locomotor activity, these doses were chosen to treat the male C57BL/6j mice on a daily basis.Results
Fourteen consecutive days of pretreatments with clorgyline, deprenyl, or pargyline (one injection per day) did not affect natural reward-supported operant behavior, since acquisition of the lever pressing responses for food pellets under an FR-1 protocol did not differ among these drug- and saline-treated mice. Likewise, 24 consecutive days of pretreatments with clorgyline did not alter acquisition of the cocaine (0.3 mg/kg per infusion)-supported operant responses under an FR-1 protocol. In contrast, 24 days of pretreatments with deprenyl and pargyline abolished the cocaine-supported operant responses under a similar protocol. Twenty-four days of clorgyline treatment enhanced serotonin contents in striatum, nucleus accumbens, and frontal cortex. Frontal cortical 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacidic acid concentrations were decreased following 24 days of pretreatments with deprenyl and pargyline. These changes were not evident in mice pretreated with clorgyline.Conclusions
We suggest that long-term treatments with MAO-B inhibitors may decrease cocaine-supported operant responses in cocaine-naïve mice by selectively decreasing frontal cortical metabolism of dopamine and serotonin.7.
The effects of chronic versus acute desipramine on nicotine withdrawal and nicotine self-administration in the rat 总被引:1,自引:1,他引:0
Rationale
Nicotine withdrawal is characterized by depression-like symptomatology that may be mediated by dysregulations in norepinephrine transmission. These aversive aspects of nicotine withdrawal and the rewarding effects of nicotine play major roles in maintaining nicotine dependence.Objectives
The aim of this work was to evaluate the effects of desipramine (DMI), a preferential norepinephrine reuptake inhibitor and antidepressant, on preclinical models of nicotine dependence in rats.Materials and methods
A rate-independent current-intensity discrete-trial threshold intracranial self-stimulation procedure was used to assess brain reward function during nicotine withdrawal induced by cessation of nicotine infusion via subcutaneous osmotic mini pumps (3.16 mg/kg/day, base). Nicotine withdrawal was also measured by somatic signs of withdrawal. DMI was administered acutely (2 or 5 mg/kg, salt) during nicotine/saline withdrawal. In other naïve rats, chronic DMI treatment via mini pump (15 mg/kg/day, salt) began after 7 days of nicotine/saline exposure and continued during administration of nicotine/saline for 14 days and during nicotine/saline withdrawal. Additional rats acquired intravenous nicotine- or food-maintained responding, were prepared with DMI/vehicle-containing mini pumps, and self-administered nicotine or food during 12 days of DMI/vehicle exposure.Results
Acute DMI administration had no effect on threshold elevations observed in nicotine-withdrawing rats. Chronic DMI administration prevented the reward threshold elevations and the increased somatic signs of nicotine withdrawal. Although chronic DMI significantly decreased nicotine self-administration, it also decreased food-maintained responding.Conclusions
The results suggest that norepinephrine reuptake inhibitors may be effective anti-smoking treatments that reduce the anhedonic depression-like and somatic components of nicotine withdrawal and may alter the rewarding effects of nicotine and food.8.
Rationale
Cocaine-induced changes in D2 receptors have been implicated in the expression of sensitized behavioral responses and addiction-like behaviors; however, the influence of D3 receptors is less clear.Objectives
To characterize the effects of repeated cocaine administration on the sensitivity of rats to D2- and D3-mediated behaviors, as well as the binding properties of ventral striatal D2-like and D3 receptors.Methods
Pramipexole was used to assess the sensitivity of rats to D3/D2 agonist-induced yawning, hypothermia, and locomotor activity, 24 h, 72 h, 10, 21, and 42 days after repeated cocaine or saline administration. The locomotor effects of cocaine (42 day) and the binding properties of ventral striatal D2-like and D3 receptors (24 h and 42 days) were also evaluated.Results
Cocaine-treated rats displayed an enhanced locomotor response to cocaine, as well as a progressive and persistent leftward/upward shift of the ascending limb (72 h–42 day) and leftward shift of the descending limb (42 days) of the pramipexole-induced yawning dose–response curve. Cocaine treatment also decreased B max and K d for D2-like receptors and increased D3 receptor binding at 42 days. Cocaine treatment did not change pramipexole-induced hypothermia or locomotor activity or yawning induced by cholinergic or serotonergic agonists.Conclusions
These studies suggest that temporal differences exist in the development of cocaine-induced sensitization of D3 and D2 receptors, with enhancements of D3-mediated behavioral effects observed within 72 h and enhancements of D2-mediated behavioral effects apparent 42 days after cocaine. These findings highlight the need to consider changes in D3 receptor function when thinking about the behavioral plasticity that occurs during abstinence from cocaine use.9.
Izabel Almeida Alves Keli Jaqueline Staudt Fernando Olinto Carreño Graziela de Araujo Lock Carolina de Miranda Silva Stela Maris Kuze Rates Teresa Dalla Costa Bibiana Verlindo De Araujo 《Pharmaceutical research》2018,35(7):132
Purpose
The present work aimed to evaluate the influence of experimental meningitis caused by C. neoformans on total plasma and free brain concentrations of fluconazole (FLC) in Wistar rats.Method
The infection was induced by the administration of 100 μL of inoculum (1.105 CFU) through the tail vein. Free drug in the brain was assessed by microdialisys (μD). Blood and μD samples were collected at pre-determined time points up to 12 h after intravenous administration of FLC (20 mg/kg) to healthy and infected rats. The concentration-time profiles were analyzed by non-compartmental and population pharmacokinetics approaches.Results
A two-compartmental popPK model was able to simultaneously describe plasma and free drug concentrations in the brain for both groups investigated. Analysis of plasma and μD samples showed a better FLC distribution on the brain of infected than healthy animals (1.04?±?0.31 vs 0.69?±?0.14, respectively). The probability of target attainment was calculated by Monte Carlo simulations based on the developed popPK model for 125 mg/kg dose for rats and 400–2000 mg for humans.Conclusions
FLC showed a limited use in monotherapy to the treatment of criptoccocosis in rats and humans to value of MIC >8 μg/mL.10.
Amir Rashidian Ahad Muhammadnejad Ahmad-Reza Dehpour Shahram Ejtemai Mehr Maziar Mohammad Akhavan Reza Shirkoohi Mohsen Chamanara Seyyedeh-Elaheh Mousavi Seyed-Mahdi Rezayat 《Inflammopharmacology》2016,24(2-3):109-118
Aim
The aim of the present study is to explore whether atorvastatin improves intestinal inflammation through the inhibition of the TLR4/NFkB signaling pathway in TNBS-induced rat colitis.Methods
Acute colitis was induced by intra-rectal administration of 100 mg/kg TNBS dissolved in 0.25 ml of 50 % ethanol. Twenty four hours after colitis induction, saline, atorvastatin (20 and 40 mg/kg) and sulfasalazine (100 mg/kg) were given to the animals by oral route. This was repeated daily for 1 week. Body weight changes, macroscopic and microscopic lesions were assessed. MPO and TNF-α activities were detected by immunohistochemistry (IHC) and the expression level of TLR4, MyD88 and NF-κB p65 proteins were measured by western blotting analysis.Results
Atorvastatin and sulfasalazine reduced the body weight loss, macroscopic and microscopic lesions. Additionally, both drugs decreased the expression of MPO and TNF-α positive cells in the colon tissue. Furthermore, they inhibited the TNBS-induced expression of TLR4, MyD88 and NF-κB p65 proteins.Conclusions
It is suggested that the anti-inflammatory effect of atorvastatin on TNBS-induced rat colitis may involve the inhibition of the TLR4/NFkB signaling pathway.11.
Remo Holanda de Mendonça Furtado Robert Patrick Giugliano Celia Maria Cassaro Strunz Cyrillo Cavalheiro Filho José Antonio Franchini Ramires Roberto Kalil Filho Pedro Alves Lemos Neto Alexandre Costa Pereira Tânia Rúbia Rocha Beatriz Tonon Freire Elbio Antonio D’Amico José Carlos Nicolau 《Am J Cardiovasc Drugs》2016,16(4):275-284
Background
Proton-pump inhibitors (PPIs) are often prescribed to patients receiving dual antiplatelet therapy (DAPT). However, this class of medication, especially omeprazole, has been associated with a reduction in clopidogrel efficacy, leading many clinicians to substitute omeprazole with ranitidine.Objectives
Our objective was to compare the antiplatelet effect of clopidogrel before and after the addition of omeprazole or ranitidine.Methods
We measured platelet aggregability at baseline and after 1 week of clopidogrel 75 mg daily. Subjects were then randomized in a double-blinded, double-dummy fashion to omeprazole 20 mg twice daily (bid) or ranitidine 150 mg bid. We repeated aggregability tests after 1 additional week, using VerifyNow P2Y12? (Accumetrics; San Diego, CA, USA), depicting aggregability as percent inhibition of platelet aggregation (IPA).Results
We enrolled 41 patients in the omeprazole group and 44 in the ranitidine group. IPA was significantly decreased after the addition of omeprazole to clopidogrel (from 26.3 ± 32.9 to 17.4 ± 33.1 %; p = 0.025), with no statistical significant changes observed in the ranitidine group (from 32.6 ± 28.9 to 30.1 ± 31.3 %; p = 0.310). The comparison of IPA in both groups at the end of the follow-up showed a trend toward significance (p = 0.07, 95 % confidence interval [CI] ?1.19 to 26.59); after excluding homozygous patients for 2C19*2 genotype, the comparison of IPA between the groups reached statistical significance (32.7 ± 30.8 vs. 17.7 ± 33.4 %, respectively, for ranitidine and omeprazole groups; p = 0.04).Conclusions
Unlike omeprazole, ranitidine did not influence platelet aggregability response to clopidogrel.Clinical Trial Registration
NCT01896557.12.
Guillaume Phan Rym Chioukh David Suhard Alexandre Legrand Charlotte Moulin Thibaud Sontag François Rebière Céline Bouvier-Capely Michelle Agarande Valérie Renaud-Salis Jean-René Jourdain 《Pharmaceutical research》2018,35(12):227
Purpose
To propose a new and effective dose regimen for stable potassium iodide (KI) repeated prophylaxis in case of prolonged exposure to radioactive iodine.Methods
The pharmacokinetics of iodine was determined in rats by compartmental analyses after intravenous and oral administrations of the optimal dose of 1 mg/kg KI, which was previously selected in a dose-effect study. The thyroid protection against iodine-125 incorporation was followed during 24 h after a single oral dosing of KI. A repeated KI prophylaxis was modeled using initial estimates of iodine pharmacokinetic parameters.Results
A dose regimen consisting in administrations of 1 mg/kg daily for 8 days was selected and studied. Plasma iodine concentrations predicted by simulation were verified by experimental data and varied after the third dose of KI between 174 and 1190 μg/l. The inhibition study of iodine-125 binding in the thyroid as a function of the time showed that the protection effect of KI could be correlated to stable iodine plasma concentrations. Hence, a theoretical decrease in iodine-125 thyroid uptake from 63 to 88% could be achieved in a 24 h-interval between two KI doses.Conclusion
Given the satisfactory levels of thyroid protection, this dose regimen could be envisaged in order to extent KI indications for repeated prophylaxis.13.
Aim and objective
6-hydroxy dopamine (6-OHDA) is a neurotoxin which on intranigral administration produces severe nigrostriatal damage with motor and cognitive deficit in animals. Curcumin (CMN) in combination with bioenhancer piperine (PP) in 6-hydroxydopamine-induced Parkinsonian rats was used to investigate the antioxidant, neuromodulatory and neuroprotective mechanisms.Materials and methods
Hemi-Parkinson’s rat model was developed with intranigral infusion of 6-OHDA (8 μg/2 μl, once, unilaterally), treatment with CMN (25 and 50 mg/kg) and combination of PP (2.5 mg/kg) with CMN (25 mg/kg) was given daily for 21 days starting from the 7th day after 6-OHDA infusion. The behavioral (locomotor, grip strength, and narrow beam walk) parameters were studied on weekly basis. On 22nd day, isolated brain preparations were subjected to biochemical (lipid peroxidation, glutathione, and nitrite), neuroinflammatory (IL-1β, IL-6, and TNF- α), and neurochemical (DA, NE, 5- HT, GABA, Glutamate, DOPAC, HVA, and 5-HIAA) analysis.Results
Oral administration of CMN had significantly prevented behavioral, neuroinflammatory, and neurochemical changes and preserved the antioxidant potential of the nigrostriatum in rats treated with 6-OHDA.Conclusion
In the present study, PP and CMN had afforded a better neuroprotective effect compared to alone treatment on behavior, biochemical, neuroinflammatory, and neurochemical parameters in rats.14.
Objective
This study focuses on the evaluation of phenolic compound ferulic acid (FA, 4-hydroxy-3-methoxycinnamic acid) in the chronic constriction injury (CCI) of sciatic nerve induced neuropathy in rats.Methods
Thirty-six animals were randomly divided into six groups. Left sciatic nerve was exposed and ligated, animals in the control, standard, and test groups were treated orally with respective drugs for 21 days. Nociceptive thresholds (THERMAL hyperalgesia, mechanical hyperalgesia, and tactile allodynia) were assessed at 0 days and thereafter every 3 days till 3 weeks. Three weeks later, the sciatic nerve tissue homogenate was prepared and subjected for estimation of oxidative markers namely total protein, nitric oxide, lipid peroxidase, interleukins (IL-1β and IL-6).Results
Pregabalin (10 mg/kg, p.o.) and ferulic acid (10, 20, 30 mg/kg, p.o.), significantly and dose dependently, decreased all nociceptive thresholds (thermal hyperalgesia, mechanical hyperalgesia, and tactile allodynia) and biochemical markers (total protein, nitric oxide, lipid peroxidase, and interleukins).Conclusion
In conclusion, the anti-hyperalgesic effect of FA in rats receiving CCI might partly be attributed to its anti-oxidant and anti-inflammatory activity and is associated with the maintenance of neuropathic pain and could be useful as an adjuvant to conventional medicines.15.
Joana Sousa Gilberto Alves Ana Fortuna Amílcar Falcão 《Pharmaceutical research》2017,34(11):2260-2269
Purpose
To evaluate the potential of levofloxacin intranasal administration as a promising alternative approach to treat local infections such as chronic rhinosinusitis, by delivering drug concentrations directly to the site of infection.Methods
Drug concentrations were measured in plasma, olfactory bulb and nasal mucosa of anterior (ANM) and posterior regions after intranasal (0.24 mg/kg) and intravenous (10 mg/kg) administration to rats, and pharmacokinetic parameters were compared between routes. For intranasal administration a thermoreversible in-situ gel was used.Results
Plasma and olfactory bulb exposure to levofloxacin was minimal following intranasal dose, preventing systemic and central nervous system adverse effects. Levofloxacin concentration-time profile in ANM revealed higher concentrations during the first 60 min of the study following intranasal administration than the corresponding ones obtained after intravenous administration. A rapid and continuous decay of levofloxacin concentration in this nasal region was observed after intranasal delivery, resulting in much lower values at the last sampling time-points.Conclusion
The higher dose-normalized concentrations and pharmacokinetic exposure parameters of levofloxacin in ANM after intranasal administration, demonstrates that intranasal delivery of the formulated gel is, by itself, advantageous for delivering levofloxacin to biophase and thus an attractive approach in management of chronic rhinosinusitis.16.
H. F. Miranda F. Sierralta V. Jorquera P. Poblete J. C. Prieto V. Noriega 《Inflammopharmacology》2017,25(1):91-97
Objective
Diabetic neuropathy (DN) is the most common complication of diabetes and pain is one of the main symptoms of diabetic neuropathy, however, currently available drugs are often ineffective and complicated by adverse events. The purpose of this research was to evaluate the antinociceptive interaction between gabapentin and minocycline in a mice experimental model of DN by streptozocin (STZ).Methods
The interaction of gabapentin with minocycline was evaluated by the writhing and hot plate tests at 3 and 7 days after STZ injection or vehicle in male CF1 mice.Results
STZ (150 mg/kg, i.p.) produced a marked increase in plasma glucose levels on day 7 (397.46 ± 29.65 mg/dL) than on day 3 (341.12 ± 35.50 mg/dL) and also developed neuropathic pain measured by algesiometric assays. Gabapentin produced similar antinociceptive activity in both writhing and hot plate tests in mice pretreated with STZ. However, minocycline was more potent in the writhing than in the hot plate test in the same type of mice. The combination of gabapentin with minocycline produced synergistic interaction in both test.Conclusion
The combination of gabapentin with minocycline in a 1:1 proportion fulfills all the criteria of multimodal analgesia and this finding suggests that the combination provide a therapeutic alternative that could be used for human neuropathic pain management.17.
Yao Z Zhao B Hoffman EP Ghimbovschi S DuBois DC Almon RR Jusko WJ 《Pharmaceutical research》2007,24(4):643-649
Purpose
Microarrays have been utilized in many biological, physiological and pharmacological studies as a high-throughput genomic technique. Several generations of Affymetrix GeneChip® microarrays are widely used in gene expression studies. However, differences in intensities of signals for different probe sets that represent the same gene on various types of Affymetrix chips make comparison of datasets complicated.Materials and Methods
A power coefficient scaling factor was applied in the pharmacokinetic/pharmacodynamic (PK/PD) modeling to account for differences in probe set sensitivities (i.e., signal intensities). Microarray data from muscle and liver following methylprednisolone 50 mg/kg i.v. bolus and 0.3 mg/kg/h infusion regimens were taken as an exemplar.Results
The scaling factor applied to the pharmacodynamic output function was used to solve the problem of intensity differences between probe sets. This approach yielded consistent pharmacodynamic parameters for the applied models.Conclusions
Modeling of pharmacodynamic/pharmacogenomic (PD/PG) data from diverse chips should be performed with caution due to differential probe set intensities. In such circumstances, a power scaling factor can be applied in the modeling.18.
Naoki Itoh Eiichi Yamamoto Tomofumi Santa Takashi Funatsu Masaru Kato 《Pharmaceutical research》2016,33(6):1440-1446
Purpose
Nanoparticles have been used in diverse areas, and even broader applications are expected in the future. Since surface modification can influence the configuration and toxicity of nanoparticles, a rapid screening method is important to ensure nanoparticle quality.Methods
We examined the effect of the nanoparticle surface morphology on the HPLC elution profile using two types of 100-nm liposomal nanoparticles (AmBisome? and DOXIL?).Results
These 100-nm-sized nanoparticles eluted before the holdup time (about 4 min), even when a column packed with particles with a relatively large pore size (30 nm) was used. The elution time of the nanoparticles increased with pegylation of the nanoparticles and protein adsorption to the nanoparticles; however, the nanoparticles still eluted before the holdup time.Conclusions
The results of this study indicate that HPLC is a suitable tool for rapid evaluation of the surface of liposomal nanoparticles.19.
Michela Blain Alexander Garrard Robert Poppenga Betty Chen Matthew Valento Melissa Halliday Gittinger 《Journal of medical toxicology》2017,13(3):259-262
Introduction
Monensin is a veterinary antibiotic with a narrow therapeutic window that has led to lethal intoxication in many animal species. Only two prior cases of human toxicity have been reported, both fatal. We present the first case of survival from severe toxicity following monensin ingestion.Case
A 58-year-old man presented with 8 days of vomiting and abdominal pain. Due to delusions of central nervous system toxoplasmosis, he ingested 300 mg of monensin. His laboratory studies revealed severe rhabdomyolysis without renal dysfunction. Total creatine kinase (CK) peaked above 100,000 U/L. His CK decreased to 5192 U/L after 15 days of aggressive hydration and sodium bicarbonate therapy. His ejection fraction on echocardiogram decreased from 69 to 56%.Discussion
Reports on acute clinical effects after human exposure to monensin are limited. Ingestion is known to cause skeletal and cardiac muscle rhabdomyolysis and necrosis. Animal studies demonstrate that monensin’s toxicity is due to increases in intracellular sodium concentrations and Ca2+ release. To date, no effective antidotal treatment has been described.Conclusions
Monensin is a veterinary medication not approved for human use by the US Food and Drug Administration. Though poorly studied in humans, this case demonstrates the severe harm that may occur following ingestion.20.