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At least 1,405 records · Page 78Linked to original sources
PubMed2005

Design, synthesis, and preliminary evaluation of gabapentin-pregabalin mutual prodrugs in relieving neuropathic pain.

As a part of a program for the development of specific analgesics in relieving neuropathic pain, the purpose of the present study was to investigate a new concept that involves the conjugation of two drugs, gabapentin and pregabalin, as mutual prodrugs using a chemical modification approach. A series of gabapentin-pregabalin diester compounds were synthesized using linear or branch bis-hydroxyl linkers. Their pharmacological properties for treating neuropathic pain were investigated in a rat model of chronic sciatic nerve constriction injury (CCI). In-vivo evaluation demonstrated that 1a and 1b composed of two gabapentin molecules as well as 3a composed of gabapentin and pregabalin with the short linear linker, were effective in reversing tactile allodynia in CCI rats. Compounds with longer or side-branched linkers showed lower efficiencies and severe adverse effects.

Amines↗
PubMed2005

Oral treatment with PD-0200347, an alpha2delta ligand, reduces the development of experimental osteoarthritis by inhibiting metalloproteinases and inducible nitric oxide synthase gene expression and synthesis in cartilage chondrocytes.

OBJECTIVE: To examine the in vivo effects of PD-0200347, an alpha(2)delta ligand of voltage-activated Ca(2+) channels and a compound chemically related to pregabalin and gabapentin, on the development of cartilage structural changes in an experimental dog model of osteoarthritis (OA). The effects of PD-0200347 on the major pathways involved in OA cartilage degradation, including matrix metalloproteinases (MMPs) and the inducible form of nitric oxide synthase (iNOS), were also studied. METHODS: OA was surgically induced in dogs by sectioning the anterior cruciate ligament. OA dogs were randomly distributed into 3 groups and treated orally with either 1) placebo, 2) 15 mg/kg/day of PD-0200347, or 3) 90 mg/kg/day of PD-0200347. Dogs were killed 12 weeks after surgery. The severity of the lesions was scored macroscopically and histologically. Cartilage specimens from the femoral condyles and tibial plateaus were processed for RNA extraction and quantitative reverse transcription-polymerase chain reaction (RT-PCR) or immunohistochemistry. Specific probes and antibodies were used to study the messenger RNA and protein levels of iNOS, MMP-1, MMP-3, and MMP-13. RESULTS: No clinical signs of drug toxicity were noted in the treated animals. Treatment with PD-0200347 at both dosages tested (15 and 90 mg/kg/day) reduced the development of cartilage lesions. There was a reduction in the score of lesions, with a statistically significant (P = 0.01) difference when the highest dosage of the drug was administered. The reduction in the score was mainly related to a decrease in the surface size of the lesions. Quantitative RT-PCR showed that PD-0200347 significantly reduced the expression of MMP-13, a key mediator in OA. Immunohistochemical analyses showed that treatment with PD-0200347 significantly reduced the synthesis of all key OA mediators studied. CONCLUSION: This study demonstrated the efficacy of PD-0200347 in reducing the progression of cartilage structural changes in a dog model of OA. It also showed that this effect is linked to the inhibition of the major pathophysiologic mediators responsible for cartilage degradation.

Administration, Oral↗
PubMed1975

Comparative respiratory depression of tillidine and morphine.

Respiratory depression induced by tilidine was compared with that of morphine in a crossover study in 6 healthy subjects. Increments of tilidine, 150 mg/70 kg, and morphine, 10 mg/70 kg, were given intravenously and displacement of each subject's CO2 response curve was measured after each dose increment. Both tilidine and morphine caused dose-related displacement of the CO2 response curves to the right. Approximately 80 to 120 mg of tilidine can be expected to induce the respiratory depression of morphine, 10 mg, when given intravenously. Subjective effects after tilidine were qualitatively similar to those of morphine but were of longer duration with nausea and vomiting more frequent. The respiratory depression of both drugs was effectively antagonized by naloxone.

Adult↗
PubMed2003

Pharmacological treatment of social anxiety disorder: a meta-analysis.

Placebo-controlled trials have evaluated the efficacy of several medications in the treatment of social anxiety disorder but information regarding their relative efficacy is lacking. We compared the efficacy of medications systematically studied for the treatment of social anxiety disorder using meta-analytic techniques. The methodology included a database search of articles published between January 1980 and June 2001 and manual searches of bibliographies in published manuscripts. Trials were included if they reported outcome data on the Liebowitz Social Anxiety Scale (LSAS) or a categorical measure of responder status. Data were extracted independently by two authors. The Q statistic was used to assess homogeneity across trials. All analyses were conducted using intent-to-treat data. There was substantial heterogeneity across trials. The medications with largest effect sizes were phenelzine [effect size, 1.02; 95% Confidence Interval (CI), 0.52-1.52], clonazepam (effect size, 0.97; 95% CI, 0.49-1.45), gabapentin (effect size, 0.78; 95% CI, 0.29-1.27), brofaromine (effect size, 0.66; 95% CI, 0.38-0.94), and the selective serotonin reuptake inhibitors (SSRIs; effect size, 0.65; 95% CI, 0.50-0.81). There were no statistically significant differences between medications or medication groups. However, formal methods of interim monitoring adapted for meta-analyses suggested strongest evidence of efficacy for SSRIs and brofaromine. Several medications are efficacious for the treatment of social anxiety disorder. The stability of the SSRI effect size estimate in conjunction with other evidence for safety and tolerability and their ability to treat comorbid conditions supports the use of SSRIs as the first-line treatment. Direct comparisons of SSRIs vs. other promising medications deserve consideration.

Acetates↗
PubMed1998

In vivo monitoring of gabapentin in rats: a microdialysis study coupled to capillary electrophoresis and laser-induced fluorescence detection.

Gabapentin (GP) is a new anticonvulsant used in refractory epilepsy. Few studies have monitored the drug in vivo. We report the combination of capillary electrophoresis and laser-induced fluorescence detection (CZE-LIFD) with brain microdialysis and plasma ultrafiltration in an attempt to measure GP and offer an alternative technique for pharmacokinetic studies. We found that CZE-LIFD is capable of linearly measuring 10(-7)-10(-9) M GP in a 1 nL volume. It was also demonstrated that it is possible to monitor GP in prefrontal cortex dialysates and plasma in rats. It is concluded that the method permits in vivo monitoring of the drug in pharmacological as well as in clinical studies.

Acetates↗
PubMed1995

Southern blot analysis of T-cell receptor gene rearrangements in cynomolgus monkeys, and identification of a progenitor cell HPRT mutation.

Increases in peripheral blood T-lymphocyte HPRT mutant frequency may reflect either a number of independent HPRT gene mutational events or clonal proliferation of a single HPRT mutant. Sequence analysis of HPRT mutations in conjunction with T-cell receptor (TCR) gene rearrangement pattern analysis can distinguish these possibilities. Our laboratory previously characterized a nonhuman primate model for in vivo mutation studies using the clonal HPRT mutation assay. In the present study we report the use of probes for human TCR beta and gamma genes to characterize TCR rearrangements in cynomolgus monkeys. Together, these methods were used to examine a monkey which exhibited a mean spontaneous HPRT mutant frequency (MF) of 16.4 x 10(-6), compared to the normal mean MF of 3.03 x 10(-6). The elevated MF resulted from the occurrence of a single HPRT mutation in a lymphocyte progenitor cell or stem cell, since T-cell clones isolated from the monkey exhibited a G to T transversion at base pair 539 in the HPRT coding region, and had unique rearrangements of TCR gamma along with an apparent germline TCR beta configuration. In a preliminary in vivo mutation study, the animal was treated with the investigational potent mutagen and antitumor agent adozelesin (U-73975). No increase in HPRT mutant frequency was observed. The HPRT mutant clones isolated after treatment showed rearrangement of both TCR gamma and beta genes. Possible explanations for these findings are discussed.

Animals↗
PubMed2006

Gabapentin in patients with the pruritus of cholestasis: a double-blind, randomized, placebo-controlled trial.

Pruritus is defined as the second order of nociception, the first being pain; thus, there is a rationale to study gabapentin, a drug that increases the threshold to experience nociception. The aim of this double-blind, randomized, placebo-controlled trial was to study the effect of gabapentin on the perception of pruritus and its behavioral manifestation, scratching, in cholestasis. The participants were 16 women with chronic liver disease and chronic pruritus. Hourly scratching activity (HSA) was continuously recorded for up to 48 hours at baseline and on treatment for at least 4 weeks in an inpatient setting. The perception of pruritus was assessed by interviews and by a visual analog score (VAS) of pruritus recorded every hour while patients were awake. Patients were randomized to the study drug (gabapentin or placebo) at a starting dose of 300 mg orally per day in divided doses to a maximum of 2,400 mg or until relief from pruritus. Gabapentin was associated with an increase in mean HSA, in contrast to the placebo, which was associated with a decrease. The mean VAS decreased significantly among those taking the placebo and in some patients on gabapentin. In conclusion, gabapentin did not provide a significant therapeutic advantage over the placebo; in fact, it was associated with an increase in the perception of pruritus and in HSA in some patients.

Adult↗
PubMed1995

Disposition of gabapentin in anuric subjects on hemodialysis.

Gabapentin is an anticonvulsant drug, which in man is cleared solely by renal excretion and is not bound to plasma proteins. Because the clearance of gabapentin is dependent on renal function, the pharmacokinetics of gabapentin were investigated in anuric subjects maintained on hemodialysis. Plasma samples were obtained over an 8-day period after administration of single oral 400-mg doses of gabapentin. Pre- and post-dialyzer plasma samples and dialysate samples from quantitative collection of dialyzer effluent were obtained during hemodialysis sessions performed 2, 4, and 7 days after dosing. A mean (SD) maximum gabapentin plasma concentration of 6.0 (2.4) micrograms/mL was achieved at 4.7 (2.1) hours post-dose. The elimination half-life of gabapentin on non-hemodialysis days averaged 132 hours. Approximately 35% of the gabapentin dose was recovered in dialysate, and mean hemodialysis clearance of gabapentin was 142 (26) mL/min; approximately 93% of the dialyzer creatinine clearance. Gabapentin elimination half-life during hemodialysis was approximately 4 hours. Systemic plasma gabapentin concentrations increased approximately 30% during the first 2 hours after hemodialysis as a result of drug redistribution in the body. It is recommended that patients with end-stage renal disease maintained on hemodialysis receive an initial 300-mg to 400-mg gabapentin loading dose. Plasma gabapentin concentrations can be maintained by giving 200 to 300 mg of gabapentin after every 4 hours of hemodialysis.

Acetates↗
PubMed2006

DNA damage-induced RPA focalization is independent of gamma-H2AX and RPA hyper-phosphorylation.

Replication protein A (RPA) is the major eukaryotic single stranded DNA binding protein that plays a central role in DNA replication, repair and recombination. Like many DNA repair proteins RPA is heavily phosphorylated (specifically on its 32 kDa subunit) in response to DNA damage. Phosphorylation of many repair proteins has been shown to be important for their recruitment to DNA damage-induced intra-nuclear foci. Further, phosphorylation of H2AX (gamma-H2AX) has been shown to be important for either the recruitment or stable retention of DNA repair proteins to these intra-nuclear foci. We address here the relationship between DNA damage-induced hyper-phosphorylation of RPA and its intra-nuclear focalization, and whether gamma-H2AX is required for RPA's presence at these foci. Using GFP-conjugated RPA, we demonstrate the formation of extraction-resistant RPA foci induced by DNA damage or stalled replication forks. The strong DNA damage-induced RPA foci appear after phosphorylated histone H2AX and Chk1, but earlier than the appearance of hyper-phosphorylated RPA. We demonstrate that while the functions of phosphoinositol-3-kinase-related protein kinases are essential for DNA damage-induced H2AX phosphorylation and RPA hyper-phosphorylation, they are dispensable for the induction of extraction-resistant RPA and RPA foci. Furthermore, in mouse cells genetically devoid of H2AX, DNA damage-induced extraction-resistant RPA appears with the same kinetics as in normal mouse cells. These results demonstrate that neither RPA hyper-phosphorylation nor H2AX are required for the formation in RPA intra-nuclear foci in response to DNA damage/replicational stress and are consistent with a role for RPA as a DNA damage sensor involved in the initial recognition of damaged DNA or blocked replication forks.

Aminoglycosides↗
PubMed2001

Gabapentin quantification in human plasma by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry. Application to bioequivalence study.

A rapid, sensitive and specific analytical method was developed and validated to quantify gabapentin in human plasma using acetaminophen as an internal standard. The method employs a single plasma protein precipitation. The analytes are chromatographed on a C4 reversed-phase chromatographic column and analyzed by mass spectrometry in the multiple reaction monitoring (MRM) mode. The method has a chromatographic run time of 4 min and a linear calibration curve over the range 50-10 000 ng x ml(-1) (r > 0.999). The between-run precision, based on the relative standard deviation for replicate quality controls, was < or = 4.8 % (200 ng x ml(-1)), 6.0% (1000 ng x ml(-1)) and 4.4% (5000 ng x ml(-1)). The between-run accuracy was +/-2.6, 4.4 and 0.5% for the above-mentioned concentrations, respectively. This method was employed in a bioequivalence study of two gabentin capsule formulations (Progresse from Biosintética, Brazil, as a test formulation, and Neurotin from Parke-Davis, as a reference formulation) in 24 healthy volunteers of both sexes who received a single 300 mg dose of each formulation. The study was conducted using an open, randomized, two-period crossover design with a 7-day washout interval. The 90% confidence interval (CI) of the individual ratio geometric mean for Progresse/Neurotin was 87.9-115.6% for AUC(0-36 h) and 88.6-111.7% for Cmax. Since both 90% CI for AUC(0-36 h) and Cmax were included in the 80-125% interval proposed by the US Food and Drug Administration, Progresse was considered bioequivalent to Neurotin according to both the rate and extent of absorption.

Acetates↗
PubMed2004

Input resistance is voltage dependent due to activation of Ih channels in rat CA1 pyramidal cells.

The contribution of the hyperpolarization-activated cation current (I(h)) to input resistance (R(N)) and resting potential (RP) was investigated during whole-cell patch-clamp recordings in CA1 pyramidal cells of rat hippocampal slices. In current-clamp mode, R(N) was determined at different membrane potentials. R(N) decreased with increasing hyperpolarization, from about 260 Momega to 140 Momega at potentials of about -60 mV and -110 mV, respectively. Both the potential of half-maximal reduction of R(N) and the potential of half-maximal I(h) activation (determined in voltage-clamp mode) were approximately -90 mV. The analysis of the voltage sag indicative of I(h) activation revealed a preferential activity of I(h) channels in a voltage range between -70 and -95 mV. ZD7288 (50 microM), a specific I(h) blocker, led to a hyperpolarization by about 4.8 mV, increased R(N) by approximately 45% within a potential range between -65 and -80 mV, and abolished the voltage dependence of R(N). Gabapentin (GBP, 100 microM), an I(h) channel agonist, led to a depolarization by about 2.4 mV and reduced R(N) by about 20% within a potential range between -65 and -80 mV. In conclusion, our data show that R(N) is voltage dependent due to I(h) channel activation and that I(h) channels are preferentially active at voltages between -70 and -95 mV. Furthermore, we demonstrated that R(N) can be modulated by antiepileptic drugs such as GBP, which may partly explain its antiepileptic effect as due to decreasing the sensitivity to excitatory input.

4-Aminopyridine↗