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Biomedical subjects

R Dixon

Publications and source records attributed to R Dixon.

At least 127 records · Page 7Linked to original sources
PubMed1989

AICA-riboside: direct quantitation in ultrafiltrates of plasma by HPLC during pharmacokinetic studies in man.

A simple HPLC procedure for the quantitation of AICA-riboside (Z) and its 5-monophosphate metabolite (ZMP) in ultrafiltrates of plasma and lysed whole blood, respectively, has been developed. Samples of plasma or previously frozen whole blood were subjected to ultrafiltration by centrifuging for 30 minutes in an Amicon Centrifree Micropartition cartridge and the filtrates analyzed directly by HPLC. Compound Z was quantitated by UV detection at 270 nm following isocratic reverse-phase chromatography on a C18 column and ZMP following isocratic chromatography on an anion exchange (SAX) column. The limits of sensitivity for Z in plasma and ZMP in blood were 0.1 and 2.5 micrograms/ml, respectively. Neither compound was protein bound and recoveries were greater than 95%. The intra- and inter-day coefficients of variation were less than 5%. The method has been used to evaluate the pharmacokinetics of Z and ZMP in man. The procedure should be applicable to the quantitation of certain other nucleosides and nucleotides in biological media.

Aminoimidazole Carboxamide↗
PubMed1988

Use of narcotic antagonists to modify stereotypic self-licking, self-chewing, and scratching behavior in dogs.

We evaluated 2 narcotic antagonists, naltrexone and nalmefene, for treatment of refractory self-licking, self-chewing, and scratching behavior in dogs. Eleven dogs with various irritative or pruritic disorders were medicated with naltrexone (1 mg/kg of body weight, sc) or nalmefene (1 to 4 mg/kg, sc), after a period of control observation during which the dogs had not been medicated. The time for which the dogs were involved in self-licking, self-chewing, or scratching was determined retrospectively by analysis of videotapes. The rates of involvement in either activity before and after treatment were calculated and compared statistically. Treatment with a narcotic antagonist significantly reduced the time spent self-licking, self-chewing, or scratching in 7 of 11 dogs, was partially effective in 3 dogs, and was ineffective in one dog. Dogs with acral lick dermatitis responded most to treatment.

Animals↗
PubMed1988

Crigler-Najjar syndrome: treatment at home with phototherapy.

An infant became jaundiced in the neonatal period. The serum bilirubin failed to fall with phototherapy. A diagnosis of Crigler Najjar type 1 syndrome was made by exclusion and confirmed by liver biopsy. The infant has been successfully treated at home with phototherapy. Liver transplantation remains a therapeutic option.

Bilirubin↗
PubMed1988

Evidence for the delivery of narcotic antagonists to the colon as their glucuronide conjugates.

Morphine-dependent rats were used to evaluate the effects of the narcotic antagonists, naloxone and nalmefene, and their glucuronide conjugates on the gastrointestinal tract and various parameters of brain-mediated withdrawal. When administered s.c. nalmefene HCl caused a dose-dependent tail skin temperature increase, whereas nalmefene glucuronide was ineffective. Nalmefene precipitated brain-mediated morphine withdrawal at doses as low as 10 micrograms/kg, whereas nalmefene glucuronide was ineffective at doses as high as 1 mg/kg. After p.o. administration of the drugs, naloxone HCl and nalmefene HCl caused diarrhea, withdrawal behavior and tail skin temperature responses by 15 min. In contrast, after p.o. administration of the glucuronide conjugate of either narcotic antagonist, diarrhea was delayed for 75 to 203 min. This latency probably reflects the required transit time to the lower gastrointestinal tract inasmuch as direct colonic administration of either nalmefene or nalmefene glucuronide caused diarrhea within 5 to 8 min. Additionally, the magnitude of brain-mediated withdrawal was smaller and its time of occurrence was delayed and compared to the diarrhea response after p.o. administration of the conjugated forms of the narcotic antagonists. Our calculations indicate that about 0.2 to 0.5% of the dose of the narcotic antagonist administered orally as the glucuronide was absorbed systemically. These results indicate that p.o. administration of the glucuronide conjugates of naloxone and nalmefene results in delivery of the narcotic antagonists to the colon. As such these conjugates may be useful in the prevention or relief of constipation caused by opiate use, without interfering with the central analgesic effects of the narcotics.

Animals↗
PubMed1988

Pharmacokinetics of a new inotropic catecholamine in dog plasma using solid phase extraction technology.

The pharmacokinetics of a new inotropic catecholamine, N-[2-(3,4-dihydroxyphenyl)-ethyl]-1-methyl-3-(3-carbomylphenyl)-pr opylamine HCL (KM-13), was studied following i.v. injection of 50 and 100 micrograms/kg doses to dogs. KM-13 was extracted from plasma using Bond-Elut CN columns and quantitated by HPLC with electro-chemical detection. The plasma concentration--time profile of KM-13 following an i.v. bolus was best fitted with a bi-exponential equation and the terminal elimination phase had a half life of about 20 min. The analytical method, with a limit of sensitivity of 2 ng/ml, would appear to have general applicability in studying the pharmacokinetics of synthetic catecholamines.

Animals↗
PubMed1987

Nalmefene: safety and kinetics after single and multiple oral doses of a new opioid antagonist.

The aim of these two studies was to evaluate the safety and pharmacokinetics of oral nalmefene, a new orally effective opioid antagonist. In the first study, single ascending doses of 50, 100, 200, and 300 mg of nalmefene HCl were administered in double-blind fashion to four groups of healthy men. There were six subjects in each group; four received nalmefene and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, such as lightheadedness, at the higher doses. Model-independent pharmacokinetic analysis of the plasma concentration-time data showed that nalmefene was rapidly absorbed and had an elimination half-life that ranged from seven to 15 hours (mean, 10.7 hr). There was a good linear relationship (r = .97) between administered dose and total area under the curve at each dose level. Only about 4% of the dose was excreted in the urine as unchanged nalmefene, whereas up to 60% was excreted as a beta-glucuronidase/sulfatase hydrolysable conjugate(s) of nalmefene. In the second study, six healthy men were initially administered a single 50-mg dose of drug, and plasma samples were obtained at selected time intervals for 48 hours. A dosing schedule of 20 mg q12h was then started and continued for seven days. Plasma samples were collected immediately before each dose and at selected times for up to 48 hours after the last dose. The drug was well tolerated by all subjects, and no clinically significant adverse effects were observed during the seven-day administration period.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1987

Noninvasive delivery of a novel inotropic catecholamine: iontophoretic versus intravenous infusion in dogs.

Using a newly developed iontophoretic delivery device, a novel inotropic catecholamine, pharmacologically similar to dobutamine, has been successfully administered to dogs by noninvasive transdermal infusion for periods of up to 1.5 h. The technique was compared with intravenous infusion and shown to be capable of achieving the same degree of cardiac contractility and steady-state plasma concentrations of the inotrope. There was also a good linear relationship between the applied current and the resulting steady-state plasma concentrations of the inotrope. Approximately 2 mA of applied current during transdermal iontophoresis produced a response equivalent to an intravenous infusion of 1 micrograms/kg/min of the drug.

Animals↗
PubMed1987

Requirements for transcriptional activation in vitro of the nitrogen-regulated glnA and nifLA promoters from Klebsiella pneumoniae: dependence on activator concentration.

Three proteins involved in nitrogen regulation in Klebsiella pneumoniae, NTRA, NTRB and NTRC, have been purified. In a defined in vitro system all three NTR proteins are required for initiation of transcription at the ntr activatable glnA and nifLA promoters. However, in crude S-30 extracts, transcription from the glnA promoter, but not the nifLA promoter, can be activated in the absence of NTRB. A higher concentration of NTRC is required for activation of nifLA transcription than for glnA transcription. Sequences located between -227 and -158 with respect to the nifL transcription start site are required for efficient activation of the nifLA promoter in vitro.

Base Sequence↗
PubMed1987

Investigation into the use of narcotic antagonists in the treatment of a stereotypic behavior pattern (crib-biting) in the horse.

Crib-biting in horses is a repetitive behavior pattern which may involve the activation of both narcotic receptors and dopamine receptors in the CNS. Crib-biting frequency, determined in 7 nontreated horses under controlled conditions, was usually linear for many hours and ranged from 0.3 to 14.9 bites/min. Intravenous or IM injections of narcotic antagonists decreased these rates to almost zero by about 20 minutes after the injection was given. The duration of the response to a single injection ranged from 20 minutes for naloxone to 4 hours or more for nalmefene and diprenorphine. Effective doses were 0.02 to 0.04 mg of naloxone/kg, 0.04 mg of naltrexone/kg, 0.08 mg of nalmefene/kg, and 0.02 to 0.03 mg of diprenorphine/kg. Crib-biting could be prevented completely for up to a week by continuous infusion of 5 to 10 mg of nalmefene/hr. Crib-biting resumed when the infusion was discontinued, and plasma nalmefene concentrations decreased to below 5 ng/ml. Doses of nalmefene as large as 0.4 mg/kg, IV, produced only minor side effects. These side effects included some passage of semifluid fecal material, intermittent penile relaxation, and mild sedation. Treated horses responded normally to external stimuli, retained their appetites, and performed appropriately when ridden. Sedation wore off during the course of prolonged infusions. Narcotic antagonists may provide a novel and effective treatment of stereotypic behavior disorders.

Animals↗
PubMed1986

The xylABC promoter from the Pseudomonas putida TOL plasmid is activated by nitrogen regulatory genes in Escherichia coli.

The xylABC promoter (OP1), located on the TOL plasmid of Pseudomonas putida contains sequences homologous to the conserved regions found in nitrogen fixation (nif) promoters and in other promoters subject to nitrogen control. XylA-lac fusions were constructed in order to monitor expression from the OP1 promoter in Escherichia coli. Transcription was activated in the presence of the heterologous regulatory genes ntrC or nifA from Klebsiella pneumoniae as well as by the homologous P. putida regulatory gene xylR. In all cases activation was also dependent on the ntrA gene, whose product has been implicated as a specific sigma factor for ntr activatable operons. The 5' ends of xylA mRNA, detected by S1 nuclease mapping of in vivo transcripts, were identical in strains containing xylR, ntrC or nifA as transcriptional activators. However, activation of the K. pneumoniae nifL or nifH promoters by xylR was not detected.

Base Sequence↗
PubMed1986

Deletion loop mutagenesis of the nifL promoter from Klebsiella pneumoniae: role of the -26 to -12 region in promoter function.

Nine single C-to-T transitions were introduced into the -26 to -12 region of the Klebsiella pneumoniae nifL promoter by bisulphite mutagenesis of M13 heteroduplexes containing a 15 nucleotide single-stranded loop. Mutant promoter fragments were inserted into translational lac fusion vectors to utilise beta-galactosidase activity as a measure of promoter efficiency. Mutations in invariant nucleotides found in the consensus sequence for nif promoters gave a strong 'down' promoter phenotype with respect to transcriptional activation. Mutations in semi-conserved residues had a much weaker down phenotype, whereas a mutation which increased homology to the consensus sequence enhanced promoter strength. One mutant showed increased activation by ntrC and decreased activation by nifA.

Bacterial Proteins↗
PubMed1986

Prolonged blockade of opioid effect with oral nalmefene.

In a placebo-controlled, double-blind study we evaluated the ability of a single 50 mg oral dose of nalmefene to block the effects of intravenous opioid challenge (2 micrograms/kg fentanyl). Fentanyl-induced respiratory depression (CO2 responsiveness), analgesia (tourniquet ischemia), and subjective effects were totally blocked for 48 hours and showed only minimal breakthrough 72 hours after nalmefene. Plasma concentration-time data for nalmefene indicate good oral bioavailability and a prolonged terminal elimination phase (mean t1/2 11.1 hours). These findings suggest that nalmefene could provide prolonged effectiveness in limiting emergence of opioid effects during addiction therapy.

Administration, Oral↗
PubMed1986

Nalmefene: intravenous safety and kinetics of a new opioid antagonist.

In a placebo-controlled, double-blind study we evaluated the safety and kinetics of a new narcotic antagonist, nalmefene, after 2, 6, 12, and 24 mg intravenous doses to healthy men. At each dose level four subjects received active drug and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, the most common of which was lightheadedness. The plasma concentration-time data were best fit with a triexponential equation, and the terminal elimination phase had a harmonic mean t1/2 of 8 to 9 hours. Only about 5% of the dose was excreted in the urine as intact nalmefene, with up to 60% excreted as nalmefene glucuronide. Although intersubject differences were noted, mean or dose-normalized mean kinetic parameters such as clearance, steady-state volume of distribution, terminal t1/2, and AUC showed no consistent trends related to increasing doses, indicating that nalmefene has linear pharmacokinetics.

Adult↗
PubMed1985

Site-directed mutagenesis of the Klebsiella pneumoniae nifL and nifH promoters and in vivo analysis of promoter activity.

The role of conserved nucleotides in nitrogen-fixation promoter function has been examined using both oligonucleotide and chemical mutagenesis to introduce base changes in the Klebsiella pneumoniae nifL and nifH promoters. Among ten mutations analysed, including six spontaneous mutations, base changes at -12, -13, -14, and -26, located in previously identified conserved sequences, perturbed the activity of the promoters, demonstrating that these sequences are required for transcription. Not all base changes produced similar strong promoter down phenotypes when the nifL and nifH promoters were compared: activation of the nifH promoter by the nifA gene product was less sensitive to base changes in conserved nucleotides than was activation of the equivalently altered nifL promoter by the nifA or ntrC products. We have found that the nifH promoter can be weakly activated by the ntrC product; this activation shows the same down response to base changes seen with ntrC activation of the nifL promoter. We present evidence that the efficient activation of the nifH promoter by nifA (but not ntrC) can be attributed to specific upstream sequences present in the nifH promoter.

Anti-Bacterial Agents↗
PubMed1985

Interaction of purified NtrC protein with nitrogen regulated promoters from Klebsiella pneumoniae.

The product of the Klebsiella pneumoniae nitrogen regulatory gene ntrC has been purified and shown to be a dimeric protein of subunit molecular weight 54Kd, designated NtrC. In an in vitro coupled transcription-translation system NtrC inhibited expression from both the ntrBC and glnA promoters. NtrC bound to both of these ntr repressible promoters with equal affinity, but did not bind to the activatable nitrogen fixation promoters nifF or nifLA. NtrC makes contact with nucleotides flanking the -10 region of the glnA (RNA2) promoter at sequences homologous with the proposed consensus binding site.

Bacterial Proteins↗
PubMed1985

Cardiotonic agents: a simple HPLC procedure for the quantitation of dobutamine and a new congener in plasma.

A simple high performance-liquid chromatographic procedure employing electrochemical detection (LC-EC) has been developed for the quantitation of the cardiotonic agent dobutamine and a new pharmacologically active congener. The drugs were extracted from plasma by adsorption on to alumina, eluted from the adsorbent with dilute perchloric acid and the eluate subjected to LC-EC. The method had a limit of sensitivity of 1 ng/ml of plasma for each drug. The applicability of the LC-EC procedure was demonstrated by determining steady-state plasma concentration profiles of dobutamine and its congener in man and dog, respectively, following i.v. infusion of the drugs.

Animals↗