Molecular aspect of HIV-1 resistance to zidovudine and its reversal.
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Biomedical subjects
Publications and source records attributed to M C Bigot.
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The development of chromatography technology, with the increasing availability of easier-to-use mass spectrometers combined with gas chromatography (GC), the use of diode-array or programmable variable-wavelength ultraviolet absorption detectors in conjunction with high-performance liquid chromatography (HPLC), and the availability of scanners capable of reading thin-layer chromatography (TLC) plates in the ultraviolet and visible regions, has made for easier, quicker and more positive identification of cannabis samples that standard analytical laboratories are occasionally required to undertake in the effort to combat drug addiction. At laboratories that do not possess the technique of GC combined with mass spectrometry, which provides an irrefutable identification, the following procedure involving HPLC or TLC techniques may be used: identification of the chromatographic peaks corresponding to each of the three main cannabis constituents-cannabidiol (CBD), delta-9-tetrahydrocannabinol (delta-9-THC) and cannabinol (CBN)-by comparison with published data in conjunction with a specific absorption spectrum for each of those constituents obtained between 200 and 300 nm. The collection of the fractions corresponding to the three major cannabinoids at the HPLC system outlet and the cross-checking of their identity in the GC process with flame ionization detection can further corroborate the identification and minimize possible errors due to interference.
Nine patients with supraventricular rhythm disorders were treated during 5-day periods with different oral doses (300, 450, 600, and 900 mg daily) of propafenone concomitantly to long-term digoxin treatment. A poor correlation (r = .398; P less than .05) was obtained when the difference between the mean digoxin serum level (calculated with the Cmin data determined each of the 5 days) observed during a given propafenone dose and the mean digoxin serum level observed before propafenone treatment, was correlated with the dose of propafenone; but an evident correlation (r = .778; P less than .01) was found when the difference in digoxin level was correlated with the plasma propafenone concentration. The propafenone effect of increasing digoxin blood levels was thus concluded to be poorly dose dependent but strongly concentration dependent. The association of propafenone to a long-term digoxin treatment can be considered with a low risk of toxicity when plasma propafenone concentration does not exceed about 1000 ng/mL. Propafenone plasma levels are unpredictable in view of their wide interindividual variation for a given dose, so their measurement is advised to detect high levels and consequently to prevent a rise in digoxin serum concentrations with the possibility of toxicity. In clinical practice, when propafenone concentration determinations are not readily available, digoxin serum levels at least have to be carefully monitored.
Patients (n = 14) who underwent thoracotomy during surgery of the oesophagus for cancer received an initial intrapleural dose of 10 ml bupivacaine hydrochloride 2.5 mg/ml followed by repeated administration every 8 hours from the first to the fourth postoperative day. The mean (+/- SD) peak plasma drug concentration (Cmax) [352 +/- 120 micrograms/L], time to peak (tmax) [0.83 +/- 0.51 h], and first-order absorption rate constant (ka) [5.46 +/- 4.95 h-1] after the twelfth dose were significantly different from the Cmax (206 +/- 81 micrograms/L), tmax (1.8 +/- 1.2h), and ka (1.8 +/- 1.47 h-1) determined after the first dose. Half-life (3.5 +/- 2.2h) and mean concentration (204 +/- 105 micrograms/L) were not significantly different on the fourth day from those on the first (4.1 +/- 2.6h and 142 +/- 71 micrograms/L, respectively). No sharp peak corresponding to systemic toxicity and no accumulation could be expected with these low doses, administered at short intervals and providing good pain relief in this surgical series.
The pharmacokinetics of fluconazole given orally (100 mg) or intraperitoneally (50 and 150 mg) were determined in 15 patients with chronic renal failure who were undergoing continuous ambulatory peritoneal dialysis. The half-life (72 to 85 hours) was intermediate between values obtained in healthy volunteers and in patients with renal insufficiency studied during an interhaemodialysis period. The peritoneal clearance, 0.26 to 0.33 L/h, led to an 18% recovery of administered drug in the dialysates after 48 hours. The peritoneal absorption was slow (time to peak plasma concentration 7 hours) but the peritoneal bioavailability was excellent at 87 +/- 5%. The mean concentrations of fluconazole up to 24 hours were 770 and 1900 micrograms/L after single intraperitoneal doses of 50 and 150 mg, respectively. The volume of distribution (40 to 60 L) did not differ from that determined in patients with normal renal function. In the case of fungal peritonitis essentially attributed to Candida spp., a 6-hour intraperitoneal infusion of fluconazole 150 mg every 2 days appears to be a good regimen to rapidly exceed minimum inhibitory concentrations and treat infection without risk of systemic dissemination of fungi or toxicity.
Single dose disposition of oral quinidine (400 mg sulfate) was studied in a control group of subjects (No. = 6) and in hospitalized alcoholic patients involving one group with (No. = 6) and one group without (No. = 11) hepatic cirrhosis. All subjects also underwent an antipyrine and a debrisoquine test. Patients with cirrhosis had a prolonged elimination half-life (29.5 +/- 5.9 h) and low clearance (24 +/- 7 ml.kg-1.h-1) of antipyrine and also a considerably higher debrisoquine metabolic ratio (18.8 +/- 3.3) than the controls, whereas the alcoholics without cirrhosis had metabolic patterns for these two test compounds comparable to those seen in the controls (antipyrine half-life: 8.8 +/- 1.1 h and 9.8 +/- 2.0 h; debrisoquine metabolic ratio: 3.6 +/- 0.7 and 3.8 +/- 1.2 for alcoholics and controls respectively). In patients with cirrhosis the apparent elimination half-life of quinidine was longer (12.8 +/- 1.8 h) whereas after oral administration clearance of quinidine (15.6 +/- 3.5 l.h-1) and quinidine/3-hydroxyquinidine ratio (9.9 +/- 2.1) were not different from controls (quinidine clearance: 13.45 +/- 1.9 l.h-1; quinidine/3-hydroxyquinidine: 10.3 +/- 2.7). A possible change in distribution patterns of quinidine in cirrhotics may explain these findings.
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Fluconazole concentrations in biological fluids were determined by high-performance gas chromatography. A simple extraction procedure with chloroform, under basic conditions and after the addition of UK-47,265 as the internal standard and with no evaporation stage, was carried out prior to analysis. A solid injector and a 15-m capillary column, coated with a nonpolar phase and connected to a nitrogen-selective detector that afforded an excellent selectivity and sensitivity, constituted the gas chromatographic system. The duration of each analysis was less than 4 min and the minimum detectable serum concentration was 50 ng/mL. In five patients undergoing chronic peritoneal dialysis, the mean serum concentrations +/- SD at 1, 6, and 48 h after the intraperitoneal administration of a single dose of fluconazole were, respectively, 325 +/- 75, 928 +/- 159, and 607 +/- 80 ng/mL.
It has been established that the use of beta-2 sympathomimetic aerosols is a safe and efficacious treatment of asthma. Unexpected cases of sudden death amongst insufficiently-treated patients or patients who stopped their treatment are not linked with the use of these drugs. To assess the risk of possible "receptor desensitization" it is necessary to notify these accidents to the Committee on Safety of Drugs and to take into consideration the opposite results of further administration and termination of treatment.
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Fifteen asthmatic patients receiving a sustained-release theophylline preparation were also treated with spiramycin for at least 5 days. The macrolide antibiotic had no significant effect on the steady-state theophylline concentration, unlike erythromycin and troleandomycin, which belong to the same class of antibiotics. The latter two drugs have different chemical structures and decrease theophylline clearance. Accordingly, spiramycin comedication does not require special serum level drug monitoring or adjustment of the dose of theophylline.
A high-performance liquid chromatographic method is described which determines noxytiolin and 1-methyl-2-thiourea concentrations in serum. Valid determination requires immediate ultracentrifugation of blood samples, rapid serum freezing, and injection into the chromatograph within 6 h. A number of pharmacokinetic parameters were calculated from serum concentration data in rabbits and humans. An unknown metabolite was detected in both species but its structure was not identified.
Prilocaine pharmacokinetics were determined in 60 patients receiving the drug by two different routes of administration (intra-articular and subcutaneous) during arthroscopy under local anesthesia with controlled pressure irrigation. Resorption of prilocaine by subcutaneous tissues was slow and did not lead to high serum levels. On the contrary, prilocaine resorption by the synovium was fast and induced a sharp serum peak (265.8 +/- 163.5 ng/ml) in the hour after the end of the examination. The drug was completely eliminated from the blood after 24 hours, as the prilocaine t1/2 is about 5 hours. The first procedure was perfected to reduce the risk of methemoglobinemia, which occurred in four of 105 patients. Applied pressure was lowered to 100 mm Hg to prevent the escape of anesthetic solution into the soft tissue of the leg, the prilocaine concentration was reduced to 1 gm/L, and the arthroscope was only set up after a delay to allow the intra-articular anesthetic effect of prilocaine to become established. So far, 200 arthroscopies have been performed with this improved protocol without any problem.
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Haloperidol serum concentrations were determined after IM or oral treatment in 15 schizophrenic patients. No correlation was found between drug levels and therapeutic effect. However, a good relationship was found between the half-life calculated after the first IM injection and the BPRS decrease after 3 weeks. Therefore a serum level study to the first day may forecast the therapeutic response.
The combined use of high-pressure liquid chromatography (HPLC) and high-resolution gas-liquid chromatography (GLC) afforded a means of isolating three substances in samples of cannabis, of determining their retention times in HPLC and in GLC with and without derivation, and of identifying them, by comparison with the data in the literature, with the three major constituents of cannabis: cannabidiol (CBD), delta-9-tetrahydrocannabinol (delta-9-THC) and cannabinol (CBN), without using either control substances or a mass spectrometer. Furthermore, calculation of the peak area ratios (formula: see text); for the different sample varieties can serve as a criterion for the differentiation of resinous cannabis and textile cannabis.
The selectivity and sensitivity provided by a wall-coated open tubular column coupled with a nitrogen-selective detector allowed rapid, accurate determination of diazepam, meprobamate, phenylbutazone, and thioridazine in serum in the same chromatographic system using 100--200 microliters of sample.