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Biomedical subjects

J Vincent

Publications and source records attributed to J Vincent.

At least 55 records · Page 3Linked to original sources
PubMed1998

Pharmacokinetics of [18F]trovafloxacin in healthy human subjects studied with positron emission tomography.

Tissue pharmacokinetics of trovafloxacin, a new broad-spectrum fluoroquinolone antimicrobial agent, were measured by positron emission tomography (PET) with [18F]trovafloxacin in 16 healthy volunteers (12 men and 4 women). Each subject received a single oral dose of trovafloxacin (200 mg) daily beginning 5 to 8 days before the PET measurements. Approximately 2 h after the final oral dose, the subject was positioned in the gantry of the PET camera, and 1 h later 10 to 20 mCi of [18F]trovafloxacin was infused intravenously over 1 to 2 min. Serial PET images and blood samples were collected for 6 to 8 h, starting at the initiation of the infusion. Drug concentrations were expressed as the percentage of injected dose per gram, and absolute concentrations were estimated by assuming complete absorption of the final oral dose. In most tissues, there was rapid accumulation of the radiolabeled drug, with high levels achieved within 10 min after tracer infusion. Peak concentrations of more than five times the MIC at which 90% of the isolates are inhibited (MIC90) for most members of Enterobacteriaceae and anaerobes (>10-fold for most organisms) were achieved in virtually all tissues, and the concentrations remained above this level for more than 6 to 8 h. Particularly high peak concentrations (micrograms per gram; mean +/- standard error of the mean [SEM]) were achieved in the liver (35.06 +/- 5.89), pancreas (32.36 +/- 20. 18), kidney (27.20 +/- 10.68), lung (22.51 +/- 7.11), and spleen (21. 77 +/- 11.33). Plateau concentrations (measured at 2 to 8 h; micrograms per gram; mean +/- SEM) were 3.25 +/- 0.43 in the myocardium, 7.23 +/- 0.95 in the lung, 11.29 +/- 0.75 in the liver, 9.50 +/- 2.72 in the pancreas, 4.74 +/- 0.54 in the spleen, 1.32 +/- 0.09 in the bowel, 4.42 +/- 0.32 in the kidney, 1.51 +/- 0.15 in the bone, 2.46 +/- 0.17 in the muscle, 4.94 +/- 1.17 in the prostate, and 3.27 +/- 0.49 in the uterus. In the brain, the concentrations (peak, approximately 2.63 +/- 1.49 microg/g; plateau, approximately 0.91 +/- 0.15 microg/g) exceeded the MIC90s for such common causes of central nervous system infections as Streptococcus pneumoniae (MIC90, <0.2 microg/ml), Neisseria meningitidis (MIC90, <0.008 microg/ml), and Haemophilus influenzae (MIC90, <0.03 microg/ml). These PET results suggest that trovafloxacin will be useful in the treatment of a broad range of infections at diverse anatomic sites.

Adult↗
PubMed1998

Comparison of azithromycin and clarithromycin in their interactions with rifabutin in healthy volunteers.

A 14-day, randomized, open, phase I clinical trial was designed to examine possible pharmacokinetic interactions between rifabutin and two other antibiotics, azithromycin and clarithromycin, used in the treatment of Mycobacterium avium complex infections. Thirty healthy male and female volunteers were divided into five groups of six participants each: 18 received 300 mg/day of rifabutin, 12 in combination with therapeutic doses of either azithromycin or clarithromycin; the remaining 12 received azithromycin or clarithromycin alone. On day 10 the study was terminated because of adverse events, including severe neutropenia. Fourteen participants who received rifabutin developed neutropenia, including all 12 participants who received azithromycin or clarithromycin concomitantly. Analyses of serum revealed no apparent pharmacokinetic interaction between azithromycin and rifabutin. However, the mean concentrations of rifabutin and 25-O-desacetyl-rifabutin (an active metabolite) in participants who received clarithromycin and rifabutin concomitantly were more than 400% and 3,700%, respectively, of concentrations in those who received rifabutin alone. Physicians should be aware that recommended prophylactic doses of rifabutin may be associated with severe neutropenia within 2 weeks after initiation of therapy, and all patients receiving rifabutin, especially with clarithromycin, should be monitored carefully for neutropenia.

Adolescent↗
PubMed1997

Phase I pilot study of the effects of trovafloxacin (CP-99,219) on the pharmacokinetics of theophylline in healthy men.

This study examined the effect of trovafloxacin (CP-99,219) on the pharmacokinetics and pharmacodynamics of a single dose of theophylline, when administered to steady-state concentrations. Twelve healthy, nonsmoking male volunteers participated. A 450-mg dose of theophylline was administered at 7:00 AM on day 1. On day 4, volunteers received 300 mg of trovafloxacin (CP-99,219) daily in the morning for 7 days. The 450-mg dose of theophylline was repeated on day 8 at 7:00 AM concomitantly with 300 mg of trovafloxacin. Theophylline concentrations in plasma and trovafloxacin in serum were determined using reverse-phase high-performance liquid chromatography. There was no significant difference between the geometric mean values for Cmax of theophylline, 6.42 micrograms/mL and 6.00 micrograms mL on days 1 and 8, respectively. A change (P = 0.032) in the geometric mean of the area under the concentration-time curve extrapolated to infinity (AUC0-infinity) for theophylline was noted for trovafloxacin was administered. Mean terminal phase elimination rate constants (Kes) were reduced (P = 0.001) by 13% after administration of trovafloxacin from day 1 to day 8. In general, changes in theophylline clearance of less than 20% are unlikely to be of clinical significance. In this study, oral administration of trovafloxacin in 300 mg doses to achieve steady-state concentration resulted in an 8.4% increase in the extent of systemic exposure (AUC0-infinity) to theophylline. Assuming that this AUC change is based on oral clearance and not absorption, one would not expect to see clinically significant changes in the pharmacokinetics of theophylline. No pharmacodynamic changes resulted from the pharmacokinetic changes of theophylline.

Administration, Oral↗
PubMed1997

Pharmacokinetics and safety of trovafloxacin in healthy male volunteers following administration of single intravenous doses of the prodrug, alatrofloxacin.

Fifteen healthy male volunteers (in four groups) received single 1 h i.v. infusions of alatrofloxacin (CP-116,517) equivalent to 30, 100, 200 or 300 mg of its active metabolite, trovafloxacin (CP-99,219). Blood and urine were sampled over 73 and 72 h, respectively, and plasma levels of alatrofloxacin and serum concentrations of trovafloxacin were determined by HPLC with UV detection. Alatrofloxacin was not detectable in plasma samples collected after the end of infusion, indicating rapid conversion to trovafloxacin. Maximum serum concentrations of trovafloxacin were achieved at the end of the infusions. Mean maximum plasma trovafloxacin concentrations for the four alatrofloxacin doses were 0.4, 1.8, 2.3 and 4.3 mg/L. The mean area under the concentration-time curve increased proportionally with the dose. The elimination half-life (T(1/2)) for trovafloxacin was independent of the dose and the mean T(1/2)s for the 100, 200 and 300 mg equivalent doses of alatrofloxacin were 10.4, 12.3 and 10.8 h. Approximately 10% of the equivalent dose was recovered as unchanged trovafloxacin in the urine. No clinical adverse or laboratory reactions were associated with i.v. administration of alatrofloxacin and its conversion to trovafloxacin. These results indicate that alatrofloxacin is rapidly converted to trovafloxacin and that the pharmacokinetic parameters for this new fluoroquinolone after i.v. administration of its parent compound are similar to those reported after oral administration of equivalent trovafloxacin doses.

Adult↗
PubMed1997

Effect of trovafloxacin, a new fluoroquinolone antibiotic, on the steady-state pharmacokinetics of theophylline in healthy volunteers.

Some fluoroquinolone antibiotics interfere with theophylline clearance, thereby raising concentrations of circulating theophylline and increasing the potential for toxicity. The effect of steady-state serum concentrations of the new fluoroquinolone trovafloxacin on the steady-state pharmacokinetics of theophylline was examined in 12 healthy male volunteers. For 7 days, the subjects received morning and evening theophylline doses adjusted to achieve steady-state plasma concentrations of 8-15 mg/L, the lower end of the therapeutic range. From day 8 to day 15, six volunteers received, in addition to theophylline, 200 mg of trovafloxacin in the morning and placebo in the evening (group A) and six received placebo twice daily (group B). Serial plasma samples obtained over 12 h and 60 h after the morning theophylline dose on days 7 and 14, respectively, were analysed for theophylline by HPLC with UV detection. There were no significant differences in mean Cmax or AUC(0-12) between the two groups on day 7 or on day 14, nor were there significant within-group differences on the two days. On day 14, mean Cmax, AUC(0-12) and T(1/2) (measured on day 14 only) in group A were 10.15 mg/L, 107.32 mg x h/L and 9.0 h, respectively. In group B, the values were 10.81 mg/L, 113.73 mg x h/L and 8.3 h, respectively. The study drugs were well tolerated, and no clinically significant changes in vital signs or laboratory test values were noted. We conclude that steady-state concentrations of trovafloxacin have no clinically significant effect on the steady-state concentrations of theophylline within the therapeutic range in healthy subjects.

Adult↗
PubMed1997

Oral bioavailability of trovafloxacin with and without food in healthy volunteers.

Two studies determined the oral bioavailability of trovafloxacin (CP-99,219) in healthy volunteers under fasted and fed conditions. In a randomized, two-way crossover study, 12 fasting subjects received two 100 mg tablets of trovafloxacin and an equivalent dose of alatrofloxacin (CP-116,517), administered by i.v. infusion over 1 h. Alatrofloxacin, the L-Ala-L-Ala prodrug of trovafloxacin, is rapidly converted in the body to trovafloxacin. After the oral dose of trovafloxacin, the mean Cmax and AUC were 2.2 mg/L and 30.4 mg x h/L, respectively. After the infusion of alatrofloxacin, the Cmax and AUC of trovafloxacin were 3.2 mg/L and 34.7 mg x h/L, respectively. The mean T(1/2) after both treatments was about 11 h. The mean Cl and Vd(ss) of trovafloxacin after the infusion of alatrofloxacin were 1.32 mL/min/kg and 1.13 L/kg, respectively. The mean oral bioavailability of trovafloxacin was estimated to be 87.6% (range 64.8-122.1%). Another randomized, open, three-way crossover study was conducted in 12 healthy male volunteers to investigate the effect of food in the gastrointestinal tract on the bioavailability of trovafloxacin. Each subject received three 100 mg tablets after fasting overnight (treatment A) or after a standard breakfast (treatment B), or 300 mg as oral aqueous suspension after fasting overnight (treatment C). Mean Tmax after treatment B occurred 2.2 h later (3.6 h vs 1.4 h) than after treatment A. Mean Cmax and AUC were 2.3 and 2.6 mg/L and 38.2 and 39.5 mg x h/L after B and A, respectively. About 5% of the administered dose was recovered unchanged in the 24 h urine sample after all three treatments. Thus, the food reduced mean Cmax by 12% but had no appreciable effect on mean AUC. The mean bioavailability of trovafloxacin administered as treatment regimen B was 96.6% relative to that of treatment A. The respective mean bioavailabilities of trovafloxacin as treatments B and A were 91.3% and 94.5% respectively of that of treatment C. The results of these studies indicate that trovafloxacin has good oral bioavailability and that the ingestion of food is unlikely to have a clinically significant effect on the bioavailability of trovafloxacin.

Administration, Oral↗
PubMed1997

Effect of Maalox and omeprazole on the bioavailability of trovafloxacin.

To determine the effect of the concurrent administration of Maalox and omeprazole in the bioavailability of trovafloxacin (CP-99,219), an open, placebo-controlled, randomized, four-way crossover study was conducted in 12 healthy male volunteers. Each received treatments of three 100 mg trovafloxacin tablets in the morning 30 min after 30 mL of Maalox (A), 30 min after placebo (B), 2 h before 30 mL of Maalox (C) and 2 h after 40 mg of omeprazole (D). For treatments A and C, Maalox was also given at 22.00 h the night before the study day, 1 and 3 h after meals and at bedtime on the study day. For B and D, placebo and omeprazole, respectively, were also given at 22.00 h the night before the study day. After treatments A and C, mean area under the curve (AUC) was reduced by 66% and 28% (14.2 and 30.2 mg.h/L), respectively, and mean T(1/2) declined by 33% and 31% (8.3 and 8.5 h), respectively, relative to the values after B (42.1 mg.h/L; 12.4 h). The mean Kel-corrected relative bioavailabilities for A and C were 50% and 104%, respectively, suggesting a large reduction in the initial absorption of trovafloxacin with A. Treatment D had no appreciable effect on mean T(1/2) but mean AUC and Cmax were reduced by 18% and 32%, respectively, relative to B. The mean relative bioavailability after D was 82%. We conclude that the concurrent administration of trovafloxacin and aluminium- and magnesium-containing antacids should be avoided but that co-administration with omeprazole is unlikely to have a clinically significant effect on the extent of absorption of the antibiotic.

Adult↗
PubMed1997

Penetration of trovafloxacin into cerebrospinal fluid in humans following intravenous infusion of alatrofloxacin.

A single-dose study was conducted to determine concentrations of trovafloxacin (CP-99,219) achieved in the cerebrospinal fluid (CSF) relative to those in the serum of healthy subjects after intravenous infusion of alatrofloxacin (CP-116,517), the alanyl-alanyl prodrug of trovafloxacin. Twelve healthy subjects were administered single doses of alatrofloxacin at a trovafloxacin equivalent of 300 mg as an intravenous infusion over 1.0 h. CSF samples were taken by lumbar puncture at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 24 h after the start of the infusion; each subject was sampled at only one time point. Serum samples were taken from each subject at the time of CSF collection. A mean concentration of 5.8 microg of trovafloxacin per ml was present in serum 1.0 h after the start of the infusion. CSF/serum ratios ranged from 0.14 to 0.33 in the postdistribution phase (5 to 24 h postinfusion), with a mean ratio of 0.25. The most common adverse events were dizziness, nausea, and rash and were mild or moderate in intensity. The potency of trovafloxacin against susceptible organisms, coupled with its rapid penetration of CSF following the intravenous administration of alatrofloxacin, suggests that it may be useful in the treatment of bacterial meningitis in humans.

Adolescent↗
PubMed1997

Excretion and metabolism of trovafloxacin in humans.

The metabolism and excretion of trovafloxacin was investigated in four healthy male volunteers after a single oral administration of 200 mg of [14C]trovafloxacin (118 microCi). Mean values of 23.1 and 63.3% of the administered dose were recovered in the urine and feces, respectively, after 240 hr. The Cmax of total radioactivity and unchanged trovafloxacin in serum was 3.2 micrograms-equiv/ml and 2.9 micrograms/ml, respectively, and peaked in 1.4 hr. The mean AUC0-infinity for radioactivity and trovafloxacin was 58.2 micrograms-eq.hr/ml and 32.2 micrograms.hr/ml, respectively. This implied that unchanged trovafloxacin constituted 55% of the circulating radioactivity. Urine and fecal samples were analyzed by LC/MS/MS for characterization of the metabolites, and the quantity of each metabolite in the matrices was assessed by means of a radioactivity detector. The profile of radioactivity in urine showed three main metabolites that were identified as the trovafloxacin glucuronide (M1), N-acetyltrovafloxacin glucuronide (M2), and N-acetyltrovafloxacin (M3). The major fecal metabolites were M3 and the sulfate conjugate of trovafloxacin (M4). Analysis of circulating metabolites from pooled serum extracts obtained at 1, 5, and 12 hr indicated that M1 was the major circulating metabolite (22% of circulating radioactivity), whereas M2 and M3 were detected in minor amounts. The results of the present study revealed that oxidative metabolism did not play a significant role in the elimination of trovafloxacin, and phase II conjugation was the primary route of trovafloxacin clearance in humans.

Administration, Oral↗
PubMed1996

18F-labeling and biodistribution of the novel fluoro-quinolone antimicrobial agent, trovafloxacin (CP 99,219).

[18F]CP 99,219 [(1 alpha, 5 alpha, 6 alpha)-7-(6-amino-3-azabicyclo [3.1.0]hex-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid] was prepared by 18F for 19F exchange followed by reverse-phase HPLC purification. Studies of the effects of reaction time and temperature on 18F incorporation demonstrated that heating 1.0 mg of CP 99,219 in 0.5 cc of DMSO with 4.5 mg of K2CO3 and 24 mg of Kryptofix for 15 min at 160 degrees C results in the optimal compromise between radiochemical yield and purity. This method routinely provides radiochemical yields of 15-30% [EOS] with radiochemical purities of > 97%. Varying the concentration of CP 99,219 in the reaction mixture had no effect on yield. Biodistribution studies in rats demonstrated that significant concentrations of drug accumulate in most tissues. The tissues with the highest concentrations of drug were intestine, liver, kidney, and stomach.

Animals↗
PubMed1996

Assessing pre-procedural subgingival irrigation and rinsing with an antiseptic mouthrinse to reduce bacteremia.

In this controlled clinical study, the authors examined the effect of subgingival irrigation and rinsing with an antiseptic mouthrinse before ultrasonic scaling of a quadrant containing inflamed gingivae. The results showed that pre-procedural subgingival irrigation and rinsing can significantly reduce the level of bacteremia associated with ultrasonic scaling. These results support the American Heart Association's recommendation of adjunctive subgingival irrigation prior to invasive procedures in patients at risk of developing bacterial endocarditis.

Adult↗
PubMed1995

[Metastatic pulmonary choriocarcinoma and pulmonary arteriovenous aneurysm].

Pulmonary metastases from a uterine choriocarcinoma are rare in France. The authors report a case of a 42 years old patient who presented more than four years after her last pregnancy with a metastasis in the left lower lobe due to a uterine choriocarcinoma. There was a favourable outcome after combined treatment with chemotherapy and surgery. The patient had been in hospital eighteen months earlier for a spontaneous left haemothorax secondary to a ruptured intrapleural pulmonary arterio-venous aneurysm (AVV) of the left lower lobe which was treated by embolisation. The aetiology of pulmonary AVV are defined, and the pathophysiology of uterine carcinoma as well as the probable association and pulmonary vascular anomalies are discussed.

Adult↗
PubMed1994

Oligonucleotides as short as 7-mers can be used for PCR amplification.

Amplification of DNA sequences using the polymerase chain reaction (PCR) requires as primers two oligonucleotides, which are carefully designed for length and G/C content. Such primers are generally between 18 and 30 bases long so that the primer sequences can amplify a unique sequence in the target genome; they should possess a minimal degree of secondary structure. We have tested the minimum length of G/C-rich and palindromic oligonucleotides to be used as primers in PCR. Oligonucleotides with sequences corresponding to the recognition sites of rare restriction enzymes were used on the DNA of vector constructs as model template DNA. Surprisingly, we found specific amplification with a low background over a wide range of temperatures for oligonucleotides as short as 7 nucleotides. This findings contradicts the previously reported empirical relationship between oligonucleotide length and ability to trigger amplification and points to the complex relationship between thermodynamic and kinetic criteria in relation to PCR. This technique should lead to new application in the cloning and screening of complex genomes.

Base Sequence↗