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Biomedical subjects

P Ardouin

Publications and source records attributed to P Ardouin.

At least 19 recordsLinked to original sources
PubMed1994

Verapamil-reversing concentrations induce blood flow changes that could counteract in vivo the MDR-1-modulating effects.

BACKGROUND: Intraarterial hepatic (IAH) administration of verapamil should achieve mdr-1-reversing concentrations with reduced cardiac toxicity. The authors have explored the tolerance of its IAH administration and its effects on doxorubicin pharmacodymamics. METHODS: Verapamil was given to rabbits by intravenous or IAH administration, and its effects on heart rates were compared. Doxorubicin then was given intravenously either with IAH verapamil or with an IAH control perfusion, and tumor and liver drug concentrations were determined. Hepatic blood flow changes were studied by the administration of 99mTc-albumin macroaggregates (99mTc-MAA) under verapamil IAH perfusions. RESULTS: Compared with the intravenous route, IAH administration of verapamil was not toxic, and cardiac effects were reduced significantly. Its effect on doxorubicin distribution was detrimental, because the tumor-liver doxorubicin concentration ratios were lower in the verapamil group (0.23 vs. 3.37; P < 0.05). Tumor doxorubicin concentrations were lower when verapamil was coinfused (43 vs. 573 ng/100 mg tissue; P < 0.05). In normal liver tissue, increased amounts of doxorubicin and metabolites were observed. The verapamil IAH perfusions with 99mTc-MAA confirmed a differential action on tumor and normal vessels; the distribution of radionuclide was diverted away from the tumor bed significantly when verapamil was administered (tumor-to-liver ratio of 25.3 control rabbits vs. 5.99 rabbits who received verapamil; P < 0.05). CONCLUSIONS: Reversing the concentrations of verapamil provoked changes in the distribution of the liver blood flow. The hemodynamic effects of verapamil regional perfusions could counteract in vivo its potential mdr-1-reversing properties.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Oral diclofenac combined with intra-portal pirarubicin: increased efficacy on liver VX2 tumour and hepatotoxicity in rabbits.

VX2 is a carcinoma established in rabbits and producing an autocrine growth factor, prostaglandin E2. Pirarubicin is a potent anti-VX2 agent. We investigated whether the oral intake of enprostil--a synthetic prostaglandin E2--or of diclofenac--a potent non-steroidal anti-inflammatory drug--increases the efficacy and decreases the hepatotoxicity of pirarubicin when injected in the portal trunk. Enprostil increased the number of hepatic tumoral nodules and induced hepatic alterations, especially venous dilatation. Paradoxically the combination of enprostil and pirarubicin was at least as effective as pirarubicin or diclofenac on VX2 cells. However, the toxicity was increased, especially with respect to sclerosing cholangitis. Diclofenac proved to be as effective as pirarubicin, and the addition of oral diclofenac to local pirarubicin injection increased its antitumoral effect (P < 0.02). However, the combination of diclofenac and pirarubicin was more toxic than pirarubicin alone and induced centrolobular necrosis and sclerosing cholangitis.

Administration, Oral↗
PubMed1993

Pharmacokinetic and pharmacodynamic advantages of pirarubicin over adriamycin after intraarterial hepatic administration in the rabbit VX2 tumor model.

Intraarterial chemotherapy with Adriamycin (ADM) has shown limited advantages over i.v. administration, with no reduction in systemic toxicities and modest decrease in peripheral plasma levels. In an effort to improve the selectivity of i.a. anthracycline chemotherapy, we compared pirarubicin (4'-O-tetrahydropyranyladriamycin, THP) and ADM in the surgically implanted VX2 rabbit tumor model. Both drugs were administered at the same dose (0.5 mg/kg) either by the intraarterial hepatic route (i.a.h.) or by the i.v. route. Anthracycline plasma and tissue levels were determined by high-performance liquid chromatography with fluorescence detection. ADM peak plasma concentration and area under the curve were not significantly reduced after i.a.h. administration compared to the i.v. route; however, ADM tumor concentration was 1.9-fold higher following i.a.h. administration compared to the i.v. infusion. After THP administration by the i.a.h. route, systemic exposure (area under the curve) was markedly reduced (8-fold) compared to the same dose administered i.v. These findings correlated well with the very low concentration of the drug in heart tissue following i.a.h. infusion. After i.a.h. administration, tumor THP concentrations were 10.5 times higher compared to the i.v. route. The pharmacokinetic advantage of i.a.h. administration of THP also led to a better antitumoral effect, as shown by a significantly lower tumor growth rate [3 +/- 2% (SD)] in the i.a.h.-treated animals compared to the i.v.-treated groups (58 +/- 9%). Administration of ADM by the i.a.h. route was also inferior to i.a.h. THP. Taken together, our results suggest a clear-cut advantage of THP over ADM for i.a.h. locoregional chemotherapy, because of higher local tumor concentrations, greater antitumoral effect, and lower systemic exposure following the i.a.h. administration of THP. This anthracycline analogue could also be of therapeutic advantage in tumors partially resistant to anthracyclines that would become vulnerable to the high local concentrations achieved with i.a.h. administration. Based on these encouraging results, clinical trials using THP administered by the i.a.h. route were initiated.

Animals↗
PubMed1993

Pharmacology and antitumour effects of intraportal pirarubicin on experimental liver metastases.

Early liver metastases have a predominant portal blood supply. Intraportal (i.port.) vein administration of cytotoxics could theoretically achieve enhanced drug concentrations in tumour cells and be effective as adjuvant therapy after resection of colorectal carcinoma. Pirarubicin (which has a higher hepatic extraction than doxorubicin) was investigated on liver metastases of the VX2 rabbit tumour, which were of less than 2 mm in diameter 7 days after cells injection into the portal vein. To evaluate antitumour activity, 24 rabbits were randomised into three groups 7 days after implantation: (a) control, (b) i.v. pirarubicin, (c) i.port. pirarubicin at doses of 2 mg kg-1 in both groups. Portal infusions led to no hematological or hepatic toxicity. Pharmacokinetic parameters showed a significantly reduced systemic exposure after i.port. administration. Fourteen days after treatment, livers and lungs were analysed. The mean number (+/- s.d.) of tumour foci was (a) 8.62 (+/- 5.4), (b) 4.62 (+/- 3.2), (c) 2.25 (+/- 1.4) (P < 0.05 a vs c). The mean tumour area was (a) 6.31 (+/- 6.1), (b) 1.31 (+/- 2.2), (c) 0.43 (+/- 0.4 cm2) (P < 0.05 a vs c) and the percentage (95% C.I.) of rabbits with lung metastasis was: (a) 87.5% (47-99%), (b) 75% (35-97%), (c) 12.5% (3-52%) (P < 0.02 b vs c). Intraportal pirarubicin seems to be well tolerated and more efficient than i.v. administration, particularly in preventing extrahepatic dissemination.

Animals↗
PubMed1985

Radioprotection of EMT6 tumor by a new class of radioprotectors based on a pseudo-peptide cysteamine combination.

Although WR-2721 preferentially protects normal tissues against irradiation, it seemed desirable to find other drugs presenting a lower toxicity and the same radioprotective properties. A new compound, I 102, was selected; it was characterized on one hand by a coupling between cysteamine and an amino-acid, and on the other hand by an acetyl-group, which protects the thiol function. The effects of WR-2721 and of I 102 were studied on EMT6 tumors grafted on BALB/c mice. Whatever the size of the tumor, the cell survival increased as a function of the time elapsed between the injection of I 102 and the end of the irradiation (TI). In contrast, the radioprotection afforded by WR-2721 was found to be independent of TI. The survival curves suggest that, like WR-2721, I 102 protects essentially oxygenated cells.

Amifostine↗
PubMed1981

Developmental aspects of pteridine metabolism and relationships with phenylalanine metabolism.

Large variations of pteridine elimination occur in childhood, due to the ontogenic development of the metabolism of tetrahydrobiopterin. The main feature is the slow maturation of biopterin synthesis whereas neopterin synthesis is high at birth; thus a high neopterin to biopterin ratio (4.4 +/- 2.1) occurs in the neonatal period, a ratio which then decreases to adult values (0.5 +/- 0.2). Comparing pteridine elimination of PKU patients with that of controls of the same age, a high excretion of biopterin and, to a lesser extent, of neopterin is found. In normal subjects, following an oral phenylalanine load, biopterin levels in urine and serum also increase, whereas variations of neopterin concentration are small. In rats, phenylalanine also leads to an increase of serum biopterin whereas liver biopterin decreases. This suggests that the main explanation for the biopterin increase in serum and in urine by phenylalanine is a release of the intracellular biopterin by the aminoacid.

Adolescent↗
PubMed1981

Diagnosis of variants of hyperphenylalaninemia by determination of pterins in urine.

Assessment of urinary pterins is proposed as a rapid method for recognition of the variants of hyperphenylalaninemia. This is achieved by means of oxidation of pterins by iodine in acidic and alkaline solutions and then by high performance liquid chromatography on a cation-exchange column with fluorimetric detection. In biopterin-synthetase deficiency, only neopterin accumulated; in dihydropteridine-reductase (DHPR) deficiency and in phenylketonuria, high levels of pterins are found, but BH4 levels, absent in the former and high in the latter, allow a differential diagnosis. Phenylalanine loads in the controls also lead to increased elimination of pterins, but with a pattern different from that found in phenylketonuria. This method can be used before dietary treatment and thus can be proposed for all newly detected hyperphenylalaninemic babies.

Adolescent↗
PubMed1981

Pterin metabolism in normal subjects and hyperphenylalaninaemic patients.

The application of high performance liquid chromatography to the estimation of urinary pterins is illustrated by results from normal subjects and from patients with phenylketonuria, dihydropteridine reductase deficiency and biopterin synthetase deficiency. In normal subjects following a phenylalanine load the is a temporary increase in pterin elimination, the pattern being different to that seen in chronic hyperphenylalaninaemia.

Adult↗
PubMed1978

[Diagnosis and management of the aminoacidopathies (author's transl)].

Since its description by Garrod, the concept of the "inborn errors of metabolism" has become a clinical reality that the physician cannot ignore. The aminoacidopathies represent a group historically notable in that they represent the first diseases recognized as metabolic in origin (alcaptonuria, albinism) and for which some measure of therapeutic success can be claimed. Dietary prophylaxis of the encephalopathy of phenylketonuria is a prominent example. Much progress has been made in the understanding of the aminoacidopathies that touch upon aspects as diverse as semiological study and prevention by pre- and neo-natal diagnosis. This brief overview presents the basic clinical, biochemical, genetic, physiopathological and therapeutic principles of these diseases. It provides representative examples of the diagnostic approach and draws particular attention to the need and the role of cross-disciplinary teamwork in the diagnosis and continuing care of the patient. While we wait for new methods of genetic correction, the main goal must be to prevent the clinical consequences of the metabolic defect.

Amino Acid Metabolism, Inborn Errors↗
PubMed1969

Patient identification for computer data linkage.

To permit linkage of computerized patient data obtained from different sources, a universal and efficient method of patient identification is necessary. A coding system of 16 characters with a high degree of discrimination is proposed. The first five characters code the individual's family name, the next four his given name; the next six digits are his date of birth expressed in day, month and year; and the last character codes his sex. This system, using readily available patient information, is simple to manipulate and generates codes that are also medically informative. When this method of identification was tested on a list of 18,000 persons, no identical codes were found.

Canada↗