Design of lifting gear for a plastination laboratory.

Conventional lifting gear based on steel components can be safely used in a laboratory where acetone is used provided that: (a) the circumstances under which significant amounts of acetone vapour will be present are known and can be controlled and (b) operating practices are imposed to prevent the use of the lifting gear at times when acetone vapour may be present in explosive concentrations.

Measurement of the T2 relaxation time of ethanol and cerebral metabolites, in vivo.

The SPACE volume selection technique was combined with a spin-echo sequence to measure the transverse relaxation time of the resonances of ethanol and cerebral metabolites in the dog brain, in vivo. The method was extended to measure brain metabolite T2 values in the rat using 1H NMR microspectroscopy. The T2 decays for the resonances of the metabolites N-acetylaspartate, creatine/phosphocreatine, and choline/phosphorylcholine were found to be biexponential with long T2 components of 490, 260, and 350 ms for the dog and 490, 220, and 355 ms for the rat brain, respectively. The existence of a second T2 component may originate from J-coupled nonresolved metabolite resonances. The relaxation decay for the ethanol triplet could be fitted to a single exponential giving a T2 relaxation time of 335 ms. However, given the large errors in the measurement of ethanol peak intensities at short echo times because of overlapping lipid signal and the effects of J-modulation, a biexponential decay with a long T2 component of 335 ms cannot be ruled out. Ambiguities regarding the reported partial detection of the 1H NMR signal of ethanol in the brain are discussed.

Oral administration of [3H]navelbine in patients: comparative pharmacokinetics using radioactive and radioimmunologic determination methods.

[3H]Navelbine (NVB) was administered orally to two patients. Drug levels in biological fluids were monitored by radioimmunoassay (RIA) and direct radioactivity (RA) determinations. NVB absorption was rapid: maximum plasma concentrations appeared in the first 2 h after oral administrations. Pharmacokinetic parameters estimated from RIA data were in complete accordance with those obtained from i.v. injections. Bioavailability (i.v./po) estimated from RIA and RA data averaged 40.6 and 93.0%, respectively. NVB urine excretion was low. Fecal excretion remained its main elimination route. Moreover, large differences were observed in area under NVB plasma concentration-time curve (AUC) values obtained by the two methods, implying intense drug bio-transformations.

The visibility of the 1H NMR signal of ethanol in the dog brain.

In vivo, high-resolution, volume-selected 1H NMR spectroscopy was used to monitor the concentration of ethanol in the dog brain following intravenous injection of ethanol. Equilibration of ethanol in the body water should result in approximately equivalent concentrations of ethanol in the blood and brain. However, the mean equilibrium brain ethanol concentration determined using N-acetylaspartate as an internal standard was only 23 +/- 5% of the blood ethanol concentration. The disparity between blood and brain ethanol concentrations was attributed to underestimation of the ethanol concentration due to overlapping resonances with NAA and to T2 attenuation or possible nondetection of the 1H signal from ethanol bound at the surface of cell membranes and partitioned into the hydrophobic core of membrane lipids.

Pharmacokinetics of navelbine after oral administration in cancer patients.

The pharmacokinetic behavior of navelbine was investigated in 19 patients presenting with advanced cancers (mainly women with breast cancer). Navelbine was given orally at seven dose levels of up to 200 mg/week. For a given dose, patients received four successive weekly treatments. Five subjects also received two different doses. After drug administration, plasma was collected for 48 or 72 h and monitored for navelbine concentration by radioimmunoassay. Absorption of navelbine was very rapid after oral administration: maximal drug concentrations were reached within the first 1 or 2 h (Tmax, 0.9-1.75 h; cmax, 70.9-832.6 ng/ml), with absorption constants ranging from 0.85 to 2.42 l/h. A comparison of dose-normalised plasma concentration profiles revealed significant time dependence in six evaluable patients (P less than 0.001). Only four subjects who received low doses (less than or equal to 100 mg/week) exhibited time-independent kinetics. All of the five patients who were treated at different doses displayed apparent dose dependence (P less than 0.001). No individual profile was characterised by both time- and dose-independent pharmacokinetics. In all, 18 patients presented biphasic plasma concentration-decay patterns, and only 1 subject exhibited monophasic decay kinetics. The navelbine pharmacokinetic parameters obtained following oral administration were similar to those observed after i.v. bolus injection and were characterised by high oral clearance (0.43-1.45 1 h-1 kg-1), a large apparent volume of distribution (27.4-45.9 1/kg), and a long terminal half-life (24.2-56.5 h). Large intra- and inter-individual variations in pharmacokinetic parameters were observed. Moreover, after a high dose of 200 mg, an enterohepatic cycle and/or a delay in navelbine's absorption at a distal intestinal site as evidenced by a marked plasma level rebound was observed.

[Clinical pharmacokinetics of navelbine after oral administration, in vitro metabolism and interindividual variability]. / Pharmacocinétique clinique de la navelbine après administration orale métabolisme in vitro et variabilité interindividuelle.

Navelbine (NVB) (5'-noranhydrovinblastine) is a new semi-synthetic vincaalkaloid (VA) exhibiting a high affinity for tubulin and considerable anticancer activity in patients. A better hematologic tolerance and a weak neurotoxicity have been reported for this drug as compared to other VA. Moreover, NVB presents a relatively high bioavailability and a good digestive tolerance, thus offering original perspectives for the treatment of ambulatory cancer patients. A clinical pharmacokinetic study of NVB was carried out on 12 patients after oral administration of the drug. The pharmacokinetic parameters were similar to those of intravenous administration and also showed a high interindividual variability. Studies on the in vitro metabolism of NVB using hepatic microsomal fractions from 22 different donors demonstrated the formation of 3 metabolites. The biotransformation rate quantitatively varies from one human liver specimen to another, a fact which could be, in part, at the origin of the interindividual variability of the therapeutic response.

In vivo high-resolution volume-selected proton spectroscopy and T1 measurements in the dog brain.

Successful in vivo NMR spectroscopy requires a combination of techniques to address the problems of volume selection, water suppression, and resolution. All this needs to be done in the very heterogeneous environment found in living organisms. Previously published techniques are used to obtain 1H spectra from a dog brain, observing metabolites with concentrations below 1 mM. Measurements of spin-lattice relaxation times (T1) are also presented. The 1H relaxation times are long (T1 greater than 1.0 s) yielding information about the fluidity of the molecular environment. Comments are made concerning the achievable linewidth in vivo and the deficiencies that phase-encoding spectroscopic methods may have in obtaining high-resolution 1H spectra.

Pharmacokinetics of a new anticancer drug, navelbine, in patients. Comparative study of radioimmunologic and radioactive determination methods.

A study was designed to investigate the fate of navelbine (NVB) and its excretion routes in two cancer patients treated with tritiated NVB (30 mg/m2) by i.v. bolus injection. Plasma and red blood cell concentrations and urine and stool elimination were monitored over long periods of time. NVB plasma and urine concentrations were measured by both radioimmunoassay (RIA) and direct radioactive (RA) determination. Samples were also analyzed by high-performance liquid chromatography to evaluate the importance of NVB metabolism. Whereas the major excretion route for NVB was the stool (from 34% to 58.4% of the total dose given over 21 days), urinary excretion was low (about 21% within the same time period), corresponding mainly to that of unchanged drug. Thus, a good correlation was found between RIA and RA determinations in urine. In contrast, plasma area under the curve (AUC) values obtained after RA and RIA analysis differed markedly (AUC RIA/AUC RA = 0.23-0.31), demonstrating that a significant proportion of the plasma-circulating drug was biotransformed, mainly during the last elimination phase. This could have important pharmacological and toxicologic implications in clinical practice.

Ca2+-ATPase deficiency in a patient with an exertional muscle pain syndrome.

31P Magnetic resonance spectroscopy studies were carried out in vivo on skeletal muscle of a patient with verapamil-responsive, chronic, progressive post-exertional muscle pain. A sister suffered from a similar complaint. The results showed that the muscle: (1) decreased its high energy phosphate content more rapidly than normal during exercise, indicating either increased utilisation or decreased production of ATP; (2) acidified more rapidly than normal during exercise suggesting an increased glycolytic rate; (3) continued in some studies to acidify markedly during the first minute after exercise, indicating that glycolysis remained active into the recovery period; (4) had phosphocreatine and ADP recovery rates consistent with normal rates of oxidative phosphorylation. On the basis of these results, it was proposed that the patient suffers from a defect in Ca2+ handling in the muscle. Subsequently, direct measurement of Ca2+-ATPase activity in the sarcoplasmic reticulum fraction from a muscle biopsy sample showed that the activity of this enzyme was reduced by about 90%.

[Cutaneous signs of Noonan's syndrome. Apropos of a case with ulerythema ophyogenes, disseminated pilar and sudoral keratosis and progressive alopecia]. / Les signes cutanés du syndrome de Noonan. A propos d'une observation avec ulérythème ophryogène, kératose pilaire et sudorale disséminée et alopécie progressive.

A case of typical Noonan syndrome (NS) with eye abnormalities, pterygium colli, cryptorchid testes, lymphoedema and asymmetrical cardiac septal hypertrophy is reported in a 8-month old infant. This case was particularly interesting since it included skin manifestations which enabled an early diagnosis to be made. Ulerythema ophryogenes has already been proposed as a cutaneous marker of NS, but the keratinization disorders in our patient also included disseminated keratosis of both hair follicles and sweat glands orifices. Abnormally brittle short curly hair has already been reported, but our patient exhibited progressive alopecia which is very rare in NS. Biochemical hair analysis did not show any abnormalities of aminoacids. All these features were suggestive of keratosis follicularis spinulosa decalvans. It therefore seems very likely that NS is associated with keratinization disorders but ulerythema ophryogenes might only be the limited form of these disorders. The other skin manifestations of NS are reviewed. Since the patient had 4 "café au lait" spots, the relation of NS with Von Recklinghausen syndrome, and neurofibromatosis-Noonan syndrome is discussed. Watson's Leopard and cardio-facial syndromes overlap with, and may represent subsets of NS.

[Clinical pharmacokinetics of vinca alkaloids]. / Pharmacocinétique clinique des vinca-alcaloïdes.

Vinca alkaloids (VA) represent a family of closely related molecules, which includes vincristine (VCR), vinblastine (VLB), vindesine (VDS) and navelbine (NVB), a new synthetic VA presently in phase II clinical trial. Development of sensitive and specific analytical tools (polyclonal and monoclonal antibodies) enabled us to investigate the kinetic behavior of VDS and NVB after IV bolus or long term administration. Following IV bolus injection, the mean pharmacokinetic parameters are: total plasma clearance: 0.53 l/h-1kg-1, 0.72 l/h-1kg-1 and apparent elimination half-life: 23.2 h, 39.5 h for VDS and NVB, respectively. Chronic treatment reveals time- and dose-dependence relationships and detailed observations of individual kinetics demonstrate an important interindividual variability for both drugs. Renal excretion of VDS and NVB is low (from 5 to 12% of the total dose), suggesting the important role of the liver in their rapid elimination.

Percutaneous absorption of p-phenylene diamine during an actual hair dyeing procedure.

Synopsis An analytical method has been developed that allows the determination of p-phenylene diamine derivatives in urinary samples collected from women after hair dyeing with commercial formulations. During an on-line flash hydrolysis of the urine, a number of metabolites of p-phenylene diamine were hydrolyzed to free p-phenylene diamine, which was then determined using gas chromatography-mass spectrometry. The excretion of metabolites of p-phenylene diamine could be followed during 24 or 48 hours after the dye had been applied. Most of the p-phenylene diamine cleaved by the flash hydrolysis procedure was, in fact, involved in the N,N'-diacetyl combination. The dose excretion for p-phenylene diamine as measured by this method was comparable to that found by other authors who made use of radioactively labelled material. The present analytical method can be used to evaluate procedures intended to decrease the percutaneous absorption of p-phenylene diamine. Thus, a five- to ten-fold decrease in its penetration was observed by protecting the scalp with clay before applying the dyeing composition.

An unusual metabolic myopathy: a malate-aspartate shuttle defect.

Studies on a 27-year-old man with a 3-year history of exercise-induced muscle pain, passage of red urine and elevated serum creatine kinase are described. Histological examination of a biopsy from quadriceps revealed non-specific myopathic changes with occasional clusters of subsarcolemmal mitochondria. The phosphorylase stain was normal. Phosphorous nuclear magnetic resonance (NMR) spectroscopy studies of gastrocnemius and flexor digitorum superficialis muscles showed no abnormalities at rest. During aerobic exercise there was an abnormally rapid decrease in phosphocreatine concentration but the pH remained within the normal range. There was a build-up of phosphomonoester (probably glucose 6-phosphate), usually indicative of a block in glycolysis. However, a primary defect in the glycolytic pathway seemed unlikely because muscle acidified normally during ischaemic exercise. Recovery from exercise was unusual in that phosphocreatine resynthesis and inorganic phosphate disappearance followed similar prolonged time courses (in control subjects the rate of inorganic phosphate disappearance was about twice as fast as the rate of phosphocreatine resynthesis). The transport of inorganic phosphate into the mitochondria appeared to be delayed. These slow recovery data suggested that oxidative metabolism was impaired. However, with all substrates tested, isolated muscle mitochondria had rates of oxygen uptake that were similar to control values, thereby ruling out a primary defect in mitochondrial respiration. A system involving several mitochondrial transport systems, the malate-aspartate shuttle, was measured. The activity in the patient's isolated mitochondria was less than 20% of the activity present in samples from control subjects. This patient is the only one so far reported with a defect involving the malate-aspartate shuttle system.

Methotrexate and 7-hydroxy-methotrexate pharmacokinetics following intravenous bolus administration and high-dose infusion of methotrexate.

The pharmacokinetics of methotrexate and 7-hydroxy-methotrexate were studied in patients undergoing very high-dose methotrexate monotherapy. The patients received, first, two methotrexate intravenous bolus test doses (50 mg/m2) one with and one without concomitant administration of folinic acid (15 mg every 6 h) in a random sequence, and, second, an 8 h infusion, individualized to achieve a peak plasma concentration of 5 X 10(-4) M methotrexate (infusion rates greater than 1000 mg/h). Methotrexate and 7-hydroxy-methotrexate concentrations were measured by specific radioimmunoassays and the data were analysed simultaneously by an integrated pharmacokinetic model. Following test dose administration, methotrexate and 7-hydroxy-methotrexate plasma concentration kinetics were best described by assuming that methotrexate elimination (and 7-hydroxy-methotrexate formation) occurred from a peripheral compartment reaching rapid equilibrium with the plasma. Folinic acid administration did not influence the disposition of either compound. Following the infusion, a significant (P less than 0.01) decrease of methotrexate total plasmatic clearance occurred without modification of 7-hydroxy-methotrexate formation and elimination.

The study of human organs by phosphorus-31 topical magnetic resonance spectroscopy.

The potential clinical use of topical magnetic resonance spectroscopy (volume selection by static magnetic field gradients) was tested in 50 studies in volunteers. Topical magnetic resonance spectroscopy (MRS) was shown to be a straightforward method for localising 31P spectra of brain and liver. However, the spherical shape and fixed position of the selected volume posed serious limitations to the study of heart and transplanted kidney by topical MRS. Phosphorus-31 spectra of approximately 30 cm-3 of brain or liver could be obtained in 8 min. Ratios of metabolite concentrations could be determined with a coefficient of variation ranging from 10% to 30%. The ratios of phosphocreatine/ATP and inorganic phosphate/ATP in brain were 1.8 and 0.3, respectively. The ratio of inorganic phosphate/ATP in liver was 0.9. Intracellular pH was 7.03 in brain and 7.24 in liver. The T1 relaxation times of phosphocreatine, inorganic phosphate and gamma-ATP in brain were 4.8 s, 2.5 s and 1.0 s, respectively.

Pharmacokinetics of methotrexate and 7-hydroxy-methotrexate after methotrexate infusions.

Methotrexate was administered by IV infusion, 2g (1.19 +/- 0.05 g/m2) over 24 hours, to a homogeneous group of patients undergoing treatment for breast cancer. Three courses were given at three week intervals. Methotrexate and 7-hydroxy-methotrexate plasma and urine pharmacokinetics were investigated. The average terminal half-lives of methotrexate and 7-hydroxy-methotrexate in plasma were 15.02 and 15.19 hours respectively. The area under concentration-time curve was 723.8 +/- 196.4 microM x h for methotrexate and 598.1 +/- 212.5 microM x h for 7-hydroxy-methotrexate. The total average urinary excretions of methotrexate and 7-hydroxy-methotrexate over a 96 hour period were 52% and 5.4% respectively. Urinary clearance of methotrexate was 3.46 +/- 1.4 1/h. In contrast, urinary excretion of 7-hydroxy-methotrexate was not linear. These results confirm the protein binding of metabolite to serum albumin and may suggest that distribution of 7-hydroxy-methotrexate is different from unchanged drug or that the metabolite can be eliminated by another route, such as bile.

Muscle metabolism in patients with peripheral vascular disease investigated by 31P nuclear magnetic resonance spectroscopy.

Eleven men with claudication and ten control subjects had calf muscle metabolism studied at rest and during exercise and the subsequent recovery period by 31P nuclear magnetic resonance (n.m.r.) spectroscopy. The muscle of patients with severe claudication had a significantly greater depletion of phosphocreatine and fall in pH during exercise and a slower recovery of phosphocreatine and pH after exercise. The muscle of patients with both mild and severe disease had slower rates of ADP recovery after exercise than that of control subjects. Surgical correction of the associated arterial stenosis abolished claudication and led to correction of the metabolic abnormalities in two patients. Claudication pain was not related to intracellular pH or concentration of phosphorus-containing metabolites. Energy production via oxidative metabolism is impaired but glycolysis may be increased in the calf muscle of patients with intermittent claudication.