The constitution of zinc and cerium sulphadiazines in aqueous preparation.
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Cerium↗
Biomedical subjects
A Bult
Publications and source records attributed to A Bult.
Structures of silver sulfonamides.
The structures of silver sulfonamides were found to depend highly on the substituent at the amide nitrogen of the sulfonamide. Silver is coordinated to that nitrogen and the sulfonamide is in the amido form if no substituent is present or if the substituent is a phenyl, acetyl, or 2-pyrimidyl group. If the substituent is a 2-thiazolyl or 2-pyridinyl group, the sulfonamide is in the imido form and silver coordinates to the nitrogen of the substituent. Depending on the number of suitable donor atoms per sulfonamide, the silver compounds are charged or uncharged and the primary amino group may be involved in complexation.
Chemical Phenomena↗
Plasma pharmacokinetics, tissue disposition, excretion and metabolism of vinorelbine in mice as determined by high performance liquid chromatography.
We have investigated the pharmacokinetics of the investigational semi-synthetic vinca alkaloid vinorelbine (navelbine, NVB). The analyses have been performed by using a sensitive and selective method based on ion-exchange normal phase high-performance liquid chromatography with fluorescence detection combined with liquid-liquid extraction for sample clean-up. Pharmacokinetic studies were performed in male FVB mice receiving 12 mg/kg NVB through intravenous injection. The results have been compared to those obtained for vinblastine (VBL). The plasma pharmacokinetics of NVB can be described by a three compartment model. The elimination half-life is significantly longer and the plasma AUC values higher for NVB compared to VBL. This is reflected in tissues, where, 24 hr after drug administration, the concentration of NVB is 5 to 10-fold higher compared to VBL. Qualitatively, the tissue distribution and retention of the drugs is very similar. The drug concentrations in most tissues decline parallel with the circulating plasma levels, whereas prolonged retention is found in tissues of lymphatic and testicular origin. Deacetylation yielding deacetylnavelbine (DNVB) is the primary metabolic route for NVB. This cytotoxic metabolite accounts for a substantial part of the overall disposition of drug. Only 58% of the administered dose is excreted in the urine (17%) and faeces (41%) as NVB or DNVB. No other metabolites have been detected.
Animals↗
Comparative open, randomized, cross-over bioequivalence study of two intravenous dexrazoxane formulations (Cardioxane and ICRF-187) in patients with advanced breast cancer, treated with 5-fluorouracil-doxorubicin-cyclophosphamide (FDC).
The purpose of this study was to compare the pharmacokinetic disposition of two intravenous dexrazoxane formulations, and their effects on doxorubicin's kinetics and metabolism. Plasma concentration versus time curves and pharmacokinetic parameters of dexrazoxane given as Cardioxane (dexrazoxane hydrochloride salt) and ICRF-187 reference formulation (dexrazoxane base) were determined and compared. Both formulations were administered as a single intravenous infusion prior to 5-fluorouracil-doxorubicin-cyclophosphamide administration. In addition, the pharmacokinetics of doxorubicin and its metabolites were studied after dexrazoxane administration. A total of 15 patients with advanced breast cancer participated in this open, randomized, cross-over study and 12 patients were evaluable. Plasma concentrations of dexrazoxane, doxorubicin and doxorubicin metabolites were determined by high-performance liquid chromatography in samples obtained in the 72 h after drug administration. No statistically significant differences were found in the tested kinetic parameters when the two products were compared by analysis of variance (ANOVA) on log-transformed data. Cardioxane fulfilled the bioequivalence criteria when compared with ICRF-187 reference formulation for all of the investigated parameters (AUC, t1/2beta, Vdss, Cl(tot), Cl(ren)). The parametric 90% confidence intervals were contained within the bioequivalence interval (0.8-1.25). Pharmacokinetic parameters and metabolism of doxorubicin were not different after the administration of either Cardioxane or ICRF-187 formulation. From the results of this study it can be concluded that the two formulations can be considered bioequivalent with regard to extent of absorption (AUC and Vdss) and elimination (t1/2beta, Cl(tot) and Cl(ren)).
Adult↗
Pharmaceutical development of a parenteral lyophilized formulation of the novel antitumor agent aplidine.
Aplidine is a naturally occurring cyclic depsipeptide isolated from the Mediterranean tunicate Aplidium albicans. Aplidine displays promising in vitro and in vivo antitumor activities against various solid human tumor xenografts and is therefore developed now for clinical testing. The aim of this study was to develop a stable parenteral pharmaceutical dosage form for clinical Phase I testing. Aplidine raw material was characterized by using several chromatographic and spectrometric techniques. These experiments showed that aplidine exists as two isomers. A stability-indicating HPLC assay was developed. Solubility testing showed that aplidine exhibits very poor aqueous solubility. Because solubilized aplidine showed substantial degradation under heat and light stress testing conditions, it was decided to develop a lyophilized dosage form. Freeze-drying was carried out with a 500 micrograms/mL solution of aplidine in 40% (v/v) tert-butanol in Water for Injection (WfI) containing 25 mg/mL D-mannitol as a bulking agent. Differential scanning calorimetry was applied to determine the optimal freeze-drying cycle parameters. The prototype, containing 500 micrograms aplidine and 25 mg D-mannitol per vial, was found to be the optimal formulation in terms of solubility, length of lyophilization cycle, and dosage requirements in the forthcoming Phase I clinical studies. Quality control of the freeze-dried formulation demonstrates that the manufacturing process does not affect the integrity of aplidine. The optimal reconstitution solution was found to be 15/15/70% (v/v/v) Cremophor EL/ethanol/WfI (CEW). Both reconstituted product and dilutions of the reconstituted product with normal saline (up to 1:100 v/v) appeared to be stable for at least 24 hours after preparation. Shelf-life data, available thus far, show that the lyophilized formulation is stable for at least 1 year when stored at +2-8 degrees C in the dark.
Antineoplastic Agents↗
In vitro hemolysis and buffer capacity studies with the novel marine anticancer agent kahalalide F and its reconstitution vehicle cremophor EL/ethanol.
An in vitro biocompatibility study was performed with the pharmaceutical formulation of the investigational, marine-derived anticancer agent kahalalide F developed for early clinical studies. The pharmaceutical formulation consists of a lyophilized product containing 150 micrograms kahalalide F, 3 mg citric acid, 3 mg polysorbate 80, and 150 mg of sucrose per dosage unit, to be reconstituted with 3 mL of a mixture composed of Cremophor EL, ethanol, and water (5/5/90% v/v/v), resulting in a solution of pH 3 and to be further diluted in normal saline for infusion. The reconstituted product, infusion solutions, and Cremophor/ethanol (CE) vehicle were tested for hemolytic potential and buffer capacity. No significant hemolysis due to the kahalalide F formulation as well as the CE vehicle was found using both a static and dynamic test model. FB-ratio's (ratio of formulation solution (F) and volume of blood simulant (B) necessary to maintain physiological pH) as a measure of the buffer capacity of the kahalalide F infusion solutions examined indicated that no vascular irritation due to pH effects is expected in the intended administration schedule in the forthcoming Phase I study.
Animals↗
Pharmacology, bio-analysis and pharmacokinetics of the vinca alkaloids and semi-synthetic derivatives (review).
Vinca alkaloids have been used as chemotherapeutic agents now for over three decades. Especially during recent years, the development of a considerable number of semi-synthetic derivatives, showing attractive properties in preclinical or clinical investigations, has been reported. In this paper we shall give a critical review of the investigations presented on this matter.
Animals↗
Ifosfamide metabolism and pharmacokinetics (review).
In this article the studies on the pharmacokinetics and metabolism of ifosfamide have been summarised. Ifosfamide is a pro-drug and requires metabolic activation to exert cytotoxic activity. The various metabolites determined after oral or intravenous administration of ifosfamide show a large inter- and intrapatient variability. Oral and intravenous fractionated treatment with ifosfamide exhibits a time-dependent increase in ifosfamide metabolic clearance which is explained by a mechanism of auto-induction of the hepatic oxygenase system. The pharmacokinetic parameters of ifosfamide do not correlate with age, sex and weight. Oral ifosfamide, at a dose higher than 1 g/m2, induces neurotoxicity in a high percentage of patients. In these cases the pharmacokinetics of ifosfamide were not aberrant. This implies that ifosfamide metabolites rather than the parent drug are likely to be responsible for the neurotoxicity. The development of more selective and sensitive analytical methodologies are necessary in order to go in more insight into the disposition of the active ifosfamide metabolites, including their clinical effects. This may lead to a further optimisation of the therapeutic use of ifosfamide.
Aging↗
The analysis of ifosfamide and its metabolites (review).
Ifosfamide is a member of the oxazaphosphorine class of cytostatic drugs. Ifosfamide has to be metabolized prior to expressing its cytotoxicity. This metabolism leads to a great variety of metabolites. An overview is given of the methods of analysis of ifosfamide and its metabolites as well as the current knowledge about its metabolism, toxicity and clinical use in relation to the bio-analysis. For ifosfamide and some of its metabolites reliable methods of analysis exist. However, for the most important metabolites, isofosforamide mustard and acrolein, progress has to be made in improving the simplicity and sensitivity of the existing methods.
Acetaldehyde↗
The influence of formulation excipients on the stability of the novel antitumor agent carzelesin (U-80,244).
The stability of carzelesin in a polyethylene glycol 400 (PEG 400)/absolute ethanol/polysorbate 80 (Tween 80) (6:3:1, v/v/v) formulation (PET formulation) was investigated as a function of the inter-batch variability of the three excipients. Twenty different PET formulations were tested and the stability of carzelesin in the PET formulation was found to be influenced by the type of PEG 400 used. Subsequent investigations showed that the pH of PEG 400, and consequently the pH of the PET formulation, was responsible for the variable stability characteristics of carzelesin in the PET formulation. The higher the pH of the PET formulation, the higher the rate of degradation of carzelesin in PET. The major degradation products were found to be U-76,073 and U-76,074.
Antineoplastic Agents↗
Pharmacokinetics of ifosfamide, 2- and 3-dechloroethylifosfamide in plasma and urine of cancer patients treated with a 10-day continuous infusion of ifosfamide.
The cytotoxic drug ifosfamide is subject to an extensive metabolism. This study reports the results of a pharmacokinetic study of the parent drug and the two dechloroethylated metabolites in 22 patients on a 10-day continuous infusion of ifosfamide. Ifosfamide causes a substantial induction of the enzymes responsible for its metabolism, resulting in a two-fold increase of the clearance. The maximal IF concentration is reached after 24 h, after which the concentration decreases to a steady-state. The dechloro-ethylated compounds can be detected in the plasma about 8 h after the start of the infusion with plasma half-lives longer than for IF. Urinary excretion studies revealed that at least a quarter of the IF dose is excreted as inactive compounds.
Adult↗
Pharmaceutical development of a parenteral formulation of the investigational anticancer drug clanfenur.
A stable parenteral dosage form for the investigational cytotoxic drug clanfenur was designed, and the bulk drug was characterized by its nuclear magnetic resonance, mass spectrometry, infrared, and ultraviolet spectra. The 1H and 13C spectra show clanfenur to be a mixture of two stereoisomers. Because of poor solubility in aqueous solution and precipitation in co-solvent, surfactant, or emulsion systems, a two-pump infusion system was developed for intravenous administration. Clanfenur, solubilized in a Cremophor EL/ethanol (1:1, w/v) solution (concentration, 15 mg/mL), can be simultaneously infused with 5% dextrose infusion fluid. Total doses of up to 1,680 mg of clanfenur (and 56 g of Cremophor EL) theoretically can be administered to patients over a 6-hour period. From accelerated stability testing of clanfenur in the Cremophor EL/ethanol (1:1, w/v) formulation, a shelf life of 3.5 years at 4 degrees C and of 4 months at 25 degrees C is calculated.
Antineoplastic Agents↗
Pharmacokinetics of ifosfamide and some metabolites in children.
The pharmacokinetics of ifosfamide and some metabolites in children was investigated. The patients received various doses of ifosfamide, mostly by continuous infusion, over several days. The penetration of ifosfamide and its metabolites into the cerebrospinal fluid was also studied in four cases. Ifosfamide and 4-hydroxyifosfamide pass the blood-brain barrier, reaching cerebrospinal fluid concentrations that are almost as high as plasma concentrations.
Adolescent↗