The isolation and identification of a toxic impurity in XP315 drug substance.

In early safety assessment studies with the experimental anti-neoplastic drug XP315, a toxic reaction was observed in dogs immediately after intravenous (iv) infusion. The reaction was characterized by severe erythema around the ears, eyes, face and body; ocular hyperemia; head shaking; swelling around the eyes, face, paws, head, neck and legs; scratching; and reddened gums, which lasted several hours after dosing. By fractionating the drug substance using preparative HPLC and then infusing the residues into dogs by iv, this reaction was traced to an impurity in the drug substance.

Effect of inline filtration on ViaSpan cold-storage solution.

The effect of filtration on the particulate load in ViaSpan cold-storage solution was studied. Commercially available inline blood transfusion filters (SQ40S, Pall Biomedical) were inserted into the delivery-set port of polyvinyl chloride bags of ViaSpan (DuPont Merck Pharmaceutical). Particles in samples collected in particle-free vials before and after filtration were counted by a light-obscuration technique.

A comparison of oral and rectal absorption of L-dopa esters in rats and mice.

Short-chain alkyl esters of L-dopa were administered to rats and mice via oral and rectal routes. Plasma L-dopa esters and L-dopa were determined in the systemic and portal circulation by HPLC. A comparison of isopropyl, butyl, and 4-hydroxybutyl esters of L-dopa demonstrated significantly higher levels of the esters in both systemic and portal blood samples following rectal administration than following oral administration.

Buccal absorption. III. Simultaneous diffusion and metabolism of an aminopeptidase substrate in the hamster cheek pouch.

The simultaneous diffusion and metabolism of the D- and L-isomers of the aminopeptidase substrate, leucine-p-nitroanilide (LPNA), were examined in vitro in the hamster cheek pouch. L-LPNA was completely hydrolyzed during diffusion across the cheek pouch, whereas D-LPNA crossed the cheek pouch intact. The metabolic barrier appeared to be localized in the epithelium of the cheek pouch.

Short-chain alkyl esters of L-dopa as prodrugs for rectal absorption.

The bioavailability of L-dopa following rectal administration of a series of short-chain alkyl esters of L-dopa was determined in rats and dogs. The esters were stable (greater than 360 min) to hydrolysis in physiological buffer. In vitro enzymatic hydrolysis of the esters in plasma was species dependent, with the hydrolytic rate being faster in rat plasma (t 1/2 less than 5 min) than dog plasma (t 1/2 = 68-181 min) or human plasma (t 1/2 = 96-238 min).

Buccal drug absorption. II: In vitro diffusion across the hamster cheek pouch.

The in vitro diffusion of a series of substituted acetanilides across the hamster cheek pouch was studied. The keratinized epithelial layer of the cheek pouch appeared to provide the major barrier to diffusion of these compounds. Linear relationships were found for plots of log epithelial permeability (Pe) versus the log of the octanol-buffer partition coefficient (PCoct; r = 0.

Application site dependent ocular absorption of timolol.

Ocular absorption of timolol in rabbits was studied after topical ocular administration of 3H-timolol in an eyedrop or in silicone cylindrical devices that released timolol at 7.2 micrograms/h. The devices were applied in either the inferior or superior conjunctival sac.

Design and synthesis of a theophylline bonded-phase column for HPLC--application to separation of aromatic carboxylic acids.

A stationary phase has been designed and synthesized in which theophylline residues are covalently bonded to a silica support through an eight carbon hydrocarbon linkage. The phase offers improved resolution in the separation of aromatic carboxylic acids over that available with conventional reversed phase supports. The column is relatively stable.

Stability of propranolol hydrochloride suspension compounded from tablets.

The stability of a propranolol hydrochloride suspension compounded from commercially available tablets was studied. Propranolol hydrochloride 10-mg tablets were triturated to a powder and incorporated into a commercially available suspension vehicle to yield a suspension with a theoretical propranolol hydrochloride concentration of 1 mg/mL. The suspension was divided into portions and stored in amber glass bottles at either room (25 degrees C) or refrigerated (2 degrees C) temperature for four months.

Aspects of the stability of isoindoles derived from the reaction of o-phthalaldehyde-ethanethiol with primary amino compounds.

The stability of a series of fluorescent isoindoles formed under analytical conditions following the reaction of o-phthalaldehyde (OPA) and ethanethiol (ET) with a series of primary amines is reported. Increasing the bulk and degree of substitution of the isoindole N-substituent resulted in substantial increases in isoindole stability. The effects of excess reagents on isoindole stability is examined and OPA is observed to accelerate isoindole degradation whilst ET provides a stabilizing effect.

Rational design and evaluation of improved o-phthalaldehyde-like fluorogenic reagents.

Evidence was presented suggesting that the fluorescent isoindole produced by reaction of o-phthalaldehyde (OPA), ethanethiol, and primary amine was formed by initial imine formation followed by conversion to an alpha-alkylaminobenzylsulfide and subsequent ring closure to form the isoindole nucleus. This mechanism suggested that the minimum structural requirement for condensation to an isoindole was an o-diacyl benzene in which one of the carbonyl groups was aldehydic. A major drawback of OPA as an analytical reagent is the limited stability of the fluorescent 1,2-disubstituted isoindole.

Development of an intravenous formulation for the unstable investigational cytotoxic nucleosides 5-azacytosine arabinoside (NSC 281272) and 5-azacytidine (NSC 102816).

In aqueous solutions 5-azacytosine arabinoside (aza-A) (NSC 281272) exhibits complex and rapid degradation of a type analogous to 5-azacytidine (aza-C) (NSC 102816). Consequently, it is not amenable for use as slow i.v.

Factors affecting the stability of fluorescent isoindoles derived from reaction of o-phthalaldehyde and hydroxyalkylthiols with primary amines.

The stability of a series of fluorescent isoindole derivatives formed in situ under analytical conditions following the reaction of o-phthalaldehyde (OPA) and 2-mercaptoethanol (2-ME) with a series of primary amines are reported. Increasing the bulk and degree of substitution at C-10 of the resulting isoindole resulted in substantial increases in product stability. The effects of excess OPA and 2-ME on isoindole stability were examined and OPA was observed to catalyze isoindole degradation while 2-ME had no effect.

Analysis of riboxamide in plasma by high-performance liquid chromatography using automated column switching.

A sensitive and highly specific assay for riboxamide (TCAR) in human and canine plasma is described. The specificity of the procedure is derived from the method of sample preparation and a high-performance liquid chromatographic separation which utilizes the different selectivities of two columns. Partial separation of TCAR from plasma is achieved on a solvent-generated anion exchanger with silica gel as the solid support.

Tumor concentration of platinum in patients with head and neck cancer.

Simultaneous concentrations of total plasma platinum, filterable platinum, intact cisplatin, and total tumor platinum were measured for 24 hours after an intravenous bolus of cisplatin in five patients. Tumor concentrations of drug were greater than could be explained on the basis of circulating plasma platinum at the time of biopsy. Intratumor platinum concentrations derived from this study provide guidance for selection of the appropriate drug concentrations for in vitro chemosensitivity testing of head and neck cancer in humans.

Evaluation of reductive amperometric detection in the liquid chromatographic determination of antineoplastic platinum complexes.

The usefulness of reductive electrochemical detection at mercury drop electrodes has been determined for platinum complexes separated by solvent-generated anion-exchange high-performance liquid chromatography. Both current-sampled dropping mercury and hanging mercury drop electrodes (DME and HMDE) provide significant advantages over UV absorbance and off-line non-flame atomic absorption detection. The effects of chromatographic and polarographic parameters on analytical system performance have been investigated.

Monitoring the reactions of cisplatin with nucleotides and methionine by reversed-phase high-performance liquid chromatography using cationic and anionic pairing ions.

Methodology, based on reversed-phase high-performance liquid chromatography, is described for monitoring the reactions of cisplatin with DNA, nucleotides, and methionine. Cisplatin was determined in DNA ultrafiltrates on solvent-generated anion exchangers which were prepared by coating the surface of a reversed-phase column with hexadecyltrimethylammonium bromide. These systems were also applicable to studies on the reactions of cisplatin with nucleotides.

High-performance liquid chromatography of cisplatin.

The retention behavior of cisplatin on a variety of stationary phases has been investigated using aqueous mobile phases modified by the addition of various electrolytes and methanol. Cisplatin is poorly retained on reverse-phase or silica columns but satisfactorily retained on chemically bonded or solvent-generated anion exchangers. The retention of the neutral complex on positively charged stationary phases is explained in terms of ion-dipole interactions and rationalized by the application of solvophobic theory.

Factors affecting the retention of quaternary ammonium ions in reversed-phase high-performance liquid chromatography.

The influence of solute structure (charge and hydrophobic substitution), organic modifier (type and concentration) and ion-pairing agent on the retention of nine quaternary- and bis-quaternary ammonium ions has been investigated in reversed-phase HPLC on ODS-silica. A functional group approach was taken to elucidate the influences of substitution on the charged nitrogen and the addition of a second positive charge to the solute molecule. These and other factors contributing to solute retention are discussed within the context of solvophobic theory.

Cation exchange contribution to the retention of specific quaternary ammonium compounds in reversed-phase high-performance liquid chromatography.

The influence of electrolytes on the retention of organic cationic solutes in reversed-phase high-performance liquid chromatography (RP-HPLC) has been investigated. The effects of the nature and concentration of electrolytes and mobile phase pH on the retention of two model quaternary ammonium compounds were studied on mu-Bondapak C18 stationary phase with aqueous methanolic eluents. The nature and concentration of inorganic cations added to the mobile phase modified the retention of the solutes.

High-performance liquid chromatography of platinum complexes on solvent generated anion exchangers. III. Application to the analysis of cisplatin in urine using automated column switching.

Platinum complexes are retained on solvent generated anion exchangers, prepared by coating reversed-phase (C-18) supports with a monolayer of hexadecyltrimethylammonium bromide. The retention mechanism is described in terms of ion--dipole interactions in the stationary phase, reinforced by a hydrophobic effect. The high degree of ligand selectivity exhibited by these systems arises from the use of purely aqueous mobile phases which maximize the differences in solute dipole and hydrophobic surface area.

Oxidative degradation of 6-selenoguanosine in aqueous solutions.

The degradation of 6-selenoguanosine (NSC 137679) (I) in water and in various buffer systems was investigated. Drug degradation in aqueous media was monitored by high-pressure of I in various chromatography. Some kinetic aspects of the degradation of I in various buffer systems at 25 degrees also were studied spectrophotometrically.