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Biomedical subjects

B Kaye

Publications and source records attributed to B Kaye.

At least 19 recordsLinked to original sources
PubMed1998

Clinical analysis of sampatrilat, a combined renal endopeptidase and angiotensin-converting enzyme inhibitor I: assay in plasma of human volunteers by atmospheric-pressure ionisation mass-spectrometry following derivatisation with BF3-methanol.

Sampatrilat is a dual inhibitor of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) under development for the treatment of hypertension and congestive heart failure. In order to support the early clinical development (with oral administration and an expected low bioavailability), a sensitive and selective assay was required. A method for plasma was developed and validated employing HPLC APCI MS-MS. The plasma samples were extracted on solid-phase extraction cartridges, derivatised with BF3-methanol, diluted, extracted again and then subjected to HPLC APCI-MS-MS. Derivatisation was necessary because the two carboxyl group in the molecule prevented efficient ionisation in the heated nebuliser source. The calibration range was from 0.5 to 20 ng ml(-1) and the lower limit of quantification was 0.5 ng ml(-1). Imprecision and inaccuracy were determined on three separate occasions at three concentrations (0.5, 5 and 20 ng ml[-1]) and shown to be lower than 10% in every case.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Clinical analysis of sampatrilat, a combined renal endopeptidase and angiotensin-converting enzyme inhibitor II: assay in the plasma and urine of human volunteers by dissociation enhanced lanthanide fluorescence immunoassay (DELFIA).

Sampatrilat is a dual inhibitor of angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) under development for the treatment of hypertension and congestive heart failure. In order to support the early clinical development (with oral administration and an expected low bioavailability), a sensitive and selective assay was required. An HPLC-atmospheric-pressure chemical ionisation mass-spectrometric (HPLC-APCI-MS-MS) assay had been already validated (R.F. Venn et al., J. Pharm. Biomed. Anal., in press), but due to its low throughput an alternative method was sought. As the molecule is peptide-like and not metabolised, we believed the immunoassay approach was appropriate. Thus we developed an immunoassay for the compound using time-resolved fluorescence as an end-point (DELFIA) with lower limits of quantification of 0.2 ng ml(-1) for the plasma assay and 5 ng ml(-1) for the assay in urine. This assay is a 96-well plate based competitive immunoassay; the end-point is the determination of a (non-radioactive) europium label by time-resolved fluorimetry. Sampatrilat is labelled with chelated europium via isothiocyanate chemistry. The advantage of this assay is its extremely high throughput, allowing rapid analysis of many thousands of samples. The DELFIA method was successfully cross-validated with the HPLC-APCI-MS-MS method.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Formation and pharmacokinetics of the active drug candoxatrilat in mouse, rat, rabbit, dog and man following administration of the prodrug candoxatril.

1. Candoxatrilat, an active neutral endopeptidase inhibitor, was released rapidly from the inactive prodrug candoxatril in vivo in mouse, rat, rabbit, dog and man. 2. Oral doses of [14C]-candoxatril were cleared rapidly, mostly by ester hydrolysis to candoxatrilat, in mouse, dog and man. A complementary intravenous study in man with [14C]-candoxatrilat showed that the active drug was virtually completely renally cleared. Neither candoxatril nor candoxatrilat underwent chiral inversion in man. 3. Systemic availability of candoxatrilat from the oral prodrug was estimated to be 88, 53, 42, 17 and 32% in mouse, rat, rabbit, dog and man respectively. Plasma clearance of candoxatril was too rapid to enable pharmacokinetic parameter calculation in mouse and rabbit; for man, the apparent oral clearance was 57.9 ml/min/kg and the elimination half-life was 0.46 h. 4. For intravenous candoxatrilat, total plasma clearance values were 32, 15, 5.5, 5.8 and 1.9 ml/min/kg for mouse, rat, rabbit, dog and man respectively. Renal clearance values were 8.7, 7.2, 2.9 and 1.7 ml/min/kg for mouse, rat, dog and man and these approximate to the respective glomerular filtration rates. Allometric scaling with respect to bodyweight across the species allowed reasonable prediction of the above two clearance parameters in man.

Absorption↗
PubMed1996

Rapid, solid phase extraction technique for the high-throughput assay of darifenacin in human plasma.

A novel method has been developed for the rapid solid phase extraction of drugs and metabolites from biological fluids, prior to further analysis. The newly designed, 96-tube micropreparation block facilitates high throughput by enabling the extraction of 96 samples simultaneously. The system is described, linked to HPLC/APCI-MS/MS, for the determination of darifenacin in human plasma. The resulting procedure, using deuterated darifenacin as internal standard, is validated over the concentration range 25-2000 pg/mliter; accuracy (0.6-4.6%) and precision (3.6-18.8%) are considered acceptable and overall recovery was determined to be approximately 50%.

Benzofurans↗
PubMed1995

Assessment of a specimen mount for biopsy of impalpable breast lesions.

Biopsy of the impalpable breast lesion is an increasing part of the surgical workload as a result of the National Breast Cancer Screening Programme. A specimen mount card has been described to orientate such specimens in three dimensions prior to radiological and pathological examination. Experience with 243 biopsies in this unit has shown it to be a useful aid in determining completeness of excision. It may also be used as a guide to further surgery when excision is incomplete and breast conservation is the treatment option of choice.

Biopsy↗
PubMed1994

Should breast biopsy cavities be drained?

A total of 112 women was entered into a randomised study to investigate the effects of suction drainage on haematoma formation in breast biopsy wounds. Of 107 evaluable patients, 52 received drainage and 55 had no drain. The wounds were examined 1 week after operation when the volume of wound haematoma was measured using ultrasonography. Haematomas were present in 48 (87%) patients with undrained wounds compared with 34 (65%) patients with drained wounds (P = 0.014, chi 2 test). Median haematoma volume was 20 ml (range 0-172.5 ml) in the undrained group compared with 2 ml (range 0-100 ml) in the drained group (P = 0.001, Mann-Whitney U test). There was one wound infection in each group. There was no difference in median pain score or duration of pain between the groups. While suction drainage significantly reduces the incidence and volume of wound haematomas, this does not appear to influence outcome.

Adult↗
PubMed1993

Doramectin--a potent novel endectocide.

Doramectin, 25-cyclohexyl-5-O-demethyl-25-de(l-methylpropyl)avermectin A1a, was selected as the best of a series of novel avermectins prepared by mutational biosynthesis. The primary evaluation of its in vivo antiparasitic activity was carried out using a rat Trichostrongylus colubriformis model and a rabbit Psoroptes cuniculi model. In each case the new avermectin performed favourably relative to dihydroavermectin B1a (DHAVM), the major component of ivermectin. Doramectin was extensively evaluated in cattle using an experimental micelle formulation, proving highly effective in cattle infected with Ostertagia ostertagi, Cooperia oncophora and Dictyocaulus viviparus when administered subcutaneously at 200 micrograms kg-1. The plasma pharmacokinetic characteristics of doramectin in cattle following intravenous administration revealed a plasma half-life of approximately 89 h. In the micelle formulation, doramectin administered subcutaneously at 400 micrograms kg-1 provided persistent activity against infection of cattle with C. oncophora and O. ostertagi for at least 8 and 12 days respectively.

Administration, Oral↗
PubMed1993

Effect of formulation on the pharmacokinetics and efficacy of doramectin.

The pharmacokinetics of doramectin, a novel avermectin, were evaluated following parenteral administration in a range of oil-based formulations in an attempt to optimise the formulation. Therapeutic and persistent efficacies against Cooperia oncophora were also evaluated. This approach led to the identification of formulations based upon sesame oil and ethyl oleate which gave more prolonged doramectin plasma concentrations with no loss in therapeutic efficacy and improved persistent efficacy following subcutaneous administration to cattle at a dosage of 200 micrograms kg-1. The importance of using both pharmacokinetic and efficacy end points to distinguish between formulations is discussed. All formulations were well tolerated as evidenced by the absence of any reaction to injection either in the form of behavioural responses, injection site swelling or postmortem lesions. Sesame oil with ethyl oleate was the best parenteral vehicle tested for doramectin, allowing the expression of a high level of therapeutic and persistent efficacy and offering the benefit of excellent injection site toleration.

Analysis of Variance↗
PubMed1992

The sensitive determination of abanoquil in blood by high-performance liquid chromatography/atmospheric pressure ionization mass spectrometry.

A method is described for the determination of abanoquil in human blood. The method is based on high-performance liquid chromatography (HPLC)/atmospheric pressure positive ion chemical ionization mass spectrometry, using (2H3)abanoquil as internal standard. Multiple reaction monitoring is employed for selectivity and sensitivity, which enables quantification over the range 10-500 pg ml-1 with acceptable precision and accuracy. This assay methodology illustrates the versatility of atmospheric pressure ionization/tandem mass spectrometry, in conjunction with HPLC, for the separation and quantification of drugs in the subnanogram per millilitre range.

Adrenergic alpha-Antagonists↗
PubMed1991

Studies on the use of gerbil-derived Babesia divergens antigen for diagnosis of bovine babesiosis.

Babesia divergens antigen obtained from bovine and gerbil erythrocytes was compared for the diagnosis of bovine babesiosis by the indirect immunofluorescence antibody test (IFAT) and the enzyme-linked immunosorbent assay (ELISA). Using a range of sera from the field and from experimental cattle, it was found that antigen from the two sources did not differ significantly in sensitivity or specificity. Antigen from gerbils may, therefore, be used for serological surveys of bovine babesiosis caused by B. divergens. The IFAT and ELISA were also compared and it was concluded that they are equally effective in the detection of positive samples. For small-scale surveys, the IFAT using gerbil-derived antigen is adequate, but for large surveys the ELISA is preferable.

Animals↗
PubMed1991

Measurement of the class III antidysrhythmic drug, UK-68,798, in plasma by radioimmunoassay.

A sensitive radioimmunoassay (RIA) for the specific determination of 1-(4-methanesulphonamidophenoxy)-2-[N-(4-methanesulphonamido -phenethyl)-N- methylamino]ethane (UK-68,798), a novel class III antidysrhythmic agent, in human plasma is described. Specific antisera were raised in sheep using desmesyl-UK-68,798-succinate-ovalbumin conjugate as the antigenic hapten carrier protein. The antisera produced exhibited high specificity for UK-68,798 compared with known metabolites from animals, other antidysrhythmic agents and co-administered drugs. Good correlation was found in a comparison of the RIA method with a high-performance liquid chromatography (HPLC) method (r = 0.997) and a 10-fold lower limit of determination was observed for the RIA method compared with the HPLC method (0.05 and 0.5 ng ml-1, respectively). The RIA method was applied to the analysis of UK-68,798 in plasma obtained from human volunteers receiving the compound.

Animals↗
PubMed1990

High-performance liquid chromatographic resolution of oxamniquine enantiomers: application to in vitro metabolism studies.

A method is described for the HPLC analysis of oxamniquine enantiomers in liver fraction incubates, using a second-generation alpha 1-acid glycoprotein-based column (Chiral-AGP). Oxamniquine is extracted from the incubation media by liquid-liquid extraction, using diethyl ether. The dried residue is redissolved in eluent, filtered, then injected directly onto the analytical column. The extraction method affords recoveries of oxamniquine of approximately 93%, at concentrations up to 525 micrograms/ml, with an average relative standard deviation of 5.9%. The limit of detection of the method (to give an SNR = 2 at 246 nm) is 0.3 ng on-column for the first eluting, laevorotatory enantiomer and 2.3 ng for the dextrorotatory isomer. The method allowed study of the depletion of oxamniquine enantiomers in liver postmicrosomal incubates. In the rat, a turnover of 21.9% was observed, with no apparent enantioselectivity. Similar observations were made for a mouse liver subcellular fraction incubation. The absence of enantioselectivity in this biotransformation may be attributable to the low substrate specificity of the oxidase or dehydrogenase enzymes involved.

Animals↗
PubMed1989

In vitro metabolism studies on oxamniquine and related compounds by chiral liquid chromatography.

A previously developed method based on alpha 1-acid glycoprotein for the resolution of the enantiomers of the Pfizer antischistosomal drug oxamniquine was used to examine possible enantioselectivity in the in vitro microsomal hydroxylation of a metabolic precursor, UK-3883, but was found to be limited by the poor operational stability of the analytical column ("EnantioPac") employed. As an alternative approach, a "Pirkle" covalently-bonded dinitrobenzoyl leucine column was used, with simple precolumn solute derivatization to the carbamate to improve chromatographic performance. The method allowed preliminary examination of the stereochemistry of the in vitro biotransformation, hydroxylation of UK-3883 to oxaminquine, which yielded evidence for substrate enantioselectivity in favour of the dextrorotatory enantiomer of UK-3883.

Animals↗
PubMed1988

Comparison of the image quality of intravenous urograms using low-osmolar contrast media.

Almost equivalent, intravenous iodine doses of the three new low-osmolar contrast media, ioxaglate (Hexabrix), iopamidol (Niopam) and iohexol (Omnipaque) have been compared for image quality on the intravenous urogram. Generally good radiographic images were obtained. Iohexol gave better results for the nephrogram and pelvicalyceal distension compared with the other contrast media, but only the nephrogram results were statistically significant. Pyelographic density and ureteric distension and density were similar with all three contrast media. In patients where low-osmolality contrast media need to be used for intravenous urography, we suggest that iohexol gives the best radiographic images. Other factors, such as cost and the relative incidence of side-effects of the low-osmolar contrast media also need to be taken into consideration.

Humans↗