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Objectives: The outcome in dogs with pulmonary hypertension associated with natural Angiostrongylus vasorum infection is unclear. This study aimed to report long-term outcome of dogs with A. vasorum and pulmonary hypertension, and to evaluate factors associated with pulmonary hypertension development. It was hypothesised that dogs with pulmonary hypertension had a shorter survival time than dogs without pulmonary hypertension., Methods: Retrospective review of clinical records of dogs diagnosed with A. vasorum. Dogs were classified as having or not having pulmonary hypertension based on clinical signs and imaging findings. Signalment, signs and outcome were recorded. DNA obtained from banked samples was genotyped for the PDE5a:E90K polymorphism, a possible factor in development of pulmonary hypertension., Results: The proportion of dogs with moderate-to-severe pulmonary hypertension and A. vasorum infection in the study population was 14 · 6%. No difference in the population characteristics or PDE5a genotype was detected between dogs with and without pulmonary hypertension. Dogs with pulmonary hypertension had a significantly shorter survival time (P = 0 · 006) and a greater risk of death within 6 months of diagnosis (odds ratio 12 · 5, 95% confidence interval 2 · 1 to 74 · 9; P = 0 · 0053)., Clinical Significance: A. vasorum-associated pulmonary hypertension is an important problem in naturally infected dogs and has a negative effect upon survival., (© 2014 British Small Animal Veterinary Association.)

Arterial aneurysms are defined as localized abnormal dilatations in an arterial wall. We report the first case of multiple true aneurysms in the female breast in a patient with a history of chronic amphetamine abuse who presented with a probable subarachnoid haemorrhage (SAH).

The World Health Organization (WHO) and other organizations report that the prevalence of human diseases during the past decade is rapidly increasing. Population growth and the pollution of water, air, and soil are contributing to the increasing number of human diseases worldwide. Currently an estimated 40% of world deaths are due to environmental degradation. The ecology of increasing diseases has complex factors of environmental degradation, population growth, and the current malnutrition of about 3.7 billion people in the world., (© Springer Science+Business Media, LLC 2007.)

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.

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.

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.

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%.

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.

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.

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.

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.

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.

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.

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.

The use of the term lazy eye blurs the distinction between amblyopia and strabismus, often causing parents to confuse the two problems. Parents often infer a causal explanation from the descriptive term, lazy eye. This misunderstanding causes parents to believe the child may outgrow the disorder. Therefore, an opportunity for early treatment during the important formative years may be lost. The correctly informed and knowledgeable parent will be more active and responsible in making sure that the child, especially the noncompliant child, follows the advised treatment.

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.

1. The extent of metabolism of oxamniquine, 6-hydroxymethyl-7-nitro-2-isopropylaminomethyl-1,2,3,4-tetrahydroquinoline, in the gut of the dog has been studied using an intestinal preparation which allows collection of the outflow from the portal vein. 2. Oxamniquine undergoes substantial conversion to 2-isopropylaminomethyl-7-nitro-1,2,3,4,-tetrahydroquinoline-6-carboxylic acid before or during absorption. 3. This oxidation is not significantly inhibited by pretreatment with pyrazole, erythromycin or gentamicin. 4. Results indicate that appreciable oxidation of oxamniquine is mediated via enzymes in the gut wall.

The metabolism of oxamniquine, 6-hydroxymethyl-7-nitro-2-isopropylaminomethyl-1,2,3,4-tetrahydroquinoline, has been studied in the mouse, rat, hamster, rabbit, rhesus monkey, dog and man. Urinary excretion is a major route of elimination in man. The compound is converted to two metabolites, the major one arising from oxidation of the 6-hydroxymethyl group to a carboxyl group and the other by oxidation of the side chain to give the 2-carboxylic acid. There is a species at the dose levels used since both acidic metabolites were found in appreciable quantities only in the urine of mouse, rabbit, hamster and dog. The 2-carboxylic acid was not found in the urine of rhesus monkey and rat and occurred in only trace amounts in human urine.

Hyoscine butylbromide (20 mg) given intravenously to 48 patients with normal oesophageal motility significantly reduced oesophageal transit of hard gelatin capsules when swallowed in the erect and supine positions with 15 ml and 60 ml water when compared to an age/sex matched group. Delayed capsule transit and possible failed or slowed drug absorption occurring as a consequence of anti-cholinergic drugs on the oesophagus, constitutes a new drug interaction.

The bioavailability of carbazeran and the metabolism of carbon-14 labelled drug have been studied in the dog and man following oral administration. The drug was moderately well absorbed in both species, but there was a marked difference in bioavailability and in routes of metabolism. In the dog, systemic bioavailability was approx. 68% and biotransformation involved mainly O-demethylation. In man, bioavailability was not measurable and carbazeran was almost completely cleared via 4-hydroxylation of the phthalazine moiety. Thus the lack of detectable pharmacological effect in man following oral administration of the drug appears to be due to presystemic metabolism by a particularly active pathway not found in the dog.

The uptake and retention of drug-related material by Schistosoma mansoni was studied in the mouse host following a single oral or intramuscular dose (50 mg/kg) of [14C]oxamniquine. Male worms took up more labelled material than did female worms but the amount in each particular sex of worm was found to be similar after both routes of administration. Exposure of worms was therefore independent of the route of administration. Six days after drug administration, at the time of an hepatic shift, significantly more drug-related material was present in male worms than in female worms. Examination of worms recovered from mice 4 h after treatment showed that metabolites of oxamniquine constituted 70--90% of the drug-related material present in the worms. Both sexes of worms were able to take up metabolites of oxamniquine in vitro.

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.

A crossover study was carried out in cattle to determine the serum pharmacokinetics of a standard dose (20 mg/kg bodyweight) of oxytetracycline given either as a conventional injectable formulation or as a long acting formulation. For reference purposes, an intravenous treatment (also given at 20 mg/kg) was included in the trial protocol. A comparison of the two treatment regimes showed that the long acting formulation gave a significantly lower peak oxytetracycline serum concentration, with a significant extension of drug serum concentration. The long acting formulation also showed a longer serum half life and a significantly greater area under the curve value, calculated from 36 hours onwards, together with serum oxytetracycline concentrations which exceeded 0.5 microgram/ml for 86.8 as opposed to 51.5 hours for the conventional formulation. It is concluded that the use of the long acting formulation in cattle leads to a more sustained serum oxytetracycline concentration than does the same dose of conventional formulation.

A questionnaire relating to presence and nature of back pain was distributed to all 10,150 employees (59% men) of an industrial complex. The questionnaire was returned by 2892 subjects (65% men). Of these, 1880 (65% of responders or 19% of total) reported a history of back pain. One hundred twenty-four described their back pain as insidious in onset, persisting for at least three months, developing at less than 40 years of age, being associated with morning stiffness, and showing improvement with exercise. Three hundred sixty-seven subjects scored four of these five features. Pelvic radiographs of 342 persons were available for blind evaluation. Sixteen patients (12 men) were shown to have definite ankylosing spondylitis (Grade III or IV sacroiliitis or HLA B27-associated Grade II sacroiliitis). Only one of these persons was known to have spondylitis. The majority of these symptomatic patients had been seen by both medical and nonmedical practitioners.

The subjective side-effects of almost equivalent intravenous iodine doses of the three new low-osmolar contrast media, ioxaglate (Hexabrix), iopamidol (Niopam) and iohexol (Omnipaque) have been recorded and are found to be generally comparable. Urticaria occurred more frequently with ioxaglate than with the other contrast media and there was a tendency for ioxaglate to cause more nausea. Pain at the injection site occurred less often with ioxaglate than with iohexol. If low-osmolar contrast media are to be used in intravenous urography the relative cost of each is important, there being as yet insufficient data concerning the relative incidences of major reactions.

The metabolism of carbazeran has been investigated in vitro using liver cytosol from dog, baboon and man. Carbazeran was not metabolized in cytosol prepared from dog liver but was rapidly metabolized to a single product in baboon- and human-liver cytosol. The product was identified as 4-hydroxy carbazeran. The enzyme responsible for the 4-hydroxylation of carbazeran in vitro was shown by the use of inhibitors to be liver aldehyde oxidase. Species differences in the metabolism of carbazeran in vitro correlate well with studies in vivo; these showed that following an oral dose to man and baboon, the compound was almost completely cleared via pre-systemic 4-hydroxylation, whereas in the dog, this metabolic route appeared unimportant.

The metabolic fate of doxazosin was investigated in man, mouse, rat and dog using 14C-labelled compound. Bioavailability and pharmacokinetic studies were also conducted with nonlabelled drug, using a specific h.p.l.c. method. Following both oral and intravenous administration, the major route of elimination of drug-related compounds was via the faeces for all species studied. Comparison of the oral and intravenous data show that doxazosin is completely absorbed in man, mouse and rat and is moderately well absorbed in dog. The drug is extensively metabolized, e.g. only about 5% of the dose was excreted unchanged in man. Metabolism in man mainly involves 6- and 7- O-demethylation and 6' and 7'-hydroxylation. These and some minor products were common to the mouse, rat or dog and man. Plasma protein binding was high in all species studied, ranging from 95.3% in the rat to 98.3% in human patients. Oral bioavailability is 60% in dog and approximately 50% in the rat, which is similar to the value of 63% reported for man at therapeutic doses. Mean plasma clearance values were 13 ml min-1 kg-1 (dogs), 30 ml min-1 kg-1 (rats) and 1.2 ml min-1 kg-1 (human subjects). Mean plasma half-life values were 5 h in dogs and 1.2 h in rats: a value of 9 h was reported for human volunteers (cf. 2.5 h for prazosin). The long plasma half-life of doxazosin provides the basis for once-daily dosing.

A method was developed to determine cefazolin in serum or urine. The drug is extracted from serum or urine with ethyl acetate, separated by TLC, and determined by fluorescence quenching densitometry. The method was developed to study the pharmacokinetics of the compound in humans.

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.