Phase I trial of piroxicam in 62 dogs bearing naturally occurring tumors

Summary Piroxicam, a nonsteroidal antiinflammatory drug, was given to 62 dogs bearing naturally occurring tumors in a phase I clinical trial. Dose escalation was performed, with oral doses ranging from 0.5 mg/kg every 48 h (q48h) to 1.5 mg/kg q48h being tested. Dose-limiting gastromestinal irritation/ulceration occurred in all four animals that received 1.5 mg/kg q48h. The maximum tolerated dose was 1 mg/kg q48h. Subclinical renal papillary necrosis occurred in two dogs (initial dosages, 1 and 1.5 mg/kg q48h, respectively). Following dose escalation, an additional group of dogs was treated with 0.3 mg/kg piroxicam q24h per os, the accepted canine dosage prior to this trial. Inclusion of this treatment group enabled evaluation of the toxicity of and tumor response to a daily dosage regimen. No complete remissions occurred in this trial. Partial remission was documented in three of ten dogs exhibiting transitional-cell carcinoma, in three of five animals bearing squamous-cell carcinoma, in one of three dogs displaying mammary adenocarcinoma, and in the one dog that exhibited a transmissible venereal tumor. The results of this study support the additional evaluation of piroxicam in a phase II clinical trial in dogs bearing naturally occurring tumors.This investigation was supported by Pfizer Inc.     

Comparison of two-dimensional vs three-dimensional camera systems in laparoscopic surgery

Background: The lack of depth perception and spatial orientation in video vision are the drawbacks of laparoscopic surgery. The advent of a three-dimensional camera system enables surgeons to regain binocular vision and may be advantageous in complex laparoscopic procedures. Methods: We prospectively studied two groups of surgeons (with and without experiences in laparoscopic surgery) who performed a designated standardized laparoscopic task using a two-dimensional camera system (Olympus OTV-S4) vs a three-dimensional camera system (Baxter-V. Mueller VS7700) and compared their time performances. Results: The results suggested that only experience in laparoscopic surgery had significant effect on individual's performance. We could not demonstrate any superiority of the 3D system over the 2D system. However, two-thirds of the surgeons commented that the depth perception did improve. Conclusions: With further refinement of the technology, the 3D system may improve its potential in laparoscopic surgery.     

High performance liquid chromatographic characterisation and quantitation of p-aminobenzoic acid N-acetylation in Chinese subjects

p-Aminobenzoic acid (PABA), p-acetamidobenzoic acid (PADB) and p-aminohippuric acid (PAH) have been separated and determined by a reversed phase, isocratic high performance liquid chromatographic (HPLC) procedure simultaneously. The mobile phase, at 1.5 ml min-1, used was 10 mM sodium hydrogen phosphate buffer, pH 3.5, containing 40% methanol. The eluent was detected at 270 nm. Linear relationship was obtained from 0 to 2.0 micrograms ml-1 of each compound with the corresponding peak-height ratio using p-methylamino-benzoic acid (PMAB) as the internal standard. Urine samples were obtained from healthy Chinese volunteers after oral dosing of 200 mg PABA which was used as a model substance for metabolic investigation of N-acetylation and other conjugation reactions. The 24 hour urinary recovery, from 43 healthy subjects, of PABA, PABA-COOH conjugates, PADB and PADB-COOH conjugates were (mean +/- S.D.) 2.9 +/- 1.5%, 5.2 +/- 3.3%, 13.9 +/- 4.0% and 42.9 +/- 9.8% of the ingested dose respectively. These accounted for 64.9 +/- 12.0% of total dose ingested in 24 hour. In contrast to previously reported findings on one Caucasian subject, no PAH was identified in the urine, and N-acetylation was the major route of metabolism of PABA apart from conjugation at the -COOH group in this group of Chinese volunteers. It is proposed that PABA metabolism may be a useful probe to study ethnic and geographic variation in N-acetylation.     

Further characterization of ts1-8, a mutant of herpes simplex virus type 1.

Our initial characterization of a herpes simplex virus type 1, temperature sensitive host shutoff mutant, called ts1-8, revealed that it has a low plaquing efficiency and exhibits a defect in the shutoff of host polypeptide synthesis and host DNA replication at the nonpermissive temperature of 39.5 degrees C. Using intratypic marker rescue experiments the ts plaquing mutation was mapped to a 557 bp region. Sequence analysis and complementation studies revealed that the low plaquing efficiency phenotype is due to a mutation in the glycoprotein B gene converting Pro-357 to Ser. This novel tsgB mutation is located in a conserved region of gB and it is distinct from the delayed host shutoff mutation (dhs).     

Nasal septum lesions caused by chromium exposure among chromium electroplating workers

A chromium electroplating worker, suffering from epistaxis during work, was found to have nasal septum perforation. To determine the etiology and prevalence of nasal septum lesions, we conducted a survey of seven chromium electroplating factories and examined 79 workers. Forty workers from three aluminum electroplating factories were also enrolled as the reference group. Subjects were thoroughly examined by an otolaryngologist and each of them provided a blood and urine sample. A questionnaire interview regarding symptoms of the upper respiratory tract, past medical history, life style, and work history was also conducted. Air chromium concentrations were measured by taking area samples for 4–6 hours. Based on field observation and chromium measurements, we divided chromium electroplating into three different exposure zones: workers directly dealing with electroplating tanks (n = 31), other process workers (n = 29), and office workers and drivers (n = 19). Among the 79 chromium electroplating workers, there were 16 cases of nasal septum perforation, and 42 with either scar formation or ulceration; 10 chromium electroplating workers developed skin ulcers after performing chrome plating. No workers from aluminum electroplating factories had any nasal septum or skin abnormalities. There was a consistent trend between the degree of chromium exposure and the signs and symptoms related to the nose, throat, and skin. Immediate improvement of occupational hygiene is warranted.     

Effect of omeprazole on the anticoagulant activity and the pharmacokinetics of warfarin enantiomers in rats

The effect of the proton pump inhibitor omeprazole on the anticoagulation and the pharmacokinetics of warfarin enantiomers was studied in rats. Omeprazole given intraperitoneally in a daily dose of 0.67 mg/kg over 8 days had no significant effect on the absorption, distribution and the total serum clearance values of the S- and R-enantiomers of warfarin. Omeprazole did not affect the pre-treatment baseline blood coagulation and the in vitro rat serum protein binding of warfarin enantiomers. In vitro study with rat liver microsomes showed that omeprazole had an inhibitory effect on the hydroxylation of warfarin enantiomers. Results obtained from in vivo urinary excretion study revealed that omeprazole inhibited the formation clearance of both S- and R-form oxidative metabolites, but increased that of the overall reductive metabolites, and the renal clearance of S- and R-enantiomers, of warfarin. As a consequence, the total serum clearance values for warfarin enantiomers remained unchanged and the hypoprothrombinaemic response produced by warfarin was not affected.     

Command hallucinations among Asian patients with schizophrenia.

OBJECTIVES: The impact of command hallucinations on patients and the determinants of patients' compliance with them are still poorly understood. The extant literature is also divided on their association with violence. This study aimed to establish the prevalence of command hallucinations and to identify the factors that affect compliance with the commands, together with patients' coping methods. METHODS: We recruited 50 consecutive male and 50 consecutive female schizophrenia inpatients who reported hearing voices in the 6 months prior to admission. We interviewed these patients, using a semistructured questionnaire. We collected information on the contents of their auditory hallucinations and their coping methods. RESULTS: Of the patients, 53 (53%) reported command hallucinations. Of these 53 patients, 58% were women and 48% were men; 62% reported complying with the commands. They were also more likely to comply with nonviolent commands. A history of self-harm predicted compliance. Those patients who did not comply with the commands adopted various methods of coping, of which praying was the most common. CONCLUSION: Command hallucinations are common in patients with schizophrenia. Patients with a history of self-harm need closer monitoring because they may be more likely to comply with these hallucinations. Assessment should also include the patient's own coping strategies, which can be incorporated into the treatment.     

Relation of alveolar size to forced vital capacity in professional divers

Eight cases have been studied in which both lung function and histological morphometric data was available on divers' lungs. A correlation was found between the increase in forced vital capacity measured at routine annual medical examination and the morphometric measurement of alveoli by mean cord length. The results suggest that reduction of forced expiratory volume in one second may be due to narrowing of small airways by distention of the alveoli.     

Proteolytic Processing Mechanisms in the Biosynthesis of Neuroendocrine Peptides: The Subtilisin-like Proprotein Convertases

The recent discovery of a novel family of precursor processing endoproteases has greatly accelerated progress in understanding the complex mechanisms underlying the maturation of prohormones, neuropeptides, and many other precursor-derived proteins. At least six members of this family have been found thus far in mammalian species, several having alternatively spliced isoforms, and related enzymes have been identified in many invertebrates, including molluscs, insects, nematodes, and coelenterates. The proprotein convertases are all dependent on calcium for activity and all possess highly conserved subtilisin-like domains with the characteristic catalytic triad of this serine protease (ordered Asp, His, and Ser along the polypeptide chain). Two members of this family, PC2(SPC2) and PC1/PC3(SPC3), appear to play a preeminent role in neuroendocrine precursor processing. Both convertases are expressed only in the brain and in the extended neuroendocrine system, while another important family member—furin/PACE (SPC1)—is expressed more ubiquitously, in almost all tissues, and at high levels in liver. SPC2 and SPC3 exhibit acidic pH optima and other properties which enhance their activity in the acidic, calcium-enriched environment of the dense-core secretory granules of the regulated pathway in neuroendocrine cells, while furin has a neutral pH optimum and is localized predominantly to the trans Golgi network where it is retained by a C-terminal transmembrane domain. Furin processes a wide variety of precursors in the constitutive pathway, such as those of growth factors, receptors, coagulation factors, and viral glycoproteins. Recent findings on the processing of proopiomelanocortin, proinsulin, proglucagon, and several other neuroendocrine precursors by SPC2 and SPC3 are discussed, along with information on the structure, properties, evolution, developmental expression, and regulation or the convertases. An inherited defect in the fat/fat mouse which affects the processing of proinsulin, and probably also many other prohormones, due to a point mutation in carboxypeptidase E has recently been identified and has begun to provide new insights into the functional integration of the individual processing steps.