Tinidazole in the prevention of wound infection after elective colorectal surgery.

During the first six months of 1978, 71 patients were the subject of a controlled trial of the use of tinidazole for the prevention of wound infection after elective colonic surgery. The trial design was prospective, randomized and double-blind with tinidazole or placebo given at the last oral intake before operation. The objective endpoint of the trial was the presence or absence of wound infection manifested by pus. All patients underwent a standard preoperative preparation of bowel washouts, and a standardized surgical technique included, in all cases, the use of wound drainage. At the end of the trial there were three wound infections in 40 patients who were given tinidazole, and eleven wound infections in 31 patients who were given placebo. The difference in wound infection rate between these two groups is significant (x2 with Yates correction = 7.3; P less than 0.01).     

Pulmonary O-methyl transferases

An investigation in vitro of pulmonary O-methyl transferases revealed the presence of microsomal phenol-O-methyl transferase and soluble and microsomal catechol-O-methyl transferases in guineapig lung tissue. Both phenol and catechol transferases also were detected in rat and rabbit lung tissue. Substrates of guinea-pig pulmonary phenol-O-methyl transferase included phenols, cresols and xylenols. but not alcohols and amines. Catechol-O-methyl transferases from both subcellular sources were found to have similar pH optima, magnesium ion requirements, K_m values, and utilized norepinephrine, isoproterenol and dopamine as substrates, but not metaproterenol and salbutamol. These data for the pulmonary enzymes are similar to published values for liver O-methyl transferases.     

Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice

High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions of the colon, stomach, esophagus, oral cavity, prostate, and breast. Inhibition of FAS with C75 has led to a significant antitumor effect in both human breast and prostate cancer xenografts. Recently, HER2/neu, which has also been identified in preneoplastic breast lesions, has been shown to regulate FAS expression through the PI3K/Akt signal transduction pathway rendering them susceptible to FAS inhibition. Utilizing the neu-N transgenic mouse model of mammary cancer, weekly treatment of the neu-N mice with C75 (30 mg/kg) for 10 weeks significantly delayed tumor progression. Only 20% of the C75-treated transgenic mice developed mammary carcinoma by 220 days, compared to 50% in the vehicle control animals. Two C75-treated animals never developed mammary cancer. Analysis of mammary tissue following 10 weeks of C75 treatment revealed a significant delay in mammary maturation as manifested by a reduction of the number and caliber of mammary ducts and budding epithelial structures. Apoptotic changes were increased, DNA synthesis was decreased, and the expressions of FAS, neu, Akt, phospho-Akt, and p21(waf1) were all decreased when compared to vehicle controls and FVB/N mice. Importantly, these effects were restricted to the breast epithelial cells that overexpressed neu, not involving other normal duct structures in the skin, liver, or kidney. C247, an FAS inhibitor chemically distinct from C75, significantly delayed mammary maturation similar to C75. Thus, pharmacological inhibition of FAS affects the expression of key oncogenes involved in both cancer development and maintenance of the malignant phenotype. Moreover, these data identify FAS as a potential novel drug target for breast cancer chemoprevention.     

GG genotype of cyclin D1 G870A polymorphism is associated with increased risk and advanced colorectal cancer in patients in Singapore

Recent studies have implicated cyclin D1 G870A single-nucleotide polymorphism (SNP) in susceptibility to and early onset of colorectal cancers (CRC). We investigated the role of cyclin D1 G870A SNP in Singapore CRC patients without dominant family history by genotyping 254 patients and 101 controls. The risk of cancer for AA individuals was less than half that of GG individuals (odds ratio (OR) 0.41; 95% confidence interval (CI) 0.18-0.96). Furthermore, AA and AG patients whose tumours were Dukes C and D (OR 0.38; 95% CI 0.17-0.83), poorly differentiated (OR 0.28; 95% CI 0.09-0.84) and left-sided (OR 0.45; 95% CI 0.21-0.98) were associated with significantly lower risk than GG patients. Young (aged 50 years or less) GG patients had a 5-year lower mean age at onset than AA/AG patients (P=0.02). Young male GG patients had worse disease-specific survival than AA/AG patients (P=0.002). Thus, contrary to Caucasians, the GG (rather than AA) genotype is associated with increased susceptibility and advanced CRC in Singapore patients, suggesting a more complex relationship between the SNP and CRC risk, possibly modulated by population differences.     

The degree of bone marrow fibrosis in chronic myelogenous leukemia is not a prognostic factor with imatinib mesylate therapy

One hundred and ten patients with Philadelphia chromosome (Ph)-positive chronic phase chronic myelogenous leukemia (CML) post-interferon-a failure treated with imatinib mesylate therapy were analyzed for the prognostic significance of marrow reticulin stain-measured fibrosis. The median time from diagnosis was 31 months. Severe reticulin (grade 3 - 4) fibrosis was observed in 67 patients (61%). Patients with severe marrow fibrosis had similar complete cytogenetic response rates with imatinib (67 vs. 58%; P = 0.45) compared with those with mild?-?moderate fibrosis. The estimated 4 year survival rates (80 vs. 88%; P = 0.27) and failure-free survival rates (69 vs. 77%; P = 0.34) were also not different. We conclude that the previously established poor prognostic significance of marrow fibrosis in CML is less relevant with imatinib therapy.     

Optically guided patient positioning techniques

Optical tracking determines an object's position by measuring light either emitted or reflected from the object. The hallmark of optical tracking systems is their high spatial resolution and measurement in real time; such systems can resolve the position of a point source within a fraction of a millimeter and report at a rate of 10 Hz or faster. Several systems have been developed for radiation therapy, all of which track infrared markers attached to the patient's external surface. The positions of the optical markers relative to the target volume, together with the desired marker positions relative to treatment isocenter, are determined during computed tomography simulation. In the treatment room, the real marker positions are measured relative to isocenter; rigid-body mathematics then determine marker displacements from their desired positions and hence target displacement from isocenter. Real-time feedback allows one to correct the patient's position. The first systems were used for intracranial stereotaxis radiotherapy; rigid arrays of optical markers were attached to the patient via a biteplate linkage. Subsequent systems for extracranial radiotherapy tracked external markers to determine patient position and/or gate the radiation beam based on patient motion. Lastly, optical tracking has been integrated with ultrasound or stereoscopic x-ray imaging to determine the position of internal anatomy targets relative to isocenter.     

History of prolonged-release formulations and the contribution of French pharmacy in this field

The second part of the XXth century have seen the creation of new systems of administration for drugs, including delayed formulation systems or prolonged-release formulations (PRF). It is first within the industry, and mainly in the USA, that such new formulations were developed, with the purpose to increase the duration of action for pharmaceutical active principles. Several approaches were proposed and developed, jointly with more and more sophisticated evaluation techniques. In France, PRF market increased progressively during the 1980's; it then decreased because of more severe restrictions by health authorities for new drug approvals. In French specialty reference book (Vidal) included 518 PRF in the year 2000, from which 121 were tablets and 118 were hard gelatine capsules.     

Simultaneous analysis of the Delta9-THC metabolites 11-nor-9-carboxy-Delta9-THC and 11-hydroxy-Delta9-THC in meconium by GC-MS

Neonates that are exposed to cannabinoids in utero may have characteristic physical and mental developmental problems throughout their lives. The early identification of exposed neonates allows early intervention and anticipation of potential problems. Testing meconium detects maternal marijuana use over the last four months of gestation, providing a better drug exposure marker than urine. However, the distribution of metabolites in meconium is not identical to urine and analytical methods must be adapted. Both the major urine metabolite, 11-nor-9-carboxy-Delta9-tetrahydrocannabinol (9-carboxy-THC), and a minor urine metabolite, 11-hydroxy-Delta9-tetrahydrocannabinol (11-hydroxy-THC), are common in meconium. Currently published methods to extract these two metabolites for instrumental analysis are time-consuming and laborious, often involving the preparation of two fractions. This study describes a simple solid-phase extraction method and an optimized hydrolysis method that allow the preparation and analysis of both metabolites in a single extract. The limit of detection by this extraction method was 5 ng/g for both metabolites with an analytical measurement range from 10 to 500 ng/g. The recovery at 100 ng/g was greater than 62% for both analytes. The analysis of 246 cannabinoid screen positive specimens illustrated the importance of including the 11-hydroxy-THC in a meconium marijuana confirmation: 16 specimens confirmed positive for 11-hydroxy-THC only, resulting in a 6.5% increase in the positivity rate compared to 9-carboxy-THC alone.