Effects of Nd-YAG laser on platelet function in vitro: A comparative study using the spectraprobe, ‘hot tip’ and bare fibres

The effects of Nd-YAG laser irradiation on platelet function in vitro were studied using platelet rich plasma obtained from the blood of healthy volunteers. Laser delivery was effected via the bare optical fibre, thermal hot tip fibre and spectraprobe and the effects of these probes on platelet function were compared. Fall in platelet count and mean platelet volume (MPV) were proportional to increasing energy delivery with all three probes, the effect being maximal with the spectraprobe, moderate with the hot tip and least with the bare optical fibre. A significant decrease in percentage aggregation of platelets in response to added ADP, collagen and ristocetin with increasing energy delivery was also observed with all three probes. The formation of preformed aggregates, however, showed an increase proportional to energy delivery with all three probes.The differential effects of the various probes used in this study on platelet function may enhance our understanding of the complex role played by platelets in the pathogenesis of complications such as arterial thrombosis and re-occlusion after laser angioplasty.     

Staged TRAM Breast Reconstruction: Combining the Advantages of Tissue Expansion with Surgical Delay

The TRAM flap has become the gold standard in breast reconstruction but suffers from the disadvantages of poor color match, different texture, and impaired sensation compared to the normal breast. This study reports on a two-stage procedure to address these problems. The first stage consists of insertion of a tissue expander and surgical delay of the TRAM flap. The second stage consists of removal of the tissue expander and transposition of a deepithelized TRAM flap into the tissue expanded cavity. (The capsule is excised.) Four cases of breast reconstruction are reported. The advantage of this procedure is that it offers the benefits of tissue expansion, viz., normal color match, texture, and sensation, and in addition, reconstruction is achieved with autologous tissue by a pedicled TRAM flap. The vascularity of the TRAM is enhanced by a surgical delay procedure.     

Pharmacokinetics, in-situ absorption and protein binding studies of a new neuroleptic agent centbutindole in rats.

The present study reports the absorption kinetics, plasma protein binding and pharmacokinetic profile of the centbutindole (I) after i.v. and oral dosing in rats. In addition, an in-situ absorption study was carried out using a closed-loop technique at pH 2.6 and 7.4. The rate of absorption at pH 2.6 was 5-fold less compared to that observed at pH 7.4. In-vitro and in-vivo protein binding (ultra filtration technique) was independent of substrate concentration over a range of 1.25-10.0 microg/ml. Pharmacokinetic parameters of I were determined in male rats after administering a single 4 mg/kg oral dose and 2 mg/kg intravenous dose. The peak serum concentration of I was found to be 50.1 ng/ml at 30 min after oral administration followed by a secondary Cmax of 43.2 ng/ml at 180 min. For the hydroxy metabolite (II), a Cmax of 6.4 ng/ml was measured at 360 min after oral administration of I. After oral dosing an irregular concentration-time profile with secondary peaks was observed for both I and II. The terminal half-lives for I and II after oral dosing were 163 and 263 min, respectively. After intravenous dosing, the levels of I decreased biexponentially with a distribution (t(1/2) alpha) and elimination (t(1/2) beta) half-lives of 5.7 and 128 min, respectively. Comparison of the AUC after oral and intravenous dosing of I indicates that only about 24% of the oral dose reaches the systemic circulation. The limited bioavailability can either be due to the poor solubility of the compound and/or extensive first pass metabolism in the gastrointestinal (GI) tract. Co-administration of polyethylene glycol (PEG) at oral dosing improves solubilization and increases bioavailability.     

Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients.

PURPOSE: To evaluate safety and preliminary efficacy of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy (RT) in unresectable head and neck cancer patients. Secondary end points were the measurement of h-R3 serum levels and the assessment of the potential mechanisms of antitumor effect on patient biopsies. Anti-idiotypic response to h-R3 was assessed. To predict pharmacologic effect, a mathematical model for antibodies recognizing antigens expressed in tumors and normal tissues was built. PATIENTS AND METHODS: Twenty-four patients with advanced carcinomas of the head and neck received six once-weekly infusions of h-R3 at four dose levels in combination with RT. Pretreatment tumor biopsies were obtained to evaluate epidermal growth factor receptor expression as an enrollment criterion. Second biopsies were taken to evaluate the proliferative activity and angiogenesis in comparison with the pretreatment samples. Patient serum samples were collected to measure h-R3 levels and anti-idiotypic response. RESULTS: The combination of h-R3 and RT was well tolerated. Antibody-related adverse events consisted in infusion reactions. No skin or allergic toxicity appeared. Overall survival significantly increased after the use of the higher antibody doses. Immunohistochemistry studies of tumor specimens before and after treatment revealed that antitumor response correlated with antiproliferative and antiangiogenic effect. One patient developed antibodies to h-R3. The mathematical model predicted that the maximum difference between the area under the curve in tumors and normal tissues is reached when the antibody has intermediate affinity. CONCLUSION: h-R3 is a well-tolerated drug that may enhance radiocurability of unresectable head and neck neoplasms.     

Zeniplatin in advanced malignant melanoma and renal cancer: phase II studies with unexpected nephrotoxicity

The antitumor activity of zeniplatin, a third-generation, water-soluble platinum compound that has shown broad preclinical antitumor activity and no significant nephrotoxicity in phase I trials, was tested in patients with advanced malignant melanoma and advanced renal cancer. Patients who had not previously been treated, except with local limb perfusion and immunotherapy, were given zeniplatin as bolus injections at 125 mg/m² every 3 weeks. The main hematological toxicity was leukopenia (7/30 patients, WHO grade ≥ 3) and the main nonhematological toxicity was nausea and vomiting (21/30 patients, WHO grade ≥ 2). Serious nephrotoxicity was observed early in the renal cancer study and, later, also in the melanoma study. Hyperhydration did not prevent the nephrotoxicity, and the studies were stopped after 6 renal cancer patients and 24 malignant melanoma patients had been included. Zeniplatin gave objective responses in 3 of the 21 evaluable malignant melanoma patients [2 complete responses (CRs) in patients with lymph-node metastases lasted 5 and 14 months, respectively; 1 partial response (PR) in a patient with lymph-node and liver metastases lasted 6 months]. In the renal cancer study, only four patients were evaluable for response and none responded. The results show that zeniplatin has some activity (14%) in patients with advanced malignant melanoma, but no conclusion can be drawn regarding the activity of zeniplatin in renal cancer as the number of patients was too low. The main toxicities were leukopenia and nausea and vomiting. Unexpected and serious nephrotoxicity was observed, and for this reason the studies were terminated before the planned number of patients had been included. A possible explanation for the nephrotoxicity may be drug interactions, but no firm conclusion can yet be drawn. Received: 16 March 1996 / Accepted: 25 March 1997     

Effects of physical training in asthma: a systematic review

OBJECTIVES: To assess the evidence for the effects of physical training on pulmonary function, symptoms, cardiopulmonary fitness, and quality of life in subjects with asthma. METHODS: A search was conducted for randomised controlled trials of subjects with asthma undertaking physical training using the Cochrane Airways Group register of controlled clinical trials, Medline, Embase, Sportdiscus, Science citation index, and Current contents index. Studies were included in the review if the subjects had asthma, were 8 years of age or older, and had undertaken physical training for at least 20 minutes per session, twice a week, for a minimum of four weeks. The eligibility of trials for inclusion in the review and the quality of the trials were independently assessed by two reviewers. RESULTS: Eight studies with a total of 226 subjects met the inclusion criteria for this review. Physical training had no effect on resting lung function but led to an improvement in cardiopulmonary fitness as measured by an increase in maximum oxygen uptake of 5.6 ml/kg/min (95% confidence interval 3.9 to 7.2). None of the studies measured quality of life. CONCLUSIONS: Physical training improves cardiopulmonary fitness without changing lung function. It is not clear if the improvement in fitness translates into a reduction in symptoms or an improvement in the quality of life. There is a need for further randomised controlled trials of the effects of physical training in the management of asthma.     

A comparative study of the utility of two superdisintegrants in microcrystalline cellulose pellets prepared by extrusion-spheronization.

This study evaluated the utility of including superdisintegrants (croscarmellose sodium or sodium starch glycolate) in microcrystalline cellulose extrusion-spheronization pellets as a means of increasing the dissolution rate of poorly water-soluble drugs. The model drug was hydrochlorothiazide, with water or water/ethanol as wetting agent for pellet preparation. Neither disintegrant had significant effects on pellet morphology, flow properties or mechanical resistance. Neither disintegrant caused disintegration of the pellet in drug dissolution medium. Nevertheless, the disintegrants afforded a modest increase in drug dissolution rate, attributable to the observed increase in pellet micropore volume. Drug dissolution rate was slightly higher in pellets prepared with sodium starch glycolate, probably because of this disintegrant's higher swelling capacity.     

Phase II trial of fortnightly irinotecan (CPT-11) in the treatment of colorectal cancer patients resistant to previous fluoropyrimidine-based chemotherapy

Introduction This phase II study investigated the anti-tumour activity and toxicity of CPT-11 (250 mg/m2 i.v. infusion over 60 minutes) administered every 2 weeks as second-line chemotherapy in patients with advanced colorectal cancer (CRC). Material and methods Patients (n=63) with histology diagnosis of advanced CRC and proven resistance to previous fluoropyrimidine therapy were enrolled. Results A total of 510 CPT-11 cycles were administered, with a mean of 8 cycles per patient (range: 1–32). The median relative dose intensity was 93%. Partial response (PR) was obtained in 11 patients (17.5%; 95%CI: 8.1%–26.7%) and 29 patients (46.0%) showed stable disease (clinical benefit of 63.5%). The median duration of response was 6.8 months (95%CI: 6.1–7.5 months), median survival was 8.8 months (95%CI: 6.3–11.5 months) and median time to disease progression was 4.5 months (95%CI: 3.9–5.0 months). Overall, this schedule of CPT-11 chemotherapy was well tolerated by the patient. Neutropenia was the most frequent grade 3/4 haematological toxicity (20.6% of patients and 4.1% of cycles). Neutropenia with concurrent fever or infection occurred in 7 patients (11.1%). Late onset diarrhoea was the most frequent grade 3/4 non-haematological toxicity (19.0% of patients and 2.3% of cycles). Other, lower-incidence, toxicities were anaemia, fever, infection, mucositis, nausea and vomiting. There were no toxic deaths. Conclusions We found that CPT-11, administered as 250 mg/m² i.v. infusion over 60 minutes every 2 weeks, was active and well tolerated schedule in the second-line chemotherapy of advanced CRC patients. This bi-weekly scheme could be used as an alternative to the weekly or the every-three-week schedule as well as in combined therapies with other chemotherapeutic agents for the treatment of advanced, metastatic, CRC.