The role of few-asperity contacts in adhesion.

The surface roughness of a few asperities and their influence on the work of adhesion is of scientific interest. Macroscale and nanoscale adhesion data have seemingly given inconsistent results. Despite the importance of bridging the gap between the two regimes, little experimental work has been done, presumably due to the difficulty of the experiment needed to determine how small amounts of surface roughness might influence adhesion data lying in between the two scales. To investigate the role of few-asperity contacts in adhesion, the pull-off force was measured between different sized atomic-force microscope (AFM) tips (with different roughnesses) and sample surfaces that had well-controlled material properties. There were seventeen tips of four different types, with radii from 200 nm to 60 microm. The samples were unpatterned single crystal silicon with a chemical silicon dioxide surface resulting from a standard silicon wafer clean. Some of the samples were treated with a few angstroms of vapor deposited diphenylsiloxane. We observed that the uncorrected (for surface roughness) pull-off force was independent of the radius of the AFM tip, which was contrary to all continuum-mechanics model predictions. To explain this behavior, we assumed that the interactions between the AFM tip and sample were additive, material properties were constant, and that the AFM tip, asperities, and sample surfaces were of uniform density. Based on these assumptions, we calculated a simple correction due to the measured root mean square (RMS) surface roughness of the AFM tips. The simple correction for the RMS surface roughness resulted in the expected dependence of the pull-off force on radius, but the magnitudes were higher than expected. Commercial and heat-treated AFM tips have minimal surface roughness and result in magnitudes that are more reliable. The relative uncertainty for the pull-off force was estimated to be 10%. In this paper, we derive how the cantilever and tip parameters contribute to the measured pull-off force and show how the corrected results compare with theory. Although much work is still needed, the work presented here should advance the understanding of adhesion between the macroscale and nanoscale regimes.

Polymers for delivering peptides and proteins.

The use of polymers for delivering peptide and protein drugs is described. Soluble-polymer technology attempts to bind a polymer to all sites on therapeutic protein molecules that cause the body to recognize the molecules as foreign. Goals include a stable linkage, water solubility, low immunogenicity, prolonged half-life, and intact biological activity. Polyethylene glycol (PEG)-adenosine deaminase (ADA), or pegademase bovine, has FDA-approved labeling as replacement therapy for ADA deficiency in patients with severe combined immunodeficiency disease who are not suitable candidates for bone marrow transplantation. Pegademase bovine reverses the toxic accumulation of adenosine and deoxyadenosine in adenosine deaminase-deficient cells, restoring the immune system. PEG-asparaginase (pegaspargase) has shown promise in patients with acute lymphocytic leukemia; allergic reactions have been minimal. Animal studies suggest that superoxide dismutase has potential use in conditions in which the body's ability to remove oxygen free radicals is reduced, such as burns and myocardial infarction; coupling with PEG may greatly increase the protein's half-life. Other PEG-conjugated proteins under investigation include PEG-catalase, PEG-uricase, PEG-honeybee venom, PEG-hemoglobin, and PEG-modified ragweed pollen extract. Dextran, albumin, DL-amino acids, and polyvinyl pyrrolidone have also been studied as protein carriers; most of the products created thus far have not shown much promise. The coupling of polymers to proteins has yielded protein drugs with intact biological activity and reduced immunogenicity, but much remains to be learned about this technology.

Transdermal clonidine for ameliorating tamoxifen-induced hot flashes.

PURPOSE: To determine the efficacy of transdermal clonidine for alleviating tamoxifen-induced hot flashes in women with a history of breast cancer. PATIENTS AND METHODS: A randomized, double-blind, crossover design was used in this prospective study. Women with a history of breast cancer who were receiving tamoxifen and suffering from hot flashes were potentially eligible for this protocol study. RESULTS: Clonidine did reduce hot-flash frequency to a degree that was statistically impressive (P < .0001), but clinically moderate (20% reduction from baseline). It also decreased hot-flash severity (P = .02, 10% reduction from baseline). Clonidine was related to increased mouth dryness (P < .001), constipation (P < .02), itchiness under the patch (P < .01), and drowsiness (P < .05). CONCLUSION: Better means are needed to alleviate hot flashes among patients in whom estrogen therapy is contraindicated.

Comparative morphine pharmacokinetics following sublingual, intramuscular, and oral administration in patients with cancer.

Previous literature reports have suggested that sublingually administered morphine sulfate results in an improved bioavailability of the drug when compared to orally administered morphine. To investigate this possibility further, we studied six cancer patients all of whom received 10 mg doses of morphine sulfate by intramuscular, oral and sublingual routes. Pharmacokinetic analyses failed to suggest an advantage of sublingual administration when compared with oral dosing. Bioavailability of morphine following intramuscular administration appeared superior to both oral and sublingual routes.

Body-composition changes in patients who gain weight while receiving megestrol acetate.

PURPOSE: Randomized placebo-controlled clinical trials have now established that megestrol acetate causes appetite stimulation and weight gain in patients with anorexia and/or cachexia. There is a paucity of available data to delineate the substance of this increased weight. PATIENTS AND METHODS: Using dual-energy x-ray absorptiometry and tritiated body water methodologies, we performed body-composition measurements in 12 patients with advanced cancer before the institution of oral megestrol acetate (800 mg/d) and at subsequent 2-month intervals. RESULTS: Seven of the 12 patients gained weight (2.1 to 16.5 kg) and had repeat body-composition measurements performed at the time of maximum weight gain. The vast majority of the gained weight was clearly from an increase in adipose tissue, while there was a suggestion that an increase in body fluid was responsible for a minority of the weight gain. CONCLUSION: Megestrol acetate-induced weight gain is primarily the result of an increase in body mass.

Cancer-associated anorexia and cachexia. Implications for drug therapy.

Anorexia and cachexia are major problems in patients with cancer. Such measures as anti-cancer therapy, dietary counselling or hyperalimentation are not very successful in reversing this phenomenon in the vast majority of cancer patients. Thus, several drugs have been evaluated as agents to ameliorate cancer-associated anorexia/cachexia. Cyproheptadine is an antiserotonergic drug which appears to cause slight appetite stimulation in patients. A randomised clinical trial, however, was unable to demonstrate any weight gain from this agent. Corticosteroids are frequently used in clinical practice for appetite stimulation in patients with advanced malignancies. Supporting this practice, 4 randomised clinical trials showed that corticosteroid medications can stimulate the appetites of advanced cancer patients. However, these studies were not able to show any substantial nonfluid weight gain in treated patients. Megestrol acetate is a progestational agent which appears to be a relatively potent appetite stimulant. Randomised studies in advanced cancer patients have shown both substantial appetite stimulation and improvement in the nonfluid bodyweights of patients receiving this drug. Preliminary evidence also suggests that this drug has antiemetic properties. Several clinical studies are currently ongoing to determine the effect of various doses of megestrol acetate in patients with cancer. Efforts are also ongoing to evaluate both anabolic steroids and hydrazine sulfate as drugs for the treatment of patients with cancer anorexia/cachexia. The preliminary nature of these investigations, however, precludes recommendations for the use of either of these latter 2 drugs in routine clinical practice.

Cancer-Associated Anorexia and Cachexia : Implications for Drug Therapy.

Anorexia and cachexia are major problems in patients with cancer. Such measures as anticancer therapy, dietary counselling or hyperalimentation are not very successful in reversing this phenomenon in the vast majority of cancer patients. Thus, several drugs have been evaluated as agents to ameliorate cancer-associated anorexia/cachexia. Cyproheptadine is an antiserotonergic drug which appears to cause slight appetite stimulation in patients. A randomised clinical trial, however, was unable to demonstrate any weight gain from this agent. Corticosteroids are frequently used in clinical practice for appetite stimulation in patients with advanced malignancies. Supporting this practice, 4 randomised clinical trials showed that corticosteroid medications can stimulate the appetites of advanced cancer patients. However, these studies were not able to show any substantial nonfluid weight gain in treated patients.Megestrol acetate is a progestational agent which appears to be a relatively potent appetite stimulant. Randomised studies in advanced cancer patients have shown both substantial appetite stimulation and improvement in the nonfluid bodyweights of patients receiving this drug. Preliminary evidence also suggests that this drug has antiemetic properties. Several clinical studies are currently ongoing to determine the effect of various doses of megestrol acetate in patients with cancer.Efforts are also ongoing to evaluate both anabolic steroids and hydrazine sulfate as drugs for the treatment of patients with cancer anorexia/cachexia. The preliminary nature of these investigations, however, precludes recommendations for the use of either of these latter 2 drugs in routine clinical practice.

Cytarabine.

Cytarabine is effective in the treatment of leukemias and CNS disease when given SQ, IM, IV, or intrathecally. Research is continuing to investigate high-dose therapy with cytarabine.

A controlled evaluation of an allopurinol mouthwash as prophylaxis against 5-fluorouracil-induced stomatitis.

Pursuant to a promising report suggesting that an allopurinol mouthwash could have a protective effect against 5-fluorouracil (5-FU)-induced stomatitis, the authors performed a randomized, placebo-controlled, double-blind, crossover study. Seventy-seven patients, receiving their first 5-day course of chemotherapy with 5-FU +/- leucovorin, were assigned to use a mouthwash containing 20 mg of allopurinol or a placebo. The mouthwash was administered every hour for four doses commencing with each chemotherapy dose. The severity of subsequent mucositis was graded (on a 0-4 scale) by the attending physician and also by a patient-completed questionnaire. There was trend toward less mucositis in the placebo group with mean physician-judged mucositis scores of 1.3 for placebo and 1.8 for allopurinol (P = 0.07) and mean patient-judged mucositis scores of 1.5 for placebo and 1.9 for allopurinol (P = 0.15). There were no substantial differences in mucositis attributable to the two mouthwashes in the patients who crossed-over on their second cycle of chemotherapy. These data demonstrate that the tested allopurinol mouthwash regimen does not offer any protective effect against 5-FU-induced mucositis.