Absorption, distribution, metabolism and excretion of intravenously and dermally administered triethanolamine in mice.

Triethanolamine (TEA) is an amino alcohol having widespread applications in consumer goods and as an industrial chemical. A number of relatively high-dose dermal toxicity studies have been conducted in rats and mice reflecting the principal route of human exposure to TEA. The absorption, distribution, metabolism and excretion (ADME) of (14)C-TEA derived radioactivity were determined in male C3H/HeJ mice following dermal application of 2000 mg/kg (neat) or, to characterize blood kinetics, intravenous (iv) injection of 1 mg/kg (14)C-TEA. Balance and excretion data were also collected in mice utilizing several dermal dosing scenarios (1000 mg/kg in acetone, 2000 mg/kg neat, 2000 mg/kg in water) and, for comparative purposes, in male Fischer 344 rats dosed dermally with 1000 mg/kg neat (14)C-TEA. Urine, feces, expired CO(2) (iv) and, where appropriate, blood were collected over a 24- or 48-hour period post-dosing. The half-life for dermal absorption of radioactivity was estimated to be 1.3 hours. Intravenously administered radioactivity was eliminated in a biphasic manner with a prominent initial phase (half-life of 0.3 hr) followed by a slower terminal phase (half-life of 10 hr). Radioactivity was excreted primarily via the urine (49-69%) as unmetabolized TEA, regardless of dosage, route or vehicle used. Fecal excretion of radioactivity comprised 16-28% of dose administered. The body burden at sacrifice (sum of liver, kidney, carcass and non-application site skin) ranged from 3 to 6% of the dose. It was concluded that TEA is absorbed extensively following dermal application to mice at dosages relevant to toxicity testing and that acetone or water vehicles do not appear to significantly alter total uptake. Significantly, the blood kinetics and ADME of TEA in mice and/or rats differs from that of a related chemical, diethanolamine, which appears to be more toxic to rodents than TEA.     

Innovation in clinical method: diabetes care and negotiating skills

The development of a method to facilitate clinical negotiationwith diabetic patients is described. The principles of the methodincorporate patient centredness, an assessment of readinessto change and some elements of motivational interviewing. Asimple low cost technology is part of the innovative method.Details of the method and its application are published beforethe results of a randomized controlled trial to ensure thatthe techniques are in the public domain before the outcome ofthe trial is known.     

Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial.

PURPOSE: A randomized trial was performed in premenopausal postoperative women with ipsilateral axillary node-positive (N+) breast carcinoma and known estrogen receptor (ER) status to assess the efficacy of an Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH)-based induction regimen and 5 or more years of tamoxifen (Tam). PATIENTS AND METHODS: Patients received 12 28-day cycles of cyclophosphamide 100 mg/m2 orally days 1 to 14, methotrexate 40 mg/m2 intravenously (IV) days 1 and 8, fluorouracil 600 mg/m2 IV days 1 and 8, prednisone 40 mg/m2 orally days 1 to 14, and Tam 10 mg orally twice daily (CMFPT), or the same regimen plus halotestin 10 mg orally twice daily (CMFPTH) alternating monthly with 22-day cycles of vinblastine 4.5 mg/m2 IV day 1, Adriamycin 45 mg/m2 IV day 1, thiotepa 12 mg/m2 IV day 1, halotestin, and Tam (ALTER). Prednisone in the ALTER regimen was stopped after the second CMFPTH cycle. After 12 cycles, patients were again randomized to stop or continue Tam. After 5 years, patients on Tam were again randomized to continue or stop Tam; the results from this randomization are still coded. Among 533 analyzed induction cases, 263 received CMFPT and 270 ALTER. Among 396 analyzed maintenance cases, 201 continued Tam and 195 were observed. Pretreatment characteristics were balanced among treatments. The median follow-up times are 5.1 years for induction and 4.1 years for maintenance. RESULTS: The time to relapse (TTR) was superior for the ALTER regimen (P = .04) and for the maintenance Tam (P = .05). Overall survival comparisons between the regimens are not statistically different. A longer TTR was associated with decreasing nodal involvement, ER+ status, and increasing age. The favorable effects of decreasing nodal involvement and ER+ status carried over to survival; a progesterone receptor-positive (PgR+) status and decreasing tumor size were also associated with longer survival. Development of amenorrhea was associated with improved TTR and survival. Toxicity was similar for the two induction regimens and for the two maintenance regimens. Overall relapse patterns were similar among the induction regimens, but continuing Tam led to fewer locoregional relapses. CONCLUSION: The results suggest significant overall TTR therapeutic benefits of an Adriamycin-containing alternating induction regimen and of continuing maintenance Tam therapy for at least 5 years.     

Cisplatin and 5-FU infusion chemotherapy in advanced, recurrent cancer of the head and neck: an Eastern Cooperative Oncology Group Pilot Study

Thirty-four patients with advanced, recurrent head and neck cancer were treated with cisplatin (100 mg/m2 on Day 1) and continuous-infusion 5-FU (1.0 g/m2/24 hours on Days 1-5) every 3-4 weeks. All but one patient had failed prior radiation therapy or surgery; 27 had failed both. Two patients were not evaluable for response because of death within the first 2 weeks from unrelated heart disease. Among 30 patients with squamous cell carcinoma, five achieved complete response (CR) (17%) and 13 achieved partial response (PR) (43%). Durations of response for patients with a CR and PR were 10.4 and 3.1 months, respectively. Median time to disease progression for all patients was 4.5 months and median survival was 9.1 months. Median survival times for all responders and for complete responders and partial responders were 12.5, 14.2, and 10 months, respectively. One additional patient with an adenocarcinoma failed to respond, while a second with an adenoid cystic carcinoma achieved a PR for 3.4 months. Toxicity was moderate: seven patients experienced Eastern Cooperative Oncology Group grade 3 mucositis, and 11 patients had grade 3-4 hematologic toxicity. There was one treatment-related death due to nephrotoxicity. This study supports other studies that show a relatively high degree of activity of cisplatin and continuous-infusion 5-FU in advanced head and neck cancer.     

The effect on motion sickness and oculomotor function of GR 38032F, a 5-HT3-receptor antagonist with anti-emetic properties.

1. The 5-hydroxytryptamine (5-HT3) receptor antagonist, GR 38032F, which possesses potent anti-emetic properties in vomiting induced by cancer chemotherapeutic drugs, has been tested to determine its value in the prophylaxis of motion sickness induced by cross-coupled stimulation. The double-blind trial compared GR 38032F with both a placebo (lactose) and with hyoscine. In addition, studies of ocular pursuit and saccadic eye movements were carried out following the administration of each drug. 2. The prophylactic effect of GR 38032F on motion-induced nausea was indistinguishable from that of placebo, whereas following hyoscine subjects showed a highly significant (P less than 0.001) increase in tolerance to cross-coupled stimulation. Tests of oculomotor function showed no effect on saccadic eye movement from either drug. However, both drugs produced a significant (P less than 0.05) though small reduction in eye velocity gain during pursuit eye movement. 3. These findings suggest that the 5-HT3 receptor is not involved in the neural pathways that bring about motion sickness, but that it may have a role in the control of ocular pursuit. The absence of an anti-motion sickness effect from a drug that is effective in the treatment of vomiting induced by cancer chemotherapy serves to emphasize that different neural mechanisms are involved in the generation of motion sickness.     

Silicon substitution in the calcium phosphate bioceramics

Silicon (Si) substitution in the crystal structures of calcium phosphate (CaP) ceramics such as hydroxyapatite (HA) and tricalcium phosphate (TCP) generates materials with superior biological performance to stoichiometric counterparts. Si, an essential trace element required for healthy bone and connective tissues, influences the biological activity of CaP materials by modifying material properties and by direct effects on the physiological processes in skeletal tissue. The synthesis of Si substituted HA (Si-HA), Si substituted alpha-TCP (Si-alpha-TCP), and multiphase systems are reviewed. The biological performance of these Si substituted CaP materials in comparison to stoichiometric counterparts is discussed. Si substitution promotes biological activity by the transformation of the material surface to a biologically equivalent apatite by increasing the solubility of the material, by generating a more electronegative surface and by creating a finer microstructure. When Si is included in the TCP structure, recrystallization to a carbonated HA is mediated by serum proteins and osteoblast-like cells. Release of Si complexes to the extracellular media and the presence of Si at the material surface may induce additional dose-dependent stimulatory effects on cells of the bone and cartilage tissue systems.     

Criterion validity of the StepWatch Activity Monitor as a measure of walking activity in patients after stroke

Mudge S, Stott NS, Walt SE. Criterion validity of the StepWatch Activity Monitor as a measure of walking activity in patients after stroke.

Objectives

To test the validity of the StepWatch Activity Monitor (SAM) in subjects with stroke against 2 criterion standards, 3-dimensional gait analysis (3-DGA) and footswitches in a variety of indoor and outdoor walking conditions, including different speeds and different terrains, and to test the accuracy of the SAM when worn on the paretic limb.

Design

Criterion standard validation study.

Setting

Gait laboratory and outside course.

Participants

Twenty-five participants with physical disability after stroke.

Interventions

Not applicable.

Main Outcome Measures

The total step count measured simultaneously by SAM and either 3-DGA or footswitches for both paretic and nonparetic limbs.

Results

The total step count measured by the SAM and 3-DGA was highly correlated (nonparetic limb, r=.959; paretic limb, r=.896). The 95% limits of agreement (LOA) (derived from Bland-Altman analysis) between the SAM and 3-DGA were within ±10 steps for SAMs worn on either the nonparetic or paretic limb. The total step count measured simultaneously by the SAM and footswitches was also highly correlated for each limb (nonparetic, r=.999; paretic, r=.963). The 95% LOA between the SAM and footswitches were ±9 steps on the nonparetic limb but higher at ±57 steps on the paretic limb. Further analysis showed that the measurement differences occurred during the outdoor component of the combined walk. The 95% LOA between footswitches on both limbs were not more than ±9 steps for walking, suggesting that the error was accounted for by the SAM on the paretic limb, which both over- and underread the total step count in the outdoor walking conditions.

Conclusions

Criterion validity of the SAM to measure steps in both clinical and natural environments has been established when used on the nonparetic limb. However, more errors are apparent when the SAM is worn on the paretic limb while walking over a variety of outdoor terrains. Validation is recommended before use in patients with neurologic conditions affecting bilateral legs because there may be more error, particularly in outdoor activities.