Selective postoperative inhibition of gastrointestinal opioid receptors.

BACKGROUND: Postoperative recovery of gastrointestinal function and resumption of oral intake are critical determinants of the length of hospital stay. Although opioids are effective treatments for postoperative pain, they contribute to the delayed recovery of gastrointestinal function. METHODS: We studied the effects of ADL 8-2698, an investigational opioid antagonist with limited oral absorption that does not readily cross the blood-brain barrier, on postoperative gastrointestinal function and the length of hospitalization. We randomly assigned 79 patients--including 1 whose surgery was canceled--to receive one capsule containing 1 mg or 6 mg of ADL 8-2698 or an identical-appearing placebo capsule two hours before major abdominal surgery and then twice daily until the first bowel movement or until discharge from the hospital. Data were analyzed for 26 patients in each of the three groups; all received opioids for postoperative pain relief. Observers who were unaware of the group assignments evaluated the outcomes. RESULTS: Fifteen patients underwent partial colectomy and 63 underwent total abdominal hysterectomy. Patients given 6 mg of ADL 8-2698 had significantly faster recovery of gastrointestinal function than those given placebo. The median time to the first passage of flatus decreased from 70 to 49 hours (P=0.03), the median time to the first bowel movement decreased from 111 to 70 hours (P=0.01), and the median time until patients were ready for discharge decreased from 91 to 68 hours (P=0.03). Effects in the group that received 1 mg of ADL 8-2698 were less pronounced. CONCLUSIONS: Selective inhibition of gastrointestinal opioid receptors by an antagonist with limited oral absorption that does not readily cross the blood-brain barrier speeds recovery of bowel function and shortens the duration of hospitalization.

Tolerability of recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in healthy subjects.

This phase I, double-blind, randomized, placebo-controlled study evaluated the safety of single and multiple (daily for 7 days) subcutaneous administrations of recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in healthy human volunteers at seven doses, ranging from 3 to 500 microg/kg/day. No serious or life-threatening adverse events occurred. The most frequently recorded adverse effects were mild injection-site pain, diarrhea, and elevation of liver function tests. No change in neurologic function was noted with these dosing regimens. We conclude that r-metHuNT3 is safe and well tolerated in the dosages used in this study.

Phase II randomized study of cisplatin plus etoposide phosphate or etoposide in the treatment of small-cell lung cancer.

PURPOSE: This randomized phase II study evaluated the efficacy and toxicity of etoposide phosphate when used in combination with cisplatin in the treatment of small-cell lung cancer. PATIENTS AND METHODS: Patients with previously untreated small-cell lung cancer were randomized to receive cisplatin in combination with either etoposide or etoposide phosphate. Molar-equivalent doses of etoposide and etoposide phosphate were used. Response rate, time to progression, survival, and toxicity were compared. RESULTS: Major response rates with etoposide phosphate and etoposide were 61% (95% confidence interval, 55% to 67%) and 58% (95% confidence interval, 52% to 64%), respectively (P = .85). No significant differences in median time to progression or survival were observed in patients who received etoposide phosphate versus etoposide. Grade 3 and 4 leukopenia occurred in 63% of patients who received etoposide phosphate compared with 77% who received etoposide (P = .16). CONCLUSION: The combination of etoposide phosphate and cisplatin is effective in the treatment of small-cell lung cancer, and can be administered with acceptable toxicity. Although this study was not designed to be a formal comparative trial, the efficacy and toxicity observed with this regimen were found to be similar to a standard etoposide/cisplatin regimen, using molar-equivalent etoposide doses. Because of its greater ease of administration, etoposide phosphate is preferable to etoposide for routine clinical use.

Clinical and pharmacokinetic overview of parenteral etoposide phosphate.

Etoposide phosphate (Etopophos, BMY-40481) is a water-soluble derivative of the widely used podophyllotoxin etoposide (VP-16). The phosphate ester renders the compound water-soluble, eliminating the need for formulation in polysorbate (Tween) 80, ethanol, and polyethylene glycol. As a result the compound can be given at high concentrations and as a bolus. In animals and in vitro, etoposide phosphate (EP) is rapidly and completely converted to VP-16. Clinical development of the i.v. formulation has focused on the identification of the maximum tolerated dose (MTD) and pharmacokinetic characteristics of the drug using a 5 daily dose schedule and a days 1, 3, and 5 schedule, with the drug being given over 30 or 5 (bolus) min. Myelosuppression was dose-limiting. Data from these trials show the rapid and complete conversion of EP to VP-16, a pharmacokinetic/pharmacodynamic relationship for myelosuppression and exposure to VP-16, and an MTD of 100 and 150 mg/m2 (molar equivalent to VP-16) when EP is given daily for 5 days and on days 1, 3, and 5, respectively. A formal randomized trial has been conducted to show the pharmacokinetic comparability of EP and VP-16. In this trial, exposure to VP-16 was the same after the parenteral administration of equimolar doses of EP or VP-16. The feasibility of bolus dosing and treatment at high concentrations has been demonstrated, with no effects on the cardiovascular system being noted. Parenteral EP is pharmacokinetically and biologically equivalent to VP-16 and has the advantages of the elimination of potentially toxic excipients; more convenient administration; and ability to be given as a bolus, at high concentrations, and as a continuous infusion.

The effect of surgical intervention for head and neck cancer on whole salivary flow: a pilot study.

For many patients, rehabilitation and quality of life after treatment of head and neck cancer are issues that confront both them and their physicians. Various levels of xerostomia are often reported as one of the side effects of treatment. This study evaluated the effects of surgical intervention (alone) that involve major salivary glands on whole salivary flow. Five subjects with head and neck cancer who lost a submandibular gland at surgery were evaluated before and after treatment to determine resting and stimulated whole salivary flow rates. Three subjects demonstrated a decrease in resting and three a decrease in stimulated flow rates compared with pretreatment levels. Two subjects rebounded to near or above presurgery flow rates. Although a trend was identified for a decrease in resting and stimulated flow rates, the sample size was too small to statistically validate this trend. The decreases in flow rates recorded at the last test were of insufficient magnitude to elicit a complaint of xerostomia.

A shifted multiplicative model cluster analysis for grouping environments without genotypic rank change.

The shifted multiplicative model (SHMM) is used with a cluster method to identify subsets of sites in an international maize (Zea mays L.) trial without genotypic rank-change. For cluster analysis, distance between two sites is defined as the residual sum of squares after fitting SHMM with one multiplicative term (SHMM1) if SHMM1 does not show genotypic rank-change. However, if SHMM1 does show genotypic rank-change, the distance between two sites is defined as the smaller of the sums of squares owing to genotypes within each of the two sites. Calculation of distance between two sites is facilitated by using the site regression model with one multiplicative term (SREG1), which can be reparameterized as SHMM1 when only two sites are considered. The dichotomous splitting procedure, used on the dendrogram obtained from cluster analysis, will first perform SHMM analyses on each of the last two cluster groups to join (end of the dendrogram). If SHMM1 does not give an adequate fit, the next step is to move down the branches of the tree until groups of sites (clusters) are found to which SHMM1 provides an adequate fit and primary effects of sites are all of the same sign. Five final groups of sites to which SHMM1 provides an adequate fit and primary effects of sites are all of the same sign were obtained. The procedure appears to be useful in identifying subsets of sites in which genotypic rank-change interactions are negligible.

Statistical techniques in ophthalmic journals.

Over the years, the use of statistics to evaluate experimental data in ophthalmology has increased. The present study sought to assess the frequency and types of statistical techniques used in ophthalmic journals. We reviewed 974 original articles from the Archives for 1970, 1980, and 1990; the American Journal of Ophthalmology for 1990; and Ophthalmology for 1990. Of the 592 articles reviewed for 1990, 391 (66.0%) contained statistics, with measures of central tendency most commonly used (385 articles [65.0%]), followed by dispersion (298 [50.3%]), t test (120 [20.3%]), and contingency tables (98 [16.6%]). A reader familiar with 10 statistical techniques would have "statistical accessibility" to 526 (88.9%) of 1990 articles. A statistically significant difference was found in the percentage of articles containing statistical methods among the journals (P = .0003; Archives, 75.3%; Ophthalmology, 66.8%; and American Journal of Ophthalmology, 55.2%).

Occlusal force after partial mandibular resection.

Surgical resection of a segment or loss of mandibular continuity can adversely affect most of the structures essential for maximum occlusal force. Five subjects who had partial mandibular resections for treatment of squamous cell carcinoma were studied. Occlusal force was recorded before and after cancer treatment and following prosthetic rehabilitation. A gnathodynamometer was used to record anterior occlusal force. Five edentulous and five dentate cancer-free subjects matched for age were studied to establish comparable normative data. The null hypothesis that partial mandibular resection would not affect maximum occlusal force was rejected (p = 0.0101). Mandibular resection did alter maximum occlusal force. The impact of the decrease in maximum occlusal force on masticatory function is yet to be determined.

Using the shifted multiplicative model to search for "separability" in crop cultivar trials.

The shifted multiplicative model (SHMM) is used in an exploratory step-down method for identifying subsets of environments in which genotypic effects are "separable" from environmental effects. Subsets of environments are chosen on the basis of a SHMM analysis of the entire data set. SHMM analyses of the subsets may indicate a need for further subdivision and/or suggest that a different subdivision at the previous stage should be tried. The process continues until SHMM analysis indicates that a SHMM with only one multiplicative term and its "point of concurrence" outside (left or right) of the cluster of data points adequately fits the data in all subsets. The method is first illustrated with a simple example using a small data set from the statistical literature. Then results obtained in an international maize (Zea mays L.) yield trial with 20 sites and nine cultivars is presented and discussed.

Comparison of high and low dose rate remote afterloading for cervix cancer and the importance of fractionation.

Analysis of the data obtained from a survey of 56 institutions treating a total of over 17,000 cervix cancer patients with high dose rate (HDR) remote afterloading, shows that the average fractionation regimen is about 5 fractions of 7.5 Gy each to Point A, regardless of stage of disease. Comparison with historical controls treated by the same clinicians at low dose rate (LDR), showed that 5-year survival was statistically significantly better for HDR versus LDR for Stage III patients (47.2% compared to 42.6%, P = 0.005) and for all patients pooled together (60.8% vs. 59.0% P = 0.045). Morbidity rates were considerably lower for HDR versus LDR for both severe (2.23% vs. 5.34%, P less than 0.001) and moderate plus severe complications (9.05% vs. 20.66%, P less than 0.001). There is an apparent geometrical advantage of HDR intracavitary therapy in that there is a reduction in the "hot-spot" rectal and bladder doses relative to Point A of, on average, (13 +/- 4)% for the HDR compared to the LDR treatments. Fractionation of the HDR treatments significantly influenced toxicity: morbidity rates were highly significantly lower for Point A doses/fraction less than or equal to 7 Gy compared with greater than 7 Gy for both severe injuries (1.28% vs. 3.44%, P less than 0.001) and moderate plus severe (7.58% vs. 10.51%, P less than 0.001). The effect of dose/fraction on cure rates was equivocal. Finally, the data showed that for conversion from LDR to HDR the total dose to Point A was reduced on average by a factor 0.54 +/- 0.06.

Initial experience with a practical hyperfractionated accelerated radiotherapy regimen.

This paper presents early results of a trial of a three-fractions-per-day (TID) regimen that is more convenient to schedule than the Continuous Hyperfractionated Accelerated Radiotherapy (CHART) protocol currently being tested in Europe. The treatment schedule used in the CHART regimen has been modified from 36 fractions of 1.5 Gy TID in 12 days to 72 fractions of 1.1 Gy in 24 treatment days, with all fractions delivered during normal working hours. With no weekend treatments, the entire course of radiotherapy is completed in less than 5 weeks. The doses used were determined using the L-Q model, with correction for incomplete repair between fractions and for accelerated repopulation of cancer cells. Comparison with historical controls shows statistically significant improvements both in CR rates for the primary tumor and in acute toxicity, as measured by reduced treatment interruptions. L-Q model calculations predict that, compared to the highest dose achieved in previous studies without exceeding tolerance, we are able to obtain a 12% increase in bioeffect dose to the primary tumor due to accelerating the treatment. An analysis of the potential tumoricidal effectiveness of this new treatment regimen shows that it should be better than several other accelerated fractionation schedules being tested for all values of Tpot. For short Tpot times, the advantage may be as much as one log cell kill, corresponding to a 10-15% potential improvement in local control.

The effect of head and neck cancer treatment on whole salivary flow.

The effects of multimodality therapy for head and neck cancer on whole salivary flow were evaluated. Eighteen subjects with head and neck cancer were studied. Resting and stimulated whole salivary flow rates were recorded, pretreatment, after individual modality therapy, and posttreatment. Twenty-four subjects with no history of head and neck cancer matched for age, and sex distribution, served as controls. Primary site, stage, major salivary glands resected, radiation fields, and dose to major salivary glands are reported. The average salivary flow rates for 18 subjects following treatment was reduced 83% for resting and 86% for stimulated saliva from pretreatment levels. The null hypothesis that the overall resting and stimulated whole salivary flow rates are unaffected by treatment (surgery and radiation) of the head and neck cancer was rejected (P values at 0.05 level of significance). Stage and location of primary, total dose delivered to and volume of gland exposure are important factors when predicting xerostomia following multimodality therapy.

Modulation of murine radiation-induced fibrosarcoma-1 tumor metabolism and blood flow in situ via glucose and mannitol administration monitored by 31P and 2H nuclear magnetic resonance spectroscopy.

The hyperglycemia-induced in situ metabolism and blood flow changes produced in s.c. implanted murine radiation-induced fibrosarcoma-1 tumors, grown on the flanks of female C3H/HeJ mice, were examined with 31P and 2H nuclear magnetic resonance. Initial experiments verified a hyperglycemic tumor acidification similar to that reported earlier with a different substrain of mice, C3H/AnF (J.L. Evelhoch et al., Proc. Natl. Acad. Sci. USA, 81: 6496-6500, 1984). Changes in the tumor pH, phosphorus metabolites, and blood flow were then compared after administration of saline, glucose, or mannitol (a nonmetabolizable glucose analogue) using a mole-equivalent dose of the sugars (i.e., 0.8 mmol/20g mouse). Neither saline (n = 8) nor mannitol (n = 6) administration had any marked effect upon tumor pH, whereas glucose administration produced a mean maximum tumor pH reduction of 0.74 +/- 0.09 (SE; n = 9) during the 2.5 h post-glucose injection. No significant changes in high energy phosphate concentrations were observed during the same period after saline injection. After glucose injection, the [phosphocreatine] gradually decreased by 64% (P = 0.0001). After the initial 1 h post-glucose injection, the [inorganic phosphate] increased by 58% (P = 0.0001), and the [nucleoside triphosphates] decreased by 29% (P = 0.0001) during the following 1.5 h. After mannitol injection, while there was no change in [inorganic phosphate] over time (P = 0.37), the [phosphocreatine] decreased by 33% (P = 0.0001) and the [nucleoside triphosphates] decreased by 21% (P = 0.0015) within 20 min, then both the [phosphocreatine] and [nucleoside triphosphates] remained at constant levels during the following 2 h. In parallel experiments, the volumetric rate of tumor blood flow and perfusion was measured by 2H nuclear magnetic resonance monitoring of 2H2O washout kinetics (S-G. Kim and J. J. H. Ackerman, Cancer Res., 48: 3449-3453, 1988); tumor blood flow decreased by 80% (P = 0.0001, n = 11), 60% (P = 0.0031, n = 4), and 20% (P = 0.058, n = 10) at 2 h after glucose, mannitol, or saline injections, respectively. These results suggest that anaerobic glycolysis is a requirement for hyperglycemic tumor acidification. However, the decrease in tumor blood flow accompanying hyperglycemic acidification suggests that flow reduction also may be a contributing or a required cofactor for acidification via inhibition of lactic acid egress.(ABSTRACT TRUNCATED AT 400 WORDS)