The role of generalized pain and pain behavior in tender point scores in fibromyalgia.

OBJECTIVE: To determine and assess the significance of the independent role of pain, pain behavior, depression, and weekly stress in tender point scores in objectively diagnosed fibromyalgia (FM) patients. METHODS: One hundred eleven patients with FM recruited from the community and private and university based clinics participated in a comprehensive evaluation of their pain, psychological distress, and pain behavior. Tender point assessment was carried out across 18 discrete sites according to American College of Rheumatology criteria. Pain was assessed with a composite index of 4 pain measures; psychological distress consisted of measures of stress and depression, and pain behavior was measured by an objective index derived from a 10 minute videotaped sequence in which 5 pain behaviors were recorded. RESULTS: Multiple regression analyses revealed that high pain, high pain behavior, and shorter illness duration were related independently to tender point scores. Measures of depression and weekly stress were not independently related to tender point scores. CONCLUSION: Tender point scores are related to generalized pain and pain behavior tendencies in patients with FM, and do not independently reflect generalized psychological distress.

A combined system for measuring animal motion activities.

In this study, we have developed a combined animal motion activity measurement system that combines an infrared light matrix subsystem with an ultrasonic phase shift subsystem for animal activity measurement. Accordingly, in conjunction with an IBM PC/AT compatible personal computer, the combined system has the advantages of both infrared and ultrasonic subsystems. That is, it can at once measure and directly analyze detailed changes in animal activity ranging from locomotion to tremor. The main advantages of this combined system are that it features real time data acquisition with the option of animated real time or recorded display/playback of the animal's motion. Additionally, under the multi-task operating condition of IBM PC, it can acquire and process behavior using both IR and ultrasound systems simultaneously. Traditional systems have had to make separate runs for gross and fine movement recording. This combined system can be profitably employed for normative behavioral activity studies and for neurological and pharmacological research.

Ultrasonic analysis of tremorine and cold tremor activity in unanesthetized rats.

In order to quantify the tremorine and cold tremor activity in unanesthetized rats, a new ultrasonic motion transducer method was used. Both kinds of activity are reported as vibratory body motion that occurred between 18-32 Hz as determined by spectral analysis. The recorded signal was analyzed and its power spectrum was obtained through a fast Fourier transform operation. It was found that a negative linear relation occurs between shiver amplitude and ambient temperature (r = 0.999). A negative linear relation also occurs between metabolic rate and ambient temperature (r = 0.997). In addition, a positive linear relation between metabolic rate and cold shiver exists (r = 0.999). Both tremorine (30 mg/kg, i.p.) and cold tremor (Ta = 2-22 degrees C) activity monitored by the ultrasonic method were completely abolished by premedication with 1 mg/kg atropine. Thus, it appears that the advantages of this tremor detection method are that is non-invasive and non-contact. Therefore, the ultrasonic method provides a good choice for quantifying tremorine and cold tremor activity in unanesthetized animals during studies of thermoregulatory physiology or motor disorders.

Effect of helical CT on the frequency of sedation in pediatric patients.

OBJECTIVE: We compared the use of sedation for helical CT examination of pediatric patients with that for conventional CT studies. MATERIALS AND METHODS: We retrospectively compared two 4-month periods of CT examinations that differed only in that conventional CT was routinely used in one period and helical CT was exclusively used in the other period. For these two periods, we compared the type and number of CT examinations, the sedation used (if any), and the age of patients who required sedation. RESULTS: We performed 1055 conventional CT examinations in 762 pediatric cancer patients. Of the 264 children who were 8 years old or younger, 107 had been sedated. In comparison, 1195 helical CT examinations were performed on 838 patients: of the 246 children 8 years old or younger, 51 received sedation. For both study groups, the mean and median age of the patients was 4 years old. The mean age of patients requiring sedation was 21 (conventional CT) or 20 months (helical CT); the median age of patients who required sedation was 2 years old for both study groups. Patients who were 8 years old or younger and who underwent helical CT required sedation 49% less frequently than such patients who underwent conventional CT. The most dramatic reduction occurred among patients who were 3 years old or younger (p < or = .004). CONCLUSION: Use of helical CT reduced the need for sedation among our pediatric patients. Fewer sedations may reduce the risk of complications, decrease disruption of the patient's normal daily activities, and improve patient throughout. The associated savings in personnel time and pharmaceutical costs can be redistributed.

Iron overload among a psychiatric outpatient population.

BACKGROUND: Iron overload has been suggested to be an unrecognized cause of psychiatric morbidity. This study sought to estimate the prevalence of iron overload in a large outpatient psychiatric clinic. METHOD: A retrospective review of screening blood chemistries was conducted on 661 active outpatients at a large, university outpatient psychiatric clinic to identify elevated iron status results (plasma iron, percentage of iron saturation) suggestive of iron overload. Patients with positive profiles were asked to undergo a subsequent blood chemistry to confirm positive results (plasma iron, percentage of iron saturation, plus plasma ferritin). Patients with positive repeated iron chemistry results were considered likely candidates for iron overload. RESULTS: Twenty-one patients (3.2%) were identified as meeting one of the criteria suggestive of iron overload on initial screening reports. Thirty-one percent of those who underwent subsequent, confirmatory testing (5/16) continued to meet one of the criteria. On the basis of these results, we estimated a 1% (3.2 x 0.31) prevalence rate of likely candidates for iron overload. A review of these patients' charts indicated that they carried an unexpectedly high rate of bipolar affective disorder (80%) as a diagnosis and were, without exception, atypical in that they were resistant to conventional psychiatric treatment and lacked a family history for this disorder. The prevalence of positive iron overload profiles on a routine blood chemistry was similar to the prevalence of positive thyroid abnormalities based on TSH results in this population. CONCLUSION: Blood chemistry profiles suggestive of iron overload may be associated with a small portion of treatment-resistant psychiatric patients. Routine screening for iron abnormalities, especially in treatment-resistant patients, should be considered. Further studies are required to determine the causal association, if any, between iron excess and primary psychiatric illnesses.

A new ultrasonic method for measuring minute motion activities of rats.

A new ultrasonic method is presented for measuring the minute motion activities of rats. A pair of low-cost 40 kHz ultrasonic transducers are used to transmit ultrasound toward a rat and receive the ultrasound reflected from the rat. The relative motion of the rat modulates the phase difference between the transmitted and received ultrasound signals. An 8-bit digital phase meter was designed to record the phase difference signal which was used to reconstruct the relative motion waveform of the rat in an 8751 single-chip microcomputer. The reconstructed data are then sent to a PC-AT microcomputer for further processing. This method employs a spectrum analysis for the reconstructed data and can measure three minute motion activities including locomotor activity (LMA), tremor and myoclonia. Finally, the method has been tested with real animal experiments. The main advantages of this new method are that it is non-invasive, non-contact, low cost and high precision. This new method could also be profitably employed for other behavioral studies and offer potential for research in basic medicine.

Estimates of inbreeding and relationship among registered Holstein females in the United States.

The estimate of inbreeding for registered Holstein females born during 1990 was 5.1 +/- 0.4% for a random sample of 600 two-line pedigrees. Previously published estimates were 4.7% for 1970, 3.8% for 1976, and 4.3% for 1982 from similar samples of pedigrees. These estimates were calculated using a base of approximately 1884, or the initiation of herd-book registration in the US. The estimate of relationship between randomly paired females born during 1990 was 10.2 +/- 0.8%; relationships were 5.2% for 1970, 7.3% for 1976, and 9.8% for 1982. Average relationship within the breed increased significantly without a corresponding increase in inbreeding. Inbreeding was also estimated for alternative base years with 10-yr increments to determine the effect of base year on estimates of inbreeding. Using 1950 as the base year, inbreeding was estimated at 0.5% for 1970, 0.3% for 1976, 1.6% for 1982, and 2.1% for 1990. Estimates using 1920 as the base year were 2.0% for 1970, 1.9% for 1976, 2.3% for 1982, and 3.2% for 1990. More recent base years gave lower estimates of inbreeding, as expected, but showed an exaggerated percentage of increase in inbreeding from 1970 to 1990. However, the annual amount of increase of inbreeding from 1976 to 1990 was not significantly affected by time of base year and ranged from 0.08 to 0.12/yr. The five most influential bulls of the breed were Pawnee Farm Arlinda Chief 1427381, Round Oak Rag Apple Elevation 1491007, S-W-D Valiant 1650414, Osborndale Ivanhoe 1189870, and Sir Pietertje Ormsby Mercedes 44931; estimated direct relationships to the breed were 0.123, 0.122, 0.096, 0.083, and 0.074, respectively.

Safe use of power injectors with central and peripheral venous access devices for pediatric CT.

PURPOSE: We report our experience in the safe use of power injectors with central and small-gauge peripheral venous access devices for intravenous administration of contrast agent to children undergoing computed tomography (CT) examinations. MATERIALS AND METHODS: We reviewed the medical records of 500 patients randomly selected from the 3121 children who underwent intravenous contrast-enhanced CT examinations at our institution from November 1993 through July 1995. RESULTS: The group of 500 patients, all younger than 18 years of age, accounts for 16 % of the contrast-enhanced CT examinations performed during the study period. Medrad MCT 311 Mark V or Medrad MCT Plus 311 power injectors were used to intravenously administer Omnipaque 300 (2 ml/kg, maximum dose = 150 ml) through venous access devices. These devices comprised Hickman or Broviac lines (n = 228), subcutaneous Port-A-Caths (n = 55), small-gauge butterfly needles (n = 215), and percutaneous intravenous central lines (n = 2). Two complications, one involving a Hickman line and the other a subcutaneous Port-A-Cath, occurred in the study population. These complications correspond to a frequency of 0.4 %. Six cases of contrast extravasation, all of them with the use of 23- (n = 1) and 25-gauge (n = 5) butterfly catheters (frequency = 0.2 %), occurred among the remaining 2621 cases. CONCLUSION: In light of the low frequency of complications, power injectors and central venous access devices or small-gauge butterfly catheters are safe systems for delivery of intravenous contrast material to pediatric patients. We feel that our strict adherence to manufacturers' guidelines and previously reported techniques partially accounts for our success with these modes of delivery.

A fixed-ratio combination of uracil and Ftorafur (UFT) with low dose leucovorin. An active oral regimen for advanced colorectal cancer.

BACKGROUND: UFT is a fixed-ratio combination of uracil and Ftorafur, a prodrug that is absorbed orally and metabolized in vivo to 5-fluorouracil (5-FU). Uracil potentiates 5-FU through interference with its catabolism. The combination of UFT and leucovorin in patients with advanced incurable colorectal cancer, to evaluate preliminary activity and toxicity in this patient population. METHODS: Twenty-one patients were treated. Twenty patients were evaluable for toxicity and response. Patients received UFT 350 mg/m2/day divided every 8 hours. Patients took a 5 mg tablet of leucovorin every 8 hours, concurrent with each UFT dose. Treatment was continued for 28 consecutive days, followed by a 7-day rest. RESULTS: Five major objective responses (one complete and four partial) were observed. Toxicity was mild, with no dose-limiting myelosuppression. Four patients experienced grade 3 diarrhea or higher, and two patients experienced dose-limiting mucositis. CONCLUSION: UFT and low dose leucovorin is a well tolerated, orally administered regimen with activity in colorectal cancer. A randomized comparison of this regimen with conventional parenteral regimens is warranted.

Calcium glucarate as a chemopreventive agent in breast cancer.

Although it appears that progress is being made in the treatment of breast cancers of all stages, the etiological agents still remain unclear and render the search for preventive agents extremely difficult. What is clearly required in this situation is a nontoxic compound that can potentially affect various pathways that may be responsible for the rising incidence of breast cancer. In this review, we present the rationale for the use of an agent such as calcium glucarate, which may both change the internal hormonal milieu and also directly detoxify any environmental agents responsible for breast cancer. It is hoped that present and future clinical trials will help to better elucidate the role for this agent in the chemoprevention of breast cancer.

Butyrate and phenylacetate as differentiating agents: practical problems and opportunities.

Differentiating agents, including butyrate, phenylacetate and several other agents, have long been known to alter abnormal or transformed cell lines in vitro to a more normal state including phenotype and function. The effect depends on prolonged exposure to a minimum concentration of the agent. In vivo studies of butyrate and analogues have been limited, largely due to rapid in vivo metabolism. A butyrate prodrug, the triglyceride tributyrin, shows great promise in achieving effective and prolonged serum levels when given orally to mice and rats, and has been recommended for human trial. In vitro, butyrate and its mono- and triglyceride have shown potent synergy with retinoic acid, suggesting a ten-fold reduction in serum level requirements. Other butyrate prodrugs have been prepared and studied; several sugar esters of butyrate show promise. Phenylacetate, a normal mammalian metabolite, is also a potent differentiating agent, but its clinical use is limited by its objectionable odor per se and in treated subjects. Phenylbutyrate, a prodrug of phenylacetate, is more acceptable and may have greater promise. The availability of effective prodrugs of effective differentiating agents, such as tributyrin and phenylbutyrate, creates many opportunities for possible therapeutic and chemopreventive applications, especially if synergy in vivo can be demonstrated with retinoids (e.g., retinoic acid) or deltanoids (e.g., active vitamin D analogues), confirming in vitro studies. Particular disease targets would include certain leukemias, thalassemia, and sickle cell anemia.

Clinical and pharmacology study of chloroquinoxaline sulfonamide given on a weekly schedule.

The in vitro human tumor colony-forming assay identified chloroquinoxaline sulfonamide (CQS) as an active agent at human plasma concentrations of > 100 micrograms/ml. In the initial phase I trial of CQS given every 28 days, peak plasma concentrations > 500 micrograms/ml were associated with reversible dose-limiting hypoglycemia and occasional cardiac arrhythmias. Therefore, we evaluated whether a weekly schedule of treatment might minimize the drug-associated toxicity while maintaining potential therapeutic concentrations. CQS was given intravenously over 1 h once per week for 4 weeks to 12 patients, beginning at a dose of 2,000 mg/m2. All patients underwent monitoring for cardiac arrhythmias and hypoglycemia. Plasma drug levels were measured following each dose. Mild hypoglycemia was the most common adverse effect. A median nadir plasma glucose concentration of 56 mg/dl was observed at a weekly dose of 2,500 mg/m2. Two patients experienced cardiac dysrhythmia while on study. Continuous electrocardiographic monitoring failed to identify any significant infusion-related arrhythmia. The median CQS plasma concentration measured 24 h following a 2,000-mg/m2 dose of CQS was > 100 micrograms/ml, and the cumulative area under the concentration x time curve (AUC) determined at concentrations of > or = 100 micrograms/ml was similar to that observed with the every-28-day schedule. The weekly schedule described herein appears to maximize the plasma AUC with an acceptable margin of safety. The recommended phase II dose and schedule for CQS is 2,000 mg/m2 given once per week. Although severe hypoglycemia is unlikely, glucose monitoring is appropriate for 6 h following CQS administration.

Clinical pharmacology of all-trans retinoic acid.

The clinical pharmacology of all-trans retinoic acid (RA) has distinct differences from that of its widely studied stereoisomer 13-cis retinoic acid (cRA). RA is much more rapidly cleared from plasma following oral administration; their respective half-lives are < 1 h and 13 h. There is extensive accumulation of the 4-oxo-cRA in plasma following repeated doses of cRA, while 4-oxo-RA is only a minor metabolite in plasma following RA administration. The extent of isomerization in vivo differs for the two retinoids. In contrast to cRA, where up to a 1:3 ratio of RA to cRA is observed in patient plasma following drug administration, cRA concentrations in excess of 10 ng/ml are rarely observed in plasma of patients receiving exogenous RA. RA administration produces autoinduction of its own oxidative catabolism; this effect does not occur with cRA. These pharmacokinetic differences have been observed in leukemia and solid tumor patients. Detailed analysis of the results of the population studied suggest that both constitutive and RA-induced hypercatabolism of RA occurs. Both of these hypercatabolic states can be modulated by concurrent administration of ketoconazole, an inhibitor of cytochrome P-450 and lipoxygenase-mediated oxidations.

A prospective randomized comparison of radiation therapy plus lonidamine versus radiation therapy plus placebo as initial treatment of clinically localized but nonresectable nonsmall cell lung cancer.

PURPOSE: By means of a multicenter, prospective randomized, placebo-controlled study, to assess the impact of adding the radiation-enhancing agent lonidamine to standard "curative-intent" radiation therapy upon overall survival, progression-free survival, and local progression-free survival of patients with clinically localized but nonresectable nonsmall cell lung cancer. METHODS AND MATERIALS: Lonidamine, or the lonidamine-placebo, was administered at a dose of 265 mg/m2 in three divided daily doses. Drug therapy began 2 days prior to the initiation of radiation therapy and continued until progression of disease mandated a change in therapy. The radiation therapy dose was 55-60 Gy, at a daily dose of 1.8 Gy and five treatments per week. Patients with clinical Stage II or III nonsmall cell lung cancer were stratified within the treatment center, and within two histologic strata: epidermoid vs. other nonsmall cell cancers. RESULTS: A total of 310 patients were enlisted on study, 152 on the placebo arm and 158 on the lonidamine arm. The median survival durations were 326 days and 392 days for the placebo and lonidamine-treated groups respectively, p = 0.41 for a comparison of the survival curves. Median progression-free survival and median local progression-free survival durations were 197 days and 341 days for placebo + radiation therapy vs. 230 days and 300 days for lonidamine + radiation therapy; p-values for the respective curves were 0.75 and 0.42. Although there were proportionately more lonidamine-treated patients than placebo-treated patients demonstrating continued local control in excess of 12 months, the numbers of patients still at risk after 24 months were too small for meaningful statistical analysis. CONCLUSION: This multicenter Phase III study failed to demonstrate a significant advantage in the lonidamine-treated population in overally patient survival, in progression-free survival, or in the median duration of local control.

Butyrate as a differentiating agent: pharmacokinetics, analogues and current status.

The field of butyrate-induced differentiation of neoplastic and non-neoplastic cells is reviewed and possible clinical correlations considered with regard to butyrate, butyrate prodrugs and butyrate analogues. These topics are discussed from the point of view of the concentrations required in vitro for biologic effect, and likely pharmacokinetic behavior in vivo.

Elevated plasma lipid peroxide content correlates with rapid plasma clearance of all-trans-retinoic acid in patients with advanced cancer.

The addition of lipid hydroperoxides greatly accelerates the rate of oxidative catabolism of all-trans-retinoic acid (RA) in human cell microsomes; hydroperoxy metabolites of the arachidonate cascade are particularly active in the microsomal system. We have measured the plasma content of lipid peroxides in cancer patients during the course of therapy with RA, seeking to assess whether a correlation exists between the rate of oxidative catabolism of exogenously administered RA and whole body lipid peroxide levels. The assay used for plasma lipid peroxides is the capacity to react with thiobarbituric acid under specified conditions; the result is expressed as TBARS (thiobarbituric acid reactive substances). RA administration produced its own accelerated clearance RA within 72 h. Patients were considered to have "normal" or "rapid" baseline catabolism of RA if their Day 1 area under RA concentration over time curve was greater or less than 300 ng.h/ml, respectively. The mean plasma TBARS levels were: 12 normal volunteers = 0.14 microM; 19 "normal" RA catabolizers = 0.25 microM; and 14 "rapid" catabolizers = 0.82 microM. P = 0.008 (rapid catabolizers versus normal volunteers) and 0.05 (rapid catabolizers versus normal catabolizers). Repeat TBARS determinations were made during the course of therapy in 17 patients, all of whom converted to "rapid" RA catabolism on therapy. An increase in plasma TBARS levels > or = 20% of baseline was observed in 5 of 5 prostate cancer patients and 8 of 12 lung cancer patients treated with continuous RA therapy for 2 and 4 weeks, respectively. These observations support the hypothesis that high levels of lipid peroxides and rapid oxidative catabolism of RA are positively correlated.

Clinical pharmacology of all-trans retinoic acid.

The clinical pharmacology of all-trans retinoic acid (RA) has distinct differences from that of its widely studied stereoisomer 13-cis retinoic acid (cRA). RA is much more rapidly cleared from plasma following oral administration; their respective half-lives are < 1 h and 13 h. There is extensive accumulation of the 4-oxo-cRA in plasma following repeated doses of cRA, while 4-oxo-RA is only a minor metabolite in plasma following RA administration. The extent of isomerization in vivo differs for the two retinoids. In contrast to cRA, where up to a 1:3 ratio of RA to cRA is observed in patient plasma following drug administration, cRA concentrations in excess of 10 ng/ml are rarely observed in plasma of patients receiving exogenous RA. RA administration produces autoinduction of its own oxidative catabolism; this effect does not occur with cRA. These pharmacokinetic differences have been observed in leukemia and solid tumor patients. Detailed analysis of the results of the population studied suggest that both constitutive and RA-induced hypercatabolism of RA occurs. Both of these hypercatabolic states can be modulated by concurrent administration of ketoconazole, an inhibitor of cytochrome P-450 and lipoxygenase-mediated oxidations.

Constitutive variability in the pharmacokinetics of the natural retinoid, all-trans-retinoic acid, and its modulation by ketoconazole.

BACKGROUND: All-trans-retinoic acid (all-trans RA) induces complete remission in most patients with acute promyelocytic leukemia (APL). However, continuous oral dosing results in progressive decline in plasma drug concentrations, which is associated with relapse and resistance to this retinoid. We speculated that the decline in drug levels, indicating acquired resistance, resulted partly from inducible cytochrome-P450 oxidative enzymes, which can catabolize all-trans RA. PURPOSE: We studied the clinical pharmacology of all-trans RA in cancer patients to determine possible mechanisms of acquired resistance and evaluated the potential for reversal by ketoconazole, an inhibitor of cytochrome-P450 oxidative enzymes. METHODS: Serial plasma samples were obtained from 54 patients with APL or advanced lung cancer after a single oral dose of all-trans RA (45 mg/m2). In the 34 patients with advanced lung cancer, all-trans RA (45 mg/m2) was administered twice daily for 4 weeks, and, on days 2, 28, and 29, serial plasma samples were again obtained after a single 45-mg/m2 dose. One hour prior to drug administration on days 2 and 29, a single oral dose (200-1200 mg) of ketoconazole was administered. Endogenous plasma concentrations of all-trans RA and 13-cis-retinoic acid were measured in a subset of these patients and in 11 with early-stage lung cancer. RESULTS: The mean area under the curve for plasma drug concentration times time (AUC) for all-trans RA on day 1 varied substantially among patients. Compared with patients with APL, the 28 patients with advanced lung cancer who completed therapy demonstrated significantly lower AUC levels on day 1 (P = .06); a subgroup with levels less than 300 ng/mL per hour on day 1 had lower endogenous plasma all-trans RA concentrations than patients with APL or early-stage lung cancer or 14 normal subjects. Following continuous oral treatment, the mean day 28 AUC for all-trans RA was significantly lower than that on day 1 (213 ng/mL per hour versus 467 ng/mL per hour; P < .01), a decline significantly attenuated by ketoconazole, which increased the mean plasma all-trans RA AUC on day 29 to 375 ng/mL per hour (P < .01). CONCLUSION: Reported variability for the pharmacokinetics of all-trans RA may result from disease-related or population-based differences in basal catabolic rates influenced by genetic or environmental factors. However, the pattern of inducible catabolism of all-trans RA is not disease specific. Ketoconazole attenuates this accelerated catabolism, suggesting that oxidation by cytochrome-P450 enzymes is an important pathway for both constitutive and induced pathways of all-trans RA metabolism.

Specific and sensitive high-performance liquid chromatographic method with fluorescence detection for measurement of lometrexol and its polyglutamates in biologic samples.

A reversed-phase high-performance liquid chromatographic (HPLC) assay is described for the quantitative determination of lometrexol in biological samples; the assay is rapid, simple, specific, and highly sensitive. The method requires the dissociation of lometrexol from folate-binding proteins present in blood and formation of a fluorescent oxidized derivative of the compound. The dissociation of lometrexol from folate-binding proteins was achieved by acidification to pH 3.5 using ammonium formate, followed by serum protein precipitation with perchloric acid. The protein-free lometrexol was subsequently oxidized by MnO2 at 90 degrees C for 10 min. Chromatographic separation of lometrexol without interference was achieved on a C18 reversed-phase column with a convex gradient, using acetonitrile-0.1% ammonium formate, pH 7.0, as the mobile phase. In human serum and urine the calibration curve was linear between 5 and 300 nM. The lower limit of quantification was 5 nM. The method has been applied successfully to measure serum and urinary levels of lometrexol in patients.