Approaches to dog health education programs in Australian rural and remote Indigenous communities: four case studies.

Dog health in rural and remote Australian Indigenous communities is below urban averages in numerous respects. Many Indigenous communities have called for knowledge sharing in this area. However, dog health education programs are in their infancy, and lack data on effective practices. Without this core knowledge, health promotion efforts cannot progress effectively. This paper discusses a strategy that draws from successful approaches in human health and indigenous education, such as dadirri, and culturally respectful community engagement and development. Negotiating an appropriate education program is explored in its practical application through four case studies. Though each case was unique, the comparison of the four illustrated the importance of listening (community consultation), developing and maintaining relationships, community involvement and employment. The most successful case studies were those that could fully implement all four areas. Outcomes included improved local dog health capacity, local employment and engagement with the program and significantly improved dog health.

Response of cows with osteomalacia grazing sub-tropical native pastures to phosphorus supplementation with loose mineral mix or feed blocks.

Osteomalacia outbreaks often occur in cattle grazing native pastures in regions with endemic phosphorous (P) deficiency. This study evaluated the responses of two groups of cows, initially with clinical signs of chronic P deficiency, to P supplements (100 g P/kg) offered ad libitum for 13 weeks as a loose mineral mix (LMM group) or the same mineral mix offered as blocks (BMM group). Half of the cows in each group were categorized as 'with' or 'without' severe osteopenia according to a test that depended on the resistance to penetration of a needle through the left lateral process of the L4-L5 lumbar vertebra. The groups grazed two paddocks that were switched each 3 weeks. The liveweight, supplement intakes, and the P-concentrations in soil, forage, blood, and external cortical bone (ECB) of the ribs were measured. The bicarbonate-extractable P in soil was 3.5 mg/kg. The mean of total P in forage (0.95 g/kg/DM), inorganic P in serum (iP, 0.96 mmol/L), and total P in the ECB of the ribs (85 mg/mL) at the beginning of the experiment were all low and consistent with severe chronic P deficiency. The P supplementation allowed clinical recovery in 18/20 cows with their serum and ECB P and calcium approaching normal values and in the two remaining cows the only sign was abnormal gait. Cows consumed more of the LMM than BMM supplement (means 8.3 and 6.6 g P/day, respectively). After 13 weeks cows initially classified as 'with severe osteopenia' and supplemented with LMM had higher (P < 0.05) final liveweight (difference = 21.6 kg), iP (difference = 0.74 mmol/L), bone Ca (difference = 65.7 mg/mL) and bone P (difference = 26.5 mg/mL) concentrations and lower (P < 0.01) final serum Ca/iP ratio (difference = -0.65) than cows with severe osteopenia but supplemented with BMM. The treatment of severe P deficiency cows grazing P deficient sub-tropical grasslands by P supplementation for 13 weeks was more effective with LMM than BMM.

Alternative rib bone biopsy measurements to estimate changes in skeletal mineral reserves in cattle.

Rib bone biopsy samples are often used to estimate changes in skeletal mineral reserves in cattle but differences in sampling procedures and the bone measurements reported often make interpretation and comparisons among experiments difficult. 'Full-core' rib bone biopsy samples, which included the external cortical bone, internal cortical bone and trabecular bone (CBext, CBint and Trab, respectively), were obtained from cattle known to be in phosphorus (P) adequate (Padeq) or severely P-deficient (Pdefic) status. Experiments 1 and 2 examined growing steers and Experiment 3 mature breeder cows. The thickness of cortical bone, specific gravity (SG), and the amount and concentration of ash and P per unit fresh bone volume, differed among CBext, CBint and Trab bone. P concentration (mg/cc) was closely correlated with both SG and ash concentrations (pooled data, r=0.99). Thickness of external cortical bone (CBText) was correlated with full-core P concentration (FC-Pconc) (pooled data, r=0.87). However, an index, the amount of P in CBext per unit surface area of CBext (PSACB; mg P/mm2), was more closely correlated with the FC-Pconc (pooled data, FC-Pconc=37.0+146×PSACB; n=42, r=0.94, RSD=7.7). Results for measured or estimated FC-Pconc in 10 published studies with cattle in various physiological states and expected to be Padeq or in various degrees of Pdefic status were collated and the ranges of FC-Pconc indicative of P adequacy and P deficiency for various classes of cattle were evaluated. FC-Pconc was generally in the range 130 to 170 and 100 to 120 mg/cc fresh bone in Padeq mature cows and young growing cattle, respectively. In conclusion, the FC-Pconc could be estimated accurately from biopsy samples of CBext. This allows comparisons between studies where full-core or only CBext biopsy samples of rib bone have been obtained to estimate changes in the skeletal P status of cattle and facilitates evaluation of the P status of cattle.

A double-blind, randomized, placebo-controlled, single-dose study of the cyclooxygenase-2 inhibitor, GW406381, as a treatment for acute migraine.

The objective of the present study was to explore the clinical efficacy and tolerability of GW406381, a cyclooxygenase-2 (COX-2) inhibitor with relatively high CNS penetration, in acute migraine. This was a double-blind, single-dose study of GW406381 compared with placebo and naproxen sodium compared with placebo (protocol number CXA20008). Three hundred and thirty-seven subjects were randomized 1:1:1 to GW406381 (70 mg), naproxen sodium (825 mg), or placebo for the treatment of one migraine headache of moderate or severe intensity in a potential 8-week period. The primary end-point was the proportion of subjects with headache relief [reduction in headache severity score from pre-dose 2 (moderate) or 3 (severe) to 0 (no pain) or 1 (mild)] at 2 h post-dose for GW406381 compared with placebo. Significantly higher proportions of subjects treated with GW406381 (50%, P = 0.032) or naproxen sodium (56%, P = 0.005) than with placebo (35%) reported headache relief at 2 h post-dose. Additional significant benefits were observed on many secondary outcomes, including proportions of subjects pain-free, for both GW406381 and naproxen sodium treatment compared with placebo. Both active treatments were well tolerated. Single-dose GW406381 (70 mg) and naproxen sodium (825 mg) were effective and well tolerated in the treatment of acute migraine.

Thyroid hormone abnormalities and outcome in dogs with non-thyroidal illness.

OBJECTIVES: To document thyroid hormone abnormalities in dogs with non-thyroidal illness and identify markers of prognostic value. METHODS: Circulating total and free thyroxine, total triiodothyronine and thyrotropin concentrations were measured in 196 dogs with non-thyroidal illness. Clinical signs, previous medications and outcome were recorded in each case. Data were analysed to determine endocrine prognostic factors, and to document the prevalence of thyroid hormone abnormalities. RESULTS: Total triiodothyronine, and total and free thyroxine concentrations were decreased in 75.9, 34.7 and 4.5 per cent of cases, respectively. Dogs which were euthanased had significantly decreased total triiodothyronine, and total and free thyroxine concentrations compared with those which made a full recovery. Total triiodothyronine concentrations were significantly lower in dogs that were euthanased compared with those which made a partial recovery. CLINICAL SIGNIFICANCE: Thyroid hormone concentrations may be used as prognostic indicators in dogs with non-thyroidal illness. Low triiodothyronine syndrome may be more common in dogs than previously recognised.

Phospholipid synthesis in the lymphomatous mouse liver studied by 31P nuclear magnetic resonance spectroscopy in vitro and by administration of 14C-radiolabelled compounds in vivo.

High phosphomonoester to ATP ratios have been found in 31P magnetic resonance spectra from livers of patients with hepatic lymphoma (Dixon et al. (1990) Br. J. Cancer 63, 953-958). The present study of a murine lymphoma showed that the phosphomonoester in the lymphomatous liver was largely phosphoethanolamine, which is an intermediate of phospholipid metabolism. A significant positive correlation was found between the concentration of phosphoethanolamine, measured by high resolution 31P nuclear magnetic resonance spectroscopy of extracts, and the degree of infiltration, assessed by quantitative histology. The phosphoethanolamine concentration reached about 10 times its normal level, but the phosphocholine concentration remained the same as in the normal liver. Radiolabelling studies showed that while the rate of phosphoethanolamine synthesis from exogenous [14C]ethanolamine was higher in the lymphomatous mouse liver than in control livers, the rate of phosphatidylethanolamine synthesis was lower in the lymphomatous liver. The rate of phosphatidylcholine synthesis in lymphoma-bearing livers was not significantly different from that in control mouse livers.

The effect of pH on the growth and motility of Rhodobacter sphaeroides WS8 and the nature of the driving force of the flagellar motor.

Rhodobacter sphaeroides WS8 grew, and swam vigorously, over the pH range 6 to 9. Sustained motility was, however, observed in populations of cells resuspended at pH values between 4.9 and 10.4, although the mean run speed was reduced at the extremes of pH. The ability of R. sphaeroides to swim in strong alkaline conditions prompted the question of whether motility at alkaline pH was powered by a sodium motive force, as has been found in the facultative alkalophilic Bacillus and Vibrio species, particularly as motility was found to be sensitive to the sodium channel inhibitor amiloride. The nature of the driving force of the flagellar motor was therefore investigated. It was found that R. sphaeroides was motile over the same pH range in the absence and presence of sodium ions. The protonophore CCCP was found to inhibit motility under all conditions, whereas monensin, an inhibitor of sodium pumps, had no effect upon motility in the presence or absence of sodium. It was concluded that the delta p is the driving force for the flagellar motor in R. sphaeroides at all values of pH. Amiloride, a specific inhibitor of the sodium-driven flagellar motor in alkalophilic Bacillus and Vibrio was shown to act non-specifically on the proton driven motor of R. sphaeroides, reducing the swimming speed of this organism in media with and without sodium to the same extent and over the complete pH range. Measurement of the delta p by using the electrochromic absorbance change of the carotenoid pigments to measure delta psi and 31P-NMR to measure delta pH showed that the maximum delta p was about -215 mV. At pH 10 the cells swam more slowly and the delta p was about -90 mV. These data suggest that the flagellar motor of R. sphaeroides is proton-driven under all conditions with a threshold for motor rotation below -90 mV and saturation at above -90 mV and below -215 mV.

Changes in phosphatidylethanolamine metabolism in regenerating rat liver as measured by 31P-NMR.

31P-NMR spectra of regenerating rat liver in vivo show increases in resonance intensities in the phosphomonoester (PME) region and decreases in the phosphodiester (PDE) region as early as 12 h post partial hepatectomy, which return to normal by 8 days. The compounds primarily responsible for these changes have been identified in perchloric acid extracts as the phosphomonoester phosphoethanolamine and the phosphodiester glycerophosphoethanolamine (GPE), indicating altered phosphatidylethanolamine metabolism. A corresponding increase in diacylglycerol (DAG) levels during regeneration indicates a possible role for a phosphatidylethanolamine-specific phospholipase C in cellular proliferation. These results suggest that changes in phospholipid metabolites previously associated with neoplastic tissue can also be induced by normal tissue undergoing rapid cellular proliferation. The spectral changes observed in the regenerating rat liver are similar to changes seen in spectra from the livers of human patients in several disease states, indicating that 31P-NMR may allow non-invasive study of cell turnover in liver disease.

The pharmacodynamics and pharmacokinetics of the 5HT1B/1D-agonist zolmitriptan in healthy young and elderly men and women.

OBJECTIVE: Zolmitriptan is a selective 5HT1B/1D-agonist for the treatment of migraine. In this study we investigated the cardiovascular and central nervous system effects and the pharmacokinetics of zolmitriptan in young and elderly adults. METHODS: Twelve young adult and 12 elderly volunteers received single doses of 5, 10, and 15 mg zolmitriptan during a randomized, double-blind, placebo-controlled study. Blood pressure, heart rate, ECG, and central nervous system effects were monitored, and pharmacokinetic parameters of zolmitriptan and its metabolites calculated. RESULTS: Zolmitriptan did not affect heart rate and had little effect on systolic blood pressure in the young adults. In the elderly, mean peak supine systolic blood pressure values were 9 to 16 mm Hg higher after zolmitriptan than after placebo. Mean peak diastolic pressure was 6 to 10 mm Hg higher in both age groups. These changes were transient. Postural changes in blood pressure were unaffected. There was a dose-related increase in sedation, but the magnitude of the effects was small. Mean observed peak plasma concentration (Cmax) and area under the plasma concentration-time profile [AUC(0-infinity)] for zolmitriptan and its active N-desmethyl metabolite were similar in both age groups but higher in young women than in young men. Metabolite/parent ratios probably the result of greater first-pass metabolism in young men. Zolmitriptan half-life was 2.8 to 3.6 hours in the elderly compared with 2.7 to 2.9 hours in young adults. Mean Cmax and AUC(0-infinity) for the inactive, N-oxide, and the indole acetic acid metabolites were higher in the elderly, associated with lower renal clearance. CONCLUSIONS: Zolmitriptan was well tolerated, with an effect of age on its effects on blood pressure and the pharmacokinetics of its metabolites. The data suggest no need for dose adjustment for age. In young subjects, concentrations were higher in women than in men, but the differences were insufficient to justify dosage adjustment.

Brain biochemistry in Williams syndrome: evidence for a role of the cerebellum in cognition?

OBJECTIVE: To determine what biochemical changes may occur in the brain in Williams syndrome (WS) and whether these changes may be related to the cognitive deficits. BACKGROUND: WS is a rare, congenital disorder with a characteristic physical, linguistic, and behavioral phenotype with known cognitive deficits. METHODS: We obtained 31P magnetic resonance spectra (MRS) from a region consisting of mostly frontal and parietal lobe of 14 patients with WS (age, 8 to 37 years) and 48 similarly-aged controls. 1H MRS (27 cm3) localized to the left cerebellum obtained from the WS cohort were compared with those from 16 chronological age- and sex-matched normal controls. A battery of cognitive tests were administered to all subjects undergoing 1H MRS. RESULTS: WS brains exhibited significant biochemical abnormalities. All 31P MRS ratios containing the phosphomonoester (PME) peak were significantly altered in WS, suggesting that PME is significantly decreased. Ratios of choline-containing compounds and creatine-containing compounds to N-acetylaspartate (Cho/NA and Cre/NA) were significantly elevated in the cerebellum in WS cf. controls, whereas the ratio of Cho/Cre was not altered. This suggests a decrease in the neuronal marker N-acetylaspartate in the cerebellum. Significant correlations were found between the cerebellar ratios Cho/NA and Cre/NA and the ability of all subjects at various neuropsychological tests, including Verbal and Performance IQ, British Picture Vocabulary Scale, Ravens Progressive Matrices, and Inspection Time. CONCLUSIONS: The correlations can be interpreted in two ways: 1) Our sampling of cerebellar biochemistry reflects a measure of "global" cerebral biochemistry and is unrelated to cerebellar function, or 2) The relations indicate that cerebellar neuronal integrity is a requirement (on a developmental time scale or in real-time) for ability on a variety of cognitive tests.

Vasopressin synergistically stimulates DNA synthesis in normal and regenerating rat liver cell cultures in the presence of hepatocyte growth factor.

Liver regeneration is significantly impaired in rats with both alpha-adrenergic hepatic denervation and hereditary vasopressin deficiency. This may implicate a direct role for these agonists in the process of compensatory hyperplasia. The mitogenic capacities of norepinephrine, vasopressin and hepatocyte growth factor (HGF), either alone or in combination were investigated by [3H]thymidine incorporation into hepatocyte cultures prepared from normal and regenerating rat livers. The results show that normal hepatocytes incorporate less [3H]thymidine in response to HGF than do regenerating hepatocytes. In addition, physiological concentrations of vasopressin cause a synergistic stimulation of [3H]thymidine uptake in rat liver cells in the presence of HGF.

Evidence for increased in vivo sodium-potassium pump activity and potassium efflux in skeletal muscle of spontaneously hypertensive rats.

We have used 87Rb nuclear magnetic resonance spectroscopy (NMR) to study in vivo rubidium kinetics in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls, using rubidium as a marker for potassium. We gave 15 male, 13-week-old SHR, mean +/- s.d. blood pressure 180 +/- 10 mmHg, and 15 age-matched normotensive controls, mean blood pressure 120 +/- 9 mmHg, a daily dose of RbCl (2 mmol/kg intraperitoneally). We made repeated NMR measurements of skeletal muscle rubidium concentrations until steady state was reached. We then withdrew rubidium and made further measurements of rubidium concentrations, at intervals, for up to 1 week after the last injection. We also measured plasma and erythrocyte rubidium concentrations by flame atomic absorption spectroscopy at similar intervals after the withdrawal of rubidium. Rubidium concentrations rose at a faster rate in SHR skeletal muscle, but the steady-state muscle rubidium concentration was the same (45 mmol/l) in both SHR and WKY rats. There was also a threefold increase in the rate of rubidium efflux from both muscle and erythrocytes in SHR. These results are consistent with a marked increase in Na+,K(+)-ATPase activity and an increase in the rate of rubidium efflux in vivo in SHR. The increased rate of rubidium efflux in SHR could represent increased K+ efflux via calcium-activated K+ channels and/or result as part of cell volume regulation secondary to increased Na(+)-H+ antiporter activity.

[131I]iodocholesterol scintiscan and a rare "functional" black adenoma of the adrenal cortex.

A rare functional black adenoma (FBA) of the adrenal cortex was found to be the cause of hypertension and cushingold features in a 34-yr-old white female. Preoperative studies included [131I]iodocholesterol scanning (ICS) of the adrenal glands, which demonstrated the increased release of cortisol from the affected adrenal gland, with the failure of the opposite adrenal gland to record. This is evidence that cortisol was suppressing adrenocorticotropin (ACTH) output by the pituitary gland. This case documents the clinical utility of "functional" imaging techniques in this clinical setting.

The prevalence and determinants of nutritional changes in chronic obstructive pulmonary disease.

Sixty outpatients with chronic obstructive pulmonary disease underwent nutritional, physiologic, and psychologic evaluation to determine the prevalence of nutritional depletion and the relationship to physiologic and psychologic factors. Weight loss was reported in 27 percent. Triceps skinfolds (TSF) were less than 60 percent of standard in 33 percent, none had mid-arm muscle circumference (MAMC) less than 60 percent of standard, and 5 percent had body weight (BW) less than 60 percent of ideal. Values for BW-percent of ideal, TSF-percent of standard, and MAMC-percent of standard were inversely correlated with the percent of estimated caloric expenditure ingested. Also, BW percent was correlated with FEV1 percent predicted, diffusion capacity percent predicted, and oxygen consumption/kg at rest (VO2 percent/kg). There were five variables that explained 62.6 percent of the variation in BW percent: VO2/kg at rest explained 22.2 percent; ventilatory equivalent 13.5 percent; PaCO2 9.8 percent; log vital capacity percent predicted 9.2 percent; and depression 7.8 percent. It is concluded that increased caloric utilization without adequate compensation in dietary intake is the reason for nutritional depletion.

Predictive clinical value of nutritional assessment factors in COPD.

Thirty-nine stable outpatients with moderate-to-severe chronic obstructive pulmonary disease (COPD) were studied prospectively to determine the predictive value of several nutritional factors on the clinical outcome. Physiologic evaluation including FEV1, diffusing capacity, PaO2, as well as nutritional evaluation including triceps skin fold (TSF), midarm muscle circumference, body weight percentage of standard, history of 5 percent weight loss in the year prior to clinic visit, and average daily caloric intake based on a three-day diet record were all done at the clinic visit. Hospitalization or death during the six months to one year following the initial evaluation were the clinical outcome factors evaluated. Five of the 16 patients (31 percent) needing hospitalization during that time had weight loss during the year prior to the initial evaluation, while eight out of the 23 (35 percent) not requiring hospitalization had weight loss. There was a significantly lower TSF percent standard (TSF%) in the subgroup who subsequently required hospitalization (p less than 0.05). Nonhospitalized patients with severe depletion of body fat (TSF% less than 60) at initial evaluation ingested significantly more calories per kilogram than the severely depleted patients requiring hospitalization in the next six to 12 months (p less than 0.05) suggesting a protective effect of increased caloric intake. Increased caloric intake did not improve mortality statistics.

Decreases in serum high-density-lipoprotein cholesterol and total cholesterol resulting from naturally produced and recombinant DNA-derived leukocyte interferons.

A three-phase study was conducted to examine the effect of leukocyte interferon administration on serum high-density-lipoprotein (HDL) cholesterol and total cholesterol levels. In the initial phase, human leukocyte interferon decreased HDL cholesterol (P less than 0.05) and total cholesterol (P less than 0.05) levels in patients with breast carcinoma. Decreases began with initiation of the interferon administration, were sustained throughout the period of treatment, and increased toward pretreatment values with discontinuation of interferon. In the second phase of the study, in neither of two comparison groups of women receiving cytotoxic chemotherapy, excluding interferon, did any similar decrease in HDL cholesterol occur. In a third comparison group of women being treated for metastatic breast carcinoma, a predicted and significant (P less than 0.01) drop in HDL cholesterol level without a concomitant lowering of total cholesterol level occurred immediately following the initiation of androgen therapy. To confirm that the observed cholesterol level decreases were associated with interferon rather than a contaminant thereof, analyses were also carried out on samples from a study utilizing interferon rather than a contaminant thereof, analyses were also carried out on samples from a study utilizing interferon produced by recombinant DNA techniques and purified to homogeneity. A similar decrease in HDL cholesterol (P less than 0.05) and total cholesterol (P less than 0.01) was observed. A definite relationship therefore appears to exist between the administration of human leukocyte interferon and decreased plasma levels of HDL cholesterol and total cholesterol.

N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington's disease mice.

Huntington's disease (HD) is an autosomal dominant condition involving progressive neurodegeneration, primarily the corpus striatum and cerebral cortex. We have used in vivo magnetic resonance spectroscopy (MRS) to assess specific neuronal markers in transgenic mice (R6/1 line) expressing exon I of the human huntingtin gene with an expanded CAG repeat. Levels of N-acetylaspartate (NAA), an indicator of healthy neuronal function, were significantly reduced (26%) in the corpus striatum of HD mice relative to wild-type littermates at 5 months of age. However, levels of cholines and creatine-phosphocreatine were not altered in the HD mice. Expression of dopamine- and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32), was assessed by immunohistochemistry in the striatum of HD mice and found to be downregulated by 5 months and, even more dramatically, at 11 months of age. In contrast, expression of calbindin was not significantly decreased in HD mice. Our results suggest that the observed decreases in DARPP-32 and NAA may contribute to aberrant receptor signalling and neuronal dysfunction in HD.

Separate quantification of doubly and singly 13C-labeled metabolites by HSQC-filtered J spectroscopy.

NMR detection of multiply labeled compounds in biological samples is often used to follow metabolic pathways. Detection of protons bound to 13C atoms offers a more sensitive approach than direct 13C detection, but generally results in the loss of carbon-carbon coupling information. We have modified an HSQC sequence to refocus the carbon chemical shifts in order to obtain a proton-correlated 13C homonuclear J spectrum, which allows us to measure singly and doubly labeled compounds in the same spectrum.

Brain biochemistry in Duchenne muscular dystrophy: a 1H magnetic resonance and neuropsychological study.

Duchenne muscular dystrophy (DMD) is a progressive muscle disorder associated with an intellectual deficit which is non-progressive. We obtained localised 1H magnetic resonance spectra from the left frontal lobe and left cerebellum of 15 boys with DMD (mean age 106 months+/-32) and 15 similarly aged control boys (mean age 115 months+/-31); all boys underwent a battery of neuropsychological tests. We found a significant (P<0.01) increase in the ratio of choline-containing compounds to N-acetylaspartate (Cho/NA) in the left cerebellum in boys with DMD compared with control boys. There was no change in the creatine/NA ratio and a significant increase (P=0.03) in the Cho/creatine ratio, suggesting that the change in Cho/NA ratio was due to an increase in choline-containing compounds; this increase has been previously observed in the brain of the murine model of DMD, the mdx mouse. No significant changes were observed in spectra obtained from left frontal lobe in DMD compared to controls. We also observed a significant association between Cho/NA in the left cerebellum, and the performance of DMD boys on the Matrix Analogies Test (MAT). The MAT is a test of visuo-spatial ability and non-verbal reasoning which requires neither manual dexterity nor a verbal response for an adequate performance. A comparison of DMD boys whose cerebellar Cho/NA fell within 2 standard deviations of the control norm (0.56+/-0.24) with DMD boys whose cerebellar Cho/NA was outside this range (i.e. >0.80) revealed a significant difference in ability on the MAT (P<0.05). DMD boys whose Cho/NA ratio is more than two standard deviations higher than controls perform significantly better on the MAT than DMD boys whose Cho/NA ratio is within the normal range. This finding suggests that the observed elevation in Cho/NA and Cho/creatine is not associated with intellectual deficit (as sampled by the MAT), and may represent a compensatory mechanism. The possible interpretations of these metabolic changes are discussed.

Single-dose, placebo-controlled, phase I study of oral dolasetron.

STUDY OBJECTIVES: To evaluate the safety, tolerability, and pharmacokinetics of single, escalating doses of oral dolasetron mesylate, a new 5-HT3 receptor antagonist. DESIGN: Double-blind, placebo-controlled, dose-escalating phase I study. SETTING: A clinical research center. PATIENTS: One hundred twenty healthy male volunteers. INTERVENTIONS: Subjects received either placebo or oral dolasetron mesylate 50, 100, 150, 200, 250, 300, or 400 mg. MEASUREMENTS AND MAIN RESULTS: Compared with placebo, subjects receiving dolasetron mesylate reported a greater frequency of headache, light-headedness, dizziness, increased appetite, and nausea. There were no clinically significant changes in mean laboratory values from before to after treatment. Adverse events were transient, mild or moderate, and similar to those after single intravenous doses of the drug. No clinically significant electrocardiographic changes occurred, but lengthening of the QRS complex duration and dose-dependent lengthening of PR and QTc intervals were observed 1-2 hours after dosing. These effects were asymptomatic and were mainly associated with higher doses (< or = 300 mg). CONCLUSION: Dolasetron mesylate is well tolerated when administered in single oral doses up to 400 mg to healthy volunteers. Clinical trials are under way to evaluate the agent's efficacy in preventing chemotherapy-induced and postoperative nausea and vomiting with doses up to 200 mg.