Distribution of intranasal C-zolmitriptan assessed by positron emission tomography.

Nine healthy volunteers aged 18-28 years were recruited into this open, single-centre, two-phase trial. In phase 1, two volunteers received a single dose of 11C-zolmitriptan 2.5 mg administered as a nasal spray and then underwent positron emission tomography (PET) scanning to determine the most appropriate times for scanning in phase 2. In phase 2, six volunteers received two doses and an additional volunteer one dose of 11C-zolmitriptan 2.5 mg intranasally. Volunteers underwent PET scanning over sectors covering one of the nasopharynx, lungs or abdomen, for up to 1.5 h postdose. The brain was also scanned and plasma zolmitriptan levels were measured. Almost 100% of the administered dose was detected in the nasopharynx immediately after dosing. This declined thereafter to about 50% at 20 min and to 35% at 80 min after dosing. Radioactivity appeared slowly in the upper abdomen, with 25% of given radioactivity detected at 20 min and persisting until 80 min after dosing. Minimal radioactivity was detected in the lungs. Radioactivity was detectable within brain tissue suggesting central penetration of zolmitriptan. Zolmitriptan in plasma had approached its maximum concentration by 15 min postdose. The data indicate initial absorption across the nasal mucosa contributing to an early systemic availability. 11C-Zolmitriptan administered intranasally was well tolerated.

The pharmacokinetics of the antimigraine compound zolmitriptan in Japanese and Caucasian subjects.

BACKGROUND: Zolmitriptan is a 5HT(1B/1D) receptor agonist effective in the acute treatment of migraine. Clinical trials in the USA and Europe have demonstrated the optimal oral therapeutic dose to be 2.5 mg. The 2.5-mg oral tablet has recently been licensed in Japan. OBJECTIVE: To compare the pharmacokinetics of zolmitriptan and its metabolites in Japanese and Caucasian subjects and evaluate the effect of gender on these pharmacokinetics in Japanese volunteers. METHODS: In this open, parallel-group study, 30 Japanese and 30 Caucasian volunteers (20-45 years) received a single 2.5-mg zolmitriptan tablet in the fasting state. Blood samples were taken up to 15 h post-dose to determine plasma concentrations of zolmitriptan and its active metabolite, 183C91. Urinary excretion of zolmitriptan, 183C91 and the inactive N-oxide and indole acetic acid metabolites were measured over 24 h. RESULTS: Japanese volunteers were, on average, smaller and lighter than Caucasian volunteers. Plasma-concentration profiles of zolmitriptan and 183C91 were similar in the two groups. Although geometric mean zolmitriptan and 183C91 area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C(max)) were slightly higher in Japanese subjects (up to 20%), these differences were not considered to be of clinical relevance as the 90% confidence interval for the ratio of AUCs fell within pre-specified limits (0.67 to 1.5). Mean zolmitriptan and 183C91 half-lives were around 2.5 h for both populations. Urinary excretion of the four analytes was similar in Japanese and Caucasians. Plasma concentrations of zolmitriptan were higher in Japanese females than males (AUC 40% and C(max) 29% higher), consistent with the results previously obtained in Caucasians. CONCLUSION: Pharmacokinetic parameters of zolmitriptan were similar between Caucasian and Japanese volunteers.

Effects of the antimigraine compound zolmitriptan ('Zomig') on psychomotor performance alone and in combination with diazepam in healthy volunteers.

Zolmitriptan (Zomig) is a 5HT1B/1D agonist which has the ability to cross the intact blood-brain barrier to access central as well as peripheral receptors. Because of the potential for central nervous system side effects, this randomized, double-blind, placebo-controlled, 6-period crossover study evaluated the effects of 2.5 and 5 mg doses of zolmitriptan on psychomotor performance and investigated any pharmacodynamic or pharmacokinetic interaction with diazepam. Twelve healthy volunteers received the following "treatments" as single doses: zolmitriptan 2.5 mg, zolmitriptan 5 mg, diazepam 10 mg, zolmitriptan 2.5 mg + diazepam 10 mg, zolmitriptan 5 mg + diazepam 10 mg and placebo. Pre-dose and at 1, 4, 8, and 24 h post-dose, the following validated battery of psychomotor tests was performed: Bond-Lader visual analogue scales (calmness, contentedness, and alertness factors), critical flicker fusion test, choice reaction time (recognition, motor, and total reaction times), finger-tapping test, number cancellation test and digit symbol substitution test. Plasma concentrations of zolmitriptan, its active metabolite, and diazepam and its active metabolites were measured at the same timepoints. Zolmitriptan 2.5 and 5 mg had no effect on psychomotor function when given alone. In contrast, diazepam 10 mg had profound effects, consistent with its sedative properties, but there was no synergism on concomitant administration of either dose of zolmitriptan. Plasma concentrations of zolmitriptan, diazepam, and their respective active metabolites were similar when the two drugs were given alone or in combination.

Dieting severity and gastrointestinal symptoms in college women.

Young women report symptoms associated with irritable bowel syndrome (IBS), such as pain, bloating, and changes in bowel movements, more often than young men. Young women with eating disorders also report these gastrointestinal symptoms frequently. We hypothesized that if dieting behaviors were associated with these symptoms, the prevalence and frequency of the symptoms would be positively related to dieting severity in young women. We interviewed 301 1st-year college women representing the continuum of dieting severity. We found that severity of dieting was positively related to frequency of abdominal pain, bloating, diarrhea, and constipation, and that the women who reported 3 or more symptoms regularly scored higher on a scale for dieting severity. Although this study did not examine the relationship between dieting severity and clinical IBS, the findings suggested that dieting is associated with gastrointestinal symptoms in young women.

Efficacy of meropenem in experimental meningitis.

Meropenem and comparator antibiotics, including ceftriaxone, ceftazidime, benzyl penicillin and a combination of ampicillin plus gentamicin, were evaluated in a model of bacterial meningitis in the guinea-pig. The model is an acute infection in which challenge with each organism, if untreated, causes an increase in numbers of white blood cells, elevation of protein concentrations and 6-8 log10 cfu/mL of bacteria in the CSF. Infections caused by Haemophilus influenzae, Neisseria meningitidis, three strains of Streptococcus pneumoniae (two penicillin-resistant), Escherichia coli, Pseudomonas aeruginosa and Listeria monocytogenes all responded to meropenem, which was as active as the comparator agents in all studies, and was more active in most. Of particular note were the results seen against S. pneumoniae (penicillin-resistant) infections, in which meropenem was significantly more effective than ceftriaxone. Also notable were results from the P. aeruginosa infection where meropenem, at low doses, was more effective than ceftazidime. Activity against L. monocytogenes was equivalent to that produced by treatment with the combination of ampicillin plus gentamicin, even when treatment was delayed. These results show that, in an animal model, meropenem penetrates into CSF in concentrations sufficient to produce significant reductions in the numbers of common and less common pathogens.

Naloxone, an opiate blocker, reduces the consumption of sweet high-fat foods in obese and lean female binge eaters.

To test the hypothesis that endogenous opiate peptides selectively influence hedonic response to sweet and high-fat foods, the opiate antagonist naloxone, opiate agonist butorphanol, and a saline placebo were administered by intravenous infusion to 16 obese and 25 normal-weight women. Twenty of the women (10 obese, 10 lean) fulfilled DSM-III-R diagnostic criteria for bulimia nervosa, as determined by psychiatric interview. During drug infusion the women tasted and rated 20 sweetened dairy products and were presented with eight snack foods of varying sugar and fat content. Naloxone suppressed hedonic responses in all subject groups and suppressed the consumption of sweet and high-fat foods in binge eaters, but not in nonbingers. Food intakes of obese women were not affected by naloxone. Butorphanol had no effect on either hedonic response or on food consumption in any group. Although opiate blockade is not a viable strategy for weight reduction in the treatment of obesity, it may be useful in the clinical management of the binge-eating disorder.

The severity of dieting and bingeing behaviors in college women: interview validation of survey data.

A combined survey and interview study was conducted to validate a categorical Dieting and Bingeing Severity Scale (DBSS), and to estimate the prevalence of eating disorders in young women. We hypothesized that assignment to the DBSS categories would be confirmed by clinical interviews such that interview-diagnosed eating disorders would be found with increasing frequency and severity at the upper end of the DBSS. Freshmen college women (n = 1367) completed a survey instrument addressing the frequency and severity of dieting, binge-eating, and other behaviors and attitudes related to weight control. Random stratified sampling procedures were used to select a subset of women (n = 306) from each DBSS category for structured clinical interviews for DSM-III-R (SCID). Survey respondents were assigned to one of six mutually exclusive DBSS categories: non-dieters (9% of sample), casual dieters (26%), moderate dieters (23%), intense dieters (21%), dieters at-risk (19%), and probable bulimia nervosa (2%). The DBSS effectively rank-ordered subjects according to the risk of having interview-diagnosed eating disorders. Women in the three most severe DBSS categories were significantly more likely to have current subthreshold and threshold level eating disorders, in particular bulimia nervosa and eating disorder not otherwise specified (EDNOS). The estimated prevalence of current bulimia nervosa was approximately 2% by both survey and interview methods. The prevalence of current EDNOS was 13%, more than six times greater than the prevalence of bulimia nervosa. The DBSS was found to be a reliable and valid measure of dieting and bingeing severity. The survey instrument may be useful in measuring the extent of, and changes in, pathological dieting in community-based samples of young women, and in studying comorbidity of dieting and bingeing severity with other psychiatric conditions including depression and substance use. The DBSS may also be useful in identifying risk factors associated with the onset of eating disorders.

Changes in resting energy expenditure and body composition in anorexia nervosa patients during refeeding.

Accurate prediction of the energy level necessary to promote weight restoration in patients with anorexia nervosa would be clinically useful. Resting energy expenditure (REE), respiratory quotient, and body composition were measured in 10 nonmedicated women with anorexia nervosa during a vigorous refeeding protocol. REE was measured three times per week by open-circuit indirect calorimetry after an overnight fast. Subjects ranged in age from 19 to 38 years and weighed 39.9 +/- 4.3 kg (mean +/- standard deviation) at admission. The refeeding protocol was as follows: phase 1, 1,200 kcal/day for 1 week (baseline); phase 2, an increase of 300 kcal/day for 1 week; phase 3, 3,600 kcal/day until target weight was reached; phase 4, 1,800 to 2,800 kcal/day (stabilization). REE was 30.0 +/- 6.4, 33.5 +/- 6.7, 37.3 +/- 6.6 and 34.5 +/- 4.4 kcal/kg body weight during phases 1, 2, 3, and 4, respectively. The Harris-Benedict equation overestimated phase 1 24-hour REE by a mean of 14% and underestimated REE in phases 2, 3, and 4 by a mean of 8%, 24%, and 23%, respectively. Skinfold measurements revealed percent body fat to be 12 +/- 4% at admission and 19 +/- 5% at discharge, with a mean of 48% of the weight gained during refeeding attributable to increased body fat. These findings indicate that refeeding in anorexia nervosa is associated with increased REE, which cannot be explained by increased body mass, and that caloric requirements for weight restoration in patients with anorexia nervosa are best determined by monitoring individual response.

The impact of sexual and physical abuse on eating disordered and psychiatric symptoms: a comparison of eating disordered and psychiatric inpatients.

The authors compared rates of physical and sexual abuse in women with eating disorders (N = 102) and general psychiatric disorders (N = 49). Relationships between sexual abuse and severity of eating disordered and psychiatric symptoms were also examined. While high rates of sexual abuse were found in the eating disordered sample, these rates were not significantly higher than those found in the general psychiatric population. No relationship between a history of sexual abuse and severity of eating disordered symptoms was found. However, within the eating disordered group, sexually abuse subjects reported more severe psychiatric disturbances of an obsessive and phobic nature than nonabused subjects. These findings suggest that while sexually abusive experiences may be related to increased psychological distress, they do not serve to increase eating disordered symptomatology.

Taste responses and preferences for sweet high-fat foods: evidence for opioid involvement.

Preferences and cravings for sweet high-fat foods observed among obese and bulimic patients may involve the endogenous opioid peptide system. The opioid antagonist naloxone, opioid agonist butorphanol, and saline placebo were administered by intravenous infusion to 14 female binge eaters and 12 normal-weight controls. Eight of the binge eaters were obese. During infusion, the subjects tasted 20 sugar/fat mixtures and were allowed to select and consume snack foods of varying sugar and fat content. Naloxone reduced taste preferences relative to baseline in both binge eaters and controls. Total caloric intake from snacks was significantly reduced by naloxone in binge eaters but not in controls. This reduction was most pronounced for sweet high-fat foods such as cookies or chocolate. No consistent effects on taste preferences or food intakes were observed with butorphanol. Endogenous opioid peptides may be involved in mediating taste responses and preferences for palatable foods, notably those rich in sugar and fat.

Stealing in eating disordered patients.

Previous studies have noted high rates of stealing behavior in patients with eating disorders. To assess the significance of stealing in eating disordered patients, the authors compared the eating and purging behavior, levels of psychologic symptomatology, and alcohol use of 181 eating disordered patients with and without a history of stealing. Overall, the patients with a history of stealing had significantly more dysfunctional eating and purging behavior. Those patients with a history of stealing reported significantly more psychological distress including more depression, interpersonal sensitivity, obsessive compulsive behavior, and hostility. The authors conclude that stealing behavior should be assessed in patients with eating disorders as a history of stealing may define a subgroup of more severely impaired patients.

Therapeutic activity of meropenem in experimental infections.

Meropenem and comparative antibiotics were evaluated in five models of infection. All antibiotics were administered parenterally; imipenem was used in combination with cilastatin but meropenem and other agents were given alone. Generalized infections in mice caused by Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Serratia marcescens, Proteus mirabilis or Pseudomonas aeruginosa all responded to low doses of meropenem or imipenem. Immunocompromised mice infected with Ps. aeruginosa responded to slightly higher doses of meropenem or gentamicin but required four to seven times the dose of other agents. Those given a greater challenge of Ps. aeruginosa were treated most successfully by meropenem. Treatment with meropenem, imipenem or ceftazidime caused significant reductions of E. coli in the urinary bladder and kidneys of mice challenged per urethram. Infection with Ps. (Xanthomonas) maltophilia localized to the subcutaneous neck tissue of guinea pigs was also treated successfully. Lung infections caused by Ps. aeruginosa in guinea pigs were treated effectively by meropenem, imipenem, and ceftazidime at the dose of 10 mg/kg but only meropenem eradicated bacteria from all the tissues examined. These results demonstrate that meropenem has excellent antibacterial activity in vivo in both normal and immunocompromised animals and in some models of infection is superior to imipenem.

In vitro antibacterial activity of SM-7338, a carbapenem antibiotic with stability to dehydropeptidase I.

SM-7338, a new carbapenem antibiotic, was demonstrated to have potent antibacterial activity against a broad spectrum of aerobes, including Staphylococcus aureus, beta-hemolytic streptococci, Streptococcus pneumoniae, Haemophilus influenzae, Neisseria spp., members of the family Enterobacteriaceae, Pseudomonas spp., and gram-positive and gram-negative anaerobes in a collection of 1,102 unselected clinical isolates. At a concentration of 0.5 micrograms/ml, SM-7338 inhibited 90% of these strains. The spectrum of activity of ceftazidime and cefotaxime was more limited, and many of the Enterobacteriaceae and Pseudomonas spp. were resistant to these agents, piperacillin, or gentamicin. A collection of ofloxacin-resistant strains was inhibited by SM-7338 or imipenem at 4 micrograms/ml. SM-7338 was more active than metronidazole and clindamycin against anaerobes. Of the carbapenems, imipenem had greater activity against staphylococci but SM-7338 was much more active against Haemophilus, Branhamella, and Neisseria spp. and all genera of Enterobacteriaceae tested. The MIC of SM-7338 for 90% of these strains ranged from less than or equal to 0.008 to 0.13 micrograms/ml. When tested against 124 strains of Pseudomonas aeruginosa, SM-7338 inhibited 76% at 0.5 microgram/ml but imipenem inhibited only 15% at this concentration. Both carbapenems exhibited similar activities against Bacteroides spp., but SM-7338 was more active than imipenem against Clostridium spp. The MBC of SM-7338 was most commonly the same as or twice the MIC. SM-7338 and imipenem showed excellent activities against bacteria elaborating chromosome- or plasmid-mediated beta-lactamases, including those conferring resistance to broad-spectrum cephalosporins. The activity of SM-7338 was generally unaffected by the culture medium used, pH, 25% human serum, and inoculum size, but the susceptibility of Xanthomonas maltophilia was medium dependent.