A phase I trial to assess the pharmacology of the new oestrogen receptor antagonist fulvestrant on the endometrium in healthy postmenopausal volunteers.

While tamoxifen use is associated with clear benefits in the treatment of hormone-sensitive breast cancer, it also exhibits partial oestrogen agonist activity that is associated with adverse events, including endometrial cancer. Fulvestrant ("Faslodex") is a new oestrogen receptor antagonist that downregulates the oestrogen receptor and has no known agonist effect. This single-centre, double-blind, randomised, parallel-group trial was conducted to determine the direct effects of fulvestrant on the female endometrium when given alone and in combination with the oestrogen, ethinyloestradiol. Following a 14-day, pretrial screening period, 30 eligible postmenopausal volunteers were randomised to receive fulvestrant 250 mg, fulvestrant 125 mg or matched placebo administered as a single intramuscular injection. Two weeks postinjection, volunteers received 2-weeks concurrent exposure to ethinyloestradiol 20 microg day(-1). Endometrial thickness was measured before and after the 14-day screening period with further measurements predose (to confirm a return to baseline) and on days 14, 28 and 42 post-treatment with fulvestrant. Pharmacokinetic and safety assessments were performed throughout the trial. Fulvestrant at a dose of 250 mg significantly (P=0.0001) inhibited the oestrogen-stimulated thickening of the endometrium compared with placebo. Neither the 125 mg nor 250 mg doses of fulvestrant demonstrated oestrogenic effects on the endometrium over the initial 14-day assessment period. Fulvestrant was well tolerated and reduced the incidence of ethinyloestradiol-related side effects. At the same dose level that is being evaluated in clinical trials of postmenopausal women with advanced breast cancer, fulvestrant (250 mg) is an antioestrogen with no evidence of agonist activity in the endometrium of healthy postmenopausal women.

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.

The effect of anastrozole on the single-dose pharmacokinetics and anticoagulant activity of warfarin in healthy volunteers.

AIMS: The aims of this study were to determine the effects of the nonsteroidal, selective aromatase inhibitor, anastrozole, at steady-state concentrations, on the pharmacokinetics and pharmacodynamics of warfarin, and to assess whether or not anastrozole alone has any anticoagulant activity. METHODS: This was a randomized, double-blind, placebo-controlled, two-way crossover trial conducted at a single centre. The study comprised two treatment periods of 11 days, separated by a 3 week washout. Healthy male volunteers (n = 16, median age 28.5 years) were randomized to receive either anastrozole (7 mg loading dose on day 1, followed by 1 mg daily on days 2-11) in the first treatment period and placebo in the second treatment period, or vice versa. In addition to their randomized treatment, all volunteers received a single dose of 25 mg warfarin on day 3 of each treatment period. Blood samples for pharmacokinetic and pharmacodynamic assessment were taken at frequent intervals during each treatment period. The safety of volunteers was monitored throughout the study. RESULTS: Administration of anastrozole resulted in no clinically significant changes in the pharmacokinetics of either R- or S-warfarin compared with placebo for AUC (ng ml-1 h) (glsmean, R-warfarin; anastrozole 93619.9, placebo 91127.91, 95%CI 0.988-1.068; S-warfarin; anastrozole 57129.21, placebo 55676.34, 95%CI 0.979-1.076), CL/F (ml min-1) (glsmean, R-warfarin; anastrozole 2.23, placebo 2.29, 95%CI 0.937-1.012; S-warfarin; anastrozole 3.65, placebo 3.74, 95%CI 0.929-1.021) and t1/2 (h) (lsmean, R-warfarin; anastrozole 55.40, placebo 55.15, 95%CI-2.083-2.592; S-warfarin; anastrozole 39.38, placebo 40.98, 95%CI-6.189-2.996). In addition, anastrozole had no clinically significant effect on the pharmacodynamic effects of warfarin, as assessed 240 h after warfarin dosing by measurement of prothrombin time (s) (glsmean, anastrozole 11.56, placebo 11.31, 95%CI 0.987-1.059), thrombin time (s) (glsmean, anastrozole 19.06, placebo 18.75, 95%CI 0.980-1.054) activated partial thromboplastin time (s) (glsmean, anastrozole 29.94, placebo 29.74, 95%CI 0.968-1.047) and factor VII (%) (glsmean, anastrozole 97.81, placebo 107.26, 95%CI 0.821-1.012). Anastrozole alone had no effect on these indicators of the clotting process. CONCLUSIONS: Overall, there was no evidence to suggest that anastrozole has any clinically relevant effects on the pharmacokinetics of warfarin. Anastrozole had no effect on clotting mechanisms or on the pharmacodynamic activity of warfarin, as assessed by prothrombin time, thrombin time, activated partial thromboplastin time, and factor VII.

Canine distemper in terrestrial carnivores: a review.

Canine distemper virus is a member of the genus Morbillivirus in the family Paramyxoviridae. Canine distemper has been recorded in domestic dogs for centuries. It is now recognized as a worldwide problem of carnivores and has the second highest fatality rate of any infectious disease, after rabies, in domestic dogs. The importance of this disease in nondomestic animals has become evident with vaccine-induced infections in a variety of species and large-scale epidemics in captive and free-ranging felids. To date, canine distemper has been reported in all families of terrestrial carnivores: Canidae, Felidae, Hyaenidae, Mustelidae, Procyonidae, Ursidae, and Viverridae. Veterinarians, including those working with nondomestic carnivores, should be familiar with the clinical signs, diagnosis, and clinical management of this disease.

Electroencephalographic and psychomotor effects of chlorpromazine and risperidone relative to placebo in normal healthy volunteers.

AIMS: To investigate the effects of single oral doses of chlorpromazine (50 mg) and risperidone (2 mg) relative to placebo on topographical electroencephalometry (CATEEMTM ) and psychomotor tests in 12 healthy male volunteers. METHODS: A double-blind, placebo-controlled, three-way crossover design using a double dummy blinding technique was utilized. Chlorpromazine was selected as representative of the 'typical' neuroleptics, being also highly sedative. Risperidone has been suggested as representative of the newer 'atypical' neuroleptics and is claimed to be only minimally sedative. Volunteers were dosed on 3 separate days with a minimum of 7 days interval between trial days. On each trial day volunteers were dosed twice. Dose 1 consisting of either chlorpromazine 50 mg or placebo to chlorpromazine, and dose 2 either risperidone 2 mg or placebo to risperidone. The volunteers were randomized so that each received either chlorpromazine or risperidone (or neither), but not both on an individual trial day. A 17 electrode quantitative topographical electroencephalograph (EEG) recording was taken for each volunteer before and after each dosing period. Seven psychomotor function tests were used to determine the effects of each treatment on psychomotor performance. RESULTS: The data confirm the cited reports of sedation following single oral doses of chlorpromazine 50 mg. However, 7 of the 12 volunteers dosed with risperidone 2 mg also reported drowsiness/lethargy which was of greater severity and duration than 5 of the 12 volunteers who reported somnolence following dosing with chlorpromazine 50 mg. Objective assessment of psychomotor impairment using a short battery of psychomotor function tests mirrored the subjective reports of somnolence in that the impairment in volunteers dosed with risperidone 2 mg was greater in extent and magnitude than in volunteers dosed with chlorpromazine 50 mg. With respect to the cortical quantitative electroencephalogram, both chlorpromazine (50 mg) and risperidone (2 mg) increased power (4.75-6.75 Hz) in keeping with cited effects of other neuroleptics on the quantitative EEG. In addition, there was a statistically significant increase (P<0.05) in alpha1 (7.0-9.5 Hz) and beta1 (12.75-18.5 Hz) wavebands in volunteers dosed with risperidone 2 mg. Furthermore, based on estimates of variability, we propose that a 3 min eyes open and 3 min eyes closed quantitative EEG recording is sufficient to maintain adequate power for this technique, whilst allowing its application to early volunteer trials of novel neuroleptic agents. CONCLUSIONS: This study demonstrates that quantitative EEG can be utilized in the profiling of neuroleptic agents, and could be readily applied to the early profiling of novel neuroleptics in limited numbers of volunteers, early in drug development. The chosen battery of psychomotor tests has clearly demonstrable sensitivity to the quantification of the subjective reports of somnolence secondary to both chlorpromazine and risperidone.

Persistence of maternal antibodies against Mycoplasma agassizii in desert tortoise hatchlings.

OBJECTIVE: To investigate Mycoplasma agassizii-specific maternal antibodies in desert tortoise (Gopherus agassizii) hatchlings. SAMPLE POPULATION: Plasma from 43 captive-reared desert tortoise hatchlings. PROCEDURE: ELISA for M agassizii-specific antibodies was performed. Four hatchlings from 4 clutches of 3 M agassizii-seropositive females with chronic upper respiratory tract disease (URTD) were tested on the day of hatching (set 1), and 20 hatchlings from 4 clutches of 4 M agassizii-seropositive females with URTD and 19 hatchlings from 4 M agassizii-seronegative healthy females were tested at 4, 8, 12, and 29 months old (set 2). Immunoblot analysis was performed to determine immunoglobulin classes in yolk and plasma of hatchlings. To determine infection status of hatchlings, yolk, egg shell membranes (set 1), and nasal lavage fluid (sets 1 and 2) were examined for M agassizii by use of polymerase chain reaction. RESULTS: Yolk and hatchling plasma had significantly lower amounts of specific antibodies than did plasma from adult females. The IgG and IgM antibodies were transferred, but M agassizii-specific antibodies were of the IgG class. Hatchlings were not infected with mycoplasmas. Offspring of sick females had significantly higher specific antibody titers than did offspring of healthy females. Titers were still significantly different in 1-year-old hatchlings. CONCLUSIONS: Desert tortoise females transfer specific IgG and IgM antibodies to their offspring that are still detectable after 1 year. CLINICAL RELEVANCE: Infection with M agassizii may be misdiagnosed in hatchlings with persistent maternal antibodies. Passively acquired antibodies may have a role in pathogenesis of mycoplasma-induced respiratory tract disease and other diseases.

Effects of zolmitriptan (Zomig) on central serotonergic neurotransmission as assessed by active oddball auditory event-related potentials in volunteers without migraine.

In this randomized, double-blind, three-period crossover trial, 24 healthy volunteers without migraine received zolmitriptan 5 mg, dexfenfluramine 15 mg or placebo orally. At 2, 6, and 24 h postdose, auditory stimuli of 1000 Hz (nontarget tone) and 2000 Hz (target tone) were randomly and binaurally presented in an active oddball paradigm (4:1 ratio). Cortical auditory evoked responses were recorded for 500 msec poststimulus. Plasma concentrations of zolmitriptan and a 17-lead quantitative EEG were assessed at the same timepoints. Relative to placebo, zolmitriptan reduced the maximum absolute amplitude, amplitude difference (from nontarget tone noise) and area under the curve of the cortical auditory target tone event-related potential (P300 ERP). The most dramatic effect of zolmitriptan was to diminish the point estimate of noise during the 200-400 msec poststimulus epoch. The effect of zolmitriptan appeared concentration dependent. The latency of the P300 ERP was unaffected by zolmitriptan and there was no clinically significant effect on the EEG. Modification by zolmitriptan of the cortical electrical activity evoked by auditory stimuli confirms a central action of this drug in humans, which appears to affect cortical information processing without global alteration of the quantitative EEG.

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.

A comparison of the pharmacokinetics of meropenem after intravenous administration by injection over 2, 3 and 5 minutes.

The pharmacokinetics of meropenem were determined in 9 healthy volunteers after the administration of 1 g dose by injection over 2, 3 or 5 min. Peak plasma concentrations were not significantly different across the three rates of administration and, due to the finite time required for complete mixing of the blood in the central compartment, did not always occur at the end of the injection. Overall exposure to meropenem was unchanged by the more rapid rates of administration. Plasma clearance, terminal half-life and volume of distribution were virtually unchanged. Within 10 min after the start of the injection, the plasma concentrations from all three injections were very similar indicating that dosing over 2, 3 or 5 min would result in similar antimicrobial cover and, therefore, comparable efficacy. Comparison of the data derived from the three injections indicated that rapid administration of meropenem did not appreciably alter its disposition pharmacokinetics. Tolerability of meropenem was unchanged with the more rapid administration rate.

Arimidex (ZD1033): a selective, potent inhibitor of aromatase in postmenopausal female volunteers.

Two multiple-dose studies were conducted in healthy post-menopausal female volunteers to investigate the pharmacokinetics and effects on endocrinology of Arimidex (ZD1033). Volunteers in the first trial were dosed with 3 mg of ZD1033 daily over 10 days to assess the effects on endocrinology of ZD1033 and establish a pharmacokinetic profile. In the second trial volunteers received 14 daily doses of either 0.5 or 1.0 mg of ZD1033 to assess the pharmacokinetics of ZD1033 and the effects of low doses of ZD1033 on serum oestradiol concentrations. Following multiple dosing a significant reduction in the concentration of serum oestradiol of approximately 80% of baseline was obtained with all three doses; no recovery in oestradiol was apparent for up to 144 h after the last dose. There was no overall difference in the level of oestradiol suppression between the 0.5 or 1.0 mg doses of ZD1033. However, comparison of the number of volunteers with oestradiol concentrations below the limits of detection of the assay, 24 h after the last dose of ZD1033, suggested that 1.0 mg was the minimal dose required for maximal suppression of oestradiol. No significant effect was recorded on serum concentrations of gonadotrophins over the dosing period. Serum concentrations of a range of adrenal steroids were not affected by administration of ZD1033; furthermore, steroid response to standard adrenocorticotrophic hormone (ACTH) challenge was unimpaired by ZD1033. Together these data demonstrate the potency, tolerability and selectivity of ZD1033. The pharmacokinetic profile of ZD1033 supports its use as a once-daily treatment given orally.

Characterization of genes encoding members of the nuclear hormone receptor superfamily from Onchocerca volvulus.

Several lines of evidence suggest that molting in parasitic nematodes is controlled through the action of steroid molting hormones, or ecdysones. In other organisms, the central mediator of steroid hormone action is the hormone receptor. These receptor molecules are members of a superfamily of proteins called the nuclear hormone receptor family. Using an oligonucleotide derived from the amino-acid sequence of the Drosophila melanogaster ecdysone receptor, genes encoding homologues of the nuclear hormone receptor family were identified in the genome of the human filarial parasite Onchocerca volvulus. The O. volvulus genome contains at least three genes that encode putative members of the nuclear hormone receptor superfamily. A complete cDNA for one of these genes, designated OvNHR-1, has been isolated and characterized. The OvNHR-1 cDNA was 2378 bp in length, and contained a single open reading frame of 1104 bp. The open reading frame encoded a peptide with all of the features characteristic of a member of the nuclear hormone receptor superfamily of proteins. OVNHR-1 appeared to be encoded by a single-copy gene. Expression of the mRNA corresponding to OvNHR-1 was developmentally regulated, with maximal expression occurring during early embryogenesis. The polypeptide encoded by the OvNHR-1 open reading frame is antigenic in a minority of individuals exposed to O. volvulus.

Canine distemper epizootic in lions, tigers, and leopards in North America.

Canine distemper virus (CDV) infection occurred in captive leopards (Panthera pardus), tigers (Panthera tigris), lions (Panthera leo), and a jaguar (Panthera onca) in 1991 and 1992. An epizootic affected all 4 types of cats at the Wildlife Waystation, San Fernando, California, with 17 mortalities. CDV-infected raccoons were thought to be the source of infection in these cats. Two black leopards died at the Naibi Zoo, Coal Valley, Illinois, and 2 tigers died at the Shambala Preserve, Acton, California. Initial clinical signs were anorexia with gastrointestinal and/or respiratory disease followed by seizures. Canine distemper virus was isolated from 3 leopards, 3 tigers, and 3 lions that died or were euthanized when moribund. Monoclonal antibody testing identified the virus isolates as CDV. Gross and histopathologic findings were similar to those found in canids with distemper with a few exceptions. There were fewer lesions in the brain, and there was a pronounced type 2 cell proliferation in the lung, with inclusion bodies and CDV antigen demonstrated by immunohistology. Neutralizing antibody to CDV was found in high titers in serum from most animals but was absent or was found only in low titers in some cats that succumbed after CDV infection. There was a marked difference in neutralizing antibody titers when tests were done with different strains of CDV.

Metabolism and enantioselective pharmacokinetics of Casodex in man.

1. Five healthy male volunteers received a single oral dose (50 mg; 42 microCi) of 14C-Casodex, a racemic compound, which has its antiandrogen activity predominantly in R-Casodex, the (-)-enantiomer, with little activity in S-Casodex, the (+)-enantiomer. 2. Plasma concentrations of R-Casodex increased slowly in all subjects to reach a peak of 559-970 ng/ml between 15 and 48 h after dosing and, thereafter, declined monoexponentially with a mean half-life of 4.2 days. Plasma concentrations of S-Casodex rose rapidly to reach a peak of 32-66 ng/ml within the first 2-5 h, and then declined monoexponentially with a mean half-life of 19 h. Plasma concentrations of the racemate were in very good agreement with the sum of the enantiomer concentrations throughout the study and were very similar to concentrations of total radioactivity over the first 4 days. 3. About 80% of the radioactive dose was recovered in urine (35.8 +/- 1.7%; mean +/- SEM) and faeces (42.6 +/- 2.9%) during a total collection over 9 days; this incomplete recovery was consistent with the slow elimination of R-Casodex. 4. T.l.c. of urine extracts indicated extensive metabolism of Casodex to two polar metabolites identified as the glucuronide conjugates of Casodex and hydroxy-Casodex; almost no parent compound was observed. Virtually all of the Casodex glucuronide excreted in urine during the first 2 days was derived from S-Casodex, consistent with the relatively low plasma concentrations and rapid elimination of this enantiomer. 5. T.l.c. of faecal extracts showed the presence of both Casodex and hydroxy-Casodex; these may have been eliminated in bile as the glucuronide conjugates, with subsequent hydrolysis in the intestinal tract.

Escherichia coli: derived murine interleukin-1 beta with N-terminus partially N alpha-acetylated.

Two forms of murine recombinant interleukin-1 beta (mrIL-1 beta) from Escherichia coli were purified by ion exchange column chromatography; each exhibited equivalent biological activity in the murine thymocyte proliferation assay. It was determined by mass spectrometry of tryptic peptides that both retained the initiating methionine but one form was N alpha-acetylated at the N-terminus.

Modulation of epidermal growth factor receptors in psoriatic lesions during treatment with topical EGF.

Active psoriatic lesions have increased EGF/TGF alpha receptors, historically known as the EGF-R. This increase is due to their persistence into the outer parakeratotic layers as measured by autoradiography, immunohistochemistry, and mRNA assays. When psoriatic lesions in patients resolve due to therapy with different modalities, the EGF-R persistently expressed in the outer layers of the epidermis either disappear or resume a basal location presumably due to receptor downregulation. To test whether EGF could downregulate EGF-R and biologically affect psoriatic epidermis, split-thickness skin grafts of active psoriatic lesions were sutured onto the dorsal surface of nude mice. After 3 weeks, the mice were treated daily for a 6-week period with placebo, or 10 or 50 micrograms/ml EGF. Immunostaining showed persistent EGF-R in all epidermal layers in the untreated, placebo-, and 10 micrograms/ml EGF-treated groups. Those grafts receiving a high dose of EGF (50 micrograms/ml) showed either no immunoreactive EGF-R or faint basilar staining. As an additional check for functional activity of the EGF-R, an abundant substrate for this receptor, PLC-gamma 1 was also evaluated following EGF treatment. A similar distribution and modulation pattern following treatment were observed in the grafts immunostained for PLC-gamma 1, suggesting that exogenous EGF treatment affected metabolic pathways subsequent to ligand receptor binding. Morphologic alterations characteristic of a regressing psoriatic phenotype (a decrease in acanthosis, thickness, and the resumption of the orthokeratotic mode of differentiation) were noted in those lesions receiving the 50 micrograms/ml EGF treatment. This study indicates that persistent EGF-R in psoriasis vulgaris are biologically active in vivo and may serve a pivotal role in the regulation of psoriatic lesions.