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Multiple Doses (multiple + dose)

Distribution by Scientific Domains

Medical Sciences	90%
Life Sciences	9%

Distribution within Medical Sciences

Pharmacology & Pharmaceutical Medicine	41%
Obstetrics & Gynecology	6%
11 Other Subdomains	47%

Selected Abstracts

Obstetric risk factors and persistent increases in brain parenchymal echogenicity in preterm infants

BJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 9 2004
Arsenio Spinillo
Objective To assess the risk of persistent (>7 days) increases in brain parenchymal echogenicity in preterm infants and their association with known obstetric risk factors. Design Case,control study of prospectively collected data. Setting A University hospital in Northern Italy. Population Eighty-five singleton infants between 24 and 34 weeks of gestation with a cranial ultrasonographic diagnosis of persistently increased parenchymal echogenicity without development of cystic degeneration, and 170 control infants with negative cranial ultrasonographic findings. Methods A comparison of the prevalence of selected obstetric risk factors between infants with persistent echo-dense lesions and negative controls. Main outcome measures Odds ratios of persistent echo-dense lesions including first-degree interactions between variables. Results After adjusting for birthweight, logistic regression analysis showed that the only factor associated with an increased risk of persistent brain echo-dense lesions in infants was multiple courses of antenatal steroids (OR = 2.14, 95% CI = 1.11,4.15, P= 0.024). In this group, the risk of persistent echo-dense lesions was particularly high in: (i) mothers receiving dexamethasone rather than betamethasone (P value for interaction = 0.015) and (ii) after expectant management of pre-eclampsia or intrauterine growth retardation (P value for interaction = 0.03). Conclusions Multiple doses of antenatal steroids, especially dexamethasone, could influence the prevalence of persistent increases in brain parenchymal echogenicity in preterm infants. [source]

Effect of multiple doses of montelukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2007
Kyoung-Ah Kim
Aims To investigate the effect of multiple dosing with montelukast, a selective leukotriene-receptor antagonist, on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans. Methods A two-period, randomized crossover study was conducted in 10 healthy subjects. After administration of oral doses of placebo or 10 mg montelukast daily for 6 days, 4 mg rosiglitazone was administered and plasma samples were obtained for 24 h and analyzed for rosiglitazone and N-desmethylrosiglitazone using high-performance liquid chromatography with fluorescence detection. Results During the montelukast phase, the total area under the time-concentration curve (AUC) and peak plasma concentration of rosiglitazone were 102% (90% CI 98, 107%) and 98% (90% CI 92, 103%) of the corresponding values during the placebo phase, respectively. Multiple dosing with montelukast did not affect the oral clearance of rosiglitazone significantly (90% CI 94, 105%; P = 0.50). The AUC ratio and plasma concentration ratios of N-desmethylrosiglitazone : rosiglitazone were not changed by multiple dosing with montelukast (90% CI 90, 103%; P = 0.14). Conclusions Multiple doses of montelukast do not inhibit CYP2C8-mediated rosiglitazone metabolism in vivo despite in vitro findings indicating that montelukast is a selective CYP2C8 inhibitor. [source]

Multiple doses of secretin in the treatment of autism: a controlled study

ACTA PAEDIATRICA, Issue 5 2002
E Sponheim
Dramatic effects on autistic behaviour after repeated injections of the gastrointestinal hormone secretin have been referred in a number of case reports. In the absence of curative and effective treatments for this disabling condition, this information has created new hope among parents. Although controlled studies on the effect of mainly one single dose have not documented any effect, many children still continue to receive secretin. Six children enrolled in a double-blind, placebo-controlled crossover study in which each child was its own control. Human synthetic secretin, mean dose 3.4 clinical units, and placebo were administered intravenously in randomized order every 4th wk, on three occasions each. The measurement instruments were the visual analogue scale (VAS) and the aberrant behaviour checklist (ABC). Statistically significant differences were found for placebo in 3 out of 6 children and for secretin in one child, using parental ratings only (VAS scores). Differences were small and lacked clinical significance, which was in accordance with the overall impression of the parents and teachers and visual inspection of graphs. Conclusion: In this placebo-controlled study, multiple doses of secretin did not produce any symptomatic improvement. [source]

Significance testing of synergistic/antagonistic, dose level-dependent, or dose ratio-dependent effects in mixture dose-response analysis

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 10 2005
Martijs J. Jonker
Abstract In ecotoxicology, the state of the art for effect assessment of chemical mixtures is through multiple dose,response analysis of single compounds and their combinations. Investigating whether such data deviate from the reference models of concentration addition and/or independent action to identify overall synergism or antagonism is becoming routine. However, recent data show that more complex deviation patterns, such as dose ratio,dependent deviation and dose level,dependent deviation, need to be addressed. For concentration addition, methods to detect such deviation patterns exist, but they are stand-alone methods developed separately in literature, and conclusions derived from these analyses are therefore difficult to compare. For independent action, hardly any methods to detect such deviations from this reference model exist. This paper describes how these well-established mixture toxicity principles have been incorporated in a coherent data analysis procedure enabling detection and quantification of dose level,and dose ratio,specific synergism or antagonism from both the concentration addition and the independent action models. Significance testing of which deviation pattern describes the data best is carried out through maximum likelihood analysis. This analysis procedure is demonstrated through various data sets, and its applicability and limitations in mixture research are discussed. [source]

Spinal Epidural Abscess as a Result of Dissemination from Gluteal Abscess Secondary to Intramuscular Analgesic Injection

PAIN PRACTICE, Issue 5 2009
Mehdi Sasani MD
Abstract Spinal epidural abscess is a collection of suppurative material that forms between the dura mater and the ligamentum flavum. If not recognized early and treated correctly, it can lead to life-threatening sepsis. Here we report the case of a female patient, 51 years of age, with difficulty walking and bilateral leg pain after having had degenerative discogenic pain for many years. The patient had occasionally received intramuscular non-steroidal anti-inflammatory drug injections. The current report is that of an unusual case of epidural abscess that formed following multiple dose of intramuscular non-steroidal anti-inflammatory drug over a 1-year period. Hematogenous or direct dissemination is the suspected cause. To prevent serious morbidity and mortality, early diagnosis is essential. Patients with localized back pain who are at risk for developing such epidural spinal abscesses should receive a magnetic resonance imaging scan with contrast enhancement without delay. The existence of predisposing factors such as intramuscular injections should be considered in the assessment of suspected spinal epidural abscess. [source]

Pharmacokinetics and pharmacodynamic effects of ABT-627, an oral ETA selective endothelin antagonist, in humans

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2000
Marianne C. Verhaar
Aims, Endothelins (ETs) may play a role in the pathogenesis of a variety of cardiovascular diseases. The present study was designed to investigate the pharmacokinetic and pharmacodynamic effects of the orally active ETA selective receptor antagonist ABT-627 in healthy humans. Methods, Healthy volunteers were included in two studies with cross-over design. Subjects received single or multiple dose (an 8 day period) administration of oralABT-627 or matched placebo, in a dose range of 0.2,40 mg. The pharmacokinetics of ABT-627 were described and its effects on systemic haemodynamics under resting conditions and on forearm vasoconstriction in response to ET-1 were assessed. Results, ABT-627 was generally well tolerated in both studies, with transient headache being the most reported adverse event (in 62%vs 4% during placebo, P < 0.05, for Study 1 and in 42%vs 60%, P = 0.2, for Study 2). ABT-627 was rapidly absorbed, reaching maximum plasma levels at ,,1 h post dose. Single dose ABT-627, at a dose of 20 and 40 mg, inhibited ET-1 induced forearm vasoconstriction at 8 h post dose. Eight days ABT-627 treatment, at a dose level of 5 mg and above, also effectively blocked forearm vasoconstriction to ET-1. ABT-627 caused a significant reduction in peripheral resistance as compared with placebo (16 ± 1 vs 19 ± 1, 18 ± 2 vs 23 ± 3, 15 ± 1 vs 17 ± 1 AU at 1, 5, 20 mg in Study 2) with only a mild decrease in blood pressure (79 ± 2 vs 84 ± 3, 80 ± 4 vs 90 ± 5, 75 ± 3 vs 79 ± 1 at 1, 5, 20 mg in Study 2). ABT-627 caused a moderate dose-dependent increase in circulating immunoreactive ET levels (a maximal increase of 50% over baseline at the 20 mg dose level). Conclusions, The oral ETA receptor blocker ABT-627 is well tolerated, rapidly absorbed, effectively blocks ET-1 induced vasoconstriction and causes a decrease in total peripheral resistance and mean arterial pressure. Our data suggest that ABT-627 may be a valuable tool in treatment of cardiovascular disease. [source]

Effects of carbaryl on green frog (Rana clamitans) tadpoles: Timing of exposure versus multiple exposures

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 11 2003
Michelle D. Boone
Abstract The majority of studies on pesticide impacts have evaluated the effects of single exposures. However, multiple exposures to a pesticide may be more prevalent. The objective of our study was to determine how multiple exposures versus single exposure at different times during development affected survival to metamorphosis, tadpole survival, tadpole mass, and tadpole developmental stage of green frog (Rana clamitans) tadpoles reared at low and high density in outdoor cattle tank ponds. Tadpoles were exposed to carbaryl zero, one, two, or three times at 14-d intervals. We applied single doses of carbaryl at one of three times, specifically during early, mid, or late development. Overall, we found that multiple exposures had a greater impact than single exposures during development. More individuals reached metamorphosis in ponds exposed to multiple doses of carbaryl compared with controls, indicating that the presence of carbaryl stimulated metamorphosis. The presence of carbaryl in the aquatic environment also resulted in more developed tadpoles compared with controls. Tadpoles in control ponds did not reach metamorphosis and were less developed than individuals exposed to carbaryl; this effect indicates that, under ideal conditions, green frogs could overwinter in ponds so that greater size could be attained before metamorphosis in the following spring or summer. Our study demonstrated the importance of including realistic application procedures when evaluating the effects of a pesticide and that multiple exposures to a short-lived pesticide are more likely to affect an amphibian population. [source]

Role of peroxynitrite in methamphetamine-induced dopaminergic neurotoxicity and sensitization in mice

ADDICTION BIOLOGY, Issue 3 2000
Syed F. Ali
Methamphetamine (METH)-induced dopaminergic neurotoxicity is thought to be associated with the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Recently, we have reported that copper/zinc(CuZn)-superoxide dismutase transgenic mice are resistant to METH-induced neurotoxicity. In the present study, we examined the role of the neuronal nitric oxide synthase (nNOS), susceptibility of nNOS knockout (KO) mice and sensitization to psychostimulants after neurotoxic doses of METH. Male SwissWebster mice were treated with or without 7-nitroindazole (7-NI) along with METH (5 mg/kg,ip,q 3h × 3) and were sacrificed 72 h after the last METH injection. Dopamine (DA) and dopamine transporter (DAT) binding sites were determined in striatum from saline and METH-treated animals. 7-NI completely protected against the depletion of DA, and DAT in striatum. In follow-up experiments nNOS KO mice along with appropriate control (C57BL/6N, SV129 and B6JSV129) mice were treated with METH (5 mg/kg,ip, q 3h × 3) and were sacrificed 72 h after dosing. This schedule of METH administrations resulted in only 10,20% decrease in tissue content of DA and no apparent change in the number of DAT binding sites in nNOS KO mice. However, this regime of METH resulted in a significant decrease in the content of DA as well as DAT binding sites in the wild-type animals. Pre-exposure to single or multiple doses of METH resulted in a marked locomotion sensitization in response to METH. However, the nNOS KO mice show no sensitization in response to METH after single or multiple injections of METH. Therefore, these studies strongly suggest the role of peroxynitrite, nNOS and DA system in METH-induced neurotoxicity and behavioral sensitization. [source]

Effects of Pregnanolone and Dehydroepiandrosterone on Ethanol Intake in Rats Administered Ethanol or Saline during Adolescence

ALCOHOLISM, Issue 7 2009
Olga V. Gurkovskaya
Background:, Adolescent alcohol use may contribute to long-term changes in the receptors and neuroactive steroids that may mediate its effects and to subsequent alcohol abuse and dependence as an adult. Therefore, in this study, ethanol preference and intake as an adult were examined after adolescent ethanol or saline administration. In addition, ethanol intake in the same groups was examined after administration of 2 neuroactive steroids with modulatory effects at GABAA receptors. Methods:, Two groups of male Long-Evans rats were administered 15 intraperitoneal (i.p.) injections of either ethanol (2 g/kg, 20% v/v) or saline between postnatal days 35 and 63. Starting on postnatal day 75, both groups were trained to consume 10% ethanol using a saccharin-fading procedure, and ethanol intake and preference were measured after a series of manipulations involving food deprivation, changes in the duration of access to ethanol, and changes in the concentrations of ethanol presented. Following these manipulations, pregnanolone (1 to 10 mg/kg) and dehydroepiandrosterone (DHEA, 1 to 100 mg/kg) were administered prior to preference sessions with an 18% ethanol solution. Results:, Adult ethanol preference and intake did not differ significantly in subjects treated with either saline or ethanol as adolescents during training, the substitution of other ethanol concentrations (3.2 to 32%), ad-lib feeding, or moderate food deprivation. Pregnanolone administration altered the intake of both adolescent-treated groups after the first injection of 3.2 mg/kg and after repeated injections with 10 mg/kg, a dose that produced sedation. In contrast, multiple doses of DHEA consistently decreased intake of an 18% ethanol concentration in both groups after repeated injections and 3 doses of DHEA (10, 32, and 56 mg/kg) administered with various ethanol concentrations dose-dependently shifted the ethanol-concentration curves for the volume and dosage of ethanol consumed downward. Conclusions:, These results indicate that chronic intermittent ethanol (CIE) administration of 2 g/kg during adolescence did not alter preference or overall consumption of ethanol in outbred rats trained to drink ethanol as an adult under the conditions tested, and that DHEA may be more effective than pregnanolone at significantly decreasing ethanol consumption. [source]

Medicine-taking behavior: Implications of suboptimal compliance in Parkinson's disease

MOVEMENT DISORDERS, Issue 11 2005
Katherine A. Grosset MBChB
Abstract Management of Parkinson's disease (PD) depends primarily on oral medication. There are several drug classes and multiple doses and formulations, which make optimizing therapy complex. Variable drug absorption and the short half-life of most antiparkinson treatments, especially levodopa, are a main focus in understanding complications and have encouraged alternative delivery systems to limit fluctuation and dyskinesia at later stages. Comparatively little attention is paid to the way patients take their oral medication. Variable medicine-taking behavior can affect the clinician's understanding of the diagnosis and rate of progression, and further prescription of PD medication. Medicine overuse in later stage PD is well documented and causes psychiatric disturbance and increases motor complications, but evidence of undertreatment and erratic intake is emerging, which is likely to affect motor control and quality of life adversely. Methods of quantifying compliance are compared for accuracy and limitations. Understanding medicine-taking behavior is a first step in optimizing therapy and requires consideration of a patient's personal beliefs about their medicines. Although the benefits of regularizing oral medicine-taking in a practical, achievable way in PD remain untested, such an approach might prolong and smooth the benefits of oral medication and is worthy of further research. © 2005 Movement Disorder Society [source]

Efficacy and safety of single- and multiple-dose ketotifen fumarate 0.025% ophthalmic solution in a pediatric population

PEDIATRIC ALLERGY AND IMMUNOLOGY, Issue 6 2004
Mark B. Abelson
Allergic conjunctivitis can seriously disrupt children's daily activities. This study assessed the efficacy (onset and duration of action) and safety of ketotifen fumarate 0.025% ophthalmic solution compared with vehicle placebo in pediatric subjects after single and multiple dosing. This was a double-masked, multicenter, fellow-eye, placebo-controlled, conjunctival allergen challenge trial. Eligible subjects (8,16-yr-olds) who produced a qualifying reaction to allergen were randomized to a single dose (one drop) of ketotifen fumarate in one eye and vehicle placebo in the fellow eye, followed by an allergen challenge at 15 min and 8 h post-dose. Subjects who had a qualifying reaction to allergen in the placebo-treated eye and a qualifying response to ketotifen in the active-treated eye following the single dose were re-randomized to a multiple-dose treatment period. They were instructed to instill one drop of ketotifen fumarate in one eye and placebo in the other eye twice daily for 4 wk. An allergen challenge was conducted 8 h after the last dose. The primary efficacy assessment was ocular itching, judged by the subject at 3, 7, and 10 min post-allergen challenge after single- and multiple-dose treatments. Other ocular signs and symptoms were assessed at 7, 10, and 15 min post-dose. A total of 133 subjects were randomized to single-dose treatment; 105 were evaluable for efficacy. Of these, 60 were re-randomized to multiple-dose treatment, and 55 were evaluable for efficacy. After single and multiple doses, ketotifen fumarate significantly inhibited ocular itching compared with placebo at all post-challenge timepoints (p < 0.001) and also significantly reduced hyperemia, chemosis, and lid swelling (p = 0.031). No drug-related systemic adverse events were reported, and ocular adverse events were comparable to placebo. No subject discontinued prematurely due to an adverse event. These results indicate that ketotifen fumarate 0.025% ophthalmic solution is an effective and safe treatment option for children with allergic conjunctivitis. [source]

A single versus multiple doses of dexamethasone in infants wheezing for the first time

PEDIATRIC PULMONOLOGY, Issue 9 2008
Suzanne Schuh MD
Abstract Rationale: Corticosteroid therapy is not routinely recommended in true bronchiolitis. However, since bronchiolitis and the first asthma attack are impossible to distinguish, some infants with the first wheezing episode receive corticosteroids. Optimal duration of corticosteroid therapy in this scenario is unknown. This study compared efficacy of multiple administrations and a single dose of dexamethasone in bronchiolitis. Methods: In this randomized double blind trial, previously healthy outpatients 2,23 months of age with bronchiolitis and Respiratory Disease Assessment Instrument (RDAI) score 6 or more received 1 mg/kg of oral dexamethasone in the Emergency Department. Prior to discharge at 4 hr they were randomized to either 4 daily doses of dexamethasone 0.15 mg/kg or placebo equivalent. Primary outcome was the proportion of subsequent hospitalizations or prescribed trials of bronchodilator/corticosteroid therapy for dyspnea by day 6 in the groups. Secondary outcomes were changes in the RDAI to day 6, and proportions with unscheduled visits by days 6 and 28. Results: The rate of primary outcome in the single dose group (SDG, N,=,64) was 9/64 or 14.1% versus 7/61 or 11.5% in the multiple dose group (MDG, N,=,61) [95% CI 0.09; 0.14]. Twelve (18.8%) children in the SDG had unscheduled medical visits by day 6 versus 11 (18.0%) children in the MDG [95% CI 0.13; 0.14]. On day 6 the RDAI decreased from 9.5,±,2.1 to 2.1,±,2.4 in the SDG and from 9.8,±,2.2 to 1.6,±,2.3 in the MDG [95% CI 0.36; 2.06]. Between days 7,28, 24/64 (37.5%) SDG infants returned for care versus 20/61 (32.8%) of the MDG [95% CI 0.12; 0.21]. Conclusions: Our study suggests that, in outpatients with bronchiolitis who receive dexamethasone, continuation of this agent beyond the initial dose does not provide significant benefit. Pediatr Pulmonol. 2008; 43:844,850. © 2008 Wiley-Liss, Inc. [source]

Safety of anthrax vaccine: an expanded review and evaluation of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS),,

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, Issue 12 2004
John L. Sever
Abstract Purpose To assess the safety of a licensed anthrax vaccine (AVA) given to more than 500,000 US military personnel, through review and medical evaluation of adverse events (AEs) reported to the Vaccine Adverse Event Reporting System (VAERS). Methods AEs were summarized by person, vaccine lot, type, frequency and impact. A Delphic approach was used to tentatively assess causality in an effort to detect serious AEs (SAEs) or other medically important AEs (OMIAEs) possibly attributable to AVA. Results The Anthrax Vaccine Expert Committee (AVEC) reviewed 1841 reports describing 3991 AEs (9.4 reports/10,000 doses of AVA) that were submitted to VAERS from 1Q1998 through 4Q2001. One hundred forty-seven reports described an SAE or OMIAE, of which 26 were tentatively rated as possible, probable or certain consequences of vaccination (injection-site reaction [12], ,anaphylactic-like reaction' [5] and eight other systemic AEs [1,2 each]). Conclusions This review produced no evidence for an unusual rate of any SAE or OMIAE attributable to AVA. It supported an earlier impression that AVA may cause significant local inflammation and should be administered over the deltoid rather than the triceps to avoid direct or compression injury to the ulnar nerve. The subjects of VAERS reports tended to be older than all recipients of AVA. Females generally had and/or reported AEs more often than males, but transient articular reactions were surprisingly more common in males. Variations in the frequency or severity (as judged by hospitalization and/or loss of duty) of reported AEs did not suggest a significant problem with (1) a particular lot of AVA, (2) recurrent AEs after multiple doses or (3) vaccination of persons with a concomitant illness or those given other vaccines or medications. Copyright © 2004 John Wiley & Sons, Ltd. [source]

Cloning and identification of EDD gene from ultraviolet-irradiated HaCaT cells

PHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 6 2006
Nishma Gupta
Ultraviolet (UV) radiation is one of the most important external stimuli that affects skin by inducing cancer, inflammation and cell death. To identify the regulation of genes regulated by UV during transformation, normal human keratinocyte cell line, HaCaT, was exposed to multiple doses of UVA+B (UVA , 150,200 mJ/cm2 and UVB , 15,20 mJ/cm2× 6). Malignant transformation was confirmed by formation of colonies on soft agar and DNA methylation assay. To identify the genes involved in this process, random amplification of polymorphic DNA using RNA from unexposed and multiple exposed cells was performed after each exposure. A few up-regulated genes were identified, cloned and sequenced. One of the genes had homology to EDD (E3 identified by differential display) that was up-regulated at second exposure but was down-regulated in colony-forming cells (cells that received six or more exposures) as determined by RT-PCR. This is a progesterone-induced gene and progesterone treatment reduced the extent of colony formation on soft agar plate. It is possible that hormone therapy may have some effects on skin cancer in vivo. [source]

Pharmacokinetics of valerenic acid after single and multiple doses of valerian in older women

PHYTOTHERAPY RESEARCH, Issue 10 2010
Gail D. Anderson
Abstract Insomnia is a commonly reported clinical problem with as many as 50% of older adults reporting difficulty in falling and/or remaining asleep. Valerian (Valeriana officinalis) is a commonly used herb that has been advocated for promoting sleep. Valerenic acid is used as a marker for quantitative analysis of valerian products with evidence of pharmacological activity relevant to the hypnotic effects of valerian. The objective of this study was to determine the pharmacokinetics of valerenic acid in a group of elderly women after receiving a single nightly valerian dose and after 2 weeks of valerian dosing. There was not a statistically significant difference in the average peak concentration (Cmax), time to maximum concentration (Tmax) area under the time curve (AUC), elimination half-life (T1/2) and oral clearance after a single dose compared with multiple dosing. There was considerable inter- and intra-subject variability in the pharmacokinetic parameters. Cmax and AUC deceased and T1/2 increased with increased body weight. The variability between the capsules was extremely low: 2.2%, 1.4% and 1.4%, for hydroxyvalerenic acid, acetoxyvalerenic acid and valerenic acid, respectively. In conclusion, large variability in the pharmacokinetics of valerenic acid may contribute to the inconsistencies in the effect of valerian as a sleep aid. Copyright © 2010 John Wiley & Sons, Ltd. [source]

Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug

THE PROSTATE, Issue 4 2006
Samuel Janssen
Abstract BACKGROUND Prostate cancer cells secrete unique proteases such as prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2) that represent targets for the activation of prodrugs as systemic treatment of metastatic prostate cancer. Previously, a combinatorial peptide library was screened to identify a highly active peptide substrate for hK2. The peptide was coupled to an analog of the potent cytotoxin thapsigargin, L12ADT, to generate an hK2-activated prodrug that was efficiently hydrolyzed by purified hK2, stable to hydrolysis in human and mouse plasma in vitro and selectively toxic to hK2 producing prostate cancer cells in vitro. METHODS In the current study, toxicology, pharmacokinetics, prodrug biodistribution, and antitumor efficacy studies were performed to evaluate the hK2-activated prodrug in vivo. RESULTS The single intravenous maximally tolerated dose of prodrug was 6 mg/kg (i.e., 3.67 µmole/kg) which produced peak serum concentration of ,36 µM and had a half-life of ,40 min. In addition, over a 24 hr period <0.5% of free L12ADT analog was observed in plasma. The prodrug demonstrated significant antitumor effect in vivo while it was being administered, but prolonged intravenous administration was not possible due to local toxicity to tail veins. Subcutaneous administration of equimolar doses produced lower plasma AUC compared to intravenous dosing but equivalent intratumoral levels of prodrug following multiple doses. CONCLUSIONS The hK2-activated prodrug was stable in vivo. The prodrug, however, was rapidly cleared and difficult to administer over prolonged dosing interval. Additional studies are underway to assess antitumor efficacy with prolonged administration of higher subcutaneous doses of prodrug. Second-generation hK2-activated thapsigargin prodrugs with increased half-lives and improved formulations are also under development. © 2005 Wiley-Liss, Inc. [source]

ORIGINAL ARTICLE: Can sugammadex save a patient in a simulated ,cannot intubate, cannot ventilate' situation?

ANAESTHESIA, Issue 9 2010
M. M. A. Bisschops
Summary Recent studies have shown that the use of high dose rocuronium followed by sugammadex provides a faster time to recovery from neuromuscular blockade following rapid sequence induction than suxamethonium. In a manikin-based ,cannot intubate, cannot ventilate' simulation, we studied the total time taken for anaesthetic teams to prepare and administer sugammadex from the time of their initial decision to use the drug. The mean (SD) total time to administration of sugammadex was 6.7 (1.5) min, following which a further 2.2 min (giving a total 8.9 min) should be allowed to achieve a train-of-four ratio of 0.9. Four (22%) teams gave the correct dose, 10 (56%) teams gave a dose that was lower than recommended, four (22%) teams gave a dose that was higher than recommended, six (33%) teams administered sugammadex in a single dose, and 12 (67%) teams gave multiple doses. Our simulation highlights that sugammadex might not have saved this patient in a ,cannot intubate, cannot ventilate' situation, and that difficulties and delays were encountered when identifying, preparing and administering the correct drug dose. [source]

Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol,conjugated uricase) in patients with treatment-failure gout: Results of a phase II randomized study,

ARTHRITIS & RHEUMATISM, Issue 9 2008
John S. Sundy
Objective To assess the efficacy of pegloticase in achieving and maintaining plasma urate levels of <6 mg/dl in gout patients in whom other treatments have failed, and to assess the pharmacokinetics and safety of pegloticase. Methods Forty-one patients were randomized to undergo 12,14 weeks of treatment with pegloticase at 1 of 4 dosage levels: 4 mg every 2 weeks, 8 mg every 2 weeks, 8 mg every 4 weeks, or 12 mg every 4 weeks. Plasma uricase activity, plasma urate, and antipegloticase antibodies were measured, pharmacokinetic parameters were assessed, and adverse events were recorded. Results The mean plasma urate level was reduced to ,6 mg/dl within 6 hours in all dosage groups, and this was sustained throughout the treatment period in the 8 mg and 12 mg dosage groups. The most effective dosage was 8 mg every 2 weeks. Twenty-six patients received all protocol doses. The percentage of the patients in whom the primary efficacy end point (plasma urate <6 mg/dl for 80% of the study period) was achieved ranged from 50% to 88%. Gout flares occurred in 88% of the patients. The majority of adverse events (excluding gout flare) were unrelated to treatment and were mild or moderate in severity. Infusion-day adverse events were the most common reason for study withdrawal (12 of 15 withdrawals). There were no anaphylactic reactions. Antipegloticase antibody, present in 31 of 41 patients, was associated with reduced circulating half-life of pegloticase in some patients. Conclusion Pegloticase, administered in multiple doses, was effective in rapidly reducing and maintaining plasma urate levels at ,6 mg/dl in most patients in whom conventional therapy had been unsuccessful due to lack of response, intolerability, or contraindication. [source]

First trimester abortion with mifepristone and three doses of sublingual misoprostol: a pilot study

AUSTRALIAN AND NEW ZEALAND JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Issue 6 2005
Kishor C. SINGH
Abstract Objective:, To evaluate the efficacy and safety of a medical abortion regimen with multiple doses of sublingual misoprostol 24 h after mifepristone. Methods:, The regimen was designed on the basis of pharmacokinetics of various routes of administration of misoprostol. Forty women 8 weeks' gestation were given mifepristone 200 mg orally, followed 24 h later by three doses of misoprostol 200 µgm sublingually 6 h apart. They were followed up on day 3 and day 14 with transvaginal ultrasound. Pain and bleeding were assessed using a visual analogue scale and acceptability, by a questionnaire. Results:, Abortion outcome was assessed in terms of onset of pain and vaginal bleeding, time of expulsion of products and duration of vaginal bleeding. Seventy-five per cent of women experienced pain within 2 h after first dose of misoprostol. Bleeding began at a mean of 1.41 h after pain and expulsion at a mean of 6.1 h after first dose of misoprostol. Complete expulsion was confirmed in all women (100%) by ultrasound on day 14. The longest duration of bleeding was 12 days (mean 7.2 days) with 87.5% bleeding for < 10 days. Acceptability was 100% but 70% perceived pain to be moderate and 67.5% bleeding to be light or slightly more than menses. Conclusions:, Medical abortion using three doses of sublingual misoprostol administered 24 h after mifepristone appears to be the most appropriate in terms of pharmacokinetics of the drugs. This pilot study associates the regimen with a short abortion process, which appears to be safe, highly efficacious and acceptable. [source]

Effect of concomitant colestipol hydrochloride administration on the bioavailability of diltiazem from immediate- and sustained-release formulations

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2002
Scott W. Turner
Abstract Effects of concomitant colestipol administration on plasma concentrations of diltiazem and desacetyldiltiazem from immediate-release (IR) and sustained-release (SR) formulations were assessed in two studies. In the first study, 12 subjects received 120-mg diltiazem hydrochloride (diltiazem) SR capsules or 120-mg diltiazem IR tablets administered alone and in combination with colestipol hydrochloride (colestipol). Following concomitant administration of SR diltiazem with colestipol, AUC0,, and Cmax, respectively, were 22 and 36% less, and were 27 and 33% lower for IR diltiazem. In the second study, subjects received 120-mg diltiazem SR capsules at staggered times, without colestipol, 1 h prior to or 4 h following multiple doses of colestipol. A 17% decrease in AUC0,, was observed when diltiazem was taken 1 h before colestipol was given, and a 22% decrease when diltiazem was taken 4 h after colestipol, relative to diltiazem SR alone. Cmax values were similarly decreased. Results from these two studies show that colestipol can cause a significant decrease in diltiazem absorption from both IR and SR dosage forms. Staggering the administration of colestipol and diltiazem SR did not blunt this effect, indicating that concomitant administration of diltiazem and colestipol should be used with caution, and that the efficacy of diltiazem should be monitored to assure adequate dosing. Copyright © 2002 John Wiley & Sons, Ltd. [source]

Clinical pharmacokinetic studies with INN 00835 (Nemifitide), a novel pentapeptide antidepressant

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2002
John P. Feighner
Abstract Nemifitide (4-fluoro-L-phenylalanyl-trans-4-hydroxy-L-prolyl-L-arginylglycyl-L-tryptophanamide ditrifluoroacetate) is a novel antidepressant, currently in phase 2/3 clinical trials. The purpose of our phase 1 clinical trials (conducted over a three year period) was to provide safety and pharmacokinetic data to support its clinical development as an antidepressant drug. Single and multiple doses ranging from 18 to 320 mg were administered subcutaneously to healthy volunteers in five phase 1 studies. Plasma concentrations of unchanged parent drug were determined by a validated LC/MS/MS method in blood samples collected at timepoints between 10 min and 72 h after dosing. Nemifitide was rapidly absorbed (Cmax at 10 min) and eliminated (t1/2 15,30 min) in most subjects. Regression and power model analyses were used to evaluate the data. The results indicate that pharmacokinetic parameters: AUC0,t, AUC 0,, and Cmax, were close to dose proportional in the dose range investigated. There was no evidence of systemic accumulation of drug following 5 daily doses. No serious adverse events or clinically significant systemic adverse events occurred at any of the doses investigated in the over 100 subjects dosed in these studies. Drug-related adverse events were limited to local and transient skin reactions (pain and/or erythema) at the injection site, especially at the high doses administered: 240 and 320 mg. Copyright © 2002 John Wiley & Sons, Ltd. [source]

Intravesical alkalinized lidocaine (PSD597) offers sustained relief from symptoms of interstitial cystitis and painful bladder syndrome

BJU INTERNATIONAL, Issue 7 2009
J. Curtis Nickel
OBJECTIVE To assess the immediate and sustained relief of the symptoms of interstitial cystitis/painful bladder syndrome (IC/PBlS) after a consecutive 5-day course of treatment with intravesical alkalinized lidocaine (PSD597), and to characterize the pharmacokinetics of single and multiple doses of intravesical PSD597 in a subgroup of patients. PATIENTS AND METHODS In all, 102 adult patients (99 women) with a clinical diagnosis of IC/PBlS were randomized from 19 centres in the USA and Canada to receive a daily intravesical instillation of PSD597 (200 mg lidocaine, alkalinized with a sequential instillation of 8.4% sodium bicarbonate solution, to a final volume of 10 mL) or placebo (double-blind), for 5 consecutive days. Patients were followed at intervals up to 29 days after the first instillation. Efficacy was assessed by changes in the Global Response Assessment (GRA), Likert scales for bladder pain, urgency and frequency, and validated O'Leary-Sant IC symptom and problem indices. RESULTS Significantly more patients treated with PSD597 rated their overall bladder symptoms as moderately or markedly improved on the GRA scale 3 days after completing the 5-day course of treatment (30% and 9.6%, respectively, for patients treated with PSD597 and placebo; P = 0.012). The treatment effects were also maintained beyond the end of treatment and are further supported by the secondary endpoints, including symptom and problem indices. The peak serum lidocaine concentration during the study was <2 µg/mL, and well below the toxic level (>5 µg/mL). CONCLUSION This preliminary study showed that PSD597 was effective for providing sustained amelioration of symptoms of IC/PBlS beyond the acute treatment phase. The drug was safe, well tolerated and devoid of the systemic side-effects often experienced with oral drug administration. Long-term studies are needed to determine the optimum regimen to maintain this favourable treatment effect. [source]

Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2010
Stanley Cohen
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , CP-690,550 is a novel JAK inhibitor in development as a therapy for rheumatoid arthritis. , Methotrexate is the cornerstone of combination treatment for rheumatoid arthritis. , The safety and tolerability of co-administration of CP-690,550 with methotrexate have not been addressed to date. WHAT THIS STUDY ADDS , This study in patients with rheumatoid arthritis shows that there are no clinically relevant effects on the pharmacokinetics of either drug following short-term co-administration. , Co-administration of CP-690,550 and methotrexate was safe and well tolerated. AIMS To investigate the effects of methotrexate (MTX) on the pharmacokinetics (PK) of CP-690,550, a novel Janus kinase (JAK) inhibitor in development as a therapy for rheumatoid arthritis (RA), to determine the effects of multiple doses of CP-690,550 on the PK of MTX, and to evaluate the short-term safety and tolerability of co-administration of CP-690,550 and MTX. METHODS This was a fixed-dose drug,drug interaction study. Twelve patients diagnosed with RA for at least 6 months were enrolled in a Phase I, open-label study of the PK of multiple doses of CP-690,550 (30 mg b.i.d.) and single doses of MTX (15,25 mg per week). RESULTS All patients completed the study and were evaluated for PK and safety. CP-690,550 exposure was not affected by co-administration with MTX; AUC12 ratio (CP-690,550 + MTX/CP-690,550) was 103.06% [90% confidence interval (CI) 99.00, 107.29]. MTX exposure decreased by 10%; AUC12 ratio (CP-690,550 + MTX/MTX) was 89.53% (90% CI 77.38, 103.57), which was not considered clinically significant. Co-administration of CP-690,550 and MTX was safe and well tolerated. There were no serious adverse events or withdrawals from the study and there was no trend in the incidence or severity of adverse events across treatments. CONCLUSIONS Co-administration of CP-690,550 and MTX was safe and well tolerated. There was no clinically significant effect on the PK profile of either drug. Therefore, dose adjustments should not be required when co-administering CP-690,550 and MTX. [source]

Ibudilast in healthy volunteers: safety, tolerability and pharmacokinetics with single and multiple doses

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2008
Paul Rolan
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Ibudilast is an oral drug approved in Asia for asthma. , Tolerability of 10-mg regimens has been described previously. , Published pharmacokinetics (PK) are limited: single or 7-day repeat oral administration of 10 mg in healthy male Asian volunteers. WHAT THIS STUDY ADDS , Safety/tolerability and PK of a single 30-mg dose and a 30-mg twice daily (b.i.d.) 2-week regimen in male and female healthy volunteers. , Higher-dose regimens are relevant for testing in new neurological indications. , LC-MS/MS analytics for quantification of plasma and urine levels of ibudilast parent and its primary metabolite (6,7-dihydrodiol-ibudilast). AIMS To investigate the safety, tolerability and pharmacokinetics (PK) of ibudilast after a single-dose and a multiple-dose regimen. METHODS Healthy adult male (n = 9) and female (n = 9) volunteers were evaluated over a 17-day stay in a Phase 1 unit. Subjects were randomized 1 : 3 to either oral placebo or ibudilast at 30-mg single administration followed by 14 days of 30 mg b.i.d. Complete safety analyses were performed and, for PK, plasma and urine samples were analysed for ibudilast and its major metabolite. RESULTS Ibudilast was generally well tolerated. No serious adverse events occurred. Treatment-related adverse events included hyperhidrosis, headache and nausea. Two subjects discontinued after a few days at 30 mg b.i.d. because of vomiting. Although samples sizes were too small to rule out a sex difference, PK were similar in men and women. The mean half-life for ibudilast was 19 h and median Tmax was 4,6 h. Mean (SD) steady-state plasma Cmax and AUC0,24 were 60 (25) ng ml,1 and 1004 (303) ng h ml,1, respectively. Plasma levels of 6,7- dihydrodiol-ibudilast were approximately 30% of the parent. CONCLUSIONS Ibudilast is generally well tolerated in healthy adults when given as a single oral dose of 30 mg followed by 30 mg b.i.d. (60 mg day,1) for 14 days. Plasma PK reached steady state within 2 days of starting the b.i.d. regimen. Exposure to ibudilast was achieved of a magnitude comparable to that associated with efficacy in rat chronic pain models. [source]

The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2007
Joachim Stangier
Aims The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double-blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects. Methods Dabigatran etexilate or placebo was administered orally at single doses of 10,400 mg (n = 40) or at multiple doses of 50,400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded. Results Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half-lives of 8,10 h and 14,17 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose-proportional increases observed in maximum plasma concentration and area under the curve. Steady-state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (Vz/F) of 1860 l (range 1430,2400 l) and the apparent total clearance after oral administration (CLtot/F) of 2031 ml min,1 (range 1480,2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration,time curves with values increasing rapidly and in a dose-dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.1 (aPTT), 3.5 (INR), 29 (TT) and 9.5-fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < 10%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild-to-moderate in intensity, occurring only in the higher, multiple dose groups. Conclusions These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted. [source]

Effect of multiple doses of montelukast on the pharmacokinetics of rosiglitazone, a CYP2C8 substrate, in humans

Pharmacokinetics and pharmacodynamics of TF-505, a novel nonsteroidal 5,-reductase inhibitor, in normal subjects treated with single or multiple doses

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2002
Tomoe Fujita
Aims To assess the tolerability, pharmacokinetics and pharmacodynamics of a novel nonsteroidal,, and,, noncompetitive,, inhibitor,, of,, type,, I,, and,, type,, II,, 5,-reductases, (,)-(S)-4-[1-[4-[1-(4-isobutylphenyl) butoxy]benzoyl]indolizin-3-yl]butyric acid (TF-505), after single and multiple oral doses in healthy volunteers. Methods In the single-dose study, six young adult males in each dose group received 25 mg or 50 mg of TF-505, and six older males (, 40 years) in each dose group received 75 mg or 100 mg of TF-505. The subjects were given the drug in ascending dose and in the fasting state. Six subjects also received 50 mg of TF-505 after breakfast in a two-period crossover manner. In the multiple-dose study, six older males in each dose group received 12.5 mg or 25 mg TF-505 after breakfast daily for 7 days. Plasma concentrations of TF-505, dihydrotestosterone (DHT) and testosterone were measured. The pharmacokinetics of TF-505 were analysed by a compartment model with first-order absorption, first-order elimination and a lag time. Pharmacokinetic and pharmacodynamic relationships were evaluated by indirect response modelling with inhibition of input. Results Maximum plasma concentration (Cmax) and the area under the concentration,time curve (AUC) increased proportionately after the single dose up to 50 mg and with the multiple doses. Linearity was not detected between 75 and 100 mg of TF-505. Dose dependency was also noted for the effect of TF-505 on DHT concentrations following single doses up to 50 mg and multiple doses. Plasma DHT concentrations decreased maximally to 58.2, 49.5, 54.2 and 49.8% of basal values at 8,12 h after single administration of 25, 50, 75 and 100 mg TF-505, respectively, and to 60.5 and 49.4% at the 7th and 5th dose following multiple doses of 12.5 and 25 mg TF-505, respectively. The predicted effect curves matched the observed data when the indirect response model was applied to the time course of the suppressant effect of TF-505 on plasma DHT concentrations after both the single and multiple studies. Fifty percent inhibitory concentrations (IC50) of 0.82, 1.48, 1.31 and 0.88 µ g ml,1, zero-order rate constants for the onset of plasma DHT concentration changes (kin) of 17.8, 17.4, 17.0 and 10.7% h,1 and first-order rate constants,, for,, increase,, in,, plasma,, DHT,, concentrations,, to,, basal,, values,, (kout),, of,, 0.17,,, 0.16,,, 0.17,, and,, 0.10 h,1,, for,, the,, single,, study,, at,, doses,, of,, 25,,, 50,,, 75,, and 100 mg, respectively, were attained. In the multiple-dose study, IC50s were 1.74 and 1.49 µg ml,1 for the 12.5 and 25 mg doses, respectively. No serious adverse events related to TF-505 were observed. Conclusions TF-505 was well tolerated in healthy male volunteers. Accumulation of TF-505 in plasma was not observed during multiple dosing. The indirect response model described the relationships between pharmacokinetics and pharmacodynamics of TF-505. Such modelling is expected to yield an appropriate dosage regimen in subsequent clinical trials. [source]

Single- and multiple-dose pharmacokinetics of ziprasidone under non-fasting conditions in healthy male volunteers

BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue S1 2000
J. J. Miceli
Aims, To evaluate the pharmacokinetics and tolerability of single and multiple oral doses of ziprasidone in healthy male volunteers, and to determine the influence of ziprasidone on serum prolactin levels. Methods, Single and multiple doses of ziprasidone were given orally (as two divided daily doses), at fixed dosages of 10 and 40 mg day,,1, and using titrated regimens of 40,80 and 40,120 mg day,,1, for 14 days. All dosages were taken immediately after food. The study adopted a randomized, double-blind, placebo-controlled design. Prolactin response, sedative properties, tolerability, and extrapyramidal symptoms were also investigated. Results, Steady-state exposure to ziprasidone was attained after 1 day of dosing. Mean Cmax and AUC(0,12 h) increased with increasing dose, with apparent dose-proportionality between the 20 and 60 mg dose levels. Trough-to-peak ratios at steady state ranged from 2 to 5. Accumulation ratios for the fixed-dose regimens were 1.49 and 1.48 at the 5 and 20 mg dose levels, respectively. Ziprasidone was associated with transient prolactin elevation but levels of prolactin returned to baseline within the dosing interval at steady state. There was a marginal, transient increase in serum prolactin levels which was not dose-related at the 80 and 120 mg day,,1 doses, and which was noted to attenuate with chronic dosing. Ziprasidone was generally well tolerated. The most frequent side-effect was mild or moderate headache. A minority of patients suffered first-dose postural hypotension. Ziprasidone was also associated with a mild sedative effect that became less pronounced as treatment continued. There were no drug-related changes in electrocardiogram or clinical laboratory variables that were of clinical importance. Conclusions, Ziprasidone is characterized by a predictable pharmacokinetic profile resulting in symptoms that reflect its pharmacological action. [source]

Adrenomedullin in the rostral ventrolateral medulla inhibits baroreflex control of heart rate: a role for protein kinase A

BRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2006
Yong Xu
1The rostral ventrolateral medulla (RVLM) is an essential vasomotor center in the brainstem which participates in maintaining resting levels of arterial pressure and for regulating baroreflex activity. We have demonstrated that microinjections of adrenomedullin (ADM), a vasoactive neuropeptide, into the RVLM cause increased resting mean arterial pressure (MAP) and heart rate (HR). However, the effect of ADM on baroreflex function remains unclear. 2The purposes of the present study were to investigate the effect of ADM in the RVLM on the regulation of baroreflex activity and to identify the underlying mechanisms. Baroreflex curves were generated with intravenous injections of multiple doses of phenylephrine and nitroprusside. The upper and lower plateaus, reflex range, MAP at the midpoint of HR range (MAP50), and gain were evaluated before and after various microinjections were made into the RVLM of urethane-anesthetized rats. 3Microinjections of ADM decreased the upper plateau, reflex range, and gain, and increased MAP50, indicating that ADM in the RVLM impairs baroreflex function. 4ADM22,52, a putative ADM receptor antagonist, significantly increased the baroreflex gain and upper plateau, demonstrating that endogenous ADM tonically inhibits the baroreflex. Coinjections of ADM22,52 with ADM blocked the ADM-induced baroreflex responses. 5ADM's effect was abolished with H-89, a protein kinase A (PKA) inhibitor. 6Our results show that ADM in the RVLM exerts an inhibitory effect on baroreflex activity via an ADM receptor-mediated mechanism, and that activation of PKA is involved in this event. British Journal of Pharmacology (2006) 148, 70,77. doi:10.1038/sj.bjp.0706698 [source]