Pharmacokinetics and bioavailability after intramuscular injection of the 5-HT1A serotonin agonist R-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in domestic goats (Capra aegagrus hircus).

To determine the bioavailability and pharmacokinetic properties of the serotonin 5-HT1A receptor agonist R-8-OH-DPAT in goats, and 0.1 mg kg-1 R-8-OH-DPAT hydrobromide was administered intramuscularly (i.m.) and intravenously (i.v.) to six goats in a two-phase cross-over design experiment. Venous blood samples were collected from the jugular vein 2, 5, 10, 15, 20, 30, 40 and 60 min following treatment and analysed by liquid chromatography tandem mass spectrometry. Bioavailability and pharmacokinetic parameters were determined by a one-compartment analysis. Mean bioavailability of R-8-OH-DPAT when injected i.m. was 66%. The mean volume of distribution in the central compartment was 1.47 L kg-1 . The mean plasma body clearance was 0.056 L kg-1  min-1 . All goats injected i.v. and two of six goats injected i.m. showed signs of serotonin toxicity. In conclusion, R-8-OH-DPAT is well absorbed following i.m. injection and the observed pharmacokinetics suggest that administration via dart is feasible. Administration of R-8-OH-DPAT hydrobromide, at a dosage of 0.1 mg kg-1 , resulted in the observation of clinical signs of serotonin toxicity in the goats. It is suggested that dosages for the clinical use of the compound should be lower in order to achieve the desired clinical effect without causing serotonin toxicity.

Estimation of Circulating Drug Metabolite Exposure in Human Using In Vitro Data and Physiologically Based Pharmacokinetic Modeling: Example of a High Metabolite/Parent Drug Ratio.

(R)-4-((4-(((4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)piperidin-1-yl)methyl)tetrahydro-2H-pyran-4-ol (TBPT), a serotonin-4 receptor partial agonist, is metabolized to two metabolites: an N-dealkylation product [(R)-3-(piperidin-4-ylmethoxy)-4-((tetrahydrofuran-3-yl)oxy)benzo[d]isoxazole (M1)] and a cyclized oxazolidine structure [7-(((4-(((R)-tetrahydrofuran-3-yl)oxy)benzo[d]isoxazol-3-yl)oxy)methyl)octahydro-3H (M2)]. After administration of TBPT to humans the exposure to M1 was low and the exposure to M2 was high, relative to the parent drug, despite this being the opposite in vitro. In this study, projection of the plasma metabolite/parent (M/P) ratios for M1 and M2 was attempted using in vitro metabolism, binding, and permeability data in static and dynamic physiologically based pharmacokinetic (PBPK) models. In the static model, the fraction of parent clearance yielding the metabolite (which also required taking into account secondary metabolites of M1 and M2), the clearance of the metabolites and parent, and an estimate of the availability of the metabolites from the liver were combined to yield estimated parent/metabolite ratios of 0.32 and 23 for M1 and M2, respectively. PBPK modeling that used in vitro and physicochemical data input yielded estimates of 0.26 and 20, respectively. The actual values were 0.12 for M1/TBPT and 58 for M2/TBPT. Thus, the ratio for M1 was overpredicted, albeit at values less than unity. The ratio for M2/TBPT was underpredicted, and the high ratio of 58 may exceed a limiting ceiling of the approach. Nevertheless, when considered in the context of determining whether a potential circulating metabolite may be quantitatively important prior to administration of a drug for the first time to humans, the approaches succeeded in highlighting the importance of M2 (M/P ratio >> 1) relative to M1, despite M1 being much greater than M2 in vitro.

Determination of influence of food intake after a single oral dose of mosapride in beagle dogs using nonlinear mixed effect modeling.

The objective of this study was to describe the population pharmacokinetics (PK) of mosapride under fasting and fed conditions. A single 5-mg oral dose of mosapride was administered to fasted (n = 15) and fed (n = 12) beagle dogs. Plasma concentrations of mosapride were subsequently measured by liquid chromatography-tandem mass spectrometry. Data were analyzed using modeling approaches with the NONMEM 7.2 software. A one-compartment open PK model utilizing model event time (MTIME) with first-order absorption and first-order elimination was found to be more appropriate than all other PK models tested. The absorption rate constants of mosapride were significantly decreased under fed conditions, compared to fasting conditions. The observed bootstrap medians of PK parameters were generally consistent with the corresponding population mean estimates. Furthermore, with the exception of some mosapride concentrations, most of observed data fell into the range of the 5th and 95th percentiles of the simulated values. Overall, the final model was able to describe the observed mosapride concentrations reasonably well. These findings suggest that food intake affects both the rate and extent of absorption of mosapride and that the pharmacological effect of mosapride can differ significantly depending on food intake.

Theoretical analysis of headache recurrence in patients administered triptans for migraine based on receptor occupancy.

BACKGROUND: In this study, we retrospectively analyzed the relationship between headache recurrence and serotonin 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Triptans marketed in Japan (sumatriptan, zolmitriptan, eletriptan, rizatriptan, naratriptan) were investigated. METHODS: Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans. We examined the relationships between recurrence rate and elimination half-lives, and Ф1B and Ф1D, as calculated from the time-course of plasma drug concentration obtained from other studies. The time until Ф1B and Ф1D became 50% or less, 40% or less, and 30% or less was calculated as duration time to examine the relationship with recurrence rate. RESULTS: For Ф1B, eletriptan remained at a low level. For Ф1D, it was indicated that all triptans obtained an occupancy of 80% or higher at maximum. For all items, though recurrence tended to be lower along with longer half-life, no significant statistical correlation was found. For both Ф1B and Ф1D, the recurrence rate tended to be lower as the duration became longer. In addition, a significant correlation was observed for Ф1D (p < 0.05). For clarifying the Ф value and time period most closely correlated with recurrence rate, recurrence and Ф1B and Ф1D at 6, 12, and 18 h after administration were calculated. The most significant correlation was observed between recurrence rate and Ф1D at 12 h after administration (p < 0.01). CONCLUSIONS: As an index for evaluating headache recurrence following triptan administration, recurrence rate and Ф1D value at 12 h after administration were found to be most closely correlated and useful for analysis. Our results indicate that headache recurrence inhibition can be evaluated using these values.

Ovarian hormones and the heterogeneous receptor mechanisms mediating the discriminative stimulus effects of ethanol in female rats.

Past studies have suggested that progesterone-derived ovarian hormones contribute to the discriminative stimulus effects of ethanol, particularly via progesterone metabolites that act at γ-aminobutyric acid type A (GABA(A)) receptors. It is unknown whether loss of ovarian hormones in women, for example, after menopause, may be associated with altered receptor mediation of the effects of ethanol. The current study measured the substitution of allopregnanolone, pregnanolone, pentobarbital, midazolam, dizocilpine, TFMPP, and RU 24969 in female sham and ovariectomized rats trained to discriminate 1.0 g/kg ethanol from water. The groups did not differ in the substitution of GABA(A)-positive modulators (barbiturates, benzodiazepines, neuroactive steroids) or the N-methyl-D-aspartate receptor antagonist dizocilpine. Similarly, blood-ethanol concentration did not differ between the groups, and plasma adrenocorticotropic hormone, progesterone, pregnenolone, and deoxycorticosterone were unchanged 30 min after administration of 1.0 g/kg ethanol or water. However, substitution of neuroactive steroids and RU 24969, a 5-hydroxytryptamine (5-HT)(1A/1B) receptor agonist, was lower than observed in previous studies of male rats, and TFMPP substitution was decreased in ovariectomized rats. Ovarian hormones appear to contribute to 5-HT receptor mediation of the discriminative stimulus effects of ethanol in rats.

Simultaneous alterations of brain and plasma serotonin concentrations and liver cytochrome P450 in rats fed on a tryptophan-free diet.

Our previous study suggested involvement of the brain serotonergic system in the regulation of liver cytochrome P450 (CYP). The aim of the present study was to demonstrate simultaneous responsiveness of liver CYP and the peripheral and brain serotonergic systems to a tryptophan deficient diet during three days and one or three weeks of ingestion. The concentrations of serotonin, noradrenaline, dopamine and their metabolites were measured in blood plasma, the hypothalamus and brain stem of male rats. The enzyme activity and protein levels in the liver were determined for isoforms CYP1A, CYP2A, CYP2B, CYP2C6, CYP2C11, CYP2D and CYP3A. A three-day tryptophan-free diet increased serotonin content in the hypothalamus (but not in the brain stem or plasma). After one week, the level of serotonin was not changed in the brain, but was markedly increased in the plasma. A three week tryptophan restriction significantly reduced the concentration of serotonin in the brain and plasma. Changes in CYP2C6 and CYP2C11 (an increase and a decrease, respectively) were maintained throughout the experiment, while those found in other CYP isoforms varied, which usually resulted in a gradual increase in the enzyme activity within three weeks. The observed alterations in liver CYPs suggest involvement of both central and peripheral serotonin in the regulation of liver CYP expression whose mechanism is discussed. In conclusion, a deficit in tryptophan in the diet may be responsible for very serious food-cytochrome P450 and food-drug metabolism interactions. Interactions of this type may also refer to drugs acting via serotonergic system.

Quantitative analysis of eletriptan in human plasma by HPLC-MS/MS and its application to pharmacokinetic study.

Authors developed a simple, sensitive, selective, rapid, rugged, and reproducible liquid chromatography-tandem mass spectrometry method for the quantification of eletriptan (EP) in human plasma using naratriptan (NP) as an internal standard (IS). Chromatographic separation was performed on Ascentis Express C18, 50 × 4.6 mm, 2.7 µm column. Mobile phase was composed of 0.1% formic acid: methanol (40:60 v/v), with 0.5 mL/min flow rate. Drug and IS were extracted by liquid-liquid extraction. EP and NP were detected with proton adducts at m/z 383.2→84.3 and 336.2→97.8 in multiple reaction monitoring (MRM) positive mode, respectively. The method was validated with the correlation coefficients of (r(2)) ≥ 0.9963 over a linear concentration range of 0.5-250.0 ng/mL. This method demonstrated intra- and inter-day precision within 1.4-9.2% and 4.4-5.5% and accuracy within 96.8-103% and 98.5-99.8% for EP. This method is successfully applied in the bioequivalence study of 24 human volunteers.

[First death case of serotonin syndrome in Japan induced by fluvoxamine and tandospirone].

We experienced the first death case of the serotonin syndrome in Japan caused by fluvoxamine and tandospirone. A 15-year-old man was transported to our hospital for shock, muscle hypertonia and hyperthermia after cardiopulmonary arrest. His serum concentrations of fluvoxamine and tandospirone were 3,554 ng/mL and 698 ng/mL respectively after 24 hours from oral intake. He was dead in spite of intensive treatments. The progress of the serotonin syndrome is usually rapid. So, it should be monitored appropriately a patient with serotonin syndrome. If he has hyperthermia, immediate paralysis should be induced. We should aware of the serotonin syndrome a case of overdose on a serotonergic agent.

Subcutaneous sumatriptan pharmacokinetics: delimiting the monoamine oxidase inhibitor effect.

BACKGROUND: The absolute bioavailability of subcutaneous (s.c.) sumatriptan is 96-100%. The decay curve for plasma concentration after 6 mg s.c. sumatriptan (ie, after T(max) = about 0.2 hours) includes a large distribution component. Metabolism by monoamine oxidase-A (MAO-A) leads to about 40% of the s.c. dose appearing in the urine as the inactive indole acetic acid. Product labeling states that co-administration of an inhibitor of MAO-A (a MAOI-A) causes a 2-fold increase in sumatriptan plasma concentrations, and a 40% increase in elimination half-life. OBJECTIVE: The objective of this study is to determine whether MAOI-A therapy should deter the use of 6 mg s.c. sumatriptan on pharmacokinetic grounds. METHODS: Summary pharmacokinetic data were taken from the literature and from GlaxoSmithKline (GSK) study C92-050. Half-times were converted into rate constants, which were then used in a parsimonious compartmental model (needing only 3 simultaneous differential equations). Acceptance criteria for the model included observed plasma sumatriptan concentrations at T(max), 1, 2, and 10 hours post-dose. A set of 1000 concentration measurements at a resolution of 36 seconds was generated. The model was then perturbed with elimination constants observed during concomitant moclobemide administration, creating a second set of concentration measurements. The 2 sets were then plotted, examined for their differences, and integrated for a second time to obtain and compare areas under the curve (AUCs). RESULTS: The greatest absolute difference between the 2 sets of measurements was 2.85 ng/mL at t = 2.95 hours. A 2-fold difference between the 2 sets occurred only after t = 5.96 hours, when the concentration in the presence of the MAOI-A was 3.72 ng/mL (or <4% of C(max)). At t = 10 hours, the concentrations in both sets were <1 ng/mL (ie, below the lower limit of assay quantitation), and AUC(0-10h) was 97.4 and 117 ng.hour/mL in the absence and presence of the MAOI-A. CONCLUSIONS: There are no pharmacokinetic grounds to deter co-administration of an MAOI-A and subcutaneous sumatriptan. The dominance of the distribution phase and completeness of absorption of a 6 mg dose of s.c. sumatriptan explains the trivial effect size of the MAOI-A on plasma sumatriptan concentrations. Importantly, these findings should not be extrapolated to other routes of administration for sumatriptan.

Anodic voltammetry of zolmitriptan at boron-doped diamond electrode and its analytical applications.

The electrooxidative behavior and determination of zolmitriptan at a boron-doped diamond electrode were investigated using cyclic, linear sweep, differential pulse and square wave voltammetric techniques. Zolmitriptan undergoes irreversible oxidation at a peak potential of about +0.9 V (vs Ag/AgCl/3 M KCl). DPV and SWV techniques are proposed for the determination of zolmitriptan in phosphate buffer at pH 3.03, which allows quantitation over the two different ranges (8 x 10(-7) - 8 x 10(-6) M and 1 x 10(-5) - 1 x 10(-4) M) in supporting electrolyte for both methods. A linear response was obtained in phosphate buffer over two different ranges (6 x 10(-7) - 8 x 10(-6) M and 1 x 10(-5) - 1 x 10(-4) M) for spiked serum samples at pH 3.03 for both techniques. The repeatability and reproducibility of the methods for all media were determined. The standard addition method was used in serum. Precision and accuracy were also checked in all media. No electroactive interferences from the excipients and endegenous substances were found in the pharmaceutical dosage form and the biological sample, respectively.

Zelrix: a novel transdermal formulation of sumatriptan.

OBJECTIVE: This study evaluated the pharmacokinetic and tolerability profiles of Zelrix (NuPathe Inc., Conshohocken, PA, USA), the novel formulation of sumatriptan (formerly known as NP101). BACKGROUND: Migraine is an episodic headache disorder characterized by a combination of neurological, gastrointestinal, and autonomic symptoms. Gastrointestinal disturbances, including nausea, vomiting, and gastric stasis are common and can result in significant impact on treatment. Triptans are 5-hydroxytriptanime(1B/1D) agonists that work on the trigeminal nerve that is activated during migraine. All triptans approved for use in the US are currently available as oral formulations; however, this may not be the ideal route of administration for many migraineurs. Sumatriptan is also available as a nasal spray and subcutaneous (s.c.) injection. Therefore, the need to develop improved methods for noninvasive parenteral delivery of triptans remains high. METHODS: This was a Phase I, single-center, open-label, crossover study that assessed the pharmacokinetic properties of a single dose of sumatriptan delivered using an iontophoretic transdermal patch in comparison with oral, injection, and nasal delivery. Subjects were healthy male and female volunteers who received each of 5 treatments: sumatriptan 100 mg oral tablets, sumatriptan 6 mg s.c., sumatriptan 20 mg nasal spray, Zelrix I (transdermal patch with 3 g of gel solution delivering 6 mg of sumatriptan transdermally), or Zelrix II (transdermal patch containing 2.6 g of gel solution delivering 6 mg of sumatriptan). RESULTS: The C(max) for Zelrix was reduced to 30% and 28% of the sumatriptan s.c. dose, thereby reducing the risk of triptan-like sensations associated with high peak plasma concentrations. Plasma concentrations for Zelrix I and Zelrix II were intermediate between those for oral and nasal sumatriptan doses tested. Transdermal patch delivery of sumatriptan to the systemic circulation reached plasma concentrations of 10 ng/mL within about 30 minutes. The mean drug delivery of Zelrix I and II was 6.11 mg (confidence intervals [CI] 5.33-6.88) and 6.09 mg (CI 5.52-6.66), respectively. The AUC(0-inf) was approximately 99% for the Zelrix I patch and 100% for the Zelrix II patch as compared with sumatriptan 6 mg s.c. dose. Both doses of sumatriptan transdermal patches were well tolerated. Skin reactions at the patch site were mild and erythema resolved in most subjects within 48-72 hours. CONCLUSIONS: The results from this study show that sumatriptan administration using a novel iontophoretic transdermal technology delivers plasma levels within the range for nasal spray, tablet, and injectable sumatriptan. Zelrix I and II were well tolerated and adverse events were mild and transient. Transdermal delivery of sumatriptan using the SmartRelief iontophoretic technology may prove beneficial for a large segment of the migraine population based upon fast, consistent delivery of drug and avoidance of common gastrointestinal disturbances associated with migraine.

Effects of long-term administration of Lactobacillus reuteri DSM-17938 on circulating levels of 5-HT and BDNF in adults with functional constipation.

Accumulated evidence shows that some probiotic strains ameliorate functional constipation (FC) via the modulation of specific gastrointestinal peptide pathways. The aims of this study were to investigate: (1) the effects of long-term administration of Lactobacillus reuteri (LR) DSM 17938 on the serum levels of serotonin (5-HT) and brain-derived neurotrophic factor (BDNF); (2) the possible link between 5-HT, BDNF, and specific constipation-related symptoms; (3) whether genetic variability at the 5-HTT gene-linked polymorphic region (5-HTTLPR) and BDNF Val66Met loci could be associated with serum 5-HT and BDNF variations. LR DSM 17938 was administered to 56 FC patients for 105 days in a randomised, double-blind manner. The fasting blood samples were collected during the randomisation visit (V1), at day 15 (induction period, V2), day 60 (intermediate evaluation, V3), and day 105 (V4) and the Constipaq questionnaire (the sum of Constipation Scoring System (CSS) and patient assessment constipation quality of life (PAC-QoL)) was administered. A group of healthy subjects was enrolled as controls (HC). At V1, the mean serum 5-HT level in the whole patient group was significantly higher (P=0.027) than in HC subjects, while serum BDNF did not. At the end of probiotic administration (V4), 5-HT and BDNF levels were significantly lower than the initial values (V1) (P=0.008 and P=0.015, respectively). 5-HT and BDNF serum concentration were significantly associated (r=0.355; P=0.007). Neither 5-HT nor BDNF serum levels correlated with the CSS item scores and with the PAC-QoL. Lastly, the regression analysis demonstrated that the presence of the S allele of the 5-HTTLPR accounted for the reduction in the 5-HT concentration at V4. In conclusion, the long-term administration of LR DSM 17938 demonstrated that such a probiotic strain could improve FC by affecting 5-HT and BDNF serum concentrations.

Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization.

5-Hydroxytryptamine (5-HT)(2C) receptor agonists hold promise for the treatment of obesity. In this study, we describe the in vitro and in vivo characteristics of lorcaserin [(1R)-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3 benzazepine], a selective, high affinity 5-HT(2C) full agonist. Lorcaserin bound to human and rat 5-HT(2C) receptors with high affinity (K(i) = 15 +/- 1 nM, 29 +/- 7 nM, respectively), and it was a full agonist for the human 5-HT(2C) receptor in a functional inositol phosphate accumulation assay, with 18- and 104-fold selectivity over 5-HT(2A) and 5-HT(2B) receptors, respectively. Lorcaserin was also highly selective for human 5-HT(2C) over other human 5-HT receptors (5-HT(1A), 5-HT(3), 5-HT(4C), 5-HT5(5A), 5-HT(6), and 5-HT(7)), in addition to a panel of 67 other G protein-coupled receptors and ion channels. Lorcaserin did not compete for binding of ligands to serotonin, dopamine, and norepinephrine transporters, and it did not alter their function in vitro. Behavioral observations indicated that unlike the 5-HT(2A) agonist (+/-)-1-(2,5-dimethoxy-4-phenyl)-2-aminopropane, lorcaserin did not induce behavioral changes indicative of functional 5-HT(2A) agonist activity. Acutely, lorcaserin reduced food intake in rats, an effect that was reversed by pretreatment with the 5-HT(2C)-selective antagonist 6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy)pyridin-3-yl-carbamoyl]indoline (SB242,084) but not the 5-HT(2A) antagonist (R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol (MDL 100,907), demonstrating mediation by the 5-HT(2C) receptor. Chronic daily treatment with lorcaserin to rats maintained on a high fat diet produced dose-dependent reductions in food intake and body weight gain that were maintained during the 4-week study. Upon discontinuation, body weight returned to control levels. These data demonstrate lorcaserin to be a potent, selective, and efficacious agonist of the 5-HT(2C) receptor, with potential for the treatment of obesity.

Pharmacokinetics and tolerability of eletriptan hydrobromide in healthy Korean subjects.

BACKGROUND: Migraine is one of the most common headache disorders that greatly affect the quality of life. Selective serotonin (5-HT) receptor agonists such as triptamine-based drugs called triptans are used for treatment of migraine. PURPOSE: This study aimed to evaluate the pharmacokinetic (PK) and tolerability profiles of eletriptan hydrobromide (eletriptan HBr), a selective 5-hydroxytryptamine (also known as serotonin) 1B/1D receptor agonist, in Koreans and compare the results to those observed in non-Koreans in a previously published study. PATIENTS AND METHODS: A randomized, open-label, single, and repeated-dose study was conducted in 16 healthy Korean male subjects using a four-treatment, four-period, and four-sequence crossover design (NCT01139515). The subjects received one of the following four treatments in each period: a single dose of 20, 40, 80 mg eletriptan HBr or a repeated oral dose of 40 mg 2 h apart. Blood samples were collected before and up to 26 h after dosing for quantification of plasma eletriptan concentration by high-performance liquid chromatography tandem-mass spectrometry. The PK parameters were estimated using noncompartmental methods. Ethnicity differences between Korean and non-Korean subjects were identified using geometric mean ratios and 90% confidence intervals (CIs) of dose-normalized maximum plasma concentration (Cmax) and dose-normalized area under the plasma concentration versus time curve from 0 h to the last measurable concentration (AUC0-t). RESULTS: After single-dose administration of eletriptan HBr to Korean subjects, the mean Cmax and AUC0-t increased linearly with dose. Comparable total systemic exposures were observed in the 2 h apart 40 mg repeated and single 80 mg dose. The geometric mean ratios (90% CIs) of the dose-normalized Cmax and AUC0-t of Korean subjects were similar to those of non-Korean subjects reported in the literature. The adverse events observed were transient and mild in severity. CONCLUSION: Eletriptan HBr showed linear PK and was well tolerated in Korean subjects. The PK and tolerability of eletriptan HBr did not differ between Korean and non-Korean subjects.

A novel nasal almotriptan loaded solid lipid nanoparticles in mucoadhesive in situ gel formulation for brain targeting: Preparation, characterization and in vivo evaluation.

This work aimed at designing efficient safe delivery system for intranasal (IN) brain targeting of the water soluble anti- migraine drug Almotriptan malate (ALM). Solid lipid nanoparticles (SLNs) were prepared by w/o/w double emulsion-solvent evaporation method. Selection of the optimized SLNs formula was based on evaluating particle size (PS), poly dispersity index (PDI) and entrapment efficiency (%EE). Optimized formula exhibited acceptable ranges; PS of 207.9 nm, PDI of 0.41 and %EE of 50.81%. Poloxamer 407 (Plx) at different concentrations (16%, 18%, 20% w/v), with different mucoadhesive polymers (Carbopol-974P, Na alginate, Na-CMC) were evaluated for gelling time and temperature, pH and mucoadhesion. The chosen mucoadhesive in-situ gel formula; 18% Plx 407 based-0.75%w/v Na-CMC, showed acceptable results, so that the optimized SLNs formula was further dispersed in it and evaluated for in vitro release, stability, in vivo and pharmacokinetics studies. Biomarkers' evaluation and histopathological examination were also investigated. Results revealed rapid ALM brain delivery of the optimized formula; Brain/blood ratios at 10 min. for NF (SLNs based IN in-situ gel), ND (Free ALM IN in situ gel) and ALM i.v. (ALM IV solution) were 0.89, 0.19 and 0.31, respectively. Toxicological results confirmed the safety of NF for nasal administration. The achieved out comings are encouraging for further clinical trials of the developed system in humans in future research.

Synergistic effects of tandospirone and selective serotonin reuptake inhibitors on the contextual conditioned fear stress response in rats.

The purpose of this study was to investigate the effects of co-administration of tandospirone (a 5-HT(1A) receptor agonist) and individual selective serotonin reuptake inhibitors (SSRIs) on the contextual conditioned fear stress, using an anxiety model in rats. One day after fear conditioning, tandospirone (0.3-3 mg/kg, s.c.), paroxetine (5-20 mg/kg, i.p.), fluvoxamine (30-60 mg/kg, i.p.) and citalopram (3-30 mg/kg, i.p.) significantly inhibited the conditioned freezing in a dose-dependent manner, whereas, 14 days after fear conditioning, the anxiolytic effects of these drugs were weakened. Fourteen days after fear conditioning, co-administration of tandospirone (0.3 mg/kg, s.c.) with each SSRI [paroxetine (5 mg/kg, i.p.), fluvoxamine (30 mg/kg, i.p.) and citalopram (10 mg/kg, i.p.)], given at subeffective doses, markedly inhibited the conditioned freezing without affecting the locomotor activities and CYP3A4-related pharmacokinetic drug-drug interaction. These results elucidate the pharmacodynamic synergistic effects of tandospirone and SSRIs. Therefore, this augmentation therapy (SSRI+5-HT(1A) receptor agonist) may prove useful for some anxiety disorders.

An evaporation-free solid-phase extraction method for rapid and accurate analysis of sumatriptan in human plasma by LC-MS/MS.

An evaporation-free solid-phase extraction (SPE) method was developed and validated for sumatriptan. High organic washing (50% methanol) and low organic elution (20% methanol) were used and the recovery was greater than 92%. The eluate was injected into a C18 column without evaporation and reconstitution. Sumatriptan was monitored in positive ion mode with mass transition of m/z 296.4-58.1 amu. The calibration curve was 1-100 ng/mL (r>or=0.9923). The inter-day and intra-day precisions ranged from 4.53 to 9.12% and 1.72 to 6.93%, respectively. This method features reduced cost and pollution, clean extract, high speed, and most importantly overall method reliability.

In vitro and in vivo evaluation of the transdermal iontophoretic delivery of sumatriptan succinate.

The objective was to evaluate the transdermal delivery of the 5-HT(1B/1D) agonist, sumatriptan from an iontophoretic patch system, in vivo. Initial in vitro experiments were conducted to optimize formulation parameters prior to iontophoretic delivery in Yorkshire swine. It was found in vitro that increasing drug load in the patch from 9.7 to 39 mg had no statistically significant effect on cumulative delivery (cf. 305.6+/-172.4 vs. 389.4+/-80.4 microg cm(-2), respectively). However, for a given drug load (39 mg) increasing formulation pH from pH 4.7 to 6.8 significantly increased the cumulative amount of sumatriptan delivered across the skin (389.4+/-80.4 vs. 652.4+/-94.2 microg cm(-2)). A biphasic current profile comprising intensities of 1.8 mA from t=0 to t=180 min and 0.8 mA from t=181 min to t=360 min was used for the in vivo experiments. Drug levels in the blood were 13.7+/-4.5 and 53.6+/-10.2 ng ml(-1) at the 30 and 60 min time-points, rising to 90-100 ng ml(-1) during the 90-180 min time-period. The in vivo results show that the pharmacokinetics following transdermal iontophoretic delivery are comparable to those after oral, nasal or rectal administration, but do not match those upon subcutaneous injection.

Uptake and biodistribution of rizatriptan to blood and brain following different routes of administration in rats.

The objective of the present study was to investigate the biodistribution profiles of rizatriptan in the blood and brain of Wistar rats after peroral, subcutaneous, intranasal and intratracheal administration with a particular view to determining the applicability of inhalation delivery to achieve rapid and high availability of the drug in both blood and the brain. Following the intratracheal administration of the drug (4.0mg/kg) to the rats, the absolute bioavailability was found to be 91.2%, significantly higher than those from intranasal or peroral routes, and T(max) in plasma and brain was attained within 2 min, significantly shorter than the T(max) of intranasal ( approximately 10 min in both plasma and brain), subcutaneous (16.7 min in plasma and 22.5 min in brain) and peroral (30.0 min in plasma and 45.0 min in brain) administration. In addition, other pharmacokinetic parameters associated with rapid onset of action including AUC(plasma/brain) and C(max), of intratracheal instillated rizatriptan appeared also to be comparable or superior to those of other delivered routes. Although AUC(brain)/AUC(plasma) ratios after intranasal delivery (43.4%) differed significantly from the ratios shown after intratracheal instillation (23.2%), the AUC(brain 0-120 min) via the latter routes was slightly but not significantly higher than that from the former routes. The results in the present study indicated that pulmonary delivery of rizatriptan may achieve maximum plasma and brain concentrations significantly more rapidly compared with intranasal, subcutaneous and peroral administration and be a promising delivery method with extremely rapid onset of action in the pain relief of migraine.

Pharmacokinetics and in vitro effects of tegaserod, a serotonin 5-hydroxytryptamine 4 (5-HT4) receptor agonist with prokinetic activity in horses.

Tegaserod, a serotonin agonist, has been shown to have prokinetic effects in horses, but pharmacokinetic information is not currently available. The pharmacokinetics and in vitro effects of tegaserod were evaluated. Tegaserod increased the contractile activity of smooth muscle preparations of the equine pelvic flexure. Pertinent pharmacokinetic parameters for a single IV and oral dose were determined. Therapeutic plasma concentrations of tegaserod were achieved by a single oral dose at 0.27 mg/kg. These findings indicate that further clinical studies are warranted to investigate potential benefits in cases of functional gastrointestinal motility disorders in horses.