Resting-state functional connectivity following a single dose treatment with CB1 neutral antagonist tetrahydrocannabivarin (THCv) in healthy volunteers

BACKGROUND: The cannabinoid cannabinoid type 1 (CB1) neutral antagonist tetrahydrocannabivarin (THCv) has been suggested as a possible treatment for obesity, but without the depressogenic side-effects of inverse antagonists such as Rimonabant. However, how THCv might affect the resting state functional connectivity of the human brain is as yet unknown. METHOD: We examined the effects of a single 10mg oral dose of THCv and placebo in 20 healthy volunteers in a randomized, within-subject, double-blind design. Using resting state functional magnetic resonance imaging and seed-based connectivity analyses, we selected the amygdala, insula, orbitofrontal cortex, and dorsal medial prefrontal cortex (dmPFC) as regions of interest. Mood and subjective experience were also measured before and after drug administration using self-report scales. RESULTS: Our results revealed, as expected, no significant differences in the subjective experience with a single dose of THCv. However, we found reduced resting state functional connectivity between the amygdala seed region and the default mode network and increased resting state functional connectivity between the amygdala seed region and the dorsal anterior cingulate cortex and between the dmPFC seed region and the inferior frontal gyrus/medial frontal gyrus. We also found a positive correlation under placebo for the amygdala-precuneus connectivity with the body mass index, although this correlation was not apparent under THCv. CONCLUSION: Our findings are the first to show that treatment with the CB1 neutral antagonist THCv decreases resting state functional connectivity in the default mode network and increases connectivity in the cognitive control network and dorsal visual stream network. This effect profile suggests possible therapeutic activity of THCv for obesity, where functional connectivity has been found to be altered in these regions.

Experience With Lacosamide in a Series of Children With Drug-Resistant Focal Epilepsy

We report our pediatric experience with lacosarnide, a new antiepileptic drug, approved by the US Food and Drug Administration as adjunctive therapy in focal epilepsy in patients more than 17 years old. We retrospectively reviewed charts for lacosamide use and seizure frequency outcome in patients with focal epilepsy (Wilcoxon signed rank test). Sixteen patients (7 boys) were identified (median dose 275 mg daily, 4.7 mg/kg daily; mean age 14.9 years, range 8-21 years). Patients were receiving a median of 2 antiepileptic drugs (interquartile range [IQR] 1.7-3) in addition to having undergone previous epilepsy surgery (n = 3), vagus nerve stimulation (n = 9), and ketogenic diet (n = 3). Causes included structural (encephalomalacia and diffuse encephalitis, 1 each; stroke in 2) and genetic abnormalities (Aarskog and Rett syndromes, 1 each) or cause not known (n = 10). Median seizure frequency at baseline was 57 per month (IQR 7-75), and after a median follow-up of 4 months (range 1-13 months) of receiving lacosamide, it was 12.5 per month (IQR 3-75), (P < 0.01). Six patients (37.5%; 3 seizure free) were classified as having disease that responded to therapy (>= 50% reduction seizure frequency) and 10 as having disease that did not respond to therapy (<50% in 3; increase in 1; unchanged in 6). Adverse events (tics, behavioral disturbance, seizure worsening, and depression with suicidal ideation in 1 patient each) prompted lacosamide discontinuation in 4/16 (25%). This retrospective study of 16 children with drug-resistant focal epilepsy demonstrated good response to adjunctive lacosamide therapy (median seizure reduction of 39.6%; 37.5% with >= 50% seizure reduction) without severe adverse events. (C) 2011 Elsevier Inc. All rights reserved.

Complexation of the anti-Trypanosoma cruzi drug benznidazole improves solubility and efficacy

The ruthenium complex,trans-[Ru(Bz)(NH3)(4)SO2](CF3SO3)(2) 1, Bz = benznidazole (N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide), is more hydrosoluble and more active (IC50try/1 h = 79 +/- 3 mu M) than free benznidazole 2 (IC50try/1 h > 1 mM). 1 also exhibits low acute toxicity in vitro (IC50macrophages > 1 mM) and in vivo (400 mu mol/kg < LD50 < 600 mu mol/kg) and the formation of hydroxylamine is more favorable in 1 than in 2 by 9.6 kcal/mol. In murine acute models of Chagas` disease, 1 was more active than 2 even when only one dose was administrated. Moreover, 1 at a thousand-fold smaller concentration than the considered optimal dose for 2 (385 mu mol/kg/day = 100 mg/kg/day), proved to be sufficient to protect all infected mice, eliminating the amastigotes in their hearts and skeletal muscles as observed in H&E micrographics.

Chloroquine is grossly under dosed in young children with malaria : implications for drug resistance

Background: Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations. Methods and Findings: Day 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m(2) were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10-14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662-988) and 758 (95% CI 640-876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10-14 taking 50 mg/kg and children aged 0-2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent. Conclusions: CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10-14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa.

Estudo de pré-formulação para dose fixa combinada dos tuberculostáticos rifampicina, isoniazida, pirazinamida e etambutol (4 em 1)

According to the global framework regarding new cases of tuberculosis, Brazil appears at the 18th place. Thus, the Ministry of Health has defined this disease as a priority in the governmental policies. As a consequence, studies concerning treatment and prevention have increased. Fixed-dose combination formulations (FDC) are recognized as beneficial and are recommended by WHO, but they present instability and loss on rifampicin bioavailability. The main purpose of this work was to carry out a pre-formulation study with the schedule 1 tuberculosis treatment drugs: rifampicin, isoniazid, pyrazinamide and ethambutol and pharmaceutical excipients (lactose, cellulose, magnesium stearate and talc), in order to develop an FDC product (150 mg of rifampicin + 75 mg of isoniazid + 400 mg of pyrazinamide + 250 mg of ethambutol). The studies consisted of the determination of particle size and distribution (Ferret s diameter) and shape through optical microscopy, as well as rheological and technological properties (bulk and tapped densities, Hausner Factor, Carr s Index, repose angle and flux rate) and interactions among drugs and drug excipient through thermal analysis (DSC, DTA, TG and your derivate). The results showed that, except isoniazid, the other drugs presented poor rheological properties, determined by the physical characteristics of the particles: small size and rod like particles shape for rifampicin; rectangular shape for pyrazinamide and ethambutol, beyond its low density. The 4 drug mixture also not presented flowability, particularly that one containing drug quantity indicated for the formulation of FDC products. In this mixture, isoniazid, that has the best flowability, was added in a lower concentration. The addition of microcrystalline cellulose, magnesium stearate and talc to the drug mixtures improved flowability properties. In DSC analysis probable interactions among drugs were found, supporting the hypothesis of ethambutol and pyrazinamide catalysis of the rifampicin-isoniazid reaction resulting in 3- formylrifamycin isonicotinyl hydrazone (HYD) as a degradation product. In the mixtures containing lactose Supertab® DSC curves evidenced incompatibility among drugs and excipient. In the DSC curves of mixtures containing cellulose MC101®, magnesium stearate and talc, no alterations were observed comparing to the drug profiles. The TG/DTG of the binary and ternary mixtures curves showed different thermogravimetrics profiles relating that observed to the drug isolated, with the thermal decomposition early supporting the evidences of incompatibilities showed in the DSC and DTA curves

Determination of the highest no-effect dose (HNED) and of the elimination pattern for cocaine in horses

Cocaine is one of the most widespread illegal stimulants utilized by the human population throughout the world. The aim of this study was to establish the highest no-effect dose (HNED) of cocaine on the spontaneous locomotor activity (SLA) of horses in a behavior chamber, and thereby to determine the maximal acceptable threshold of the urinary drug concentration in horses. Twelve English thoroughbred mares received 0.02, 0.03, 0.04, 0.08 or 0.12 mg kg(-1) cocaine i.v. or saline solution (control). It was noted that doses above 0.04 mg kg(-1) induced a significant increase in SLA (P < 0.05, Tukey's test). No significant increase in SLA was seen in the mares that received 0.03 mg kg(-1), but the animals showed important behavioral changes that did not occur after the 0.02 mg kg(-1) dose. It was concluded that the HNED of cocaine for horses in a behavior chamber is 0.02 mg kg(-1). After injection of this dose in five horses, urine samples were collected at predetermined intervals through vesical catheterization. The concentrations of cocaine, norcocaine, benzoylecgonine and ecgonine methyl ester were quantified by liquid chromatography/electrospray ionization tandem mass spectrometry. Cocaine and norcocaine concentrations remained consistently below the level of detection. Benzoylecgonine reached a mean (+/- SEM) maximum concentration of 531.9 +/- 168.7 ng ml(-1) after 4 h, whereas ecgonine methyl ester peaked 2 h after injection at a concentration of 97.2 +/- 26.5 ng ml(-1). The maximum admissible concentration for cocaine and/or metabolites in the urine of horses is difficult to establish unequivocally because of the substantial individual variation in the drug elimination pattern observed in horses, which can be inferred by the large standard error of the means obtained. Copyright (C) 2002 John Wiley Sons, Ltd.

Inclusion complex of piroxicam with beta-cyclodextrin and incorporation in cationic microemulsion. In vitro drug release and in vivo topical anti-inflammatory effect

Topical formulations of piroxicam were evaluated by determination of their in vitro release and in vivo anti-inflammatory effect. The in vitro release assay demonstrated that the microemulsion (ME) systems provided a reservoir effect for piroxicam release. However, the incorporation of the ME into carboxyvinilic gel provoked a greater reduction in the release of piroxicam than the ME system alone. Anti-inflammatory activity was carried out by the cotton pellet granuloma inhibition bioassay. Topical anti-inflammatory effect of the piroxicam inclusion complex/ME contained in carboxyvinilic gel showed significant inhibition of the inflammation process (36.9%, P < 0.05). Subcutaneous administration of the drug formulations showed a significant effect on the inhibition of inflammation, 68.8 and 70.5%, P <0.05, when the piroxicam was incorporated in ME and in the combined system beta -cyclodextrin (B-CD)/ME, respectively, relative to the buffered piroxicam (42.2%). These results demonstrated that the ME induced prolonged effects, providing inhibition of the inflammation for 9 days after a single dose administration. (C) 2001 Elsevier B.V. B.V. All rights reserved.

Social defeat stress in rats: escalation of cocaine and speedball binge self-administration, but not heroin

Exposure to intermittent episodes of social defeat stress can increase drug seeking and leads to intense drug taking in rats.This study investigated the consequences of repeated, intermittent social defeat stress on patterns of drug self-administration in rats with access to heroin, cocaine, or a heroin-cocaine combination (speedball).Male Long-Evans rats were either handled (controls) or subjected to 25-min social defeat stress episodes on days 1, 4, 7, and 10 during confrontations with an aggressive resident. Ten days following the last defeat, rats were assessed for locomotor cross-sensitization in response to heroin or cocaine. Animals were then prepared with intrajugular catheters for drug self-administration. Separate groups of controls and defeated rats were examined for self-administration of heroin (experiment 1), a heroin-cocaine combination (experiment 2), or cocaine (experiment 3). Drug self-administration patterns were evaluated using fixed or progressive ratio schedules of reinforcement during limited access sessions or a 24-h unlimited access binge.Rats with a history of intermittent social defeat stress showed sensitized locomotor behavior when challenged with heroin or cocaine relative to controls. During the 24-h binge session, defeated rats escalated cocaine-taking behavior (ca. 110 mg/kg vs. 66 mg/kg in controls), persisted in self-administering cocaine or the heroin-cocaine mixture for more hours, and showed a tendency for increased heroin-cocaine intake, but no effects on heroin taking.A history of social defeat stress seems to preferentially promote escalated intake of cocaine but not heroin, unless a heroin-cocaine combination is available.

Pharmacokinetics of intraosseous and central venous drug delivery during cardiopulmonary resuscitation

We compared the pharmacokinetics of intraosseous (IO) drug delivery via tibia or sternum, with central venous (CV) drug delivery during cardiopulmonary resuscitation (CPR).Methods: CPR of anesthetized KCl arrest swine was initiated 8 min post arrest. Evans blue and indocyanine green, each were simultaneously injected as a bolus with adrenaline through IO sternal and tibial needles, respectively, n = 7. In second group (n = 6) simultaneous IO sternal and IV central venous (CV) injections were made.Results: Peak arterial blood concentrations were achieved faster for sternal IO vs. tibial IO administration (53 +/- 11 s vs. 107 +/- 27 s, p = 0.03). Tibial IO dose delivered was 65% of sternal administration (p = 0.003). Time to peak blood concentration was similar for sternal IO and CV administration (97 +/- 17 s vs. 70 +/- 12 s, respectively; p = 0.17) with total dose delivered of sternal being 86% of the dose delivered via CV (p = 0.22).Conclusions: IO drug administrations via either the sternum or tibia were effective during CPR in anesthetized swine. However, IO drug administration via the sternum was significantly faster and delivered a larger dose. (C) 2011 Elsevier B.V. All rights reserved.

Effect of high-dose fentanyl on renal function in dogs

OBJETIVOS: Estudamos os efeitos de alta dose de fentanil (F) em atributos de função renal (FR) do cão. DESENHO: Anestesiamos com pentobarbital sódico (PS) 16 cães divididos aleatoriamente em 2 grupos: manutenção com PS (Gi) e PS com F (0,05 mg.kg-1) (G2). INTERVENÇÃO: os cães foram ventilados artificialmente e tiveram cateterizadas as veias femorais esquerda e direita e a artéria femoral esquerda para infusão de drogas e coleta de dados hemodinâmicos e de sangue para dosagens laboratoriais. Coletou-se urina durante todo experimento. MENSURAÇÃO: Determinaram-se os valores de atributos de FR.. RESULTADOS: PS não mudou a FR e o comportamento de G1 deveu-se à expansão do volume extracelular. O F diminuiu significativamente freqüência cardíaca, pressão arterial média, clearance de creatinina, volume urinário, clearance osmolar e excreção fracionária de sódio e potássio. CONCLUSÕES: A diminuição da FR foi provavelmente devida às alterações hemodinâmicas induzidas pelo F, não se descartando possível ação da aldosterona.

Induction of luteolysis in mares utilizing a micro-dose of prostaglandin F-2 alpha in the sacral lumbar space

An experiment was conducted to examine the luteolytic effectiveness of using low or micro doses of PGF(2 alpha) when administered at the (BAI HUI) acupuncture point, which is frequently used to treat ovarian disturbances in Veterinary Acupuncture. The results indicate that PGF(2 alpha) given at a very low micro dose of 0.5mg (one tenth the conventional recommended dose) when administered at the BAI HUI acupuncture point located at the sacral lumbar space is equally effective at inducing luteolysis in mid-luteal phase mares as conventional PGF(2 alpha) i.m. treatment using a tenfold higher dose. Therefore, based on the results of the present study we suggest that the BAI HUI sacral lumbar route somehow provides an extremely efficient pathway for the drug to the ovarian level.

Short and long period optimization of drug doses in the treatment of AIDS

Técnicas de otimização numérica são úteis na solução de problemas de determinação da melhor entrada para sistemas descritos por modelos matemáticos e cujos objetivos podem ser expressos de uma maneira quantitativa. Este trabalho aborda o problema de otimizar as dosagens dos medicamentos no tratamento da AIDS em termos de um balanço entre a resposta terapêutica e os efeitos colaterais. Um modelo matemático para descrever a dinâmica do vírus HIV e células CD4 é utilizado para calcular a dosagem ótima do medicamento no tratamento a curto prazo de pacientes com AIDS por um método de otimização direta utilizando uma função custo do tipo Bolza. Os parâmetros do modelo foram ajustados com dados reais obtidos da literatura. Com o objetivo de simplificar os procedimentos numéricos, a lei de controle foi expressa em termos de uma expansão em séries que, após truncamento, permite obter controles sub-ótimos. Quando os pacientes atingem um estado clínico satisfatório, a técnica do Regulador Linear Quadrático (RLQ) é utilizada para determinar a dosagem permanente de longo período para os medicamentos. As dosagens calculadas utilizando a técnica RLQ , tendem a ser menores do que a equivalente terapia de dose constante em termos do expressivo aumento na contagem das células T+ CD4 e da redução da densidade de vírus livre durante um intervalo fixo de tempo.

Comparison of clinical features and drug therapies among European and Latin American patients with juvenile dermatomyositis

ObjectiveTo compare the demographic features, presenting manifestations, diagnostic investigations, disease course, and drug therapies of children with juvenile dermatomyositis (JDM) followed in Europe and Latin America.MethodsPatients were inception cohorts seen between 1980 and 2004 in 27 paediatric rheumatology centres. The following information was collected through the review of patient charts: sex; age at disease onset; date of disease onset and diagnosis; onset type; presenting clinical features; diagnostic investigations; course type; and medications received during disease course.ResultsFour hundred and ninety patients (65.5% females, mean onset age 7.0 years, mean disease duration 7.7 years) were included. Disease presentation was acute or insidious in 57.1% and 42.9% of the patients, respectively. The course type was monophasic in 41.3% of patients and chronic polycyclic or continuous in 58.6% of patients. The more common presenting manifestations were muscle weakness (84.9%), Gottron's papules (72.9%), heliotrope rash (62%), and malar rash (56.7%). Overall, the demographic and clinical features of the 2 continental cohorts were comparable. European patients received more frequently high-dose intravenous methylprednisolone, cyclosporine, cyclophosphamide, and azathioprine, while methotrexate and antimalarials medications were used more commonly by Latin American physicians.ConclusionThe demographic and clinical characteristics of JDM are similar in European and Latin American patients. We found, however, several differences in the use of medications between European and Latin American paediatric rheumatologists.

Autoradiographic investigation of effects of high-dose colchicine on dentinogenesis in rat incisors

Twelve female Wistar rats received 1.5 mg/kg of colchicine (CLC) intravenously. Control animals were similarly injected with isotonic saline solution. The animals were killed 5 h, 24 h, 3 days and 7 days after injection. Ninety minutes prior to sacrifice, all animals received an intraperitoneal injection of 3H-proline. Autoradiograms of maxillary incisors showed that CLC increased the retention of the labeled precursor in the odontoblasts. It was also shown that the odontoblasts in the different sectors of the rat incisor present different sensitivities to the CLC action.

Associacao de opioides lipofilicos a bupivacaina na anestesia peridural. Ha vantagem no aumento da dose do opioide?

Background and Objectives: - The effects of associating lipophilic opioids to local anesthetics in epidural anesthesia are not well defined. There are still questions and controversies about opioid doses to be used and their major effects in the epidural block. This study aimed at evaluating the epidural block effects in humans of the association of different fentanyl and sufentanil doses to bupivacaine with 1:200.000 epinephrine. Methods: - A double-blind randomized study was performed in 94 patients of both genders, physical status ASA I, aged between 18 and 60 years, submitted to lower abdomen, perineal or lower limb surgery. Patients without preanesthetic medication were epidurally injected with 100 mg (20 ml) 0.5% bupivacaine, 0.1 mg (0.1 ml) 1%o epinephrine plus a combination of the following drugs: BUPI Group (15 patients): 2 ml of 0.9% saline solution (SS); FENT50 Group (19 patients): 50 μg (1 ml) fentanyl + 1 ml SS; FENT100 Group (20 patients): 100 μg (2 ml) fentanyl; SUF30 Group (20 patients): 30 μg (0.6 ml) sufentanil + SS (1.4 ml); SUF100 Group (20 patients): 50 μg (1 ml) sufentanil + SS (1 ml). The following parameters were studied: onset of sensory block, analgesic block (onset time) in T12, T10 and T8, analgesic block duration in T10 and T12, motor block degree, consciousness degree, need for supplemental perioperative sedation and analgesia, hypotension, bradycardia and peri and post operative side-effects, analgesia duration, proportion of patients needing supplemental analgesia and evaluation of postoperative pain (pain analog visual scale). Results: Groups were demographically uniform. The addition of fentanyl or sufentanil did not alter major characteristics of perioperative epidural block and has not significantly increased postoperative analgesia duration as compared to the use of bupivacaine only. However, the addition of lipophilic opioids has increased the quality of perioperative anesthetic block, translated into a lesser need for supplemental analgesia (p < 0.02). The increased dose of fentanyl and especially of sufentanil has increased the incidence of perioperative drowsiness (p < 0.001) without significant increase in other side effects. Conclusions: In the conditions and doses used, the addition of lipophilic opioids to bupivacaine and the increased dose of lipophilic opioids have improved anesthetic block quality without changes in the epidural block characteristics or a significant increase in side effects, with the exception of drowsiness mainly caused by sufentanil. However, they were not able to provide a significant increase in postoperative analgesia duration.