Estudo observacional do uso da hipodermóclise em cuidados paliativos oncológicos

Hipodermóclise (HDC) é uma importante técnica alternativa para a administração de medicamentos e fluidos pela via subcutânea. É usada com frequência para o controle dos sintomas em pacientes em cuidados paliativos com dificuldade de acesso venoso e que são incapazes de tolerar medicação oral. No entanto, raros estudos abordaram o uso da HDC de uma forma global, para reposição hidroeletrolítica e terapia medicamentosa, tanto na forma contínua quanto intermitente, observando detalhes e complicações do seu uso. Os objetivos deste estudo incluíram caracterizar o uso da HDC para administração de medicamentos, soluções e eletrólitos e avaliar as possíveis complicações locais, identificando também outros fatores que influenciam sua ocorrência. Estudo observacional prospectivo com coleta de dados em prontuário e acompanhamento diário de pacientes internados com câncer avançado, da equipe de Cuidados Paliativos do Instituto do Câncer do Estado de São Paulo (ICESP) em uso de HDC, verificando local de punção, medicamentos administrados e possíveis complicações, acompanhando os detalhes de seu uso. A análise estatística não-paramétrica e método de regressão logística foram realizados. Foram acompanhados 99 pacientes com 243 punções, das quais 166 (68,3%) em coxa e 46 (18,9%) em abdome. Os medicamentos mais utilizados foram morfina em 122 (50,2%) punções, seguido de dipirona em 118 (48,6%) e dexametasona em 86 (35,4%). A solução mais prescrita foi a glicofisiológica em 38 (15,6%) punções, pelo seu aporte calórico. 13,6% das punções (33 de 243) tiveram complicações, sendo apenas seis casos maiores (edema). Complicações ocorreram mais frequentemente até o segundo dia da punção e foram associadas com o número (p=0,007) e o volume (p=0,042) de medicamentos administrados e também com a solução glicofisiológica (p=0,003) e os eletrólitos cloreto de potássio (p=0,037) e cloreto de sódio (p=0,013). Este estudo permitiu o conhecimento de fatores associados a complicações e propõe algumas recomendações, como: individualização da terapia, especialmente relacionada com o volume de escolha, número de medicamentos administrados e evitar a adição de eletrólitos na solução glicofisiológica

Untersuchungen über die Verwendbarkeit von Scopolamin-Morphium als Sedativum und vorbereitendes Narcoticum beim Pferd.

Inaug.-diss. - Hannover, 1912.

Experimentelle Untersuchungen üben die Wirkung der fraktionierten Dosierung von Morphium bei Hunden.

Inaug.-diss.--Hannover,1913.

Opioids Inhibit Lateral Amygdala Pyramidal Neurons by Enhancing A Dendritic Potassium Current

Pyramidal neurons in the lateral amygdala discharge trains of action potentials that show marked spike frequency adaptation, which is primarily mediated by activation of a slow calcium-activated potassium current. We show here that these neurons also express an alpha-dendrotoxin- and tityustoxin-Kalpha-sensitive voltage-dependent potassium current that plays a key role in the control of spike discharge frequency. This current is selectively targeted to the primary apical dendrite of these neurons. Activation of mu-opioid receptors by application of morphine or D-Ala(2)-N-Me-Phe(4)-Glycol(5)-enkephalin (DAMGO) potentiates spike frequency adaptation by enhancing the alpha-dendrotoxin-sensitive potassium current. The effects of mu-opioid agonists on spike frequency adaptation were blocked by inhibiting G-proteins with N-ethylmaleimide (NEM) and by blocking phospholipase A(2). Application of arachidonic acid mimicked the actions of DAMGO or morphine. These results show that mu-opioid receptor activation enhances spike frequency adaptation in lateral amygdala neurons by modulating a voltage-dependent potassium channel containing Kv1.2 subunits, through activation of the phospholipase A(2)-arachidonic acid-lipoxygenases cascade.

Comparison of the pharmacokinetics of oxycodone and noroxycodone in male dark agouti and Sprague-Dawley rats: Influence of streptozotocin-induced diabetes

Purpose. The aims of this study are to evaluate whether cytochrome P450 (CYP)2D1/2D2-deficient dark agouti (DA) rats and/or CYP2D1/2D2-replete Sprague-Dawley (SD) rats are suitable preclinical models of the human, with respect to mirroring the very low plasma concentrations of metabolically derived oxymorphone seen in humans following oxycodone administration, and to examine the effects of streptozotocin-induced diabetes on the pharmacokinetics of oxycodone and its metabolites, noroxycodone and oxymorphone, in both rodent strains. Methods. High-performance liquid chromatography-electrospray ionization-tandem mass spectrometry was used to quantify the serum concentrations of oxycodone, noroxycodone, and oxymorphone following subcutaneous administration of bolus doses of oxycodone (2 mg/kg) to groups of nondiabetic and diabetic rats. Results. The mean (+/- SEM) areas under the serum concentration vs. time curves for oxycodone and noroxycodone were significantly higher in DA relative to SD rats (diabetic, p < 0.05; nondiabetic, p < 0.005). Serum concentrations of oxymorphone were very low (< 6.9 nM). Conclusions. Both DA and SD rats are suitable rodent models to study oxycodone's pharmacology, as their systemic exposure to metabolically derived oxymorphone (potent mu-opioid agonist) is very low, mirroring that seen in humans following oxycodone administration. Systemic exposure to oxycodone and noroxycodone was consistently higher for DA than for SD rats showing that strain differences predominated over diabetes status.

Postoperative analgesic requirements - total laparoscopic hysterectomy versus vaginal hysterectomy

Background: There is limited information available on the requirement for postoperative analgesic drugs in patients submitted to total laparoscopic hysterectomy (TLH) compared with patients undergoing vaginal hysterectomy (VH). Aim: To compare the postoperative analgesic requirements in patients who underwent a TLH with patients who had a VH. Methods: Chart review of 53 patients who had TLH and 47 who had VH and were seen postoperatively by an acute pain management service in order to assess postoperative analgesic requirements. Patient controlled analgesia (PCA) was part of the standard protocol for postoperative pain management. Analgesic requirement was recorded as the mean doses of morphine and number of days that patients used non-steroidal anti-inflammatory drugs (NSAIDs), oxycodone and tramadol. Results: The requirement for total morphine was approximately half the dose in patients who had a TLH (10.8 +/- 12.6 mg) compared with patients who had a VH (19.4 +/- 21.9 mg) (P 0.017). The length of use of NSAIDs was significantly reduced in patients who had undergone a TLH (2.0 +/- 0.95 days) as compared with patients who had a VH (2.85 +/- 1.1 days) (P < 0.0001). Conclusions: Patients submitted to TLH require less postoperative analgesic drugs when compared with patients who had VH. Prospective randomised trials are warranted to compare analgesic requirements between patients submitted to TLH and VH.

Dissection of peripheral and central endogenous opioid modulation of systemic interleukin-1 beta responses using c-fos expression in the rat brain

In opiate addicts or patients receiving morphine treatment, it has been reported that the immune system is often compromised. The mechanisms responsible for the adverse effects of opioids on responses to infection are not clear but it is possible that central and/or peripheral opioid receptors may be important. We have utilised an experimental immune challenge model in rats, the systemic administration of the human pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) to study the effects of selectively blocking peripheral opioid receptors only (using naloxone methiodide) or after blocking both central and peripheral opioid receptors (using naloxone). Pre-treatment with naloxone methiodide decreased (15%) IL-1 beta-induced Fos-immunoreactivity (Fos-IR) in medial parvocellular paraventricular nucleus (mPVN) corticotropin-releasing hormone (CRH) neurons but increased responses in the ventrolateral medulla (VLM) C1 (65%) and nucleus tractus solitarius (NTS) A2 (110%) catecholamine cell groups and area postrema (136%). However no effect of blocking peripheral opioid receptors was detected in the central nucleus of the amygdala (CeA) or dorsal bed nucleus of the stria terminalis (BNST). We next determined the effect of blocking both central and peripheral opioid receptors with naloxone and, when compared to the naloxone methiodide pre-treated group, a further 60% decrease in Fos-IR mPVN CRH neurons induced by IL-1 beta was detected, which was attributed to block of central opioid receptors. Similar comparisons also detected decreases in Fos-IR neurons induced by IL-1 beta in the VLM A1, VLM C1 and NTS A2 catecholamine cell groups, area postrema, and parabrachial nucleus. In contrast, pre-treatment with naloxone increased Fos-IR neurons in CeA (98%) and dorsal BNST (72%). These results provide novel evidence that endogenous opioids can influence central neural responses to systemic IL-1 beta and also suggest that the differential patterns of activation may arise because of actions at central and/or peripheral opioid receptors that might be important in regulating behavioural, hypothalamic-pituitary-adrenal axis and sympathetic nervous system responses during an immune challenge. (c) 2005 Elsevier Ltd. All rights reserved.

Opioids and NMDA receptors: Neuro-excitation and abnormal pain behaviours

In the clinical setting, chronic administration of high doses of systemic morphine may result in neuro-excitatory behaviours such as myoclonus and allodynia in some patients. Additionally, high doses of m-opioid agonists such as morphine administered chronically by the intrathecal route in both rats and humans, as well as DAMGO in rats, have been reported to produce neuro-excitatory behaviours. However, more recently, it has begun to be appreciated that even at normal analgesic doses, opioids such as morphine are capable not only of activating pain inhibitory systems (analgesia/antinociception), but they also activate pain facilitatory systems such that post-opioid allodynia/hyperalgesia may be evident after cessation of opioid treatment. Whilst it is well documented that opioid receptors mediate the inhibitory effects of opioid analgesics, the excitatory and pro-nociceptive effects of opioids appear to involve indirect activation of N-methyl-D-aspartate (NMDA) receptors, such that the extent of pain relief produced may be the net effect of these two opposing actions. Apart from the NMDA-nitric oxide (NO) pro-nociceptive signaling cascade, considerable evidence also implicates dynorphin A as well as the endogenous anti-opioid peptides cholecystokinin (CCK), neuropeptide FF (NPFF) and orphanin FQ/nociceptin, in mediating opioid-induced neuro-excitation and abnormal pain behaviours. Apart from the neuro-excitatory effects that may be produced by the parent opioid, systemic administration of some opioid analgesics such as morphine and hydromorphone in rats and humans results in their rapid conversion to 3-glucuronide metabolites that also contribute significantly to the neuro-excitatory and abnormal pain behaviours produced

Ethanol intake of paediatric intensive care patients

Background - Limiting the amount of alcohol in children's medicines is advisable but as alcohol is the second most common solvent used in liquid preparations, paediatric patients with increased medication intake may be exposed to a considerable alcohol intake. Few medicines are specifically designed for children in Paediatric Intensive Care (PICU), and therefore adult formulations are frequently administered, with high medication use further exposing a PICU patient to undesired alcohol intake. Aims - This small pilot study aimed to examiine the intake of a sample of PICU patients, highlight common medicines used on PICU containing alcohol, provide alternatives where possible and where alternatives are not possible, provide the prescriber with a list of the higher alcohol containing medicines. Method - A retrospective medication chart review was undertaken as a two point snap shot. Data collected included age, weight, medications prescribed and the formulations used at time of the study. The patients' sedation score was recorded. The electronic medicine compendium (EMC) was consulted for any ethanol content for the commercially available products. The manufacturer was contacted for ethanol content of all ‘specials’ and any commercial products found to contain ethanol from the EMC. The PICU patient's daily intake of ethanol was calculated. The calculation was converted to an adult equivalent alcohol unit intake and although this method of conversion is crude and does not take physiological differences of adult and children into account, it was done in order to provide the clinician with commonly used terminology in deciding the risk to the patient. Results - Twenty-eight patients were prescribed a range of 69 different medications. Of the 69 medicines, 12 products were found to contain ethanol. Patient ages ranged from a 26 week premature infant to 15 years old, weights ranges from 0.7 kg to 45 kg. Only 2 out of the 28 patients did not receive ethanol containing medications, and most patients were prescribed at least two medicines containing ethanol. Daily ethanol intake uncorrected for weight ranged from 0.006 ml to 2.18 ml (median 0.26 ml). Converting this to adult units per week, alcohol intake ranged from 0.07 to 15.2 units (median 1.4 units). The two patients receiving above 15 units/week adult equivalent were prescribed an oral morphine weaning regimen, therefore the high alcohol exposure was short term. The most common drugs prescribed containing alcohol were found to be nystatin, ranitidine, furosemide and morphine. No commercially available alcohol-free oral liquid preparations were found for ranitidine, furosemide or morphine at the time of the study. Correlation of the sedation score against ethanol intake was difficult to analyse as most patients were actively sedated. Conclusions - Polypharmacy in PICU patients increases the exposure to alcohol. Some commercially available medicines provide excessive ethanol intake, providing the clinician with ethical, potentially economical dilemmas of prescribing an unlicensed medicine to minimise ethanol exposure. Further research is required to evaluate the scope of the problem, effects of exposure and provision of alcohol free formulations.

Unused medicines with potential for misuse or abuse in primary care

To assess the quantity and nature of prescribed medicines with potential for misuse returned to community pharmacies and general practice surgeries. Setting Community pharmacies (n = 51, 85% total) and general practice surgeries (n = 42, 69%) within the boundaries of Eastern Birmingham Primary Care Trust, UK. Method Medicines returned spontaneously by patients to participating sites were collected over eight weeks in May and June 2003. Data were recorded for each medicinal item including: patient sex, recommended International Non-proprietary Name (rINN), strength, form, legal classification, quantity and number of doses per day. Medicines were categorised into BWF therapeutic groups. A 'medicinal item' was defined as the total number of dose units of a medicine of the same form, strength and date of issue, returned for a given patient. Key findings Medicines were returned from 910 patients comprising 3765 medicinal items (2782 (73.9%) prescription-only medicines and 356 (9.5%) controlled drugs). Substantial amounts of unused, prescribed medicines with potential to cause harm or for misuse were returned, with analgesics, psychoactive and antiepileptic agents comprising 19.4% of returned medicinal items. Medicines of note that were returned included paracetamol-containing medicines (16 630 tablets), morphine (56 g), diamorphine (4.3 g), tramadol (2840 tablets and capsules), benzodiazepines (677 tablets) and tricyclic antidepressants (2831 tablets). Conclusions Substantial quantities of prescribed medicines with potential to cause harm or be misused are routinely present in the community. The management of these unused medicines, and in particular controlled drugs, Is currently inadequate and further work is required to identify the legislative and patient-centred processes required to minimise the potential for these medicines to be misused or cause harm. © 2007 The Authors.

Should topical opioid analgesics be regarded as effective and safe when applied to chronic cutaneous lesions?

Objectives: The induction of analgesia for many chronic cutaneous lesions requires treatment with an opioid analgesic. In many patients suffering with these wounds such drugs are either contraindicated or shunned because of their association with death. There are now case reports involving over 100 patients with many different types of chronic superficial wounds, which suggest that the topical application of an opioid in a suitable gel leads to a significant reduction in the level of perceived pain. Key findings: Some work has been undertaken to elucidate the mechanisms by which such a reduction is achieved. To date there have been no proven deleterious effects of such an analgesic system upon wound healing. Although morphine is not absorbed through the intact epidermis, an open wound provides no such barrier and for large wounds drug absorption can be problematic. However, for most chronic cutaneous lesions, where data has been gathered, the blood levels of the drug applied ranges from undetectable to below that required for a systemic effect. Summary If proven, the use of opioids in this way would provide adequate analgesia for a collection of wounds, which are difficult to treat in patients who are often vulnerable. Proof of this concept is now urgently required. © 2011 Royal Pharmaceutical Society.

An investigation of the relationship between antemortem and postmortem drug concentrations in blood

In the field of postmortem toxicology, principles from pharmacology and toxicology are combined in order to determine if exogenous substances contributed to ones death. In order to make this determination postmortem and (whenever available) antemortem blood samples may be analyzed. This project focused on evaluating the relationship between postmortem and antemortem blood drug levels, in order to better define an interpretive framework for postmortem toxicology. To do this, it was imperative to evaluate the differences in antemortem and postmortem drug concentrations, determine the role microbial activity and evaluate drug stability. Microbial studies determined that the bacteria Escherichia coli and Pseudomonas aeruginosa could use the carbon structures of drugs as a source of food. This would suggest prior to sample collection, microbial activity could potentially affect drug levels. This process however would stop before toxicologic evaluation, as at autopsy blood samples are stored in tubes containing the antimicrobial agent sodium fluoride. Analysis of preserved blood determined that under the current storage conditions sodium fluoride effectively inhibited microbial growth. Nonetheless, in many instances inconsistent drug concentrations were identified. When comparing antemortem to postmortem results, diphenhydramine, morphine, codeine and methadone, all showed significantly increased postmortem drug levels. In many instances, increased postmortem concentrations correlated with extended postmortem intervals. Other drugs, such as alprazolam, were likely to have concentration discrepancies when short antemortem to death intervals were coupled with extended postmortem intervals. While still others, such as midazolam followed the expected pattern of metabolism and elimination, which often resulted in decreased postmortem concentrations. The importance of drug stability was displayed when reviewing the clonazepam/ 7-aminoclonazepam data, as the parent drug commonly converted to its metabolite even when stored in the presence of a preservative. In instances of decreasing postmortem drug concentrations the effect of refrigerated storage could not be ruled out. A stability experiment, which contained codeine, produced data that indicated concentrations could continue to decline under the current storage conditions. The cumulative data gathered for this experiment was used to identify concentration trends, which subsequently aided in the development of interpretive considerations for the specific analytes examined in the study.

Covalent protein adduction by drugs of abuse

Recreational abuse of the drugs cocaine, methamphetamine, and morphine continues to be prevalent in the United States of America and around the world. While numerous methods of detection exist for each drug, they are generally limited by the lifetime of the parent drug and its metabolites in the body. However, the covalent modification of endogenous proteins by these drugs of abuse may act as biomarkers of exposure and allow for extension of detection windows for these drugs beyond the lifetime of parent molecules or metabolites in the free fraction. Additionally, existence of covalently bound molecules arising from drug ingestion can offer insight into downstream toxicities associated with each of these drugs. This research investigated the metabolism of cocaine, methamphetamine, and morphine in common in vitro assay systems, specifically focusing on the generation of reactive intermediates and metabolites that have the potential to form covalent protein adducts. Results demonstrated the formation of covalent adduction products between biological cysteine thiols and reactive moieties on cocaine and morphine metabolites. Rigorous mass spectrometric analysis in conjunction with in vitro metabolic activation, pharmacogenetic reaction phenotyping, and computational modeling were utilized to characterize structures and mechanisms of formation for each resultant thiol adduction product. For cocaine, data collected demonstrated the formation of adduction products from a reactive arene epoxide intermediate, designating a novel metabolic pathway for cocaine. In the case of morphine, data expanded on known adduct-forming pathways using sensitive and selective analysis techniques, following the known reactive metabolite, morphinone, and a proposed novel metabolite, morphine quinone methide. Data collected in this study describe novel metabolic events for multiple important drugs of abuse, culminating in detection methods and mechanistic descriptors useful to both medical and forensic investigators when examining the toxicology associated with cocaine, methamphetamine, and morphine.

Targeted Brain Derived Neurotropic Factors (BDNF) Delivery across the Blood-Brain Barrier for Neuro-Protection Using Magnetic Nano Carriers: An In-Vitro Study

Parenteral use of drugs; such as opiates exert immunomodulatory effects and serve as a cofactor in the progression of HIV-1 infection, thereby potentiating HIV related neurotoxicity ultimately leading to progression of NeuroAIDS. Morphine exposure is known to induce apoptosis, down regulate cAMP response element-binding (CREB) expression and decrease in dendritic branching and spine density in cultured cells. Use of neuroprotective agent; brain derived neurotropic factor (BDNF), which protects neurons against these effects, could be of therapeutic benefit in the treatment of opiate addiction. Previous studies have shown that BDNF was not transported through the blood brain barrier (BBB) in-vivo.; and hence it is not effectivein-vivo. Therefore development of a drug delivery system that can cross BBB may have significant therapeutic advantage. In the present study, we hypothesized that magnetically guided nanocarrier may provide a viable approach for targeting BDNF across the BBB. We developed a magnetic nanoparticle (MNP) based carrier bound to BDNF and evaluated its efficacy and ability to transmigrate across the BBB using an in-vitro BBB model. The end point determinations of BDNF that crossed BBB were apoptosis, CREB expression and dendritic spine density measurement. We found that transmigrated BDNF was effective in suppressing the morphine induced apoptosis, inducing CREB expression and restoring the spine density. Our results suggest that the developed nanocarrier will provide a potential therapeutic approach to treat opiate addiction, protect neurotoxicity and synaptic density degeneration.

Influence de l'inflammation sur le métabolisme catalysé par les cytochromes P450 chez le rat : approches in vitro et implications sur la pharmacocinétique d'agonistes delta

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.