Sufentanil-2-hydroxypropyl-beta-cyclodextrin inclusion complex for pain treatment: Physicochemical, cytotoxicity, and pharmacological evaluation

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Acupuntura e implante de fragmentos de ouro em pontos de acupuntura e pontos Acupuntura e implante de fragmentos de ouro em pontos de acupuntura e pontos gatilho para o tratamento de displasia coxo-femoral em Pastor Alemão

Background: Canine hip dysplasia (HD) is characterized by hip joint laxity and subluxation. It is the most common cause of osteoarthritis in dogs, especially in larger breeds. Its management includes nutritional supplements, nonsteroidal anti-inflammatory drugs, physical therapy, acupuncture or surgical procedures. Implantation of gold beads in acupuncture points and trigger points around a joint has been used in the treatment of osteoarthritis in dogs for at least 30 years. Gold bead implants(GBI) acts as continuous acupuncture stimulation and trigger point treatment in canine HD with long lasting results. Electrophysiological investigations of trigger points reveal dysfunctional muscle spindles which indicate that the electrical activity of active loci arises from extrafusal motor endplates.Case: This is a report on the use of acupuncture and GBI for bilateral HD in a nine year old female German Shepherd. The patient has a HD non-responsive to anti-inflammatory drugs and was unable to stand up or walk by its own. Radiographs showed marked dysplasia, significant subluxation with the femoral head partly out of a shallow acetabulum and massive secondary arthritic bone changes, mainly on the right side. The animal was submitted to eight acupuncture sessions with seven days interval. After the first acupuncture session the use of NSAID was interrupted. After eight weeks the dog was considered rehabilitated and underwent GBI in acupoints and trigger points as maintenance treatment. During the one-year follow-up period the improvement remained unchanged with no need of analgesics.Discussion: It has been suggested that acupuncture or GBI can treat the chronic pain resulting from osteoarthritis induced by HD. According to AP theory, GBI is permanent and long-lasting acupoint stimulation. Moreover, the method is inexpensive, quick and easy to perform, with no postoperative pain or need of exercise restriction. Although gold is extremely corrosion-resistant, the surface of the gold implants stimulates a reaction from the immune system causing an oxidative liberation of gold ions with anti-inflammatory actions. It is well known that gold ions are effective inhibitors of the respiratory burst of neutrophils and monocytes and the proliferation of lymphocytes. These findings suggest that gold implantation, on a local scale, mimics the anti-inflammatory and pain-relieving effect of drugs with chemically bound gold ions. The relatively slow speed of the process results in a limited liberation of gold ions securing that they are taken up almost exclusively by cells close to the implant. The nine year old female German shepherd had a positive response to acupuncture with pain relieve and locomotor rehabilitation. For the nine year old female German shepherd previous acupuncture sessions to GBI resulted in no post-implant worsening period. Indeed, the association acupuncture/GBI does not have the anti-inflammatory drugs undesirable effects and brings long lasting results. In conclusion, GBI therefore should be considered for canine HD when conservative or medical treatments fail to give the desired effect.

Thermal decomposition of some analgesic agents

Thermogravimetry, derivative thermogravimetry (TG, DTG) and differential scanning calorimetry (DSC), were used to study the thermal behaviour of mefenamic acid, ibuprofen, acetaminophen, sodium diclofenac, phenylbutazone, dipyrone and salicylamide. The results led to thermal stability data and also to the interpretation concerning the thermal decomposition. © 1996 Akadémial Kiadó.

Cardiorespiratory, endocrine and metabolic changes in ponies undergoing intravenous or inhalation anaesthesia

Six Welsh gelding ponies (weight 246 ± 6 kg) were premedicated with 0.03 mg/kg of acepromazine intravenously (i.v.) followed by 0.02 mg/kg of detomidine i.v. Anaesthesia was induced with 2 mg/kg of ketamine i.v. Ponies were intubated and lay in left lateral recumbency. On one occasion anaesthesia was maintained for 2 h using 1.2% halothane in oxygen. The same group of ponies were anaesthetized 1 month later using the same induction regime and anaesthesia was maintained with a combination of detomidine, ketamine and guaiphenesin, while the ponies breathed oxygen-enriched air. Electrocardiogram, heart rate, mean arterial blood pressure, cardiac output, respiratory rate, blood gases, temperature, haematocrit, glucose, lactate and cortisol were measured and cardiac index and systemic vascular resistance were calculated in both groups. Beta-endorphin, met-enkephalin, dynorphin, arginine vasopressin (AVP), adrenocorticotrophic hormone (ACTH) and catecholamines were measured in the halothane anaesthesia group only and 11-deoxycortisol during total intravenous anaesthesia (TIVA) only. Cardiorespiratory depression was more marked during halothane anaesthesia. Hyperglycaemia developed in both groups. Lactate and AVP increased during halothane anaesthesia. Cortisol increased during halothane and decreased during TIVA. There were no changes in the other hormones during anaesthesia. Recovery was smooth in both groups. TIVA produced better cardiorespiratory performance and suppressed the endocrine stress response observed during halothane anaesthesia.

REDUCAO DA CONCENTRACAO ALVEOLAR MINIMA DO ISOFLURANO E DO SEVOFLURANO PELO SUFENTANIL

Background and Objectives - Inhalational anesthetics have a mild analgesic effect. The reduction of alveolar concentration (MAC) of potent volatile anesthesics by increasing plasma concentrations of opioids is desired in inhalational anesthesia. The purpose of this study was to determine the role of sufentanil in reducing sevoflurane and isoflurane MAC. Methods - Thirty eight adult patients of both genders, physical status ASA I or II, submitted to major abdominal procedures were randomly allocated into two groups. Group I (n = 24) received inahalational anesthesia with sevoflurane and Group II (n = 14) received inhalational anesthesia with isoflurane, both diluted in a mixture of N2O (1 liter) and O2 (0.5 liter). A semi-closed system with CO2 absorber and partial reinhalation was used. Ventilation was mechanically controlled. Sufentanil infusion was administered aiming at obtaining 0.5 ng.ml-1 of plasma concentration. Sufentanil plasma concentration was previously calculated by a computer software. End-tidal concentrations were obtained through a gas analyzer and measured at 15 minutes (M1), 30 minutes (M2), 60 minutes (M3), 90 minutes (M4) and 120 minutes (M5). Systolic and diastolic blood pressure (SBP and DBP) and heart rate (RR) were measured during the same periods with the addition of M0 (pre-anesthetic period). Hourly consumption of the inhalational anesthetic agent (IAC), extubation time (ET = time between admission to the recovery room and extubation) and stay in the post anesthesia recovery room (PA-RR) were also measured. Results - Type and duration of surgeries were similar for both groups. There were no statistically significant differences in MAC, SBP, DBP, RR, IAC, TE and PA-RR between groups. Systolic blood pressure in group I (sevoflurane) showed differences among periods F = 3.82 p < O.05; (M2 = M3)(M4 = M5) and M1 had a intermediate value. MAC in group I showed differences among periods F = 9.0 p < 0.05; M1 < M3. MAC in group II also showed differences among periods F = 13.03 p < O.05; M1 < (M2,M3,M4,M5). Conclusions - Both groups had similar behavior when associated to sufentanil in major abdominal surgeries. Group II showed a higher cardiac and circulatory stability.

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.

Comparacao da recuperacao de anestesia venosa com propofol e anestesia inalatoria com sevoflurano para laparoscopia ginecologica

Backgrounds and Objectives: Both continuous venous anesthesia with propofol and inhalational anesthesia with sevoflurane propitiate fast arousal with few side effects. The aim of this study was to compare the arousal and post anesthestic recovery times in patients submitted to these two agents. Methods: Forty three patient aged 18 to 50 years, physical status I or II, submitted to gynecological laparoscopy were distributed in two groups: G1 - propofol in continuous infusion of 115 μg.kg -1.min -1 and G2 sevoflurane. All the patients were pre-medicated with 7.5 mg midazolam, sufentanil 0.5 μg.kg -1, propofol 2 mg.kg -1, atracurium 0.5 mg.kg -1, N 2O in 50% of oxygen in a no-rebreathing system. The depth of the anesthesia and arousal time were assessed by the Bispectral index (BIS). The time between end of anesthesia and eye opening, time for command response and time for orientation were also evaluated. Results: The times recorded in minutes were: G1 - eye opening 8.2 ± 2.9, command response 8.6 ± 3.1, orientation 9.8 ± 3.4, recovery 31.6 ± 3.8; G2 - eye opening 4.5 ± 3, command response 4.9 ± 3.4, orientation 6.2 ± 3.4, recovery 66 ± 8. Except the recovery time, all the values were larger in G1. Conclusions: Both intravenous propofol or inhalational sevoflurane were considered excellent anesthetic techniques as to recovery time and recovery room discharge. Sevoflurane provided an earlier arousal with a longer recovery room stay as compared to propofol.

Morfina nasal: Avaliacao da analgesia e dos efeitos colaterais no tratamento da dor pos-operatoria em criancas

Background and Objectives - Postoperative pain is one of the major discomforts but often under treated, especially in the pediatric patient. The aim of this study was to evaluate nasal morphine postoperative analgesia as an alternative drug administration route and show its applicability, effectiveness, tolerability and side effects. Methods - Participated in this study 20 patients aged 3 to 13 years, physical status ASA I and II sequentially submitted the different small and medium-size surgeries. Analgesia was obtained with nasal morphine hydrochloride in aqueous solution in variable concentrations of 2%, 1%, 0.5%, 0.25% and 0.125%. The dose for each instillation has been 0.1 mg.kg -1 at three-hour intervals for 36 postoperative hours. Quality of analgesia in pre-verbal age patients was evaluated by a pain intensity scale based on facial expression and crying, sleep, motor activity, sociability and food ingestion was used. Standardized evaluations were performed at 3-hour intervals. A four-grade scale was used to evaluate tolerability, where: 1) Good; 2) Regular; 3) Bad; 4) Very bad. Result - Postoperative analgesia results have proven to be good and safe, especially from the third evaluation on (6 hours). Drug tolerability has been good, although side effects were observed, especially nausea and vomiting. Conclusions - Patients and relatives accepted the method very well. The nasal route was considered an adequate way for opioid administration although more studies are needed to accept it as a routine for postoperative morphine analgesia.

Estudo das propriedades analgésicas da Achillea millefolium L. (Asteraceae)

This study was designed to separately evaluate the analgesic capacity of 15% tea from Achillea millefolium leaves and florid ends. Three different tests were performed. The animals were separated in 3 groups: group I (control) that received water, group II that received florid end tea, and group III that received leaf tea. The first test was the writhing test induced by intraperitoneal injection of acetic acid in male Swiss mice. The second test consisted of the measurement of tail flick reflex latency (TFRL) in male Wistar rats after receiving a painful thermal stimulus. The groups received the teas or water per os, prior to observation. In the third test, the Wistar rats were submitted to an approximately 1 cm long incision in their tails to test the effect of the teas on induced inflammatory pain. The results showed that the effect of the 15% leaf tea on the mice writhing and TFRL test were not statistically significant. The florid ends tea showed a significantly increase in number of writhes in mice and TFRL in rats after administration. With regard to the effect of the teas on inflammatory pain, ingestion of both preparations caused an increase in the force threshold necessary for the avoidance reflex, indicating antihyperalgesic action of both the leaf and florid ends 15% teas of Achillea millefolium.

Anti-ulcerogenic and analgesic activities of the leaves of Wilbrandia ebracteata in mice

Wilbrandia ebracteata (Cogn.) Cogn. is a medicinal plant belonging to the Cucurbitaceae family used popularly as an antiulcer and analgesic medicine. The hydromethanol extract of leaves was investigated to determine its anti-ulcerogenic (ethanol and indomethacin induced gastric damage) and analgesic (writhing and tail-flick tests) activities in mice (efficacy), its acute toxicity (safety), and its phytochemistry (quality control). Oral administration of leaf extract at a dose of 1000 mg/kg body wt. significantly reduced 73.3% of the total area of lesion in ethanol-induced gastric damage, but was inactive in an indomethacin-induced gastric damage test. The hydromethanol extract was also inactive in both analgesic tests. Oral administration of the leaf extract did not produce mortality in mice, while the LD50 value of the roots was 22.10 mg/kg body wt. in female mice and 58.31 mg/kg body wt. in male mice. Leaves of W. ebracteata reacted positively for steroids, flavonols, flavanones, saponins, tannins and xanthones and negative for other compounds, including cucurbitacins. Leaf extract of W. ebracteata was active as an anti-ulcerogenic, probably through increasing gastric defensive factors, and flavonoids might be the main constituent responsible for this activity.

Cardiopulmonary effects of buprenorphine in horses

Objective - To investigate the effects of buprenorphine on cardiopulmonary variables and on abdominal auscultation scores in horses. Animals - 6 healthy adult horses. Procedures - Horses were restrained in stocks and allocated to 2 treatments in a randomized crossover design, with 1-week intervals between each treatment. Saline (0.9% NaCl) solution was administered IV as a control, whereas buprenorphine (10 μg/kg, IV) was administered to the experimental group. Cardiopulmonary data were collected for 120 minutes after buprenorphine or saline solution administration. Abdominal auscultation scores were monitored for 2 and 12 hours after drug administration in the control and experimental groups, respectively. Results - Following control treatment, horses remained calm while restrained in the stocks and no significant changes in cardiopulmonary variables were observed throughout the study. Buprenorphine administration caused excitatory phenomena (restlessness and head shaking). Heart rate, cardiac index, and arterial blood pressure were significantly increased after buprenorphine administration until the end of the observational period (120 minutes). Minimal changes were found in arterial blood gas tensions. Abdominal auscultation scores decreased significantly from baseline for 4 hours after buprenorphine administration. Conclusions and Clinical Relevance - Buprenorphine induced excitement and hemodynamic stimulation with minimal changes in arterial blood gas tensions. These effects may impact the clinical use of buprenorphine in horses. Further studies are indicated to investigate the effects of buprenorphine on gastrointestinal motility and fecal output.

Evaluation of the anti-inflammatory, analgesic and antipyretic activities of the natural polyphenol chlorogenic acid

Phenolic compounds are numerous and ubiquitous in the plant kingdom, being particularly present in health-promoting foods. Epidemiological evidences suggest that the consumption of polyphenol-rich foods reduces the incidence of cancer, coronary heart disease and inflammation. Chlorogenic acid (CGA) is one of the most abundant polyphenol compounds in human diet. Data obtained from in vivo and in vitro experiments show that CGA mostly presents antioxidant and anti-carcinogenic activities. However, the effects of CGA on the inflammatory reaction and on the related pain and fever processes have been explored less so far. Therefore, this study was designed to evaluate the anti-inflammatory, antinociceptive and antipyretic activities of CGA in rats. In comparison to control, CGA at doses 50 and 100 mg/kg inhibited carrageenin-induced paw edema beginning at the 2nd hour of the experimental procedure. Furthermore, at doses 50 and 100 mg/kg CGA also inhibited the number of flinches in the late phase of formalin-induced pain test. Such activities may be derived from the inhibitory action of CGA in the peripheral synthesis/release of inflammatory mediators involved in these responses. On the other hand, even at the highest tested dose (200 mg/kg), CGA did not inhibit the febrile response induced by lipopolysaccharide (LPS) in rats. Additional experiments are necessary in order to clarify the true target for the anti-inflammatory and analgesic effects of CGA. © 2006 Pharmaceutical Society of Japan.

Molecular hybridization: A useful tool in the design of new drug prototypes

Molecular hybridization is a new concept in drug design and development based on the combination of pharmacophoric moieties of different bioactive substances to produce a new hyrid compound with improved affinity and efficacy, when compared to the parent drugs. Additionally, this strategy can results in compounds presenting modified selectivity profile, different and/or dual modes of action and reduced undesired side effects. So, in this described several example of different strategies for drug design, discovery and pharmacomodulation focused on new innovative hybrid compounds presenting analgesic, anti-inflammatory, platelet anti-aggregating, anti-infections, anticancer, cardio- and neuroactive properties.

Efeito sinérgico entre a dexmedetomidina e a ropivacaína 0,75% na anestesia peridural

BACKGROUND. This study aimed to evaluate clinical characteristics of epidural anesthesia performed with 0.75% ropivacaine associated with dexmedetomidine. METHODS. Forty patients scheduled for hernia repair or varicose vein surgeries under epidural anesthesia participated in this study. They were assigned to: Control Group (n = 20), 0.75% ropivacaine, 20 ml (150 mg); and Dexmedetomidine Group (n = 20), 0.75% ropivacaine, 20 ml (150 mg), plus dexmedetomidine, 1 μg.kg -1. The following variables were studied: total analgesic block onset time, upper level of analgesia, analgesic and motor block duration time, intensity of motor block, state of consciousness, hemodynamics, postoperative analgesia and incidence of side-effects. RESULTS. Epidural dexmedetomidine did not affect onset time or upper level of anesthesia (p > 0.05) however it prolonged sensory and motor block duration time (p < 0.05) and postoperative analgesia (p < 0.05), and also resulted in a more intense motor block, 1 (p < 0.05). Values of bispectral index were lower in Dexmedetomidine Group (p < 0.05). There was no difference in incidence of hypotension and bradycardia (p > 0.05). Occurrence of side-effects (shivering, vomiting and SpO 2 < 90%) was low and similar between groups (p > 0.05). CONCLUSION. There is clear synergism between epidural dexmedetomidine and ropivacaine, further this drug association does not bring about additional morbidity.

Contribuição do uso de medicamentos para a admissão hospitalar

According to the Word Health Organization, adverse drug reactions (ADR) are any harmful and non intentional answer which occurred in doses normally used in human beings. The ADR can be responsible for 2.4% to 11.5% of hospital admissions. Therefore, this study aimed at knowing the admitted patient's demographic profile due to possible ADR, identifying the most frequent drugs and complaints, and evaluating the incidence of hospital admission related to drug use. Patients who were 18 years old or more and were admitted during a period of one month to a medical clinical of a general hospital were interviewed for one month about drug use before being admitted, as well as regarding to the complaint which led them to hospital. These information were analyzed according to official data, like MICROMEDEX® and WHO criteria as well. It was observed that the admission due to drug use occurred in most part of the cases in elderly [47.5% (66/139)] and women [62% (87/139)]. The most frequent drugs used were: omeprazole (16), analgesics (31), antihypertensive (31), simvastatin (7) and formoterol fumarate (6), and the symptoms were normally associated to the digestive (20.5%), circulatory (20.2%), respiratory (18.2%) and central nervous systems (13.9%). It was estimated that 15.5% (139/897) of the hospital admission occurred possibly due to the drug use. The data found by present study suggests some strategies in order to prevent ADR in the context of primary health care services, such as monitoring drug therapy, manly for patients with chronic diseases, elderly and polimedicated people; and pharmaceutical care including dispensation and purchasing of the drugs, a lot of them dispensed over the counter (OTC).