Uso de misoprostol em obstetrícia / Misoprostol use in obstetrics

PONTOS-CHAVE O misoprostol é um análogo da prostaglandina E1 (PGE1) que consta na Lista de Medicamentos Essenciais da Organização Mundial da Saúde (OMS) desde 2005 O Brasil possui uma das regulações mais restritivas do mundo relacionadas ao uso do misoprostol, estabelecendo que o misoprostol tem uso hospitalar exclusivo, com controle especial, e venda, compra e propaganda proibidas por lei Atualmente, o misoprostol é a droga de referência para tratamento medicamentoso nos casos de aborto induzido, tanto no primeiro trimestre gestacional quanto em idades gestacionais mais avançadas O misoprostol é uma medicação efetiva para o preparo cervical e indução do parto O misoprostol é um medicamento essencial para o manejo da hemorragia pós-parto

Pharmacokinetics and ex vivo anti-inflammatory effects of oral misoprostol in horses.

BACKGROUND: Misoprostol is an E prostanoid (EP) 2, 3 and 4 receptor agonist that is anecdotally used to treat and prevent NSAID-induced GI injury in horses. Misoprostol elicits anti-inflammatory effects in vivo in men and rodents, and inhibits TNFα production in equine leucocytes in vitro. OBJECTIVE: Define the pharmacokinetic parameters of oral misoprostol in horses, and determine the inhibitory effect of oral misoprostol administration on equine leucocyte TNFα production in an ex vivo inflammation model. STUDY DESIGN: Pharmacokinetic study, ex vivo experimental study. METHODS: Six healthy adult horses of mixed breeds were used. In phase one, horses were given 5 µg/kg misoprostol orally, and blood was collected at predetermined times for determination of misoprostol free acid (MFA) by UHPLC-MS/MS. Pharmacokinetic parameters were calculated. In phase two, horses were dosed as in phase one, and blood was collected at T0, 0.5, 1 and 4 h following misoprostol administration for leucocyte isolation. Leucocytes were stimulated with 100 ng/mL LPS, and TNFα mRNA concentrations were determined via quantitative real-time PCR. RESULTS: About 5 µg/kg oral misoprostol produced a rapid time to maximum concentration (Tmax ) of 23.4 ± 2.4 min, with a maximum concentration (Cmax ) of 0.29 ± 0.07 ng/mL and area under the curve (AUC0-∞ ) of 0.4 ± 0.12 h ng/mL. LPS stimulation of equine leucocytes ex vivo significantly increased TNFα mRNA concentrations, and there was no significant effect of misoprostol even at the Tmax . MAIN LIMITATIONS: Only a single dose was used, and sample size was small. CONCLUSIONS: Misoprostol is rapidly absorbed following oral administration in horses, and a single 5 µg/kg dose had no significant inhibitory effect on ex vivo LPS-stimulated TNFα mRNA production in leucocytes. Further studies analysing different dosing strategies, including repeat administration or combination with other anti-inflammatory drugs, are warranted.

Toxicidad del misoprostol sobre la gestación: Revisión de la literatura / Developmental toxicity of misoprostol: An update

Misoprostol, a synthetic analog of prostaglandin E1, is currently used in Chile and other countries as an antiulcer medication, mainly for the prevention of non-steroidal anti-infammatory-induced gastric ulcers. Due to its uterotonic properties, it is also indicated in obstetrics for induction of labor and termination of pregnancy. In this last case, misoprostol is either used alone or in combination with other oxytocic drugs such as methotrexate or mifepristone. The use of misoprostol as an abortifacient agent is considered to be safe since it rarely causes serious side effects. However up to 15 percent of misoprostol-induced-abortions may not be successful, even under medical supervision, leading to in utero exposure to the drug and to the induction of a series of birth defects including limb and joints defects and Moebius syndrome. Reports from the nineties failed to show a strong epidemiological association between in utero drug exposure and induction of defects, a situation that has changed now that the number of cases reported has increased. Since the practice of abortion is illegal in Chile, many women turn to off-medical procedures to interrupt their pregnancy and use misoprostol as an easy and cheap alternative, readily available in the INTERNET. The lack of medical supervision in these cases may lead to situations that favor the induction of congenital defects. Here, we present an updated review of scientifc data, to evaluate the risk of birth defects in babies exposed to the drug during pregnancy termination failed attempts.

Eficácia de dinoprostone e misoprostol para indução do trabalho de parto em nulíparas / Efficacy of dinoprostone and misoprostol for labor induction in nulliparous women

OBJETIVO: verificar a eficácia e a segurança de dinoprostone e misoprostol para indução do parto vaginal, com ou sem o uso de ocitocina em nulíparas. MÉTODOS: realizou-se estudo retrospectivo, observacional, envolvendo 238 pacientes que foram submetidas à indução do parto de janeiro de 2008 a fevereiro de 2010 com uso de misoprostol 25 mcg via vaginal ou pessário contendo 10 mg de dinoprostone. Desse grupo, foram selecionadas 184 pacientes, que apresentavam as seguintes características: nulíparas, gestação entre 37 e 42 semanas, feto único, apresentação cefálica, membranas íntegras e índice de Bishop < 3. Os resultados obstétricos e neonatais foram analisados e comparados entre ambos os grupos. A análise estatística foi realizada com o teste t, Chi quadrado e exato de Fisher, adotando-se como nível de significância valores p<0,05. RESULTADOS: a taxa de parto vaginal não foi estatisticamente diferente em pacientes que utilizaram misoprostol e dinoprostone (43,2 versus 50 por cento, p=0,35), respectivamente. O amadurecimento do colo foi superior no grupo com misoprostol (87,3 versus 75,6 por cento, p=0,04). Foi necessária a utilização da ocitocina em 58,8 por cento no grupo com misoprostol e 57,3 por cento no grupo com dinoprostone após o amadurecimento do colo. Falha de indução foi a principal indicação do parto cesárea em ambos os grupos, sem diferença estatística significante. Eventos adversos maternos e fetais, como taquissistolia e índices de Apgar foram similares. CONCLUSÃO: dinoprostone e misoprostol são eficazes para indução do parto vaginal, embora seja necessária a associação com ocitocina, apresentando perfil de segurança semelhante, sendo misoprostol mais eficiente no amadurecimento do colo uterino.

PURPOSE: to determine the efficacy and safety of dinoprostone and misoprostol for the induction of vaginal childbirth, with or without the use of oxytocin in nulliparous women. METHODS: in this retrospective observational study, 238 patients were subjected to the induction of delivery from January 2008 to February 2010 with the use of misoprostol 25 mcg by the vaginal route or a pessary containing 10 mg of dinoprostone. A total of 184 patients were selected, with the following characteristics: nulliparous, gestational age of 37-42 weeks, singleton pregnancies, cephalic presentation, intact membranes, and Bishop score < 3. Obstetric and neonatal data were analyzed and compared between groups. The Student t-test, chi-square test and Fisher's exact test were used for statistical analysis, with the level of significance set at p<0.05. RESULTS: the rate of vaginal childbirth did not differ significantly in patients who used misoprostol and dinoprostone (43.2 percent versus 50 percent; p = 0.35, respectively). The ripening of cervix was higher in the group treated with misoprostol (87.3 percent versus 75.6 percent, p=0.04). The use of oxytocin was necessary in 58.8 percent of the misoprostol group and 57.3 percent in the dinoprostone group after the ripening of cervix. Failed induction was the primary indication of caesarean section delivery in both groups, with no significant difference between them. Fetal and maternal adverse events, such as tachysystole and Apgar scores were similar. CONCLUSION: dinoprostone and misoprostol are both effective for vaginal childbirth induction, although they need to be combined with oxytocin. They showed a similar safety profile, with misoprostol being more efficient regarding cervical ripening.

Clinical use of misoprostol in nonpregnant women: review article.

Misoprostol, a prostaglandin E1 derivative, has been widely used in nonpregnant women because of its cervical ripening and uterotonic effects. A large number of studies have demonstrated its effectiveness in enhancing ease of cervical dilation. This review article describes its pharmacokinetic profile and the relationship between prostaglandins and cervical ripening and uterine contraction and provides a review of the clinical use of misoprostol in nonpregnant women including cervical priming before hysteroscopy, before insertion of an intrauterine device, in endometrium biopsy, preoperatively in myomectomy, and before intrauterine insemination to improve pregnancy rates. Adverse effects are also described.

Medical and surgical options for induced abortion in first trimester.

Medical abortion has been shown to be an effective alternative to surgery for termination of pregnancy in the late as well as the early first trimester of pregnancy. This review discusses the development, application and the current issues with medical and surgical abortion in the first trimester. Studies comparing the two approaches are also assessed as well as potential research directions in this area.

Farmacocinética e farmacodinâmica do misoprostol em Obstetrícia / Pharmacokinetics and pharmacodynamics of misoprostol in Obstetrics

Nos últimos anos a antecipação do parto vem sendo uma prática frequente na Obstetrícia. O misoprostol é um produto sintético, metil análogo da prostaglandina E1 que tem recebido maior atenção, principalmente para a indução do trabalho de parto e do abortamento, além de outras indicações, como controle da hemorragia pós-parto e para promover modificações na cérvice uterina, facilitando a realização de procedimentos como histeroscopia e colocação de dispositivo intrauterino. A administração do misoprostol atualmente é realizada por diferentes vias: oral, vaginal, bucal, sublingual e retal. Assim, é prudente o conhecimento da farmacologia, dos efeitos e mecanismos de ação do misoprostol nas diferentes formas de administração, com base nas evidências científicas e de acordo com os graus de recomendação. O maior pico do nível plasmático de misoprostol, em ordem decrescente, é do grupo sublingual, oral, vaginal com adição de água e vaginal. A biodisponibilidade é também maior na via sublingual. Entretanto, o nível plasmático é mantido por um maior período de tempo quando a via vaginal é utilizada.

Anticipation of delivery has been a frequent practice in Obstetrics nowadays. Misoprostol is a synthetic metyl analogue of prostaglandin E1 that has been used mainly for induction of labor and abortion, as well as for other indications like prevention and control of postpartum hemorrhage. In Gynecology, its use has been introduced to induce cervical modifications for facilitating gynecologic procedures as hysteroscopy and intrauterine device insertion. Misoprostol administration can be done by different routes: oral, vaginal, buccal, sublingual and rectal. Therefore, it is prudent to study pharmacokinetics and pharmacodynamics of this drug and its various routes of administration, according to scientific evidences and grades of recommendation. The highest plasmatic peak of misoprostol, in decreasing order, is sublingual, oral, vaginal and vaginal plus water administration route. Bioavailability is also greater for sublingual route. Notwithstanding, plasmatic levels are maintained for more time when vaginal route is used.

Sustained intravesical drug delivery using thermosensitive hydrogel.

PURPOSE: Direct instillation of drug solutions into the bladder through a urethral catheter (i.e., intravesical therapy) evades systemic adverse effects of drugs used for bladder diseases. However, conventional vehicles for these drugs fail to extend duration of drug exposure in the bladder beyond the first voiding of urine postinstillation. The current study seeks to overcome the aforementioned inherent limitation of intravesical drug administration by using thermosensitive hydrogel as a matrix for sustained intravesical drug delivery. METHODS: Under halothane anesthesia, normal adult female Sprague-Dawley rats were catheterized with PE-50 tubing to instill either 0.02% w/v solution of fluorescein isothiocyanate (FITC) or the same amount of FITC in a 30% w/v dispersion of thermosensitive [Poly(ethylene glycol)-Poly[lactic acid-co-glycolic acid]-Poly(ethylene glycol)) (PEG-PLGA-PEG) polymer in a 0.1 M phosphate buffer. After instillations, rats were kept in metabolic cages for urine collection. Fluorescence emanating from FITC was measured in the urine at various time points up to 24 h after instillation. A rat model of cyclophosphamide-induced cystitis was chosen for the efficacy study using misoprostol as a model drug entrapped in the thermosensitive hydrogel in place of FITC. Efficacy of hydrogel containing misoprostol was compared against rat groups instilled with saline, hydrogel, and misoprostol independently. RESULTS: Prolonged drug exposure to the bladder afforded by hydrogel was evident from the time course of FITC elimination in the urine and by the green fluorescence of FITC seen at the bladder surface when isolated 24 h after instillation. Rats instilled with free FITC voided almost all of the fluorescence in the urine within the first 8 h, whereas rats instilled with hydrogel encapsulated FITC showed sustained release up to 24 h after instillation. Using a cyclophosphamide-induced cystitis model, rats instilled with misoprostol, a synthetic PGE1 analog, showed significantly reduced frequency of urine voiding (p < 0.05) as compared to the rats instilled with saline. Histological examination of the urothelium showed near normal morphology in rats instilled with misoprostol in hydrogel, whereas extensive tissue damage was observed in rats instilled with saline. CONCLUSION: Our study showed that PEG-PLGA-PEG polymer could be used as a viable sustained drug delivery system for intravesical therapy of diseases of the bladder such as cystitis using misoprostol.

Misoprostol therapeutics revisited.

Misoprostol, a prostaglandin E1 analog, is a racemate of four stereoisomers. On administration it rapidly de-esterifies to its active form, misoprostolic acid. Misoprostolic acid is 85% albumin bound and has a half-life of approximately 30 minutes. It is excreted in urine as inactive metabolites. No significant drug interactions have been reported. Besides its gastrointestinal protective and uterotonic activities, misoprostol regulates various immunologic cascades. It inhibits platelet-activating factor and leukocyte adherence, and modulates adhesion molecule expression. It protects against gut irradiation injury, experimental gastric cancer, enteropathy, and constipation. It improves nutrient absorption in cystic fibrosis. Misoprostol has utility in acetaminophen and ethanol hepatotoxicity, hepatitis, and fibrosis. It is effective in asthmatics and aspirin-sensitive asthmatic and allergic patients. It lowers cholesterol and severity of peripheral vascular diseases, prolongs survival of cardiac and kidney transplantation, synergizes cyclosporine, and protects against cyclosporine-induced renal damage. It works against drug-induced renal damage, interstitial cystitis, lupus nephritis, and hepatorenal syndrome. It is useful in periodontal disease and dental repair. Misoprostol enhances glycosoaminoglycan synthesis in cartilage after injury. It prevents ultraviolet-induced cataracts and reduces intraocular pressure in glaucoma and ocular hypertension. It synergizes antiinflammatory and analgesic effects of diclofenac or colchicine and has been administered to treat trigeminal neuralgic pain. It reduces chemotherapy-induced hair loss and recovery time from burn injury, and is effective in treating sepsis, multiple sclerosis, and pancreatitis.

Labor induction with misoprostol versus dinoprostone: a meta-analysis of seven randomized trials

Comparar a eficácia e a segurança de dois análogos das prostaglandinas, misoprostol e dinoprostone na indução do parto em gestações de terceiro trimestre com feto vivo e cérvice desfavorável ao uso de ocitocina, conforme relatos recentes na literatura...

Methotrexate and misoprostol for abortion.

PIP: Methotrexate, a folic acid antagonist, is approved by the US Food and Drug Administration for use in rheumatoid arthritis, psoriasis, and various types of cancer, including choriocarcinoma, and has also been used to terminate ectopic pregnancies. Misoprostol, a prostaglandin, is approved for the prevention of gastric ulcers induced by nonsteroidal anti-inflammatory drugs. In France, the UK, and Sweden, misoprostol and another prostaglandin is used with mifepristone (RU486) to induce abortion in early pregnancy. Recent articles in the press have suggested that in early pregnancy, an intramuscular injection of methotrexate and oral or vaginal administration of misoprostol offers a medical alternative to a surgically induced abortion. This paper describes the mechanisms of action, pharmacokinetics, clinical use, and adverse effects of the two drugs. It is concluded that an intramuscular injection of methotrexate followed up to seven days later by the intravaginal administration of misoprostol can terminate an early intrauterine pregnancy. Headache, nausea, vomiting, diarrhea, and prolonged bleeding have occurred. However, in the few studies published to date, no serious complications have been reported.^ieng

Polymer delivery of the active isomer of misoprostol: a solution to the intestinal side effect problem.

SC-53450 is a new polybutadiene-based polymer system with an acid labile diisopropyl silyl ether linker to which the active isomer of misoprostol (SC-30249) is attached covalently at position C-11. It was studied in rats and dogs to define its profile of gastrointestinal effects relative to misoprostol-hydroxypropyl methylcellulose (HPMC) and the systemic availability of prostaglandin from the polymer. Results of rat studies indicate that SC-53450 has a spectrum of mucosal protective activity similar to misoprostol-HPMC, being protective against indomethacin-induced gastric, cysteamine/indomethacin-induced duodenal and indomethacin-induced lower small bowel damage. SC-53450, in contrast to misoprostol-HPMC, was not diarrheagenic in the rat when administered intragastrically. The observation that SC-53450 is more than 4 times more potent than misoprostol-HPMC suggests the possibility of sustained gastric availability of the prostaglandin SC-30249. SC-53450 exhibited gastric antisecretory activity in histamine-stimulated gastric fistula dogs and protected against acidified aspirin-induced gastric damage in normal fasted beagles. Rat and dog experiments indicate that little, if any, polymer-derived prostaglandin is available systemically, suggesting SC-53450 will have reduced abuse potential in abortion induction. SC-53450 is a potential candidate to replace the present misoprostol formulation in the marketplace for the prevention of nonsteroidal anti-inflammatory drug-induced gastric damage.

Misoprostol in the intestinal lumen protects against radiation injury of the mucosa of the small bowel.

Systemically administered misoprostol, a PGE1 analog, has been shown to be an intestinal radioprotector. The purpose of this study was to determine if administration of misoprostol into the intestinal lumen can also reduce the severity of acute radiation enteritis. The rat small bowel was operatively exteriorized and segmented by means of suture ties. The remainder of the intestine and the rat were shielded in a lead box. Misoprostol was introduced into the lumen in various doses. After 30 min exposure to misoprostol, the isolated, exteriorized, segmented bowel was subjected to 11 Gy X irradiation. Five days later the animals were sacrificed and the intestines harvested for evaluation. Surviving crypt numbers per circumference and mucosal height were the criteria used for quantification of damage. Mucosa exposed to misoprostol at the time of radiation delivery showed significantly increased crypt numbers and mucosal height compared to adjacent saline-filled intestine.

Uso del misoprostol por vía vaginal para la inducción del trabajo de parto en pacientes con muerte fetal intrauterino / Use of vaginal misoprostal for induction of delivery in patients with intrauterine fetal death

Se estudian 16 pacientes con diagnóstico de sindrome de muerte fetal que representa 21.62 del total de pacientes con óbito fetal, este estudio se realizo desde Junio a Diciembre de 1992 en el Hospital Materno Infantil Germán Urquidi de Cochabamba. El Misoprostol es una análogo de la prostaglandulina. El uso oral, es un citoprotector de la mucosa gástrica; en nuestro estudio la vía de administración fue la vaginal en fondo de saco posterior en dosis individuales.