Lumbar Spinal Stenosis and Potential Management With Prostaglandin E1 Analogs.

ABSTRACT: Lumbar spinal stenosis is one of the most commonly diagnosed spinal disorders worldwide and remains a major cause for surgery in older adults. Lumbar spinal stenosis is clinically defined as a progressive degenerative disorder with low back pain and associated neurogenic intermittent claudication. Conservative and surgical management of lumbar spinal stenosis has been shown to be minimally effective on its symptoms. A treatment option that has not been investigated in the United States is the utilization of prostaglandin E1 analogs, which have been used primarily in Japan for the treatment of lumbar spinal stenosis since the 1980s. The vasodilatory and antiplatelet aggregation effects of prostaglandin E1 presumably improve symptoms of lumbar spinal stenosis by increasing blood flow to the spinal nerve roots. This brief report examines the potential vascular pathology of lumbar spinal stenosis, reviews evidence on the use of prostaglandin E1 analog limaprost in Japan for lumbar spinal stenosis, and briefly discusses misoprostol as a possible alternative in the United States. The studies summarized in this report suggest that prostaglandin E1 analogs may provide benefit as a conservative treatment option for patients with lumbar spinal stenosis. However, higher-quality studies conducted in the United States and comparison with other currently used conservative treatments are required before it can be recommended for routine clinical use.

Misoprostol protects mice against severe Clostridium difficile infection and promotes recovery of the gut microbiota after antibiotic perturbation.

Clostridium difficile infection (CDI) is one of the most common nosocomial infections worldwide and an urgent public health threat. Epidemiological and experimental studies have demonstrated an association between nonsteroidal anti-inflammatory drug (NSAID) exposure and enhanced susceptibility to, and severity of, CDI. NSAIDs target cyclooxygenase enzymes and inhibit the production of prostaglandins (PGs), but the therapeutic potential of exogenous introduction of PGs for the treatment of CDI has not been explored. In this study, we report that treatment with the FDA-approved stable PGE1 analogue, misoprostol, protects mice against C. difficile-associated mortality, intestinal pathology, and CDI-mediated intestinal permeability. Furthermore, we report that the effect of misoprostol on the gastrointestinal tract contributes to increased recovery of the gut microbiota following antibiotic perturbation. Together, these data implicate PGs as an important host-factor associated with recovery to C. difficile-associated disease and demonstrate the potential for misoprostol in the treatment of CDI. Further studies to explore the safety and efficacy of misoprostol treatment of CDI in humans is needed.

Discovery of orally available 8-aza-5-thiaProstaglandin E1 analogs as highly selective EP4 agonists.

Analogs 8-aza-16-aryl prostaglandin E(1) (PGE(1)) and 8-aza-5-thia-16-arylPGE(1) were synthesized and evaluated with respect to their subtype receptor affinity and EP4 agonist activity for the purposes of identifying subtype-selective EP4 agonists that demonstrate oral efficacy. Using an inhibition assay of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production in rats, representative compounds were evaluated for their pharmacokinetic profiles and in vivo efficacy. Structure-activity relationships (SARs) were characterized and presented. Of the compounds tested, several demonstrated better oral exposure and/or in vivo efficacy compared with the previously reported analog 2a.

O uso do misoprostol para indução do parto de feto vivo / The misoprostol use in labor initiation with live fetus

A partir da década de 1980, o misoprostol inicialmente usado em Gastroenterologia, logo foi adotado para uso obstétrico, tanto legal quanto ilegal. De droga vista com desconfiança inicialmente, tornou-se método de escolha nos melhores centros obstétricos. Este estudo teve como objetivo uma atualização do uso do misoprostol para a indução do parto de feto vivo nas várias vias e formas de aplicação. Foi feita uma avaliação das várias vias de aplicação e as dosagens recomendadas pelos autores referendados, com análise crítica da sua efetividade. Conclui-se pela efetividade e segurança do método, ser no momento o método recomendado pelo Ministério da Saúde e pela Federação Brasileira das Associações de Ginecologia e Obstetrícia.

From the 1980s, misoprostol used initially in Gastroenterology, was soon adopted for obstetrics use, legal or illegal. It was considered an unbelieved drug at the begining, but now is the first choice in the best obstetric centers. The purpose of this study was to update the misoprostol use in labor induction with live fetus, at several ways and administration forms. An evaluation of the several administration ways and of the recommended doses by referenced authors was done, with critical analysis of its efficacy. By the method's effectiveness and security it was concluded that the misoprostol is recommended to labor induction for the Brazylian Health Minister, and the Brazilian Federation of Gynecology and Obstetrics.

Cervical priming with misoprostol prior to transcervical procedures.

Cervical priming with misoprostol has shown to facilitate transcervical procedures and to reduce side-effects. Cervical priming is recommended by several evidence-based guidelines prior to surgical abortion, dilatation and curettage, hysteroscopy and intrauterine device insertion. It is effective in pregnant as well as in non-pregnant women while the results in post-menopausal women are conflicting. Misoprostol is the best suited prostaglandin for a number of reasons: it has a short half-life, few side effects, it is stable at room temperature, it is relatively cheap and the dosage can easily be adjusted according to the clinical need. Various doses, routes, and time intervals between misoprostol application and the intervention have been evaluated. A single dose of 400 microg given sublingually or vaginally 3h before the intervention has given the best efficacy with the least side effects. Higher doses or longer intervals do not improve the effect on the cervix. Pain is a frequent side effect, but usually responds well to NSAIDs. Other side effects are rare.

Intravaginal gemeprost and second-trimester pregnancy termination in the scarred uterus.

OBJECTIVE: To investigate the effectiveness and complication rate of intravaginal gemeprost, a prostaglandin E(1) analogue, for second-trimester pregnancy termination in women with a scarred uterus. METHODS: Of 439 women undergoing induced abortion between the 13th and the 23rd week of pregnancy, 67 had a scarred uterus because of 1 or more cesarean sections or myomectomy. All women received a 1 mg dose of gemeprost intravaginally every 3 h, up to 5 times over 24 h. Those who did not respond received further cycles of gemeprost treatment. RESULTS: The rate of successful abortions among women with uterine scars was not different from that observed in the nulliparous controls, but previously vaginal delivery was associated with a shorter induction to abortion interval. The rate of severe complications did not differ between the groups, and was about 1%. CONCLUSION: The rate of complications following intravaginal administration of a PGE(1) analogue for second-trimester pregnancy termination was similar in women with a scarred or unscarred uterus.

Intraplantar PGE2 causes nociceptive behaviour and mechanical allodynia: the role of prostanoid E receptors and protein kinases.

BACKGROUND AND PURPOSE: Receptor subtypes involved in PGE(2)-induced nociception are still controversial. The present study investigated the prostanoid E receptor (EP) subtypes and the protein kinase (PK) pathways involved in the nociception induced by PGE(2) injection in the mouse paw. EXPERIMENTAL APPROACH: Paw-licking and mechanical allodynia were measured in vivo and protein kinase activation ex vivo by Western blots of extracts of paw skin. KEY RESULTS: Intraplantar (i.pl.) injection of PGE(2) into the mouse paw caused nociceptive behaviour of short duration with mean ED(50) of 1.43 nmol. PGE(2) produced a longer-lasting mechanical allodynia, with an ED(50) of 0.05 nmol. Intraplantar injection of antagonists at EP(3) or EP(4), but not at EP(1) or EP(2) receptors inhibited PGE(2)-induced paw-licking. Paw-licking caused by PGE(2) was blocked by an inhibitor of PKA but only partially decreased by inhibition of the extracellular-regulated kinase (ERK). Selective inhibitors of PKC, c-Jun N-terminal kinase (JNK) or p38, all failed to affect PGE(2)-induced paw-licking. An EP(3) antagonist inhibited PGE(2)-induced mechanical allodynia. However, inhibitors of PKA, PKC or ERK, but not p38 or JNK, also partially inhibited PGE(2)-induced mechanical allodynia. Western blot analyses confirmed that i.pl. injection of PGE(2) activated PKA, PKCalpha, and mitogen activated kinases (MAPKs) in the paw. Co-treatment with EP(3) or EP(4) receptor antagonists reduced PGE(2)-induced PKA and ERK, but not PKCalpha activation. CONCLUSIONS AND IMPLICATIONS: The present results indicate that the nociceptive behaviour and mechanical allodynia caused by i.pl. PGE(2) are mediated through activation of distinct EP receptors and PK-dependent mechanisms.

Uso do Misoprostol para indução do parto / Misoprostol for labor induction

O Misoprostol, análogo sintético da PGE1, vem sendo usado para indução do parto desde 1991. Diversos ensaios clínicos têm comprovado sua efetividade em comparação a outros métodos de indução, como ocitocina, prostaglandina E2 vaginal, cateter de Foley e solução salina extra-amniótica. Na revisão sistemática disponível na Biblioteca Cochrane, conclui-se que o misoprostol é mais efetivo que os métodos convencionais para amadurecimento do colo e indução do parto. A taquissistolia, entretanto, é mais freqüente com o misoprostol, embora não tenham sido demonstrados efeitos perinatais adversos decorrentes da hiperatividade uterina. Diversos esquemas posológicos e vias de administração estão disponíveis, mas a via vaginal oferece vantagens em relação à oral, devido a um perfil farmacocinético mais favorável. A dose de 50 ug via vaginal resulta em intervalo mais curto até o parto, porém o risco de taquissistolia e hiperatividade é menor com a dose de 25 ug. Desta forma, a recomendação American College of Obstetricians and Gynecologists, é que se utilizem doses mais baixas, como 25 ug a cada três a seis horas. Recentemente, outras vias de administração têm sido propostas (sublingual, bucal, retal), sendo necessários ensaios clínicos controlados comparando as diversas vias e esquemas

Effects of orally administered OP-1206 alpha-CD with loxoprofen-Na on walking dysfunction in the rat neuropathic intermittent claudication model.

An orally active prostaglandin E1 analogue, OP-1206 alpha-CD improves walking dysfunction in the rat spinal stenosis model. Loxoprofen-Na, a non-steroidal anti-inflammatory drug, is used to relieve chronic pain in patients with lumbar spinal canal stenosis. To determine whether the OP-1206 alpha-CD in combination with loxoprofen-Na could induce a greater therapeutical effect on walking dysfunction and spinal cord blood flow (SCBF) than OP-1206 alpha-CD treatment alone after chronic spinal stenosis in the rat. Spinal stenosis was induced by placing two pieces of silicon rubber strips in the lumbar (L4 and L6) epidural space of rats. After surgery, walking function was measured using a treadmill apparatus and SCBF was measured using a laser-Doppler flow meter. Drugs were administered orally twice a day for 11 days from the day 3 post-surgery. OP-1206 alpha-CD elicited a significant improvement of walking dysfunction on days 7 and 14 post-surgery and significantly increased spinal cord blood flow on day 15, whereas walking dysfunction and SCBF of rats treated with loxoprofen-Na alone remained unchanged. Combined treatment of OP-1206 alpha-CD with loxoprofen-Na did not provide additive therapeutical effect. These results suggest that a significant improvement seen after OP-1206 alpha-CD treatment is primarily mediated by improvement of the local spinal cord blood flow. This effect is not ameliorated or potentiated by a combined treatment with loxoprofen-Na.

Medical termination of pregnancy at 9-12 weeks of gestation.

Current RCOG guidelines advise that surgical termination should be offered to those within the 9-12 weeks gestation band. While auditing the quality of services offered for termination of pregnancy in our unit, it became apparent that many women presenting at this gestation were requesting a medical method. There has been little clinical research into medical method of abortion at this gestation. The aim of the study was to assess the efficacy of medical methods of termination at 9-12 weeks gestation. A retrospective analysis of 25 cases who underwent medical termination using a regime of mifepristone followed 48 hours later by a course of vaginal gemeprost was undertaken. Complete abortion was achieved in 96% of cases; 92% of women required no more than two pessaries to achieve complete abortion. All but one patient was suitable for discharge on the same day. One woman underwent surgical evacuation in view of heavy bleeding. We conclude that medical TOP is a safe alternative to surgical method at 9-12 weeks' gestation.

Misoprostol y embarazo / Misoprostol and pregnancy

Se analiza el uso de la droga Misoprostol en el área obstétrica: Aborto. Inducción de parto. Sangramiento post parto. Se describen ventajas, desventajas, dosificación y contraindicaciones

[Spontaneous abortion. Drug treatment versus surgery]. / Spontan abort. Medicinsk versus kirurgisk behandling.

INTRODUCTION: Studies of conservative management of early miscarriage have questioned the need for post abortem curettage. METHODS: A prospective, randomised study was carried out to clarify the effect of vaginal administration of a prostaglandin E1 analogue (gemeprost) versus surgical management (curettage) of miscarriages at up to twelve weeks of gestation. A questionnaire revealed discomfort as bleeding and pain. RESULTS: The study comprised 61 patients: group 1 (n: 27) with an endometrial thickness less than 10 mm managed by expectancy, and group 2 with an endometrial thickness greater than 10 mm; group 2 was randomised to group 2A (n: 17), given gemeprost, and group 2B (n: 17), underwent curettage. On entry the mean gestational ages were 51 and 67.5 days for groups 1 and 2, respectively; transvaginal ultrasonography revealed a mean endometrial thickness of 8 mm in group 1 and 19 mm in group 2. One week later this was reduced to 4 mm in group 1 and 5.7 mm in group 2. The duration of vaginal bleeding was similar in all groups, with a mean of 1 week (2-3 days of moderate/heavy bleeding and 6-10 of no bleeding or spotting). The discomfort experienced was similar in all groups (a mean of 36-48 hours of moderate/strong pain and 7-10 days of no or insignificant pain). DISCUSSIONS: Conservative treatment can substitute general anesthesia and curettage in the management of complete spontaneous abortions with fresh vaginal bleeding and an endometrial thickness of up to 10 mm. Vaginal administration of 1 mg gemeprost can substitute general anesthesia and curettage in the management of incomplete spontaneous abortions of up to 12 weeks of gestation and absence of a gestation sac.

[Reintroduction of medical abortion in Denmark]. / Reintroduktion af medicinsk abort i Danmark.

Medical termination of early pregnancy with mifepristone (RU 486) followed by a prostaglandin analogue (Cervagem) is a fairly new abortion method in surgical and gynaecological departments in Denmark. Sixty-two patients were evaluated during the period December 1, 1997 to the June 10, 1998 at Kalundborg hospital. The success rate was 97%. Side effects were rare. The study illustrates the need for strong analgesics in half of the patients. In conclusion RU 486 followed by a prostaglandin analogue provides an efficient and attractive alternative to surgical abortion methods.

[Retrospective analysis (1996-1998) of the treatment results with PgE2 (3 mg) of pregnant women with induced birth indications because of unsatisfactory cervix condition]. / Retrospektiven analiz ot prilozhenieto na PgE2 (3 mg) pri nezadovolitelno s'stoianie na matochnata shiika pri bremenni s indikatsii za induktsiia na razhdaneto (1996-1998).

The aim of the retrospective analysis is to estimate the results of PGE treatment/or cervical ripening with Bishop score < or = 4--effectiveness and safety. The research includes 60 patients with different induction indications. The comparative analysis has been carried out between 2 groups of patients with premature ruptiere of the ammotic membranes. The first group includes 22 patients treated only with Pg; and the second one includes 18 patients treated only with....

[Vasospastic angina pectoris following abortion induced by prostaglandin analogue]. / Vasospastisk angina pectoris ved medicinsk provokeret abort med prostaglandinanalog.

A case of vasospastic angina pectoris with loss of consciousness, bradycardia and seizures induced by medical abortion following administration of mifepristone and gemeprost is reported. The patient had a history of smoking and migraine, and former treatment with ergot alkaloids or serotonin agonists had also resulted in chest pain and lipothymia. The case underlines the importance of obtaining a detailed history of vasospastic disorders in women referred for medical abortion.

[Futile intra-amnion Rivanol administration and prostaglandin labor induction in uterus unicornis unicollis with a noncommunicating right-sided horn]. / Frustrane intraamniale Rivanolapplikation und Prostaglandininduktion bei Uterus unicornis unicollis mit nichtkommunizierendem rechtem Horn.

We report on the futile use of labour-inducing agents in a patient with a Mullerian duct abnormality. In the 20th week of gestation, foetal death had been diagnosed in the rudimentary right horn. It is suggested that induction as well as continuation of effective contractions depends on the intact uterus (cervix, lower uterine segment, and corpus).

A randomized trial of 2 regimens for the administration of vaginal prostaglandins (gemeprost) for the induction of midtrimester abortion.

The most frequently used method for second trimester termination of pregnancy is administration of gemeprost (16, 16-dimethyl-trans delta 2-prostaglandin E1methyl ester) as a vaginal pessary. This provides a safe and effective method for achieving abortion. The current prescribing advice is to insert the pessaries into the posterior vaginal fornix every 3 hours. This study compares this to a 6-hourly regimen. The median abortion interval in the 6-hour group was shorter than the 3-hour group (15 versus 16 hours respectively) but the cumulative abortion rates were similar (98% in the 3-hour group and 91.8% in the 6-hour group). The 6-hour group required a significantly lower total dose of gemeprost to induce abortion. There was no difference in the rates of side-effects in the 2 groups but those receiving pessaries every 6 hours required less analgesia. This study finds no advantage in giving gemeprost every 3 hours.