Improvement in fetal pulmonary hypertension and maturity after reversal of ductal constriction: prospective cohort study.

OBJECTIVES: To test the hypotheses that estimated mean pulmonary arterial pressure (MPAP) decreases and pulmonary vascular maturation, assessed by the ratio of pulmonary arterial flow acceleration time to ejection time (AT/ET ratio), increases after reversal of fetal ductus arteriosus constriction by reducing maternal intake of the causal agent (prostaglandin inhibitors, such as polyphenol-rich foods or non-steroidal anti-inflammatory drugs), and that these effects are independent of gestational age, which are inferences not yet demonstrated in the clinical setting. METHODS: This was a prospective cohort study comparing Doppler echocardiographic ductal flow dynamics, MPAP and pulmonary arterial flow AT/ET ratio in third-trimester fetuses (≥ 28 weeks' gestation) with ductus arteriosus constriction, at the time of diagnosis and after 2 weeks of reduced maternal intake of prostaglandin inhibitors either by suspending the use of pharmacological agents with potential for prostaglandin inhibition or by restricting the consumption of polyphenol-rich foods. MPAP was estimated using the Dabestani equation (MPAP = 90 - (0.62 × AT)), and pulmonary vascular maturity was assessed using the AT/ET ratio, according to reported validation studies. Student's t-test was used for comparison of variables at diagnosis with those after reversal of ductal constriction. Change in MPAP and pulmonary AT/ET ratio between the two assessments was compared with the expected change in the same gestational period in normal fetuses based on reference curves of MPAP and pulmonary AT/ET ratio constructed in normal fetuses from healthy pregnant women at 19-37 weeks' gestation, encompassing the same gestational age range as the study group (28-37 weeks). RESULTS: Seventy pregnancies with fetal ductus arteriosus constriction were included in the study. After 2 weeks of reduced maternal intake of prostaglandin inhibitors, normalization of mean systolic (change from 1.86 ± 0.34 m/s at diagnosis to 1.38 ± 0.41 m/s; P < 0.001) and diastolic (change from 0.41 ± 0.11 m/s to 0.21 ± 0.065 m/s; P < 0.001) ductal velocities and of mean pulsatility index (change from 1.99 ± 0.20 to 2.55 ± 0.42; P < 0.001) was demonstrated. MPAP decreased between the assessments (change from 66.7 ± 6.90 mmHg at diagnosis to 54.5 ± 6.70 mmHg after 2 weeks; P < 0.001) and mean pulmonary AT/ET ratio increased (change from 0.20 ± 0.06 to 0.33 ± 0.07; P < 0.001). Change in MPAP between diagnosis and after 2 weeks of reduced maternal intake of prostaglandin inhibitors was -12.2 ± 0.30 mmHg, which was 5.3-times higher than that in 305 normal fetuses over 2 weeks during the same gestational period (-2.3 ± 0.19 mmHg) (P < 0.001), and change in pulmonary AT/ET ratio between the two assessments was 0.13 ± 0.08, which was 8.7-times higher than that in normal fetuses in the same gestational period (0.015 ± 0.08) (P < 0.001). CONCLUSIONS: Resolution of fetal ductal constriction is followed by a fall in MPAP and by an increase in pulmonary vascular maturity, to a significantly greater degree than is observed in normal fetuses in the same gestational-age period. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

[Aspirin and preeclampsia]. / Aspirine et prééclampsie.

Indications for aspirin during pregnancy are a matter of debate and there is a recent trend to an extended prescription and an overuse of aspirin in pregnancy. Aspirin is efficient in secondary prevention of preeclampsia essentially in patients with a personal history of preeclampsia. The effect of aspirin on platelet aggregation and on the TXA2/PGI2 balance is dose-dependent. The optimum dosage, from 75mg/day to 150mg/day, needs to be determined. Fetal safety data at 150mg/day are still limited. The efficacy of aspirin seems to be subject to a chronobiological effect. It is recommended to prescribe an evening or bedtime intake. Aspirin, in primary prevention of preeclampsia, given to high-risk patients identified in the first trimester by screening tests, seems to reduce the occurrence of early-onset preeclampsia. Nevertheless, there are insufficient data for the implementation of such screening procedures in practice.

Indomethacin increases severity of Clostridium difficile infection in mouse model.

AIM: To evaluate the effect on the nonsteroidal anti-inflammatory drug indomethacin on Clostridium difficile infection (CDI) severity. MATERIALS & METHODS: Indomethacin was administered in two different mouse models of antibiotic-associated CDI in two different facilities, using a low and high dose of indomethacin. RESULTS: Indomethacin administration caused weight loss, increased the signs of severe infection and worsened histopathological damage, leading to 100% mortality during CDI. Indomethacin-treated, antibiotic-exposed mice infected with C. difficile had enhanced intestinal inflammation with increased expression of KC, IL-1ß and IL-22 compared with infected mice unexposed to indomethacin. CONCLUSION: These results demonstrate a negative impact of nonsteroidal anti-inflammatory drugs on antibiotic-associated CDI in mice and suggest that targeting the synthesis or signaling of prostaglandins might be an approach to ameliorating the severity of CDI.

Botulinum toxin treatment in glaucomatous patients: a pilot study.

PURPOSE: The purpose was to evaluate the efficacy of the treatment of iatrogenic entropion (IE), in patients affected by primary open angle glaucoma (POAG), by botulinum toxin injections (BTI). PATIENTS AND METHODS: 20 patients of the "Glaucoma Center" of the Hospital "Umberto I" (Rome) were examined. These patients had POAG and used prostaglandin analogues (PA). Mean age was 75.5 years old (range 68-83); they had been suffering from PAOG since 10 years and were not affected by other relevant systemic diseases. One to three BTI were made into the lower orbicularis muscle using a 0.3 G needle (0.025 to 0.05 units for each injection site). RESULTS: The results were particularly significant in 18 out of 20 patients. Two patients showed slight improvements. A rating scale ranging from 0 to 6 points (0 corresponded to 'no effect' and 6 to the 'complete' resolution of the entropion) was used to evaluate the goals of the treatment. The average rating was 5.37 points. CONCLUSIONS: The entropion due to glaucoma therapy with PA can be successfully treated with BTI in the orbicularis muscle, despite offering temporary therapeutic effects.

Clinical efficacy and safety of a multimodality skin brightener composition compared with 4% hydroquinone.

There are numerous common skin disorders involving hyperpigmentation, including solar lentigines, postinflammatory hyperpigmentation, melasma, freckles, and dyschromia from photoaging. While these conditions are of an aesthetic nature, there is great interest in newer, safer, and more effective treatment modalities. Topical hydroquinone (HQ) has been the gold standard of skin lighteners for many years. However, regulatory authorities around the world are now questioning its safety. A randomized, double-blind, half-face study was conducted in females with moderate to severe facial hyperpigmentation to assess the efficacy and tolerability of 3 new skin brightener formulations containing SMA-432, a prostaglandin E2 inhibitor, compared with 4% HQ. Each subject was assigned 2 of the 4 test materials and was instructed to apply the product on the assigned side of the face twice daily for 12 weeks. Evaluation visits were conducted at baseline and at 4, 8, and 12 weeks. At each visit, subjects were evaluated by a blinded investigator for clinical efficacy and tolerability using grading scales. Standardized digital photography and Chroma Meter assessments were also taken. Self-assessment questionnaires were completed at weeks 4, 8, and 12. Sixty-eight Caucasian subjects (136 half faces) completed the study. All test materials significantly reduced Overall Hyperpigmentation and improved the Investigator's Global Hyperpigmentation Improvement rating at weeks 4, 8, and 12 compared with baseline. SMA-432 exhibited a dose-dependent improvement in hyperpigmentation. There were no major tolerability issues with any of the test materials. Self-assessments were generally favorable for all test materials. At the completion of the trial, subjects rated one of the tested multimodality brightener compositions as the most favorable product and 4% HQ as the least favorable. This study demonstrated that the new non-HQ-containing skin brightener formulations were as effective and equally well tolerated as the gold standard, 4% HQ, in females with facial hyperpigmentation.

Pharmacological Management of PDA: oral versus intravenous medications.

Patent ductus arteriosus is a common problem in very low birth weight infants. Prostaglandin synthesis inhibitors such as indomethacin and ibuprofen are widely used preferred medications for ductal closure but the question of which one should be preferred is controversial. There are some studies in the literature comparing their pharmacokinetics, efficacy, side effects and long-term outcomes. In this review we aimed to focus on prostaglandin synthesis inhibitors with their pharmacodynamic and pharmacokinetic in relation to oral and intravenous forms. Oral ibuprofen seems to be an effective and cheap alternative to the intravenous forms. Studies in extremely low birth weight infants that also evaluate the neurodevelopment will clarify its use.

Comparative impact on prostanoid biosynthesis of celecoxib and the novel nonsteroidal anti-inflammatory drug CG100649.

Nonsteroidal anti-inflammatory drugs (NSAIDs) elevate cardiovascular risk by disrupting cyclooxygenase-2 (COX-2)-dependent biosynthesis of prostacyclin (PGI(2)). CG100649 is a novel NSAID proposed to inhibit both COX-2 and carbonic anhydrase (CA)-I/-II. We compared its impact on prostanoid biosynthesis with that of celecoxib, an NSAID purposefully designed to selectively inhibit COX-2. In a controlled, double-blind randomized trial, single oral doses of 2 or 8 mg CG100649, 200 mg celecoxib, or placebo were well tolerated by healthy volunteers (n = 23). Both CG100649 and celecoxib had the effect of depressing urinary excretion of 2,3-dinor-6-keto-PGF(1α) (PGI-M); the effect of CG100649 was dose-dependent and more sustained (up to 240 h after the dose) than that of celecoxib. Neither CG100649 nor celecoxib significantly inhibited COX-1-dependent prostanoid formation. CA inhibition was not detected after administration of CG100649, despite its partitioning asymmetrically into erythrocytes. CG100649 and celecoxib are both relatively selective inhibitors of COX-2, but they differ in duration of action. Whether they have similar impact on cardiovascular events remains to be determined.

Clinical efficacy and safety of a multimodality skin brightener composition compared with 4% hydroquinone.

There are numerous common skin disorders involving hyperpigmentation, including solar lentigines, postinflammatory hyperpigmentation, melasma, freckles, and dyschromia from photoaging. While these conditions are of an aesthetic nature, there is great interest in newer, safer, and more effective treatment modalities. Topical hydroquinone (HQ) has been the gold standard of skin lighteners for many years. However, regulatory authorities around the world are now questioning its safety. A randomized, double-blind, half-face study was conducted in females having moderate to severe facial hyperpigmentation to assess the efficacy and tolerability of 3 new skin brightener formulations containing SMA-432, a prostaglandin E2 inhibitor, compared with 4% HQ. Each subject was assigned 2 of the 4 test materials and was instructed to apply the product on the assigned side of the face twice daily for 12 weeks. Evaluation visits were conducted at baseline and at 4, 8, and 12 weeks. At each visit, subjects were evaluated by a blinded investigator for clinical efficacy and tolerability using grading scales. Standardized digital photography and Chroma Meter assessments were also taken. Self-assessment questionnaires were completed at weeks 4, 8, and 12. Sixty-eight Caucasian subjects (136 half faces) completed the study. All test materials significantly reduced overall hyperpigmentation and improved the Investigator's Global Hyperpigmentation Improvement rating at weeks 4, 8, and 12 compared with baseline. SMA-432 exhibited a dose-dependent improvement in hyperpigmentation. There were no major tolerability issues with any of the test materials. Self-assessments were generally favorable for all test materials. At the completion of the trial, subjects rated one of the tested multimodality brightener compositions as the most favorable product and 4% HQ as the least favorable. This study demonstrated that the new non-HQ-containing skin brightener formulations were as effective and equally well tolerated as the gold standard, 4% HQ, in females with facial hyperpigmentation.

Different mechanisms in formation and prevention of indomethacin-induced gastric ulcers.

Indomethacin is an indol derivative, non-steroidal, anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic effects. Indomethacin became the first-choice drug to produce an experimental ulcer model as a result of having a higher ulcerogenic potential than other non-steroidal anti-inflammatory drugs (NSAIDs). There have been several conflicting reports about the ulcerogenic mechanism of indomethacin; the mechanism is still unclear. It has been suggested that indomethacin induces gastric damage via inhibiting the release of protective factors like cyclooxygenase-1 (COX-1), prostaglandin E2 (PGE2), bicarbonate, and mucus; increasing aggressive factors like acid; and increasing oxidant parameters while decreasing antioxidant parameters. Classic antiulcer drugs are known to produce antiulcer effects by activating against indomethacin (increasing PGE2, mucus, and bicarbonate production; inhibiting acid secretion; decreasing oxidant parameters; and increasing antioxidants). However, some antiulcer drugs have been shown to inhibit indomethacin-induced ulcers without affecting acid and mucus secretion or oxidant parameters, as well as to inhibit the production of protective factors like COX-1, PGE2, and bicarbonate, and to reduce antioxidant parameters. In order to resolve the contradictions in the abovementioned data, this review hypothesized a relationship between indomethacin-induced ulcers and alpha 2 adrenergic receptors. It is suggested that blockage of alpha 2 adrenergic receptors may be responsible for the increase in the aggressive factors induced by indomethacin, and stimulation of alpha 2 adrenergic receptors may be responsible for the increase of protective factors induced by antiulcer drugs.

[Theophylline, a new look to an old drug]. / Teofilina, una nueva mirada a un medicamento antiguo.

OBJECTIVES: To emphasize the safety and efficacy of theophylline in chronic inflammatory respiratory diseases. To mention its immunomodulatory effects. DATA SOURCES: PubMed search using the keywords: theophylline, histone deacetylase, antiinflammatory, asthma, chronic obstructive pulmonary disease (COPD), corticoresistance. RESULTS: Theophylline is a methylxantine, that inhibits phosphodiesterase (PDE), induces histone deacetylase and antagonizes adenosine. Its main effect is to relax airway smooth muscle. The immunomodulatory effects of theophylline are obtained at low plasma concentrations (less than 10 mg/L). The combination of inhaled corticoesteroids and theophylline exerts a synergistic antiinflammatory effect that improves asthma control and reduces COPD exacerbations. Histones are a group of transcriptional cofactors involved in chromatin remodeling. Histone deacetylases (HDACs) suppress inflammatory gene expression. In patients with COPD and severe asthma there is a reduction in HDAC-2 secondary to the increased oxidative and nitrative stress. HDAC-2 is required by corticosteroids to switch off activated inflammatory genes, then its reduction favors corticosteroid resistance. Theophylline via HDAC-2 induction and PDE inhibition, suppresses inflammatory gene expression, and inhibits free oxygen radicals production. CONCLUSIONS: Theophylline at low plasma concentrations exerts antiinflammatory effects, restoring corticosteroid sensitivity in COPD and severe asthma.

The translational therapeutics of prostaglandin inhibition in atherothrombosis.

Prostaglandins, products of the cyclo-oxygenase (COX) enzymes, can both promote and restrain atherothrombosis. While non-steroidal anti-inflammatory drugs (NSAIDs) selective for inhibition of COX-2 predispose to myocardial infarction, heart failure, hypertension and stroke, suppression of products of COX-1, such as thromboxane (Tx) A2, underlie cardioprotection from low-dose aspirin. Data from clinical pharmacology, rodent models, human genetics, observational studies and randomized trials provide insight into the implications of inhibiting COX product synthesis or function. Many lines of evidence afford a mechanistic explanation for the cardiovascular (CV) hazard from NSAIDs. Elucidation of the biology of this pathway using diversified approaches is also relevant to understanding the implications of substrate rediversion following inhibition of enzymes downstream of COXs, such as the microsomal PGE synthase (mPGES)-1 and of combining D prostanoid antagonism with niacin to attenuate facial flushing.

NSAID-induced gastrointestinal damage and the design of GI-sparing NSAIDs.

NSAIDs are among the most widely used medications, but the side effects of these drugs frequently include gastrointestinal (GI) ulceration and bleeding. COX-2 inhibitors were designed that were claimed to be devoid of ulcer-promoting effects; however, this promise has been unfulfilled, and there are concerns about the cardiovascular safety of COX-2 inhibitors. Several novel approaches to developing GI-sparing NSAIDs have been used, with promising preclinical and clinical results. Selective inhibition of terminal PG synthases, and NSAIDs modified to slowly release gastroprotective gaseous mediators (ie, nitric oxide or hydrogen sulfide) may offer renewed hope for developing anti-inflammatory therapies with greatly reduced GI toxicity.

Continuous infusion versus intermittent bolus doses of indomethacin for patent ductus arteriosus closure in symptomatic preterm infants.

BACKGROUND: Indomethacin is a prostaglandin inhibitor used for the prevention and the treatment of patent ductus arteriosus (PDA). Although a 3-dose schedule has been commonly used, there is no consensus on optimal dosage and duration of indomethacin therapy for PDA closure. There are potential adverse effects of indomethacin use in premature infants such as a reduction in cerebral, mesenteric and renal blood flow and platelet dysfunction. Administering indomethacin continuously over 36-hours has been suggested as a safer and more effective option to prevent such adverse effects. OBJECTIVES: To compare the efficacy and safety of continuous infusion versus bolus administration of indomethacin in closing a symptomatic PDA in preterm infants. SEARCH STRATEGY: The standard search strategy of Cochrane Neonatal Review was used: MEDLINE and EMBASE (1966 - March 2007), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007), bibliographies of reviews and trials were examined for references to other trials, previous symposia proceedings published in Pediatric Research (Pediatric Academic Societies Annual Meeting Abstract Book, 1972 - 2006). No language restrictions were applied. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials comparing continuous indomethacin infusion to bolus doses for closure of a symptomatic PDA in preterm infants with a symptomatic PDA diagnosed clinically and/or by echocardiography. DATA COLLECTION AND ANALYSIS: The methodological quality of each study was assessed. Authors were contacted regarding missing data as well as to inquire about the outcomes that were not reported. Meta-analysis was performed to calculate relative risk (RR), risk difference (RD) and 95% confidence intervals (CI). MAIN RESULTS: Only two small trials comparing continuous versus bolus indomethacin were eligible. Analysis of these studies showed that, although the primary outcome of PDA closure on days two and five slightly favored bolus administration, there was no statistical difference between the two groups. The estimates for PDA closure were RR 1.57 (95% CI 0.54, 4.60), RD 0.10 (95% CI -0.13, 0.33) for day 2 and RR 2.77 (95% CI 0.33, 23.14), RD 0.15 (95% CI -0.13, 0.42) for day five. There was no statistical difference between the bolus and continuous groups for the secondary outcomes of reopening of PDA, neonatal mortality, intraventricular hemorrhage (IVH) and necrotizing enterocolitis (NEC). These analyses were based on a very small number of events reported by these trials. None of the trials reported on outcomes such as requirement for retreatment with indomethacin or surgical ligation, mortality, bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), neurodevelopmental outcome and isolated intestinal perforation. The review demonstrated that there was a decrease in cerebral blood flow velocity after bolus injections and that the difference between the bolus and continuous infusion groups remained significant for 12 - 24 hour. In one study (Christmann 2002), the decrease in blood flow was maximum at 10 minutes [MD -46.40 (95% CI -75.41, -17.39)], while the other study (Hammerman 1995) reported a maximum drop at 30 minutes [MD -55.60 (95% CI -62.92, -48.28)]. Similar decrease in blood flow to the renal and mesenteric circulations following bolus administration was reported in one study (Christmann 2002). In both of these circulations, the decrease was maximum 30 minutes after the bolus injection [typical estimates for renal and mesenteric circulations, respectively: MD -42.00 (95% CI -76.59, -7.41) and MD -26.50 (95% CI -45.34, -7.66)] and lasted about two hours. None of the trials detected predefined levels of decreased urine output and increased levels of BUN and creatinine. AUTHORS' CONCLUSIONS: Due to a paucity of events and lack of precision, the available data was found to be insufficient to draw conclusions regarding the efficacy of continuous indomethacin infusion versus bolus injections for the treatment of PDA. Although continuous indomethacin seems to cause less alterations in cerebral, renal and mesenteric circulations, the clinical meaning of this effect is unclear. Definitive recommendations about the preferred method of indomethacin administration i.e. continuous versus bolus infusions for the treatment of PDA in premature infants cannot be made based on the current findings of this review.

Suspected panosteitis in a camel.

CASE DESCRIPTION: A 6-month-old male Bactrian camel was examined because of a 3-week history of lameness of the left hind limb. CLINICAL FINDINGS: Lameness was initially detected in the left hind limb but resolved and was detected in the right hind limb during treatment. Lameness increased during periods of rapid growth. Radiography revealed multiple small opacities of the medullary cavity of several long bones throughout treatment. Core bone biopsies of lesions in the tibiae revealed lamellar bone with areas of loose connective tissue, osteoblasts in the medullary cavity, and periosteal new bone formation, all which were consistent with panosteitis. TREATMENT AND OUTCOME: Palliative treatment was attempted with epidural and transdermal administration of analgesics. Flunixin meglumine was administered PO, which coincided with an abrupt increase in serum creatinine concentration. Performance of multiple diagnostic bone biopsies led to remission of clinical signs of pain. CLINICAL RELEVANCE: Panosteitis should be a differential diagnosis for shifting limb lameness in young camels. Bone biopsies can be useful for diagnosis of panosteitis and possible relief of pain associated with the disease. Bactrian camels may be susceptible to the renal toxicity of flunixin meglumine, especially when dehydrated.

Modulation of prostaglandin activity, part 1: prostaglandin inhibition in the management of nonrheumatologic diseases: immunologic and hematologic aspects.

Prostaglandins (PGs) are active biologic substances that are involved in a wide range of physiologic processes; when their production is out of balance, they are factors in the pathogenesis of illness. Modulation of PGs by inhibition or stimulation is promising for the management of various conditions. PG inhibitors are widely used to relieve pain and inflammation in patients with rheumatologic disease. Interest in the use of PG inhibitors to prevent cancer and cardiovascular events is growing. More than 27 y ago, investigators found that PG depresses antibody production in vivo; reduces serum iron, hemoglobin, and leukoid series in bone marrow during acute and chronic blood loss; reduces albumin during antigenic stimulation; suppresses hypercalcemia after bleeding; and reduces fasting blood sugar and hyperglycemia after ether anesthesia and bleeding. Chronic conditions that produce large quantities of PGs are associated with immunosuppression and secondary anemia. Investigators in the present study hypothesized (1) that the overproduction of PGs is responsible for immunosuppression and secondary anemia in conditions associated with increased PG synthesis, such as pathologic inflammation, malignancy, trauma, and injury, and (2) that PG inhibitors reverse immunosuppression and secondary anemia, thereby enhancing the immune response. This is supported by many reports that show the immunosuppressive effects of PGs and their role in the immunosuppression associated with pathologic inflammation, burns, trauma, and tumors. Inhibition of PGs can be achieved through the use of synthetic medicines and natural products. This article reviews the effects of PGs and inhibition of increased synthesis of PGs on the lymphoid system, hematologic indices, and bone marrow elements in trauma, injury, burns, and tumors. The Medline database (1966-2006) was used in this study. Investigators in the present study and others have provided evidence that shows the involvement of PGs in immunosuppression and secondary anemia, as well as the efficacy of inhibited overproduction of PGs in many pathologic conditions other than rheumatologic disease.

Gastrointestinal effects of selective and non-selective non-steroidal anti-inflammatory drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed group of drugs. Patients receiving NSAIDs often experience abdominal discomfort, and some of them develop serious gastrointestinal complications, such as ulceration, bleeding, perforation, or obstruction. Gastrointestinal side effects of NSAIDs are mostly attributed to cyclooxygenase (COX) inhibition resulting in reduction of prostaglandin in gastric mucosa. Topical irritant effects are also contributed to their systemic effect of prostaglandin inhibition. Anti-inflammatory effects of NSAIDs are mediated by COX-2 inhibition, while COX-1 inhibition is responsible for gastric prostaglandin inhibition. Management of gastrointestinal complications of NSAIDs is costly. In order to prevent or treat the gastrointestinal complications of NSAIDs, anti-ulcer drugs can be used concomitantly. Other alternative is the application or substitution of COX-2 selective inhibitors, which spare gastric mucosal prostaglandin synthesis and do not damage the gastric mucosa. Application of COX-2 selective inhibitors as a first line treatment for arthritic disorders may not be cost-effective, if patients do not have any risk factors including advanced age, history of complicating peptic ulcer, concomitant anticoagulant and corticosteroid medication. Patients with risk factors or those developing gastrointestinal complications during the course of NSAID treatment can be treated with COX-2 selective inhibitors if necessary.

The potential danger of COX-2 inhibitors.

Cyclooxygenase (COX)-2 inhibitors have a major effect on ovulation and may impair fertilization, decidualization, implantation, and parturition, as well as female fertility. Women attempting to become pregnant need to pay more attention to their use of COX-2 inhibitors.

Prostaglandin inhibitors in preterm labour.

Prematurity accounts for the majority of neonatal morbidity and mortality in the developed world. The process of labour resembles inflammation, with prostaglandin and cytokine production both before and during labour. Anti-inflammatory drugs therefore have the potential to prevent preterm delivery. Indomethacin is the only tocolytic drug proven to delay delivery beyond 37 weeks and to reduce the incidence of low birth weight (<2500 g). There are, however, fetal side-effects such as ductal constriction and impaired renal function associated with its use. It is the type 2 isoform of cyclo-oxygenase (COX-2), which is important for the production of prostaglandins within intrauterine tissues and that up-regulation of COX-2 is associated with labour. Although indomethacin is currently the most common non-steroidal anti-inflammatory drug (NSAID) used in the treatment of preterm labour, it was hoped that COX-2-selective drugs, used as tocolytics, would target COX-2 activity and potentially spare COX-1-specific fetal side-effects. Experience with sulindac and nimesulide has been linked with both constriction of the ductus arteriosus and oligohydramnios. It is unclear whether this is due to COX-2-dependent side-effects, or due to accumulation of drug in the fetal circulation leading to levels that would cause COX-1 inhibition. Currently, the use of COX-2-selective drugs should therefore be confined to randomized controlled trials.