Diagnostic and prognostic role of nitroglycerin-induced dilation in patients with suspected vasospastic angina, combined with ergonovine provocation test.

The diagnostic and prognostic role of nitroglycerin-induced dilation (NID) combined with ergonovine provocation test in patients with suspected VSA patients is not clear. A total of 438 consecutive patients who underwent the ergonovine provocation test for the diagnosis of vasospastic angina (VSA) were enrolled. Patients with VSA (n = 52) had a significantly greater coronary response to ergonovine (- 84.3 ± 10.5% vs. - 38.4 ± 17.9%, p < 0.001) and NID (26.3 ± 31.0% vs. 12.5 ± 19.0%, p < 0.001) than non-VSA patients. However, positive NID (more than 13.8% dilation, n = 170) showed a poor accuracy (AUC 0.64 [95% CI: 0.56-0.73], p = 0.001, sensitivity 60.4%, specificity 61.3%) for the diagnosis of VSA by ergonovine provocation test. Major adverse cardiovascular events (MACE) occurred more frequently in the VSA group than in the non-VSA group (9.6% vs. 2.2%, p = 0.006). In addition, the positive NID group showed a lower rate of MACE than the negative NID group (1.2% vs. 4.3%, p = 0.021). Interestingly, the group of VSA with negative NID had poor prognosis than any other combinations (Log-rank, p < 0.0001). Although NID had a limited role in the detection of VSA defined by ergonovine provocation test, NID combined with the ergonovine provocation test has an additive prognostic role in the clinical outcomes in patients with suspected VSA.

The neuroprotective effect of oxytocin on vincristine-induced neurotoxicity in mice.

Vincristine (VCR) is commonly used to treat a variety of hematological malignancies and solid tumors in pediatric and adult patients. However, peripheral neuropathy is a dose-limiting side effect that leaves some patients with functional disability and long-term pain. Oxytocin (OT) has demonstrated analgesic and anti-inflammatory properties, but there is no evidence regarding its effects on VCR-induced neurotoxicity. Therefore, we evaluated the potential protective effects of OT on VCR-induced neurotoxicity. In vitro, VCR (0.005 ∼ 0.1 µmol/l) and OT (10-8 ∼ 10-5 mol/l) were added into cultured primary dorsal root ganglion (DRG) neurons of mice. The length of neurites was counted by using immunofluorescence. In vivo, neurotoxicity was induced in mice by administration of VCR (0.1 mg/kg, intraperitoneal injection for 14 days) with or without pretreatment of OT (0.1 mg/kg or 1 mg/kg). Atosiban, an OT receptor (OTR) antagonist and OTR knockout (KO) mice were used for evaluating effects of OTR. Mechanical hyperalgesia was measured by using von Frey filaments. Histology of plantar skin, sciatic nerve and DRG was observed by using transmission electron microscopy (TEM) and hematoxylin-eosin (HE) staining. Results indicated that OT alleviated VCR-induced neurite damage in cultured primary DRG neurons in vitro. In vivo, OT ameliorated VCR-induced hyperalgesia. Histologically, OT attenuated the VCR-induced damages of nerve endings, myelin sheaths and Schwann cells in sciatic nerve and DRG. These effects were antagonized by atosiban. In addition, OTR knockout mice exhibited more severe hyperalgesia than wild-type mice. Globally, these results indicated that OT may have neuroprotective effects on vincristine-induced neurotoxicity in mice.

RQ-00434739, a novel TRPM8 antagonist, inhibits prostaglandin E2-induced hyperactivity of the primary bladder afferent nerves in rats.

AIMS: To examine the effects of RQ-00434739, a novel selective TRPM8 antagonist, on deep body temperature (DBT) and normal bladder sensory function and overactivity and its associated facilitation of mechanosensitive primary bladder single-unit afferent activities (SAAs) induced by intravesical l-menthol or prostaglandin E2 (PGE2) instillation in rats. MAIN METHODS: The effect of RQ-00434739 on DBT was evaluated using intravenous administration of RQ-00434739 (1 mg/kg) or its vehicle under urethane anaesthesia. Cystometry (CMG) was performed on conscious and freely moving rats. SAAs were measured from the left L6 dorsal root under urethane anaesthesia, and the fibers were grouped as Aδ- or C-fiber based on their conduction velocity. For both CMG and SAA measurements, after baseline recording with saline instillation, further recording was performed with intravesical l-menthol (6 mM) or PGE2 (60 µM) instillation after pretreatment with intravenous RQ-00434739 (1 mg/kg) or its vehicle. KEY FINDINGS: RQ-00434739 did not significantly affect DBT. In CMG measurements, RQ-00434739 administration increased mean voided volume. Both l-menthol and PGE2 instillation decreased mean voided volume following vehicle pretreatment, whereas such effects were not observed following RQ-00434739 pretreatment. In SAA measurements, either l-menthol or PGE2 instillations increased SAAs of C-fibers, but not SAAs of Aδ-fibers, in the presence of vehicle. RQ-00434739 pretreatment significantly inhibited the l-menthol- and PGE2-induced activation of C-fiber SAAs. SIGNIFICANCE: The present results demonstrate that blockade of TRPM8 channels can inhibit the pathological activation of mechanosensitive C-fibers and suggest that RQ-00434739 may be a promising therapeutic drug candidate for bladder hypersensitive disorders without affecting DBT.

Preclinical toxicity screening of intrathecal oxytocin in rats and dogs.

BACKGROUND: Anatomic, physiologic, and behavioral studies in animals suggest that spinally released oxytocin should produce analgesia in humans and may also protect from chronic pain after injury. In this article, the authors report preclinical toxicity screening of oxytocin for intrathecal delivery. METHODS: Intrathecal oxytocin, 11 µg (6 U) or vehicle, was injected intrathecally in 24 rats, followed by frequent behavioral assessment and histologic examination of spinal contents 2 or 14 days after injection. In three dogs, a range of intrathecal oxytocin doses (18 to 550 µg in 0.5 ml) was injected followed by physiologic, biochemical, and behavioral assessments. Ten dogs were then randomized to receive five daily injections of intrathecal oxytocin, 550 µg in 0.5 ml, or vehicle with similar assessments and, necropsy and histologic analysis were conducted 2 days later. RESULTS: In rats, intrathecal oxytocin resulted in transient scratching and itching behaviors, without other differences from vehicle. There was no behavioral, gross anatomic, or histologic evidence of neurotoxicity. Dose ranging in dogs suggested mild effects on motor tone, blood pressure, and heart rate at the 550 µg dose. Repeated boluses in dogs did not produce behavioral, biochemical, neurological, gross anatomic, or histologic evidence of neurotoxicity. CONCLUSIONS: Substances, including natural neurotransmitters, may be toxic when administered in pharmacologic doses in the spinal cord. This preclinical toxicity screen in two species suggests that bolus injections of oxytocin in concentrations up to 1,100 µg/ml are unlikely to cause neurotoxicity. The authors also support cautious clinical application of intrathecal oxytocin under regulatory supervision.

Repeated intranasal oxytocin administration in early life dysregulates the HPA axis and alters social behavior.

Agonistic interactions are a powerful stressor. Conversely, positive social interactions can reduce the adverse effects of social stress. This possibly occurs through the action of oxytocin (OT), a neuropeptide able to reduce activation of the hypothalamo-pituitary-adrenal (HPA) axis. We hypothesized that repeated OT intranasal administration to neonatal pigs could provide long-lasting protective effects against social stress. In each of six litters, two pigs per litter received 0.5 mL of saline containing 24 IU (or 50 µg) of OT intranasally and two control littermates received 0.5 mL of saline as a control at 1, 2 and 3 days of age. Contrary to our predictions, when socially mixed after weaning at 17 days of age, neonatally OT-administered pigs received more aggressive interactions and performed more aggressive interactions in return, showed greater locomotion, spent less time in social contact, and had greater cortisol concentrations than control pigs. When this social mixing was repeated at 8 weeks of age, OT pigs still performed more aggressive interactions and had greater adrenocorticotropic hormone concentrations than control pigs. A dexamethasone suppression test and corticotropic releasing hormone administration challenge at 11 weeks of age revealed that OT pigs were less responsive to dexamethasone than control pigs, suggesting a deficient HPA axis' negative feedback control. Postnatal repeated OT administration altered social behavior and resulted in a long-term dysregulation of the HPA axis. These findings highlight the complex, fine-tuning of the neurobiological mechanisms regulating the development of social behavior and suggest caution in the application of neonatal peptide treatments during early development.

Further validation of a model of fibromyalgia syndrome in the rat.

UNLABELLED: We have recently developed an animal model of fibromyalgia syndrome in the rat. In this model, rats exposed to unpredictable sound stress develop a delayed onset enhancement and prolongation of cytokine-induced mechanical hyperalgesia in muscle and skin. In this study, we tested the hypothesis that our model also manifests symptoms of common comorbid diagnoses: irritable bowel syndrome, temporomandibular disorder, and anxiety. Both visceral sensitivity and cytokine hyperalgesia in masseter muscle were present in the stressed rats. Furthermore, in an established model of irritable bowel syndrome-water avoidance-we observed significant muscle hyperalgesia. Finally, using the elevated plus maze to assess for anxiety level, we observed a significantly higher anxiety level in sound stress-exposed rats. Thus, unpredictable sound stress produces a condition in the rat with several features-delayed onset visceral and temporomandibular hyperalgesia and increased anxiety, as well as cutaneous and muscle hyperalgesia-commonly found in patients with fibromyalgia syndrome. PERSPECTIVE: A stress model-unpredictable sound-in the rat exhibits several features (cutaneous, musculoskeletal, and visceral hyperalgesia, as well as anxiety) that are found in patients with fibromyalgia syndrome. Thus, this model may be used to test hypotheses about the underlying mechanisms and response to therapy in patients with fibromyalgia.

Moebius syndrome and holoprosencephaly following exposure to misoprostol.

Moebius syndrome is a rare disease characterized by congenital facial paralysis and abducens palsy. Involvement of other cranial nerves, orofacial dysmorphism, and limb abnormalities are frequently associated. Reported here is the case of a 10-month-old child born with Moebius syndrome and presenting with holoprosencephaly, following exposure in utero to misoprostol. To our knowledge, this is the first published case report describing this association. The etiologic hypotheses of Moebius syndrome are also discussed.

In vitro determination of the mechanism of the uterine stimulatory effect of Newbouldia laevis.

The uterine stimulatory effect of the ethanol leaf extract of Newbouldia laevis (Beauv.) Seemann ex Bureau (Bignoniaceae) was evaluated in the presence of some antagonists in vitro in an attempt to elucidate the mechanism of action of the extract. The extract was tested in the presence and absence of phentolamine (4.09 and 40.91 nM), diphenhydramine (4.45 and 44.47 nM), atropine (1.18 and 11.91 nM), and verapamil (2.03 and 20.35 nM). The effect of the antagonists on the extract and on oxytocin used as a reference drug in this study was evaluated. The EC(50) and E(max) were determined and statistically analyzed using one way ANOVA and Dunnett's post hoc test. There was no significant difference in the EC(50) and E(max) of the extract and oxytocin in the presence of phentolamine. Diphenhydramine and atropine significantly inhibited (p <0.01) the extract but both drugs had no effect on oxytocin. However, significant differences (p <0.01) were observed in the EC(50) and E(max) of the extract and oxytocin in the presence of verapamil. These results suggest that the leaf extract of N. laevis contracts the uterus by opening voltage-operated calcium channels and/or by activation of muscarinic receptors.

Safety and efficacy of blue cohosh (Caulophyllum thalictroides) during pregnancy and lactation.

BACKGROUND: There is a lack of basic knowledge on the part of both clinicians and patients as to the indications for use and safety of herbal medicines in pregnancy and lactation. This is one article in a series that systematically reviews the evidence for commonly used herbs during pregnancy and lactation. OBJECTIVES: To systematically review the literature for evidence on the use, safety and pharmacology of blue cohosh, focusing on issues pertaining to pregnancy and lactation. METHODS: We searched 7 electronic databases and compiled data according to the grade of evidence found. RESULTS: According to a survey of midwives in the United States, approximately 64% of midwives reported using blue cohosh as a labour-inducing aid. There are three case reports in the scientific literature that blue cohosh taken at the time of delivery may cause; 1) perinatal stroke, 2) acute myocardial infarction, profound congestive heart failure and shock and 3) severe multi-organ hypoxic injury. There is one case report that blue cohosh possesses abortifacient properties. There is in vitro evidence that blue cohosh may have teratogenic, embryotoxic and oxytoxic effects. In lactation, the safety of blue cohosh is unknown. CONCLUSIONS: Based on the available scientific information, blue cohosh should; 1) be used with extreme caution during pregnancy, 2) be used only under medical professional supervision and 3) not be available to the public as an over-the-counter product. There is an urgent need to conduct a retrospective or prospective cohort study of midwifes using blue cohosh in order to determine its safety. Key words: Blue cohosh, caulophyllum thalictroides, pregnancy, lactation, breastfeeding, systematic review.

Safety and efficacy of chastetree (Vitex agnus-castus) during pregnancy and lactation.

BACKGROUND: There is a lack of basic knowledge on the part of both clinicians and patients as to the indications for use and safety of herbs used during pregnancy and lactation. This is one article in a series that systematically reviews the evidence for herbs commonly used during pregnancy and lactation. OBJECTIVES: To systematically review the literature for evidence on the use, safety and pharmacology of chastetree, focusing on issues pertaining to pregnancy and lactation. METHODS: We searched 7 electronic databases and compiled data according to the grade of evidence found. RESULTS In pregnancy, there is poor evidence based on theoretical and expert opinion and in vitro studies that chastetree may have estrogenic and progesteronic activity, uterine stimulant activity, emmenagogue activity and prevent miscarriages. In lactation, theoretical and expert opinion conflict as to whether chastetree increases or decreases lactation. CONCLUSIONS: Given its relatively common use amongst women of childbearing age, it is likely that some women may consume chastetree while unknowingly pregnant. Complementary and alternative medicine, midwifery and medical practitioners should be aware of this fact when prescribing chastetree to women of childbearing age, particularly when the patient is planning a family. Key words: Chastetree, vitex agnus-castus, pregnancy, lactation, breastfeeding, systematic review.

Continuous infusion of PGE2 is catabolic with a negative bone balance on both cancellous and cortical bone in rats.

It is well documented that intermittent PGE(2) treatment increases both trabecular and cortical bone mass. However, the effects of continuous PGE(2) administration remain undocumented. The aim of the study was to investigate the effects of continuous prostaglandin E(2) (PGE(2)) on different bone sites in skeletally mature rats. Six-month-old Sprague Dawley rats were treated with PGE(2) at 1 or 3 mg/kg/d continuously via infusion pump for 21 days. Two other groups of rats received PGE(2) at the same doses by intermittent (daily) subcutaneous injections and served as positive controls. Histomorphometry was performed on cancellous bone of the proximal tibial metaphysis and cortical bone of the tibial shaft. As expected, intermittent PGE(2) treatment increased both cancellous and cortical bone mass by stimulating bone formation at the cancellous, periosteal and endocortical bone surfaces. In contrast, continuous PGE(2) treatment decreased cancellous bone mass with bone resorption exceeding bone formation. In addition, continuous PGE(2) treatment increased endocortical and intracortical bone remodeling, inducing bone loss which was partially offset by stimulating periosteal expansion. We conclude that continuous PGE(2) treatment induces overall catabolic effects on both cancellous and cortical bone envelopes, which differs from intermittent PGE(2) treatment that is anabolic. Lastly, we speculate that superior bone mass may be achieved by co-treatment of continuous PGE(2) in combination with an anti-catabolic agent.

Leminoprazole protects cultured gastric mucosal cells against damage caused by ethanol, indometacin and taurocholate.

We examined whether or not leminoprazole (an acid pump inhibitor) protects cultured rabbit gastric mucosal cells against various forms of cell damage. Exposure of mucosal cells to ethanol, indometacin or taurocholate for 1 h caused a reduction in their viability. Pretreatment of the cells with leminoprazole for 2 h concentration-dependently and significantly prevented the viability loss induced by each noxious agent, although the drug alone did not affect cell viability. Cytoprotection by leminoprazole was expressed after a 2-hour lag period. The effects of leminoprazole were potently inhibited by cycloheximide and actinomycin D. These results indicate that leminoprazole directly acts on gastric mucosal cells, making the cells resistant to damage, and that its cytoprotection might be mediated through de novo synthesized proteins.

Potentiation by indomethacin of receptor-mediated catecholamine secretion in rat adrenal medulla.

Effects of indomethacin on catecholamine secretion evoked by receptor agonists, muscarine, bradykinin or histamine, in rat adrenal chromaffin cells were studied. Indomethacin at 200 microM increased a sustained component of secretion during stimulation with muscarine, bradykinin and histamine by a factor of 2.3, 2.1 and 2.9, respectively, whereas it did not significantly alter basal, high-K(+)- and nicotine-evoked secretions. Although indomethacin at above 400 microM dose-dependently increased basal secretion, the amount of secretion induced by indomethacin alone was much smaller than that in muscarine-evoked secretion as compared at the same concentration of indomethacin applied. Bradykinin-evoked secretion and its potentiation by indomethacin were not inhibited by 20 microM nifedipine but were suppressed by 0.5 mM Ni2+. The cyclooxygenase inhibitor, ibuprofen (200 microM) did not mimic the effect of indomethacin; prostaglandin E2 (20 microM) and arachidonic acid (100 microM) did not significantly alter either bradykinin-evoked secretion itself or its potentiation by indomethacin. Bradykinin increased the intracellular free Ca2+ concentration, [Ca2+]i, in cells loaded with indo-1, and this response was enhanced in the presence of indomethacin. These results suggest that indomethacin may promote Ca2+ entry to potentiate agonist-evoked catecholamine secretions through a novel action that is not directly related to the inhibition of cyclooxygenase activity with indomethacin.

Effects of baicalein on prostanoid generation from the lung and contractile responses of the trachea in guinea pig.

Effects of baicalein on release of slow reacting substance of anaphylaxis (SRS-A) or leukotriene (LT) from the sensitized guinea pig lung after antigen challenge and tonus of guinea pig tracheal muscles were studied. Baicalein inhibited release of SRS-A from sensitized guinea pig lung after antigen challenge. High-performance liquid chromatography (HPLC) analysis revealed that released SRS-A consisted to LTC4 and D4. Baicalein also reduced release of LTC4 and D4 from the sensitized lung after antigen challenge. Baicalein relaxed the isolated guinea pig tracheal smooth muscle contracted by LTD4, carbachol or histamine. However, this compound produced a contraction when the tracheal muscle was contracted by prostaglandin F2 alpha(PGF2 alpha). This contraction by baicalein was abolished by pretreatment with indomethacin, a cyclooxygenase inhibitor. Baicalein elicited a relaxation in the normal non-sensitized preparation but a contraction in the tissue isolated from actively sensitized guinea pig in 4 among 7 cases. Baicalein also produced a contraction in the trachea pretreated with phorbol dibutyrate and contracted by carbachol, which was eliminated after treatment with indomethacin. The results suggest that baicalein exerts action via, at least, two different mechanisms, the inhibition of releasing SRS-A (LTs) and direct relaxing effects on the trachea. Besides, baicalein seems to produce contraction under certain conditions, which may involve stimulation of the cyclooxygenase pathway.