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The aim of this study was to evaluate the relaxant and anti-inflammatory effects of two thalidomide analogs as phosphodiesterase-4 (PDE-4) inhibitors in pregnant rat uterus. Uteri from Wistar female rats were isolated at 19 day of pregnancy. Uterine samples were used in functional studies to evaluate the inhibitory effects of the thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe), on prostaglandin-F2α (PGF2α)-induced phasic, K + -induced tonic, and Ca 2+ -induced contractions. Accumulation of cAMP was quantified in uterine homogenates by ELISA. Anti-inflammatory effect was assessed by using ELISA for determination of the pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin (IL)-1β, and anti-inflammatory IL-10, from uterine explants stimulated with lipopolysaccharide (LPS). Nifedipine, forskolin and rolipram were used as positive controls where required. Both thalidomide analogs induced a significant inhibition of the uterine contractions induced by the pharmaco- and electro-mechanic stimuli. Nifedipine and forskolin were more potent than the analogs to inhibit the uterine contractility, but these were more potent than rolipram, and 4APDPMe was equieffective to nifedipine. Thalidomide analogs increased uterine cAMP-levels in a concentration-dependent manner. The LPS-induced TNFα and IL-1β uterine secretion was diminished in a concentration-dependent fashion by both analogs, whereas IL-10 secretion was increased significantly. The thalidomide analogs induced utero-relaxant and anti-inflammatory effects, which were associated with the increased cAMP levels as PDE-4 inhibitors in the pregnant rat uterus. Such properties place these thalidomide analogs as potentially safe and effective tocolytic agents in a field that urgently needs improved pharmacological treatments, as in cases of preterm labor., Competing Interests: CONFLICTS OF INTEREST: The authors declare no conflicts of interest.

Uterine relaxation is crucial during preterm labor. Phosphodiesterase-4 (PDE-4) inhibitors have been proposed as tocolytics. Some thalidomide analogs are PDE-4 inhibitors. The aim of this study was to assess the uterus-relaxant properties of two thalidomide analogs, methyl 3-(4-nitrophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4NO2PDPMe) and methyl 3-(4-aminophthalimido)-3-(3,4-dimethoxyphenyl)-propanoate (4APDPMe) and were compared to rolipram in functional studies of spontaneous phasic, K⁺-induced tonic, and Ca 2+ -induced contractions in isolated pregnant human myometrial tissues. The accumulation of cAMP was quantified in HeLa cells. The presence of PDE-4B2 and phosphorylated myosin light-chain (pMLC), in addition to the effect of thalidomide analogs on oxytocin-induced pMLC, were assessed in human uterine myometrial cells (UtSMCs). Thalidomide analogs had concentration-dependent inhibitory effects on spontaneous and tonic contractions and inhibited Ca 2+ -induced responses. Tonic contraction was equipotently inhibited by 4APDPMe and rolipram (IC 50 = 125 ± 13.72 and 98.45 ± 8.86 µM, respectively). Rolipram and the thalidomide analogs inhibited spontaneous and tonic contractions equieffectively. Both analogs increased cAMP accumulation in a concentration-dependent manner ( p < 0.05) and induced changes in the subcellular localization of oxytocin-induced pMLC in UtSMCs. The inhibitory effects of thalidomide analogs on the contractions of pregnant human myometrium tissue may be due to their PDE-4 inhibitory effect and novel mechanism as calcium-channel blockers.

Aloysia triphylla is traditionally utilized for the treatment of menstrual colic (primary dysmenorrhea) in Mexico. Citral is the main chemical component found in Aloysia triphylla leaves extract. Primary dysmenorrhea is a very frequent gynecological disorder in menstruating women, affecting 30-60% of them. It is usually treated with non-steroidal anti-inflammatory drugs (NSAIDs); although their effect is rapid, they possess many side effects. Due to these shortcomings, Mexican folk therapy is considered as a feasible alternative. The effects of the hexane extract of Aloysia triphylla and citral on uterine contractions were evaluated in vitro as well as their anti-inflammatory properties and gastric wound capabilities were assessed in vivo. The inhibitory effects on the contractions were analyzed using isolated uterus strips from estrogen primed rats. Contractions were induced by KCl 60 mM, oxytocin 10 mIU/mL, charbacol 10 µM and PGF(2α) 5 µM. The anti-inflammatory effect was assessed on carrageenan-induced rat hind paw edema model. The inhibitory concentration-50 (IC(50)) of the hexane extract of Aloysia triphylla upon each contractile response was for KCl 44.73 ± 2.48 µg/mL, oxytocin 42.16 ± 3.81 µg/mL, charbacol 41.87 ± 1.73 µg/mL and PGF(2α) 28.70 ± 2.40 µg/mL in a concentration-dependent way. The extract of Aloysia triphylla produced a significant inhibitory effect on PGF(2α)-induced contraction compared to its inhibitory actions on the others. Citral exhibited the same inhibitory effect on the contraction induced by PGF(2α). The oral administration of the extract (100-800 mg/kg) and citral (100-800 mg/kg) showed anti-inflammatory activity; furthermore, the maximal dose utilized did not produce gastric injury. These results were compared with anti-inflammatory effects and gastric damage produced by 30 mg/kg of indomethacin p.o. The spasmolytic and anti-inflammatory effects support the traditional use of Aloysia triphylla leaves in the treatment of the primary dysmenorrhea in Mexican communities.

Aromadendranes belong to a class of sesquiterpenes present in higher plant essential oils and marine animals. Although the biological activities include antifungal, antibacterial, antiviral, plant growth regulatory, antifeedant, repellent and cytotoxic, there is only one precedent for spasmolytic effects. In a previous report we have shown that the aromadendrene molecule known as spathulenol, isolated from Lepechinia caulescens, efficiently relaxes rat uterus rings and therefore in the present work we describe structure-activity relationships of thirteen aromadendranes, most of them having the trans-fused perhydroazulene skeleton, with spasmolytic activity.

Heliopsis longipes is an herbaceous plant found in Mexico. Heliopsis longipes is traditionally used for its analgesic and anesthetic properties. Plant extracts may represent a therapeutic advantage for the clinical treatment of pain. Therefore, the main objective of this study was to determine the possible antihyperalgesic effect produced by the Heliopsis longipes ethanolic extract (HLEE) in the Hargreaves model of thermal hyperalgesia in the mouse. HLEE was administrated systemically to mice and the antihyperalgesic effect was evaluated using the thermal hyperalgesia test. Oral Administration of HLEE produced a dose-dependent antihyperalgesic effect. Previously, it was reported that Heliopsis longipes extract was able to release GABA in mice temporal cortex slices. Therefore, it is likely that the antihyperalgesic effect observed in our study could result from GABA liberation and its inhibition of excessive excitation of nociceptive circuits in the thalamus and cortex evoked by tissue injury. Our results suggest that HLEE may represent a therapeutic advantage for the clinical treatment of inflammatory pain.

The Casimiroa pringlei essential oil was analyzed to determine its chemical composition. Its effect on rat uterine smooth muscle was studied and compared with verapamil. Pure commercial piperitone, eucalyptol, and alpha-terpineol, the major constituents of C. pringlei essential oil, were tested on the uterine tonic contraction induced by high-potassium depolarizing solution (KCl 60 mM).

Lepechinia caulescens Ortega Epling (Lamiaceae) is a perennial herb used in Mexican folk medicine to treat diabetes, hypertension, gastrointestinal infections, dysmenorrhea and as abortifacient. In this study, a bioassay-guided fractionation of the hexanes extract of the leaves, evaluating the capacity to relax contraction of rat uterus rings induced by KCl (60mM), was made. The results indicated that, from the four isolated terpenes, spathulenol (1) was the most potent spasmolytic agent, followed by methyl 9alpha,13alpha-epidioxyabiet-8(14)-en-18-oate (2), 9alpha-hydroxydehydroabietyl alcohol (4) and dehydroabietic acid (3) studied at 10 and 30 microg/mL. The spasmolytic activity of 1 was totally reverted by addition of increasing extracellular Ca2+ concentrations ([Ca2+]o), while incubation of uterus rings with 1 in calcium free solutions reduced the contraction produced by [Ca2+]o in a concentration-dependent manner. Moreover, the presence of L-NAME (100 microM) or propranolol (10 microM) did not block the spasmolytic effect. These results suggest that 1 induces a greater blocking action on voltage-operated calcium channels. EtOAc and MeOH extracts of the leaves, which showed slight relaxing activity, led to 4 and rosmarinic acid (5).

Persistent pulmonary hypertension of the newborn (PPHN) is a cardiopulmonary disorder characterized by systemic arterial hypoxemia secondary to elevated pulmonary vascular resistance with resultant shunting of pulmonary blood flow to the systemic circulation. PPHN is a serious illness that becomes progressively worse and is sometimes fatal. Management of the disease includes treatment of underlying causes, sedation and analgesia, maintenance of adequate systemic blood pressure, and ventilator and pharmacologic measures to increase pulmonary vasodilatation, decrease pulmonary vascular resistance, increase blood and tissue oxygenation, and normalize blood pH. Inhaled nitric oxide (NO) has been one of the latest measures to successfully treat PPHN. If all other treatments fail, extracorporeal membrane oxygenation (ECMO) can be used. Recently, preclinical and clinical studies have demonstrated the utility of the selective inhibitor of phosphodiesterase type 5 (PDE5), sildenafil, in decreasing pulmonary hypertension (HP). Sildenafil was first employed to offset rebound pulmonary hypertension in infants upon withdrawal of NO treatment. Later, several case reports demonstrated the effectiveness of sildenafil in the treatment of PPHN. Two randomized blinded studies with sildenafil in infants with PPHN were published in 2006. In both studies, the patients treated with sildenafil showed a steady improvement in pulse oxygen saturation over time. Likewise, the frequency death was lower in the groups treated with sildenafil. Recent evidence shows the utility of sildenafil in the treatment of PPHN. However, since existing data are limited there is an urgent need for multicenter blinded, placebo controlled, randomized trials.

The aim of this pilot study was to compare the efficacy and tolerability of the non-steroidal anti-inflammatory drug (NSAID), diclofenac (2-(2,6-dichloranilino) phenylacetic acid), for treatment of acute pain originated by lower-limb fracture and surgery, with that of diclofenac plus B vitamins. This clinical trial was single-center, prospective randomized and double-blinded. After giving informed consent, patients with lower-limb closed fractures rated their pain on a 10-cm visual analog scale (VAS). Patients were then randomized to receive 75 mg diclofenac or 75 mg diclofenac plus B vitamins (thiamine, pyridoxine and cyanocobalamin) twice daily (all intramuscularly). Patient evaluations of pain intensity were recorded throughout two periods: twenty-four hours pre-surgically and twenty-four hours postsurgical. Twenty-four hours after the first drug administration, patients underwent elective lower-limb surgery. Standardized general anesthetic techniques were used for all patients. Fourteen patients completed the study. The subjects' assessments of limb pain on the visual analog scale showed a significant reduction from baseline values regardless of the treatment group when surveyed at 12, 24, 36 and 48 hr post operation. All treatments showed a similar profile in pain reduction. There were reports of pain in the administration site, but in general, all the regimens were well tolerated.

It has been shown that the association of opioids analgesic agents with non-steroidal anti-inflammatory drugs (NSAIDs) can increase their antinociceptive activity, allowing the use of lower doses and thus limiting side effects. Therefore, the goal of the present study was to examine the possible pharmacological interaction between acemetacin and two opioids in the Hargreaves model of thermal hyperalgesia in the mouse. Acemetacin, codeine, nalbuphine or fixed-dose ratios acemetacin-codeine and acemetacin-nalbuphine combinations were administrated systemically to mice and the antihyperalgesic effect was evaluated using the thermal hyperalgesia test. All treatments produced a dose-dependent antihyperalgesic effect. ED40 values were estimated for all the treatments and an isobologram was constructed. The derived theoretical ED40 for the acemetacin-codeine and acemetacin-nalbuphine combinations were 55.9+/-4.9 mg/kg and 40.3+/-3.8 mg/kg, respectively, being significantly higher than the actually observed experimental ED40, 14.5+/-1.7 mg/kg and 12.7+/-2.2 mg/kg, respectively. These results correspond to synergistic interactions between acemetacin and opioids on the Hargreaves model of thermal hyperalgesia. Highest doses of the individual drugs or the combinations did not affect motor coordination in the balancing test on a rota-rod. Data suggest that low doses of the acemetacin-opioids combination can interact synergistically at systemic level and therefore this drugs association may represent a therapeutic advantage for the clinical treatment of inflammatory pain.

This study investigated the effect of an acute bout of exercise (>85% VO2Max) on biochemical, hemodynamic and oxidative stress variables in sedentary and physically active subjects with type 2 diabetes (T2D). Blood measurements were taken before and after a treadmill test on 12 sedentary non-diabetes subjects (ND), 12 sedentary type 2 diabetes (T2S) and 9 physically active T2D subjects (T2DA). T2DS subjects before and after the treadmill test showed a higher plasma glucose (123.2 +/- 19.0 mg/dL versus 108.9 +/- 16.8 mg/dL, p < 0.001), HbA1C (8.7 +/- 2.4% versus 7.3 +/- 1.2%, p < 0.001) and body fat% (21.3 +/- 5.7% versus 34.6 +/- 4.5%, p < 0.001) than T2DA subjects. T2DA had higher VO2Max (37.7 +/- 3.5 versus 29.5 +/- 3.2, p < 0.05), time on treadmill (22.3 +/- 2.1 min versus 16.1 +/- 2.1 min, p < 0.05), hemoglobin (17.9 +/- 0.9 g/dL, p < 0.05) and lower blood pressure levels in comparison to ND and T2DS subjects. Thiobarbituric acid substances (TBARS) in T2DS were higher than in T2DA subjects (0.27 +/- 0.1 nmol/mL versus 0.21 +/- 0.1 nmol/mL, p < 0.05). Glutathione (GSH) levels were similar among the groups. Physically active type 2 diabetes subjects had a more favorable biochemical, hemodynamic and oxidative stress profile than sedentary subjects. The coexistence of a poor cardiopulmonary performance and high oxidative stress environment can determine a profile of high risk for serious cardiovascular events in patients with diabetes.

Dysmenorrhea is defined as cramping pain in the lower abdomen occurring just before or during menstruation. Non-steroidal anti-inflammatory drugs (NSAIDs) are the mainstay of treatment, with the addition of oral contraceptive pills when necessary. With the widespread availability of over-the-counter NSAIDs, it is often assumed that women are treating themselves adequately. Unfortunately, this is not always the case. Therefore we evaluated the use of drugs for treating primary dysmenorrhea in Mexican students. A multiple-choice questionnaire was administered to 285 psychology students (20.6 +/- 2.4 yrs; range, 17-33 yrs), to assess the prevalence of dysmenorrhea and medications employed. The reported prevalence of dysmenorrhea among these women was 67%. Dysmenorrhea was mild in 34% moderate in 43% and severe in 21%. Of the dysmenorrheic sample, only 33.5% consulted physician in 2.6 +/- 0.2 cycles per year for their problem and the most common prescriptions were an over-the-counter medication with paracetamol pamabrom and pyrilamine maleate (Syncol; 22.4%) naproxen (18.4%), metamizole plus butylhyoscine bromide (10.2%), ibuprofen (6.1%) and butylhyoscine bromide (6.1%). On the other hand, self-medication was practiced by 64.9% of the women with dysmenorrhea in 6.1 +/- 3.8 cycles per year and the most common drugs by self-medication were Syncol (35.5%), naproxen (16.9%), metamizole plus naproxen butylhyoscine bromide (13.7%), an over-the-counter medication with adiphenine and propyphenazon (Espasmo-cibalgina; 10.5%), paracetamol (5.6%) butylhyoscine alone (4%) and ibuprofen (4%). Our data suggest that dysmenorrheic women use numerous drugs by self-medication for pain but infrequently accessed formal medical care.

Objectives: The primary was to assess the frequency of therapeutic non-compliance due to ADRs in a cohort of patients with recently diagnosed systemic hypertension. The secondary objectives were to evaluate the blood pressure control during the follow-up in the whole cohort and in patients who received non-steroidal anti-inflammatory drugs (NSAIDs)., Methods: A cohort of 73 recently diagnosed ambulatory hypertensive patients was followed-up for 6 months. Validated questionnaires for identification of therapeutic scheme changes and ADRs were applied monthly, during each medical visit., Results: Family physicians selected monotherapy in 79% of patients. The frequency of therapeutic non-compliance was 44%; non-compliance secondary to ADR was 7%. Systolic and diastolic blood pressure at the beginning of the study were 140 +/- 15/90 +/- 15 mm Hg for the whole cohort. At the end of the study the figures were 130 +/- 11/85 +/- 6 (p < 0.001). Patients receiving non-steroidal anti-inflammatory drugs (NSAIDs) had higher blood pressure levels than the groups of patients not receiving such kind of drugs (134 +/- 10 vs. 128 +/- 8 mm Hg, p = 0.025 and 88 +/- 7 vs. 83 +/- 5 mm Hg, p = 0.05)., Conclusions: The drugs used in the present study as monotherapy are considered acceptable choices for hypertension treatment. The frequency of therapeutic non-compliance was within the limits reported in the literature and the frequency of therapeutic non-compliance secondary to ADRs in this cohort was lower than that reported in the literature. Higher blood pressure was found in the group of patients receiving NSAIDs.

There is evidence that local peripheral administration of codeine and morphine produces antinociception through the activation of the ATP-sensitive K(+)-channel. Therefore we evaluated the participation of this channel in the antinociceptive action produced by nalbuphine in the formalin test. Female Wistar rats (160-200 g) were injected in the dorsal surface of the right hind paw with 50 microl of formalin (5%). Nociception was quantified as the number of flinches of the injected paw during 1 hr, whereas a reduction of the number of flinches was considered antinociception. Rats received a s.c. injection (50 microl) into the dorsal surface of the right hind paw of vehicle or increasing doses of nalbuphine (100-400 microg/paw) 20 min before formalin injection into the ipsilateral paw. To determine whether nalbuphine-induced peripheral antinociception was mediated by K(+)-channels, the effect of pretreatment (10 min before formalin injection) with the appropriate vehicle or the ATP-sensitive K(+)-channel inhibitor glibenclamide (25-100 microg/paw) on the antinociceptive effect induced by local peripheral nalbuphine (400 microg/paw) was assessed. Morphine was used as positive antinociceptive control. Local peripheral injection of nalbuphine produced a dose-dependent antinociception during both phases of the test. Local pretreatment with glibenclamide prevented nalbuphine-induced antinociception in a dose-dependent fashion in both phases of the test. Our data suggest that nalbuphine activates ATP-sensitive K(+)-channels in order to produce its peripheral antinociceptive effect.

Brickellia paniculata has been used as spasmolytic in Mexican traditional medicine. Xanthomicrol and 3alpha-angeloyloxy-2alpha-hydroxy-13,14Z-dehydrocativic acid (AAHDD) are two of the main leaf components with antispasmodic activity. However, their mechanism of action remains unknown. An in vitro comparative study between xanthomicrol and AAHDD on rat uterus precontracted by either KCl (60 mM) or oxytocin (10 mIU/ml) was carried out to investigate the mechanism of action of these compounds on smooth muscle. Relaxant effect was measured as median inhibitory concentration (IC(50)) and maximal effect as maximal relaxant response (R(max)). Xanthomicrol was significantly more potent than AAHDD in inhibiting contractions induced by KCl 60 mM, whereas AAHDD was more potent than xanthomicrol in inhibiting contractions induced by oxytocin 10 mIU/ml. These results suggest that xanthomicrol induces a greater blocking effect on voltage-operated calcium channels than on receptor-operated gates.

The ovarian steroids regulate the sensitivity of a population of uterine receptors to prostaglandin F(2alpha), serotonin and oxytocin. However, the uterine sensitivity to prostaglandin F(2alpha) and oxytocin does not coincide with the estrogen-induced increase in the number of receptors. Anatomical differences affect the uterine sensitivity to agonists. We investigated whether anatomical differences between ovarian and cervical uterine regions modulate the hormone-regulated sensitivity to prostaglandin F(2alpha), serotonin and oxytocin. Non-cumulative concentration-response curves for these agonists were recorded for ovarian and cervical uterine segments from adult ovariectomized rats treated with 17beta-estradiol, 17beta-estradiol+progesterone, or vehicle. The ovarian segments displayed a higher maximal response (E(max)) to prostaglandin F(2alpha) and a lower E(max) to serotonin than the cervical segments. Both uterine segments displayed a similar sensitivity to oxytocin. The ovariectomized controls displayed the highest E(max) and the lowest effective concentration 50 (EC(50)) for oxytocin and prostaglandin F(2alpha). Anatomical differences between ovarian and cervical uterine regions modulate the hormonal regulation of uterine sensitivity to serotonin and prostaglandin F(2alpha) in the non-pregnant rat uterus.

There is a broad epidemiologic evidence related with the increase of the incidence and prevalence of diabetes mellitus type 2 throughout the world, especially in Western populations, at rates considered epidemic. Cerebrovascular disease and myocardial infarction are two of the most important complications of this disease and they have very high social and economic consequences. Treatment of this disease is directed good metabolic control, diminishing toward obtain co-morbidity, and reducing acute and chronic diabetic complications. Diet, hypoglycemic drugs or insulin, and programs of physical activity are used for this purpose. This document presents some thoughts on the difficulties related with the prescription of physical exercise in the diabetic patient and a brief proposal to solve those problems in the clinical practice.

Oxidative stress has been defined as a loss of counterbalance between free radical or reactive oxygen species production and the antioxidant systems, with negative effects on carbohydrates, lipids, and proteins. It is also involved in the progression of different chronic diseases and apoptosis. Diabetes mellitus is associated to a high oxidative stress level through different biochemical pathways, i.e. protein glycosylation, glucose auto-oxidation, and the polyol pathway, mainly induced by hyperglycemia. Oxidative stress could also be involved in the pathogenesis of atherosclerotic lesions and other chronic diabetic complications. Measurement of oxidative stress could be useful to investigate its role in the initiation and development processes of chronic diabetic complications and also to evaluate preventive actions, including antioxidative therapy. Different attempts have been made to obtain a practical, accurate, specific, and sensitive method to evaluate oxidative stress in clinical practice. However, this ideal method is not currently available to date and the usefulness of the current methods needs to be confirmed in daily practice. We suggest quantifying oxidated and reduced glutation (GSSG/GSH) and the thiobarbituric reactive substances (TBARS) with currently alternatives. Currently available alternative methods while we await better options.