Analgesia additive interaction between tadalafil and morphine in an experimental animal model.

Since both morphine and tadalafil have been proven to exert some of their analgesic activity through modulation of the NO-cGMP pathway, the aim of the current study is to evaluate the pharmacologic interaction between tadalafil and morphine to decrease the dose of morphine and subsequently its side effects. The assessment was carried out through isobolographic analysis relative to ED50s of both morphine and tadalafil obtained by tail-flick test on BALB/c mice. Morphine and tadalafil ED50s calculated from the dose-response curves were 8303 and 2080 µg/kg, respectively. The experimental ED50 values of morphine and tadalafil in their mixture were 4800 and 1210 µg/kg, respectively. Those results showed an additive interaction between morphine and tadalafil presented by a total fraction value for the mixture of 1160 µg/kg. This outcome can be interpreted by the fact that both drugs share common pathways, namely, NO-cGMP and opioid receptors. As a conclusion, the morphine and tadalafil combination showed an additive effect against acute pain, which is mediated through the central nervous system, thus providing a rationale for combining them to decrease morphine dose and thus minimizing its side effects.

Antinociceptive effect of tadalafil in various pain models: Involvement of opioid receptors and nitric oxide cyclic GMP pathway.

Nitric oxide has been proven to play an important role in nociception, accordingly, its promoters, phosphodiesterase inhibitors have been investigated as pain response modulators. Aiming to evaluate the central antinociceptive effect of tadalafil, a phosphodiesterase 5 inhibitor, and to determine its EC50, tail flick and hot plate tests were employed. On the other hand, tadalafil antinociceptive peripheral effect was assessed through acetic acid-induced writhing model. Formalin test was used to appraise both non-inflammatory and inflammatory pain responses. In order to elaborate the involvement of opioid receptors and nitric oxide/cyclic guanosine monophosphate/potassium-ATP pathway in tadalafil-induced analgesia, mice were pretreated with naloxone, l-nitro-arginine-methyl-ester (l-NAME), methylene blue, and glibenclamide. The results illustrated that tadalafil had a significant antinociceptive effect in the tail flick, hot plate, acetic acid-induced writhing and formalin tests indicating the involvement of peripheral and central analgesic mechanisms. Moreover, tadalafil mechanism of action involved several receptors and mediators, specifically NO/cGMP pathway and opioid receptors. In the formalin test, naloxone significantly blocked the effect of tadalafil in the first phase and partially in the second phase which is an inflammatory pain-dependent aspect. l-NAME, methylene blue and glibenclamide partially blocked the effect of tadalafil in the first phase and enhanced its effect in the second phase which is related to nitric oxide role in the inflammatory process. As a conclusion, tadalafil possesses a potential analgesic effect via the involvement of opioid and nitric oxide pathways.

Investigation of chronic efficacy and safety profile of two potential anti-inflammatory bipyrazole-based compounds in experimental animals.

PURPOSE: Although nonsteroidal anti-inflammatory drugs are widely used to treat a variety of disorders, their administration is associated with gastrointestinal side effects, acute kidney injury and liver enzymes' elevation. Accordingly, researchers are encouraged to create novel agents with better safety profile. The aim of the current study was to evaluate the chronic efficacy and safety profile of two compounds previously proven to have acceptable acute anti-inflammatory and analgesic activities. MATERIALS AND METHODS: Doses were determined through formalin-induced mice paw edema-based dose-response curves. Granuloma weight was used to assess the chronic effect of the investigated compounds as compared to the vehicle and diclofenac representing the positive and the negative controls, respectively. Mice kidneys, livers and stomachs were histologically examined. Moreover, troponin I, alanine aminotransferase, aspartate aminotransferase, serum creatinine and blood urea nitrogen levels were measured. RESULTS: The results highlight that the granulomas and exudates developed in mice after 7 days of treatment, with compound I and compound II were significantly lower than that of the negative control group. Moreover, compound I showed significantly better anti-inflammatory effect than diclofenac. Troponin level was undetected in all groups. Histopathological examination of the stomach revealed normal mucosa for both tested compounds and controls. Likewise, kidneys showed neither significant histologic alteration nor biomarkers increase as compared to the control over both 7- and 30-day treatment periods. Mice that received the tested compounds or diclofenac exhibited transient liver damage specifically; congestion, vacuolization, necrosis and inflammation after 7 days of treatment which decreased significantly after 30 days of treatment as emphasized by the Suzuki score and biomarker levels. CONCLUSION: Since the tested compounds, specifically compound I, presented a satisfactory chronic safety profile as well as anti-inflammatory effect, it is worth conducting further molecular pharmacological, toxicological and bioavailability studies to elucidate the efficacy of these potential anti-inflammatory bipyrazole compounds.

Comparative study on the effect of cinnamon and clove extracts and their main components on different types of ATPases.

The effect of the commonly used spice extracts cinnamon and clove and their main ingredients on the activity of various ATPases were investigated. Water extracts of both spices inhibited the activity of rat liver Na+/K+ ATPase, and Cu2+-ATPase, but stimulated F0F1ATPase. Similar effects were obtained with cinnamaldehyde and eugenol the major components of cinnamon and clove, respectively with eugenol being more potent. The 50% inhibition of the P-type Na+/K+ ATPase was obtained at 4.7 +/- 0.04 mM for cinnamaldehyde and 1.1 +/- 0.02 mM for eugenol. The 50% inhibition of the CPx-type Cu2+ ATPase was obtained at 0.94 mM for cinnamaldehyde and 0.65 mM for eugenol. On the other hand both compounds stimulated significantly the mitochondrial F0F1ATPase. The shared structural and functional similarities between the P- and the CPx-classes of ATPases may underlie the common effect exhibited by both but not the F-ATPase. Our results identify Na+/K+ ATPase, Cu2+-ATPase and F0F1ATPase as possible intracellular targets for the action of spices' components that result in: a decrease in ATP level, defects in proton and ion transports leading to electrolyte imbalance and derangements in mitochondrial function.

Fragrance chemicals lyral and lilial decrease viability of HaCat cells' by increasing free radical production and lowering intracellular ATP level: protection by antioxidants.

We investigate in this study the biochemical effects on cells in culture of two commonly used fragrance chemicals: lyral and lilial. Whereas both chemicals exerted a significant effect on primary keratinocyte(s), HaCat cells, no effect was obtained with any of HepG2, Hek293, Caco2, NIH3T3, and MCF7 cells. Lyral and lilial: (a) decreased the viability of HaCat cells with a 50% cell death at 100 and 60 nM respectively; (b) decreased significantly in a dose dependant manner the intracellular ATP level following 12-h of treatment; (c) inhibited complexes I and II of electron transport chain in liver sub-mitochondrial particles; and (d) increased reactive oxygen species generation that was reversed by N-acetyl cysteine and trolox and the natural antioxidant lipoic acid, without influencing the level of free and/or oxidized glutathione. Lipoic acid protected HaCat cells against the decrease in viability induced by either compound. Dehydrogenation of lyral and lilial produce α,ß-unsaturated aldehydes, that reacts with lipoic acid requiring proteins resulting in their inhibition. We propose lyral and lilial as toxic to mitochondria that have a direct effect on electron transport chain, increase ROS production, derange mitochondrial membrane potential, and decrease cellular ATP level, leading thus to cell death.

Atypical systemic leishmaniasis to be considered in the differential of patients presenting with depressed immunity.

BACKGROUND: Systemic leishmaniasis has been known to present with prolonged fever, hepatosplenomegaly and wasting. Beside this classical form, a sub-clinical form has been identified. It is described with either one or two of the above symptoms missing; other findings have been reported instead, such as lymphadenopathy and anemia. In this report, we reveal a third unsuspected form which we are referring to as "atypical". METHODOLOGY/PRINCIPAL FINDINGS: Patients suspected to be immune-deficient were referred to our immunology specialized laboratory to study some aspects of their immune functions (not normally covered in the general laboratory). Multiple specialized tests were performed, including microscopic examinations using appropriate stains, and mainly cultures of biopsies on several types of specialized media. 19·4% of 160 patients were found to have close to normal laboratory profiles, but exhibited dysfunctional macrophages laden with Leishmania parasites. CONCLUSIONS/SIGNIFICANCE: Findings such as the ones we obtained allowed us to uncover the presence of patients with an atypical form of systemic leishmaniasis. It presents with symptoms masquarading a condition in which the immune system is non functional. This predisposes patients to recurrent secondary infections resulting in clinical pictures with a great variety of signs and symptoms. These findings alerted us to the fact that systemic leishmaniasis presents with a much wider spectrum of signs and symptoms than so far suspected and is far more common than diagnosed to date. Furthermore, among these 31 patients was a number of adults. This proved that in our area systemic leishmaniasis is surely not limited to the pediatric age group. Our recommendation is to entertain the diagnosis of atypical systemic leishmaniasis in any patient with an unexplained depressed immunity state and in whom no obvious immunologic defect can be identified.

Detection of Leishmania parasites in the blood of patients with isolated cutaneous leishmaniasis.

BACKGROUND: The consequences of the spread of Leishmania parasites to the blood from lesions in patients with cutaneous leishmaniasis are numerous. To assess the magnitude of this invasion we conducted the present study on patients referred to the American University of Beirut Medical Center for cutaneous leishmaniasis. METHODS: Patients referred for the management of cutaneous leishmaniasis were included in the study. Skin and blood cultures for Leishmania were taken from these patients. RESULTS: One hundred sixty-two patients were proven to have cutaneous leishmaniasis by pathology; 52% were males and 44% females (gender information was missing for 4%). Patient age ranged from 5 months to 70 years. None of the patients had received treatment for Leishmania. We obtained parasite isolates from 85 patients (52.5%), proven by cultures from skin and blood/blood components. Interestingly, the parasite was isolated in the blood and blood components of 50 patients (30.9%). Isoenzyme analysis confirmed the fact that the organisms in blood and skin were the same; from the 28 isolates that were positive in both skin and blood, eight isolates were Leishmania major and two were Leishmania tropica. The remaining isolates, whether positive in both blood and skin or in either of these tissues, skin or blood and its products, were Leishmania infantum sensu lato. CONCLUSIONS: In the current study, the detection rate of parasites in the blood of patients with cutaneous leishmaniasis was high. This illustrates the invasive characteristic of the parasite that has escaped the skin. Testing should be considered in areas other than Lebanon, especially around the Mediterranean basin. Whether these findings support the administration of systemic treatment for cutaneous leishmaniasis or not needs to be confirmed in larger prospective studies.