Protective effects of Stephania pierrei tuber-derived oxocrebanine against LPS-induced acute lung injury in mice.

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) have high mortality rates. Though corticosteroids are commonly used for the treatment of these conditions, their efficacy has not been conclusively demonstrated and their use can induce various adverse reactions. Hence, the application of corticosteroids as therapeutic modalities for ALI/ARDS is limited. Meanwhile, the aporphine alkaloid oxocrebanine isolated from Stephania pierrei tubers has demonstrated anti-inflammatory efficacy in murine/human macrophage cell lines stimulated by lipopolysaccharide (LPS). Accordingly, the primary objectives of the present study are to investigate the anti-inflammatory effects of oxocrebanine on LPS-induced murine alveolar epithelial (MLE-12) cells and its efficacy against LPS-induced murine ALI. Results show that oxocrebanine downregulates the abundance of interleukin (IL)-1beta, IL-6, and inducible nitric oxide synthase, as well as the phosphorylation of nuclear factor-kappaB (NF-κB), stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), p38, protein kinase B (Akt), and glycogen synthase kinase-3beta signalling proteins in LPS-induced MLE-12 cells. Moreover, in a murine ALI model, oxocrebanine lowers lung injury scores and lung wet/dry weight ratios while reducing inflammatory cell infiltration. It also suppresses LPS-induced tumour necrosis factor-alpha and IL-6 in the bronchoalveolar lavage fluid and plasma. Moreover, oxocrebanine downregulates NF-κB, SAPK/JNK, p38, and Akt phosphorylation in the lung tissues of LPS-treated mice. Taken together, the foregoing results show that oxocrebanine provides significant protection against LPS-induced ALI in mice primarily by suppressing various inflammatory signalling pathways in alveolar epithelial cells and lung tissues. Hence, oxocrebanine might prove effective as an anti-inflammatory agent for the treatment of lung inflammation.

Distinct AMPK-Mediated FAS/HSL Pathway Is Implicated in the Alleviating Effect of Nuciferine on Obesity and Hepatic Steatosis in HFD-Fed Mice.

Nuciferine (Nuci), the main aporphine alkaloid component in lotus leaf, was reported to reduce lipid accumulation in vitro. Herein we investigated whether Nuci prevents obesity in high fat diet (HFD)-fed mice and the underlying mechanism in liver/HepG2 hepatocytes and epididymal white adipose tissue (eWAT) /adipocytes. Male C57BL/6J mice were fed with HFD supplemented with Nuci (0.10%) for 12 weeks. We found that Nuci significantly reduced body weight and fat mass, improved glycolipid profiles, and enhanced energy expenditure in HFD-fed mice. Nuci also ameliorated hepatic steatosis and decreased the size of adipocytes. Furthermore, Nuci remarkably promoted the phosphorylation of AMPK, suppressed lipogenesis (SREBP1, FAS, ACC), promoted lipolysis (HSL, ATGL), and increased the expressions of adipokines (FGF21, ZAG) in liver and eWAT. Besides, fatty acid oxidation in liver and thermogenesis in eWAT were also activated by Nuci. Similar results were further observed at cellular level, and these beneficial effects of Nuci in cells were abolished by an effective AMPK inhibitor compound C. In conclusion, Nuci supplementation prevented HFD-induced obesity, attenuated hepatic steatosis, and reduced lipid accumulation in liver/hepatocytes and eWAT/adipocytes through regulating AMPK-mediated FAS/HSL pathway. Our findings provide novel insight into the clinical application of Nuci in treating obesity and related complications.

The role of diallyl thiosulfinate associated with nuciferine and diosgenin in the treatment of premature ejaculation: A pilot study.

OBJECTIVE: To assess the efficacy and safety of an association of diallyl thiosulfinate with nuciferine and diosgenin in the treatment of a group of patients suffering from premature ejaculation (PE), primary or secondary to erectile dysfunction (ED). MATERIALS AND METHODS: From July 2015 to October 2016, 143 patients (mean age 25.3; range 18-39) affected by PE completed the study and were finally analyzed in this phase I study. All patients, after clinical assessment and laboratory evaluation were asked to take an association of diallyl thiosulfinate with nuciferine and diosgenin as oral tablet, once a day, on alternate days, for three months. At the baseline and after three months of treatment, each patient was asked to complete the following questionnaires: International Index of Erectile Function (IIEF-5), Premature Ejaculation Diagnostic Tool (PEDT), Male Sexual Health Questionnaire (MSHQ). RESULTS: A statistical significant improvement in terms of erectile function, comparing the IIEF-5 value at baseline and follow- up visit was found (respectively IIEF-5: 8.7 vs 14.01; p < 0.001). Moreover, at follow-up visit, 97/143 men (67.8%) referred a subjective improvement of the erection quality and a better control of the ejaculation (PROs). The IELT improved too between the baseline evaluation and the follow-up visit (p < 0.001). CONCLUSION: In conclusion, our study, even if supported by preliminary results, showed how Diallyl Thiosulfinate, Nuciferine and Diosgenin is able to improve the control of ejaculation in patients suffering from PE, primary or secondary to ED without any significant adverse effects.

Synthesis and Structure-Activity Relationships of a Series of Aporphine Derivatives with Antiarrhythmic Activities and Acute Toxicity.

Some aporphine alkaloids, such as crebanine, were found to present arrhythmic activity and also higher toxicity. A series of derivatives were synthesized by using three kinds of aporphine alkaloids (crebanine, isocorydine, and stephanine) as lead compounds. Chemical methods, including ring-opening reaction, bromination, methylation, acetylation, quaternization, and dehydrogenation, were adopted. Nineteen target derivatives were evaluated for their antiarrhythmic potential in the mouse model of ventricular fibrillation (VF), induced by CHCl3, and five of the derivatives were investigated further in the rat model of arrhythmia, induced by BaCl2. Meanwhile, preliminary structure-activity/toxicity relationship analyses were carried out. Significantly, N-acetamidesecocrebanine (1d), three bromo-substituted products of crebanine (2a, 2b, 2c), N-methylcrebanine (2d), and dehydrostephanine (4a) displayed antiarrhythmic effects in the CHCl3-induced model. Among them, 7.5 mg/kg of 2b was able to significantly reduce the incidence of VF induced by CHCl3 (p < 0.05), increase the number of rats that resumed sinus rhythm from arrhythmia, induced by BaCl2 (p < 0.01), and the number of rats that maintained sinus rhythm for more than 20 min (p < 0.01). Therefore, 2b showed remarkably higher antiarrhythmic activity and a lower toxicity (LD50 = 59.62 mg/kg, mice), simultaneously, indicating that 2b could be considered as a promising candidate in the treatment of arrhythmia. Structural-activity analysis suggested that variationsin antiarrhythmic efficacy and toxicity of aporphines were related to the C-1,C-2-methylenedioxy group on ring A, restricted ring B structural conformation, N-quaternization of ring B, levoduction of 6a in ring C, and the 8-, 9-, 10-methoxy groups on ring D on the skeleton.

Acetylated derivative of glaucine inhibits joint inflammation in collagenase-induced arthritis.

CONTEXT: Osteoarthritis (OA) has become by far the most common joint disorder. A number of studies using OA animal models have explored the effects of agents that can modulate bone metabolism. OBJECTIVE: In the present study, we investigated the effect of acetylated derivative of plant alkaloid glaucine (ADG) on experimental OA in mice. MATERIALS AND METHODS: Arthritis was induced by two intraarticular (i.a.) injections of collaganase. Histopathological changes were observed through hematoxylin and eosine (H&E), safranin O and toluidine blue staining. Differentiation of bone marrow (BM) cells was evaluated by tartarate-resistant acid phosphatase (TRAP) assay. The expression of phospho-Janus kinase 2 (pJAK2) and phospho signal transducer and activator of transcription3 (pSTAT3) expression in the joints was determined by immunohistochemistry. RESULTS: We established that ADG significantly decreased cell infiltration (2.32 ± 0.14 versus 1.62 ± 0.13), cartilage loss (2.42 ± 0.12 versus 1.12 ± 0.10) and bone erosion (1.76 ± 0.13 versus 1.04 ± 0.14) in arthritic mice. It appeared that the substance inhibited in a dose-dependent manner osteoclast differentiation in vitro. ADG suppressed the expression of pJAK2 in the joint and partially affected the expression of pSTAT3. CONCLUSION: Present results suggest that ADG is a suitable candidate for further development as an anti-arthritic agent.

Nuciferine stimulates insulin secretion from beta cells-an in vitro comparison with glibenclamide.

ETHNOPHARMACOLOGICAL RELEVANCE: Several Asian plants are known for their anti-diabetic properties and produce alkaloids and flavonoids that may stimulate insulin secretion. MATERIALS AND METHODS: Using Vietnamese plants (Nelumbo nucifera, Gynostemma pentaphyllum, Smilax glabra, and Stemona tuberosa), we extracted two alkaloids (neotuberostemonine, nuciferine) and four flavonoids (astilbin, engeletin, smitilbin, and 3,5,3'-trihydroxy-7,4'-dimethoxyflavone), and studied their insulin stimulatory effects. RESULTS: Nuciferine, extracted from Nelumbo nucifera, stimulated both phases of insulin secretion in isolated islets, whereas the other compounds had no effect. The effect of nuciferine was totally abolished by diazoxide and nimodipine, and diminished by protein kinase A and protein kinase C inhibition. Nuciferine and potassium had additive effects on insulin secretion. Nuciferine also stimulated insulin secretion in INS-1E cells at both 3.3 and 16.7 mM glucose concentrations. Compared with glibenclamide, nuciferine had a stronger effect on insulin secretion and less beta-cell toxicity. However, nuciferine did not compete with glibenclamide for binding to the sulfonylurea receptor. CONCLUSIONS: Among several compounds extracted from anti-diabetic plants, nuciferine was found to stimulate insulin secretion by closing potassium-adenosine triphosphate channels, explaining anti-diabetic effects of Nelumbo nucifera.

[Acute glaucine syndrome in the physician's practice: the clinical picture and potential danger].

The author describes a clinical symptom complex which appears in some patients as a central nervous system side-effect of conventional doses of glaucine, a non-narcotic antitussive preparation, used in outpatients; the symptom complex is described by the author as acute glaucine syndrome (AGS). Clinical manifestations of AGS are the following: 1) very prominent fatigue, which occurs acutely after taking a conventional dose of glaucine and making any kind of professional activity impossible at the moment; 2) very prominent sleepiness, which occurs acutely together with fatigue and is always combined with it; 3) unusual clear but somewhat estranged perception of the environment: the patient sees and understands everything and is oriented well enough, but cannot take a clear and adequate action, 4) full recovery of the impaired functions after the drug is discontinued; 5) AGS recurrence after the drug is taken again. The hallucination-like effect of glaucine, described earlier by the author of this article, which is manifested by bright and colorful visual images, may be considered a facultative AGS component. The author stresses a potential danger of AGS development in persons who control moving mechanisms or vehicles and adduces some clinical observations.

Efficacy and tolerability of glaucine as an antitussive agent.

One hundred and thirty out-patients, affected by acute and chronic cough caused by upper respiratory tract inflammation, took part in two clinical studies aimed at evaluating the efficacy and tolerability of glaucine , a new antitussive agent. The first study involved 90 patients in a double-blind comparative trial of glaucine and codeine: both treatments were administered as a syrup at a dosage of 30 mg 3-times daily for 7 days. The cough suppressant effect of the two treatments was checked by the physician and the patient using a 4-point scale (from absent to severe), and by the patient using a visual analogue scale. Mean scores of the physician's evaluation decreased from 3.0 to 1.10 after codeine and from 3.0 to 0.47 after glaucine (p less than 0.001 between treatments). Mean values of the patients' visual analogue scales decreased from 83 mm to 17 mm after codeine, and from 85 mm to 7 mm after glaucine (p less than 0.001 between treatments). Constipation and nausea were reported by 9 patients on codeine and by no patient on glaucine (p less than 0.01). One patient on codeine was withdrawn from the study after 3 days because of vomiting, constipation and nausea. The second study was an open trial in 40 patients who received glaucine capsules at a dosage of 30 mg 3-times daily for 28 days. The antitussive effect of the treatment was evaluated on the basis of the same criteria as in the first study. The mean score of the physician's evaluation decreased from 3.0 to 0.15 (p less than 0.001); the mean value of the patients' visual analogue scales decreased from 93 mm to 1 mm (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Double-blind comparison of the respiratory and sedative effects of codeine phosphate and (+/-)-glaucine phosphate in human volunteers.

1 Two antitussive agents (+/-)-glaucine phosphate and codeine phosphate have been compared with placebo with respect to ventilation, ventilatory response to carbon dioxide, pulse, blood pressure, digit symbol substitution, sedation score and the Zahlen-Verbindung test performance in ten healthy volunteers (22-36 years). The study was double-blind and the two doses of each antitussive agent and the placebo were administered as a syrup. 2 Both codeine phosphate and (+/-)-glaucine phosphate displaced the ventilatory response to carbon dioxide to the right. 3 The effect of codeine phosphate on the ventilatory response to carbon dioxide was not dose dependent: 30 mg produced greater effects than the 60 mg dose. 4 Only the highest dose of (+/-)-glaucine phosphate (60 mg) caused respiratory depression and this was associated with sedation and decreased performance in the digit symbol substitution test. 5 Neither antitussive agent had significant effects upon pulse or blood pressure and codeine phosphate had no detectable sedative activity.

An abbreviated phase II trial of thalicarpine.

Thalicarpine, a plant alkaloid of novel structure, was evaluated in a phase II clinical trial. Fourteen previously treated patients with advanced malignant disease were given thalicarpine at a dose of 1100 mg/m2 weekly as a constant 2-hour iv infusion. Common toxic effects included nausea, ECG changes, arm pain, and lethargy; less frequent effects included vomiting, tachycardia, hypotension, pain distant from infusion site, urticaria, chills, diarrhea, and mydriasis. There was no hematologic, hepatic, or renal toxicity. There were no complete or partial objective responses. Although the drug's true response rate in any given tumor type cannot be determined, its absence of activity in man, to date, and the recent closing of its IND, make further clinical investigation with thalicarpine unlikely.

Possible association of schizophrenia with a disturbance in prostaglandin metabolism: a physiological hypothesis.

Schizophrenia may be associated with increased prostaglandin synthesis in certain parts of the brain. This hypothesis is based on the following findings: (1) Catalepsy, which is the nearest equivalent in animals to human catatonia, develops in cats when prostaglandin E1 is injected into the cerebral ventricles and when during endotoxin or lipid A fever the prostaglandin E2 level in cisternal c.s.f. rises to high levels; however, when fever and prostaglandin level are brought down by non-steroid anti-pyretics which inhibit prostaglandin synthesis, catalepsy disappears as well. (2) Febrile episodes are a genuine syndrome of schizophrenia.

Phase I study of thalicarpine (NAC-68075), a plant alkaloid of noval structure.

An initial clinical trial of daily and weekly X 6 ihtravenous infusions of thalicarpine, a plant alkaloid of novel structure, was carried out in 36 patients. Twenty-eight patients received 33 courses of single-dose administration at doses of 200-1900 mg/m2. At the maximum tolerable dose of 1400 mg/m2, toxic effects included arm pain (nine or ten), central nervous system depression (seven of ten), nausea and vomiting (two of ten), hypotension (two of ten), hypertension (two of ten), arrhythmia (premature ventricular contractions) (one of ten), and electrocardiographic changes (mainly T-wave flattening) (five of ten). At the maximum tolerable dose for weekly administration, 1100 mg/m2/week X 6, arm pain was seen in seven of eight, central nervous system depression in three of eight, hypotension in one of eight, and electrocardiographic changes in three of eight. The recommended dose for phase II trials is 1100 mg/m2/week by a 2-hour intravenous infusion.