Overview of the preclinical pharmacological properties of Nigella sativa (black seeds): a complementary drug with historical and clinical significance.

Nigella sativa (N. sativa, black seeds; or sometimes known by many other names such as the blessed seed by the Arabs, black cumin in the Holy Bible, black caraway and Kalonji in South Asia) has been traditionally used for many years not only as a food but also as complementary drug. It is the objective of this communication to review the evidence-based pre-clinical pharmacological actions of N. sativa as a basis of its existing and potential new human clinical uses. Primary PubMed literature searches and secondary Medline searches were conducted to define N. sativa pre-clinical pharmacological and toxicological actions using a retrospective narrative review of the published studies. The ground seeds, its oil and its various extracts exhibit very broad pharmacological actions in laboratory studies, which are predictive of human clinical efficacy. In laboratory studies, N. sativa possesses anti-inflammatory, analgesic, anti-diabetic, anti-hyperlipidemic, anti-convulsant, anti-microbial, anti-ulcer, anti-hypertensive, anti-asthmatic and anti-cancer activities. Its mode of action is mediated via several mechanisms, which include anti-oxidant, immunomodulating, cytoprotective and an inhibitory effect on some mediators of inflammation. Although the seeds contain many chemical components, thymoquinone and alpha-hederin are proven to be pharmacologically active. Despite N. sativa broad and worldwide pharmacological characterization, only limited non-clinical safety studies were reported. N. sativa has many potentially important therapeutic applications. The black seeds clearly warrant formal preclinical drug development consideration to investigate the pharmacology of its components, to standardize the contents of the dosage forms, to define the methods of the pharmaceutical preparation, to determine its pharmacokinetics characteristics and its safety profile. It is our opinion that N. sativa should be considered for clinical development initially for unmet therapeutic uses, especially in the fields of oncology, neurology, rheumatology, pulmonary medicine, infectious diseases and endocrinology.

Prostaglandins and brain-gut axis.

Prostaglandins (PGs) have well documented physiological and pharmacological actions on the gastrointestinal (GI) tract. This communication reviews the evidence for peripheral and central nervous system (CNS) physiological actions of PGs in order to determine their role in the brain-gut axis, if any. PGs are widely distributed in nearly all cells peripherally and centrally. Laboratory and clinical evidence indicate that there is a direct relationship between altered GI physiological functions and peripheral PGs biosynthesis. Either local or parenteral administration of natural E-series PGs alters GI physiological functions particularly those relating to mucosal defense. Furthermore, the cyclooxygenase enzymes (COX), which are responsible for the PGs biosynthesis, have been localized in the brain as well as peripherally. However, increased levels of PGs in the brain have been associated with pathological processes such as inflammation, pain, fever and addiction. Although PGs have been shown to modulate CNS effects of catecholaminergic, serotoninergic and cholinergic neurons, there is no meaningful information concerning their direct central effect on GI function. The evidence for a clear physiological role of central PGs on the GI tract is not convincing. At this time, we conclude that PGs primarily manifest their activity on the GI tract by peripheral rather than by central mechanisms.

1',1'-Dimethylheptyl-delta-8-tetrahydrocannabinol-11-oic acid: a novel, orally effective cannabinoid with analgesic and anti-inflammatory properties.

1',1'-Dimethylheptyl-Delta-8-tetrahydrocannabinol-11-oic acid (CT-3) is a novel cannabinoid that is under development by Atlantic Pharmaceuticals as an anti-inflammatory and analgesic drug. The objective of the study was to investigate the effects of CT-3 on overt symptom complex (Irwin's test), nociception, gastrointestinal (GI) ulceration, and pharmacological availability after intragastric (i.g.) and intraperitoneal (i.p.) administration. Analgesic studies were assessed in the hot-plate (55 degrees C) and the tail clip tests in mice and in the tail clip test in rats. In addition, pharmacological interaction of CT-3 with the solvent dimethyl sulfoxide (DMSO) was investigated in rats. In mice, CT-3 decreased spontaneous motor activity and induced dose-dependent, analgesic activity in the tail clip and hot-plate tests, with potency similar to morphine sulfate after i.g. and i.p. administration. However CT-3 showed more prolonged duration of analgesic action than morphine. In rats, CT-3 showed marked analgesia in the tail clip test and had similar i.p. and i.g. median effective dose (ED(50) values; 5 mg/kg). CT-3 was devoid of GI ulceration when administered with DMSO either acutely at doses below 100 mg/kg or chronically at a dosage of 30 mg/kg/day for 5 days. In contrast, indomethacin induced GI ulceration and deaths. The concurrent use of DMSO with CT-3 decreased its analgesic action, increased its adverse central nervous system effects, and induced GI ulceration. The evidence indicates that CT-3 exhibits a large dissociation between its anti-inflammatory/analgesic effects and its ulcerogenic actions. CT-3 warrants clinical development as a novel anti-inflammatory and analgesic drug.

Effects of tolcapone, a catechol-O-methyltransferase inhibitor, and Sinemet on intestinal electrolyte and fluid transport in conscious dogs.

Tolcapone (T) is a novel catechol-O-methyltransferase (COMT) inhibitor recently introduced for the treatment of Parkinson's disease. In clinical efficacy studies, T has been associated with a low incidence of diarrhea. The objectives of the study were to examine whether T and its adjunctive drug Sinemet (S) could influence intestinal fluid and electrolyte transport as a possible cause for the diarrhea. The studies were conducted in conscious dogs surgically prepared with Thiry-Vella loops constructed from a 40-cm jejunal segment. A physiologically buffered test solution was perfused into the orad stoma and collected from the caudad stoma. Secretions were collected at 15-min intervals and analyzed for volume, electrolytes, lipid phosphorus, and protein. The acute oral administration of T (10 and 30 mg/kg doses) was well tolerated. Concurrent acute administration of S (25 mg/kg) with T (30 mg/kg) was also well tolerated. The acute oral administration of T induced a dose-dependent efflux of intestinal fluid and electrolytes (sodium, potassium, chloride, and bicarbonate) secretion (P < 0.05). The oral coadministration of S (25 mg/kg) with T (30 mg/kg) accelerated the onset of the stimulation of intestinal secretion. Despite the significant stimulation of intestinal secretion, none of the dogs developed diarrhea, indicating the importance of intestinal compensatory mechanisms. Neither T nor T&S affected calcium, lipid, or protein efflux rates, suggesting that the stimulated secretion was not a consequence of intestinal mucosal injury. The chronic (seven-day) administration of T and T&S was associated with reduced intestinal secretory responses when compared with the acute administration of the same drugs; S enhanced the T-induced tolerance development. The basis for such tolerance is unknown. In conclusion, the stimulatory systemic actions of tolcapone on intestinal secretion may, under certain conditions, contribute to the induction of diarrhea in susceptible patients.