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.

Synthesis and biological evaluation of omega-homologues of prostaglandin E1.

The synthesis and biological activities of some compounds with novel modifications of the omega side chain of prostaglandin E1 (PGE1) are described. The preparation of (+/-)-omega-Me-PGE1 (3) (+/-)-omega-Pr-PGE1 (5), and (+/-)-omega-Bu-PGE1 (6) is outlined. The compounds were evaluated for in vitro smooth muscle stimulating activity on isolated gerbil colon preparations, for hypotensive action in anesthetized rats, and for gastric antisecretory effects in histamine-stimulated Heidenhain pouch dogs. Structural changes in the omega position of the noncarboxyl side chain of PGE1 influenced the biological potency of the resulting compound when compared to the reference standard PGE1 (2). The homologues demonstrated interesting separation of biological activities; for example, 4 showed potent hypotensive activity (84% of PGE1, it showed very low smooth muscle stimulating activity. Compound 3 possessed the same order of potency as 2 in the gastric antisecretory assay.

3,3-Diphenyl-3-(2-alkyl-1,3,4-oxadiazol-5-yl)propylcycloalkylamines, a novel series of antidiarrheal agents.

A series of 4-amino-2,2-diarylbutyronitriles (3) prepared for testing as inhibitors of gastrointestinal propulsive activity did not show any enhancement over such existing agents as diphenoxylate and loperamide. However, conversion of the nitrile group to a 2-methyl-1,3,4-oxadiazol-5-yl function led to compounds 5g and 5j, statistically equipotent to diphenoxylate and loperamide in the mouse and showing a very low order of analgesic activity. Structural modifications determined that the best separation of antipropulsive and analgesic effects was obtained when the amino group was bicyclic and the oxadiazole ring had a 2-methyl substituent. The most potent compounds were and analogues of diphenoxylate and loperamide where the oxadiazole ring was present, but these compounds had marked analgesic activity.

Synthesis and gastric antisecretory properties of 4,5-unsaturated derivatives of 15-deoxy-16-hydroxy-16-methylprostaglandin E1.

The synthesis and gastric antisecretory activities of the delta 4,5-cis, delta 4,5-trans, and 4,5-acetylenic analogues of 15-deoxy-16-hydroxy-16-methyl prostaglandin E1 methyl ester are described. The key step in the preparation of these compounds involved the stereospecific conjugate addition of a cuprate reagent to the appropriate cyclopentenones. Although the trans and acetylenic derivatives were weak inhibitors of gastric acid secretion, the cis olefin was more potent and longer acting than the saturated parent compound. Selectivity with respect to unwanted diarrheagenic effects was found to be improved over that of both the parent 16-hydroxy compound and the reference standards, (15S)-15-methyl- and 16,16-dimethylprostaglandin E2.

Synthesis and gastric antisecretory properties of 15-deoxy-16-hydroxyprostaglandin E analogues.

The preparation and gastric antisecretory activity of a series of 15-deoxy-16-hydroxyprostaglandin analogues are described. The compounds were tested intravenously in histamine-stimulated Heidenhain pouch dogs in relation to the reference standards PGE1 and PGE1 methyl ester (PGE1ME). The parent compound of this seris, (+/-)-15-deoxy-16alpha,beta-hydroxyprostaglandin E1 methyl ester (3), was found to be equipotent to the reference standard PGE1ME. Methylation at C-16 of 3 produced 8 which was found to be some 40 times more potent than PGE1. In sharp contrast, addition of two methyl groups to 3 at C15 or C17 markedly reduced the antisecretory action. The 16-ethyl analogue of 3 also showed reduced potency. Removal or epimerization of the C-11 hydroxy group of 8 reduced the activity. Likewise, hydrogenation or changing the stereochemistry of the 13,14 double bond from trans to cis decreased the activity. On the other hand, omega-homologation of 8 or the introduction of a cis-5,6 double bond did not affect the potency. From these studies, it appears that 8, 16, and 17 possess optimum gastric antisecretory effects in this series.

The effect of epidermal growth factor on circulating levels of IGF and IGF-binding proteins in adult Goettingen minipigs.

It has recently been demonstrated that epidermal growth factor (EGF) administration to neonatal rodents causes growth retardation with concomitant reductions in circulation levels of IGF-I. We describe the effects of systemic EGF administration for 4 weeks on circulating levels of IGF-I and IGF-binding proteins (IGFBPs) and on thyroid hormones (tri-iodothyronine, T3; thyroxine, T4) in sexually mature pigs. Goettingen minipigs of either sex were treated with placebo (n = 5) or EGF (30 micrograms/kg per day, n = 6) s.c. for 4 weeks (in relation to an oesophageal sclerotherapy regimen). Blood samples were taken under anaesthesia before and after 1, 2, 3 and 4 weeks of treatment. Circulating levels of IGF-I, insulin, glucose, T3 and T4 were analysed every week and IGFBPs every second week. IGF-I was not reduced significantly after 1 week but significantly reduced after 2 and 3 weeks of EGF treatment. A similar decline was observed for the major IGFBP, IGFBP-3, which was reduced after 2 and 4 weeks. IGFBP-1, IGFBP-2 and IGFBP-4 increased throughout the treatment period (all significantly at week 4). EGF treatment induced increased circulating T3 after 2, 3 and 4 weeks of EGF treatment. In conclusion, we report that EGF treatment for 4 weeks in Goettingen minipigs reduces circulating IGF-I and IGFBP-3, increases circulating IGFBP-1, IGFBP-2 and IGFBP-4, and induces a slight hyperthyroidism as judged from increased circulating levels of T3.

Tissue distribution of 131I-labelled epidermal growth factor in the pig visualized by dynamic scintigraphy.

We visualized the metabolism of intravenously injected 131I-labelled epidermal growth factor in the pig using dynamic scintigraphy combined with repetitive samplings of blood, urine and bile. The labelled peptide was recognized in the samples by means of immunoprecipitation and high pressure liquid chromatography. The plasma elimination was extremely rapid, and it was described with a triexponential equation, C(t) = A*e -alpha*t+B*e-beta*t+C*e-gamma*t. The first two exponentials denoted the distribution phase, and the third the elimination phase. T1/2 alpha ranged from 0.4-0.7 min, T1/2 beta from 2.0-2.2 min and T1/2 gamma from 53.3-97.6 min. Concomitant with the rapidly declining plasma concentration, the gamma camera visualized the uptake by the liver and the kidneys. The liver was the principal organ for clearance and degradation of the labelled peptide, but only 0.12-0.30% of the injected dose was excreted into the bile. The renal uptake and the urinary excretion accounted for 6.6-13.0 and 2.5-4.9% of the given dose, respectively.

Novel therapeutic approaches to gastric and duodenal ulcers: an update.

Over the last 25 years, a remarkable revolution in the pathophysiology and treatment of gastric and duodenal ulcers has occurred. Effective therapies were developed not only to heal ulcers, but also to cure most patients. The two principal causes for gastric and duodenal ulcers are either infection with Helicobacter pylori or the use of non-steroidal anti-inflammatory drugs (NSAIDs). With H. pylori eradication, gastric and duodenal ulcers are rapidly becoming historical diseases. This communication reviews the salient pharmacology of the novel anti-ulcer drugs currently in development, with particular emphasis on the treatment of gastric and duodenal ulcers. Intense research is currently focused on the development of proton pump inhibitors primarily for the treatment and prevention of gastroesophageal reflux disease. The older proton pump inhibitors, omeprazole and lansoprazole, are effective in healing gastric and duodenal ulcers. Furthermore, both drugs are effective in eradicating H. pylori when given with various antibiotics. Pantoprazole, rabeprazole and esomeprazole are new proton pump inhibitors, which appear to have comparable therapeutic profiles with omeprazole and lansoprazole. Rebamipide is a new mucosal protective drug, which is effective in healing gastric ulcers. Polaprezinc and nocloprost are also mucosal protective drugs, which are in clinical development. However, none of these three cytoprotective drugs have been evaluated for their efficacy in eradicating H. pylori when given in combination with antibiotics. Likewise, no published literature exists on the use of these drugs for preventing NSAID-induced ulcers. With the rapid eradication of H. pylori currently happening in the developed world, the therapeutic challenge is now directed toward preventing NSAID-associated ulcer. Significant reduction of NSAID-induced ulcers is achieved by using continuous prophylactic anti-ulcer therapy (misoprostol or omeprazole) or by using NSAIDs possessing selective COX-2 inhibitory activity. However, outcome clinical studies are needed to compare the adjuvant anti-ulcer therapies given with COX-1 inhibitors versus the selective COX-2 inhibitors given alone.

Effects of E prostaglandins, diphenoxylate and morphine on intestinal motility in vivo.

The mechanism of the gastrointestinal motility effects of diphenoxylate and morphine in preventing E prostaglandin (PG) diarrhea was investigated. Duodenal motility studies were conducted in the anesthetized dog. Two contractile force transducers were oriented to record contractions from both the circular and longitudinal muscles. In some experiments the basic electrical rhythm (BER) was also recorded. Blood pressure was monitored from the femoral artery and drug injections were made in the femoral vein. Diphenoxylate shared with morphine the capacity to stimulate circular muscle contractions which correlated with the appearance of spike potentials on the BER. Prostaglandin E1 methyl ester (PGE1ME) showed marked relaxation of the circular muscle and abolishment of spike potentials. PGE1ME also blocked the stimulatory effects of diphenoxylate and morphine on the circular muscle. PGE1ME and PGE2 were found to be equally potent in producing diarrhea in mice. Diphenoxylate and morphine were found to be equally potent in inhibiting PG's diarrhea. These studies suggest that the constipating actions of diphenoxylate and morphine are a consequence of the increased circular muscle activity of the intestine.

Preventive effects of recombinant human epidermal growth factor on the oesophageal epithelium in pigs subjected to sclerotherapy.

OBJECTIVE: To investigate the role of epidermal growth factor (EGF), a small (relative molecular mass 6000) polypeptide with mitogenic properties in the protection of gastrointestinal mucosal integrity. DESIGN: A prospective, randomized and blinded study. METHODS: Twenty-four minipigs with surgically induced portal hypertension underwent four consecutive weekly sessions of oesophageal sclerotherapy with 5 ml 1% polidocanol and were concomitantly treated with either a placebo or human recombinant EGF administered subcutaneously. Mucosal damage was evaluated on a weekly basis by endoscopic estimation of the size of the ulcerated area and by post-mortem morphometry. The EGF-induced morphological changes in the oesophageal epithelium were also evaluated histologically. RESULTS: In sclerosed and non-sclerosed parts of the oesophagus EGF significantly increased the thickness of the oesophageal epithelium (P < 0.03), but failed to reduce significantly the degree of oesophageal damage associated with sclerotherapy (P = 0.11). CONCLUSIONS: Systemic EGF treatment induces proliferation of the oesophageal mucosa, and EGF may therefore have the potential to reduce sclerotherapy-induced oesophageal damage.

Impedance planimetric characterization of the distal oesophagus in the Goettingen minipig.

Regional differences in biomechanical properties of the oesophagus were studied in 15 healthy Goettingen minipigs by means of impedance planimetry. The investigation was performed during anaesthesia by stepwise pressure-induced balloon distensions with concomitant measurement of pressure and luminal cross-sectional area (CSA) in the oesophagus 5 and 10 cm above the gastro-oesophageal junction. The circumferential wall tension, circumferential strain and incremental elastic modulus were computed from the measurements of pressure and CSA at steady-state conditions. Probably due to the anaesthesia, only scant peristalsis was recorded and the CSA always reached steady state during the balloon distensions. The CSAs were highest in the distal oesophagus (P < 0.001). At the highest induced pressure, the CSAs were 605 +/- 32 and 453 +/- 29 mm2 (mean +/- SEM) for the locations 5 and 10 cm from the gastro-oesophageal junction. The tension-strain distributions were non-linear and the curve obtained 5 cm above the gastro-oesophageal junction was shifted to the right when compared with the curve obtained from 10 cm above this junction. Fitting of the function tension = exp(a+b strain) to the data gave determination coefficients higher than 0.97 and P values lower than 0.001 for both measuring points. The constant a differed between the two locations in the oesophagus (P < 0.05). In conclusion, the pressure-CSA and the tension-strain distributions differed between the two measuring points suggesting that the elastic properties are different.

Future treatment of peptic ulcer: is there room for anti-infective drugs?

Several major Laboratories have recently given up their search for uncovering innovative antiulcer drugs despite the fact that none of the available drugs meet the ideal aims of therapy: to relieve pain, to heal the ulcers and to prevent the recurrences. Furthermore, no single antiulcer drug has proven effective in managing ulcer-related complications or ulcers associated with oncology and sclerotherapy treatment. Recent research suggests that the eradication of H. pylori infection is associated with decreased rate of duodenal ulcer recurrences, however, appropriate and convenient eradication therapy needs to be developed. Moreover, we must also continue to search for ideal drugs effective for the treatment of ulcers and their complications.

Prevention and treatment of ulcers induced by nonsteroidal anti-inflammatory drugs: an update.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are most frequently used for the treatment of rheumatic disease due to their anti-inflammatory and analgesic properties. All NSAIDs have the potential to cause damage to the gastrointestinal (GI) tract and have been associated with the induction of peptic ulcers and massive life-threatening bleeding. The therapeutic approaches for the treatment and prevention of NSAID-induced ulcers is critically reviewed using data derived from carefully controlled, world-wide clinical studies with anti-ulcer drugs. Histamine (H2) antagonists, omeprazole, sucralfate and E-prostaglandin (PGE) analogs are effective for the treatment of NSAID-induced gastric and duodenal ulcers, if NSAIDs are discontinued. However, if NSAIDs are continued while GI damage is present, the PGE analogs misoprostol, arbaprostil and enprostil have shown efficacy in healing NSAID-induced ulcers. Furthermore, one limited clinical study demonstrated that omeprazole has efficacy in healing NSAID-associated ulcers. Neither H2 antagonists, sucralfate and sulglycotide (a cytoprotective drug) have shown efficacy in preventing NSAID-induced gastric ulcers. However H2 antagonists have shown efficacy in preventing NSAID-induced duodenal ulcers. In contrast, only misoprostol prevents the development of NSAID-induced gastric and duodenal ulcers. Such pharmacological observations suggest that the pathophysiologic mechanisms for the induction of NSAID-induced gastric ulcer are distinctly different from those of NSAID-induced duodenal ulcers. Mild diarrhea and GI intolerance were the predominant adverse reactions experienced by patients receiving synthetic PGEs, particularly enprostil and arbaprostil. From the published data, we conclude that misoprostol is the only anti-ulcer drug proven to be well tolerated and effective for the treatment and prevention of NSAID-induced gastric and duodenal ulcers in patients receiving chronic NSAIDs therapy.

Treatment and prevention of nonsteroidal anti-inflammatory drug induced gastrointestinal mucosal injury.

It is generally recognized that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can cause varying degrees of gastroduodenal mucosal damage. These agents are most frequently used by physicians for rheumatic diseases because of their high effectiveness in reducing joint pain and swelling. Four classes of drugs, namely histamine (H2) blockers, antacids, sucralfate and prostaglandins are available for treatment of gastric mucosal damage caused by NSAIDs. All these drugs are very effective in healing gastric and duodenal injury if nonsteroidal anti-inflammatory drugs are discontinued. However, current data suggest that if nonsteroidal anti-inflammatory drugs are continued while gastrointestinal damage is present there may be significant differences among these drugs in healing of gastric mucosal damage. Synthetic prostaglandins are therapeutically superior over other forms of treatment when nonsteroidal anti-inflammatory drugs are continued in the presence of gastric mucosal injury. This article is a review of such data from the literature for a) the treatment and b) the prevention of gastrointestinal damage due to aspirin and nonsteroidal anti-inflammatory drugs.

Protective effects of prostaglandins against nonsteroidal anti-inflammatory drug-induced gastrointestinal mucosal injury.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are an integral part of the therapy of rheumatic diseases. All NSAIDs have the potential to cause damage to the gastrointestinal (GI) tract and have been implicated as a cause of peptic ulceration and massive life-threatening bleeding, often without warning symptoms. The basis of the damaging actions of NSAIDs on the GI tract is believed to be a consequence of two events: depletion of endogenous prostaglandins (PGs) and a direct damaging action on the mucosal integrity. Current evidence indicates that PGs play an important role in maintaining the integrity of the GI tract against ulcerogenic stimuli and are therefore ideally suited to counteract the NSAID-induced deleterious actions on the mucosa. With the exception of synthetic prostaglandins, the current therapeutic interventions used for the treatment of NSAID injury are not ideal. Misoprostol, a synthetic E-prostaglandin analogue, has been found to prevent and heal GI lesions induced by NSAIDs. The basis for the protective effect of prostaglandins is a consequence of their gastric antisecretory and mucosal protective properties. The mucosal protective effects of misoprostol are multifactorial and include, in part, the stimulation of mucus and bicarbonate secretion, an increased or sustained mucosal blood flow and the stabilization of the barrier function of the stomach. Misoprostol represents a major new advance in our therapeutic armamentarium for the treatment and prevention of NSAID-induced GI mucosal injury.

Ureteric growth in a Goettingen minipig induced by epidermal growth factor. A case report.

We have recently discovered that prolonged systemic administration of epidermal growth factor (EGF) induces a remarkable growth of all wall layers of the urinary tract in minipigs. In the present paper, we report the most pronounced changes induced by 4 weeks of systemic EGF challenge in two pigs treated for four weeks with either solvent or EGF (30 micrograms/kg/day), respectively. The EGF treated ureter was longer and thicker with an approximately four fold increase in diameter. All wall layers were enlarged. The urothelium was increased from 5 to 10 cellular rows with basal hyperplasia and an increased number of goblet cells and cells with intracytoplasmic lumina in the luminal half. In the muscular coat, the bundles of hypertrophied cells and intervening connective tissue were enlarged. The present paper suggests a possible in vivo approach to increase the amount of tissue needed in reconstructive surgery of the urinary tract.

Options in the treatment and prevention of NSAID-induced gastroduodenal mucosal damage.

Aspirin and other nonsteroidal antiinflammatory drugs (NSAID) have been associated with various degrees of gastroduodenal damage. The agents currently available for the treatment of gastric mucosal damage caused by NSAID are histamine2-receptor antagonists, antacids, sucralfate and prostaglandins. Although all of these agents are effective in healing gastric and duodenal injury if NSAID are discontinued, currently available data suggest that there may be significant differences among these drugs in healing gastric mucosal injury if NSAID are continued in the presence of such injury. In particular, the synthetic prostaglandin misoprostol appears to be therapeutically superior to agents in the other drug classes in such a context. Reviewed herein are data from the literature on both treatment and prevention of gastrointestinal damage due to NSAIDs.

Cardiovascular and gastrointestinal toxicity of selective cyclo-oxygenase-2 inhibitors in man.

It is well established that the use of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) increase the vulnerability of the gastrointestinal (GI) mucosa for the development of peptic lesions and serious ulcer complications. In addition, selective and traditional NSAIDs have also been associated with increased frequency of cardiovascular toxicity, especially in susceptible patients. The objective of this communication is to provide an overview of the salient GI and cardiovascular (CV) toxicity for these drugs. Traditional NSAIDs inhibit the constitutional cyclooxygenase-1 (COX-1) enzyme responsible for eicosanoids biosynthesis not only in joints, a beneficial effect, but also in the stomach, a detrimental effect. Selective NSAIDs were specifically designed to preferentially inhibit the cyclooxygenase-2 (COX-2), an inducible enzyme mediating the production of inflammatory eicosanoids in the joints but sparing the endogenous protective eicosanoids in the stomach. Selective COX-2 inhibitors (COXIBs) have been shown to possess much improved GI tolerability and reduced GI related adverse events when compared with nonselective COX-1 inhibitors. An unexpected CV toxicity had emerged during the COXIBs post marketing outcome studies. Many subsequent studies were carried out to define the CV risks associated with COXIBs and NSAIDs. All COX inhibitors had shown this CV toxicity. In many clinical studies, rofecoxib use was associated with significantly more elevated CV risk when compared with celecoxib and non selective NSAIDs. The COX inhibitors associated CV toxicity has multiple manifestations, which include the induction of myocardial infarction (MI), edema, thrombosis, blood pressure destabilization and death. Patients at risk of CV disease or with a history of CV disease were the most significant determinants of CV events after receiving COX inhibitors. This CV toxicity not only led to the marketing withdrawal of rofecoxib and valdecoxib but also resulted in more restricted, but essentially identical, product labels in the United States for celecoxib and traditional NSAIDS. This CV toxicity is dose and treatment duration dependent and appears to be compound specific rather than COX specific. Additional comprehensive, long-term, prospective investigations comparing the CV and GI safety profile of marketed NSAIDs against each other and against selective inhibitors are needed to address the controversy of COX inhibitors.

Overview of the mucosal protective effects of misoprostol in man.

Misoprostol, a novel synthetic analog of prostaglandin E1 has been evaluated for its potential mucosal protective properties in healthy human subjects using randomized, double-blind, placebo-controlled studies. Misoprostol significantly reduced established aspirin-induced gastric microbleeding. Likewise, misoprostol significantly inhibited aspirin-induced fecal blood loss when administered concurrently with aspirin. The reduction of gastrointestinal blood loss was neither a consequence of the inhibition of gastric secretion, nor a change in aspirin absorption. In addition, misoprostol effectively attenuated the transmucosal potential difference drop induced by sodium taurocholate. In endoscopic studies, misoprostol significantly inhibited damage to the gastroduodenal mucosa induced by aspirin, tolmetin and ethanol. In the ethanol study, the protective effects of misoprostol were significantly and profoundly greater than that afforded by cimetidine administered at an effective gastric antisecretory dose. These studies indicate that misoprostol has mucosal protective property in man. The basis for this mucosal protective effect is not fully known, but laboratory and clinical evidence indicate a direct effect on the barrier functions of the stomach, an increased or maintenance of gastric mucosal blood flow and an enhanced mucus and bicarbonate secretion. The implications of these findings suggest that misoprostol may be useful in the prevention and treatment of acute gastroduodenal mucosal lesions and inflammation.