Ahmad Al-Saffar | Uppsala University (original) (raw)

Papers by Ahmad Al-Saffar

Annals of the New York Academy of Sciences, 1982

Thesis (doctoral)--Karolinska Institutet, 1985. Includes bibliographical references.

Handbook of Experimental Pharmacology, 2015

Although the basic structure of the gastrointestinal tract (GIT) is similar across species, there... more Although the basic structure of the gastrointestinal tract (GIT) is similar across species, there are significant differences in the anatomy, physiology, and biochemistry between humans and laboratory animals, which should be taken into account when conducting a gastrointestinal (GI) assessment. Historically, the percentage of cases of drug attrition associated with GI-related adverse effects is small; however, this incidence has increased over the last few years. Drug-related GI effects are very diverse, usually functional in nature, and not limited to a single pharmacological class. The most common GI signs are nausea and vomiting, diarrhea, constipation, and gastric ulceration. Despite being generally not life-threatening, they can greatly affect patient compliance and quality of life. There is therefore a real need for improved and/or more extensive GI screening of candidate drugs in preclinical development, which may help to better predict clinical effects. Models to identify drug effects on GI function cover GI motility, nausea and emesis liability, secretory function (mainly gastric secretion), and absorption aspects. Both in vitro and in vivo assessments are described in this chapter. Drug-induced effects on GI function can be assessed in stand-alone safety pharmacology studies or as endpoints integrated into toxicology studies. In silico approaches are also being developed, such as the gut-on-a-chip model, but await further optimization and validation before routine use in drug development. GI injuries are still in their infancy with regard to biomarkers, probably due to their greater diversity. Nevertheless, several potential blood, stool, and breath biomarkers have been investigated. However, additional validation studies are necessary to assess the relevance of these biomarkers and their predictive value for GI injuries.

Regulatory Peptides, 1984

The effect of i.v. infusions of bombesin and somatostatin, administered either separately or in c... more The effect of i.v. infusions of bombesin and somatostatin, administered either separately or in combination, on migrating myoelectric complexes (MMCs) in the small intestine were studied in conscious, fasted rats. The myoelectrical activity was recorded by means of three bipolar electrodes chronically implanted into the duodenum and jejunum. Infusion of bombesin (0.5, 0.9 and 3 pmol . kg-1 . min-1) interrupted the MMC and induced irregular spiking activity similar to that observed on feeding. Only after the highest dose a consistent inhibition of the MMCs and a significant increase (P less than 0.05) of the spiking activity were achieved at all recording levels. Somatostatin (90 pmol . kg-1 . min-1) did not interrupt the MMC, but reduced significantly the incidence of the activity fronts and spiking activity of the MMCs (P less than 0.05). The effects of bombesin (3 pmol . kg-1 . min-1) on the MMC pattern were inhibited by simultaneous infusion of somatostatin (P less than 0.05). In a second series of experiments, using anesthetized rats, infusion of bombesin (0.5 and 3 pmol . kg-1 . min-1) increased the plasma concentration of neurotensin- gastrin-like immunoreactivities in a dose-dependent manner. The results show that bombesin alters the myoelectrical activity of the small intestine from a fasting to a fed pattern. Since the effect of bombesin was inhibited by the hormone release inhibitor somatostatin, it is suggested that the effect of bombesin on MMC may be secondary to the release of gastrointestinal peptides, such as neurotensin or gastrin.

Journal of Pharmacological and Toxicological Methods, 2008

... Title. Correction of QT intervals in dogs with tachycardia. Challenge to atropin. View Full T... more ... Title. Correction of QT intervals in dogs with tachycardia. Challenge to atropin. View Full Text (Elsevier ScienceDirect user account required). Author(s). Pehrson, R., Forsberg, T., Al-Saffar, A.,. Journal. Journal of Pharmacological and Toxicological Methods. Vol. 58, No. ...

Acta Physiologica Scandinavica, 1983

The aim of the present study in the rat was to localize the gastrointestinal site(s) of NTLI rele... more The aim of the present study in the rat was to localize the gastrointestinal site(s) of NTLI release and to investigate the importance of bile and pancreatic juice for fat-induced NTLI release. Administration of Intralipid (2 ml) into the stomach and oleic acid (0.5 ml) into the duodenum increased the plasma concentration of NTLI (p-NTLI). The increase in p-NTLI levels occurred only when the jejunum and ileum were exposed to Intralipid but not when the exposure was limited to the stomach and duodenum. Exclusion of pancreatic juice significantly reduced the p-NTLI response and exclusion of both bile and pancreatic juice completely abolished the p-NTLI response to duodenally-administered oleic acid. The results indicate that neurotension is released by a direct luminal exposure of the neurotensin containing N-cells to fatty acids. It seems probable that fatty acids have to be transformed to a micellar form in order to release NTLI.

Acta Pharmacologica Sinica, 2007

1 The purpose of this study was to develop and validate an integrated pharmacokineticpharmacodyna... more 1 The purpose of this study was to develop and validate an integrated pharmacokineticpharmacodynamic model for the anti-lipolytic eects of the adenosine A 1 -receptor agonist N 6 -(psulphophenyl)adenosine (SPA). Tissue selectivity of SPA was investigated by quanti®cation of haemodynamic and anti-lipolytic eects in individual animals. 2 After intravenous infusion of SPA to conscious normotensive Wistar rats, arterial blood samples were drawn for determination of blood SPA concentrations, plasma non-esteri®ed fatty acid (NEFA) and b-hydroxybutyrate levels. Blood pressure and heart rate were monitored continuously. 3 The relationship between the SPA concentrations and the NEFA lowering eect was described by the indirect suppression model. Administration of SPA at dierent rates and doses (60 mg kg 71 in 5 min and 15 min, and 120 mg kg 71 in 60 min) led to uniform pharmacodynamic parameter estimates. The averaged parameters (mean+s.e., n=19) were E max : 780+2% (% change from baseline), EC 50 : 22+2 ng ml 71 , and Hill factor: 2.2+0.2. 4 In another group, given 400 mg kg 71 SPA in 15 min, pharmacodynamic parameters for both heart rate and anti-lipolytic eect were derived within the same animal. The reduction in heart rate was directly related to blood concentration on the basis of the sigmoidal E max model. SPA inhibited lipolysis at concentrations lower than those required for an eect on heart rate. The EC 50 values (mean+s.e., n=6) were 131+31 ng ml 71 and 20+3 ng ml 71 for heart rate and NEFA lowering eect, respectively. 5 In conclusion, the relationship between blood SPA concentrations and anti-lipolytic eect was adequately described by the indirect suppression model. For SPA a 6 fold dierence in potency was observed between the eects on heart rate and NEFAs, indicating some degree of tissue selectivity in vivo.

The paracetamol (PCM) and sulfapyridine (SP) double marker technique is based on combined gastric... more The paracetamol (PCM) and sulfapyridine (SP) double marker technique is based on combined gastric administration of PCM and sulfasalazine followed by plasma concentration measurements for PCM and SP. PCM is rapidly absorbed from the duodenum and can be regarded as a marker for gastric emptying (GE). Sulfasalazine is poorly absorbed from the small intestine but is extensively metabolized in the colon by bacteria into SP. As SP is only absorbed from the colon it serves as a marker for small intestinal transit time (SITT). The double marker method is used to identify and characterize effects on GE and SITT. The aim of the present investigation was to demonstrate how semi-mechanistic modeling of PCM and SP could facilitate characterization and the understanding of pharmacologically induced changes in GI transit under fed and fasting conditions. Two double marker validation studies were performed in dogs with erythromycin (1 mg/kg) and atropine (0.06 mg/kg), both of which have been descr...

Digestive diseases and sciences, 1997

The lipopolysaccharide (endotoxin) of gram-negative bacteria has systemic effects in animals and ... more The lipopolysaccharide (endotoxin) of gram-negative bacteria has systemic effects in animals and man. Our aim was to investigate the effects of E. coli lipopolysaccharide on motility and transit through the small intestine in rats and to analyze plasma and tissue concentrations of intestinal neuropeptides. When lipopolysaccharide (20-160 micrograms/kg) was administered intravenously, the migrating myoelectric complex was replaced by spike bursts accompanied by rapid transit. Tissue concentrations of substance P and neurokinin A decreased, while plasma levels of calcitonin gene-related peptide increased N omega-Nitro-L-arginine, N omega-L-arginine methyl ester, dexamethasone, or indomethacin prevented these changes in myoelectric activity and tissue contents of neuropeptides. All of these compounds, except indomethacin, prevented the increased rate of transit. Thus, lipopolysaccharide changes motility through the nitric oxide and arachidonic pathways, resulting in rapid transit throu...

Scandinavian journal of gastroenterology. Supplement, 1984

The physiological significance of neurotensin, with respect to gut motility in man, may be to med... more The physiological significance of neurotensin, with respect to gut motility in man, may be to mediate postprandial, fat-induced changes in the motility pattern of the gastrointestinal tract. There is strong experimental evidence that this effect of neurotensin is endocrine-mediated. The role of neurotensin as a paracrine hormone, neurotransmitter or neurocrine hormone remains to be determined.

Scandinavian journal of gastroenterology, 1984

The relation between the occurrence of the migrating myoelectric complexes (MMC) and the transit ... more The relation between the occurrence of the migrating myoelectric complexes (MMC) and the transit of small-intestinal contents was studied in fasted, conscious rats. MMC were monitored by means of three bipolar electrodes implanted along the small intestine 5, 20, and 35 cm distal to the pylorus. In the presence of an MMC, the radioactive marker was transported along the small intestine as one main peak and recovered aboral to the activity front. Intravenous infusion of bombesin, 3 pmol X kg-1 X min-1, disrupted the MMC and induced irregular spiking activity at all recording levels. Furthermore, during bombesin infusion the radioactive marker was propelled a considerable distance, although the transit was significantly retarded in comparison to that in the presence of an MMC (p less than 0.01). The results indicate that the small-intestinal contents are propelled aboral to an activity front. Continuous irregular spiking activity during bombesin infusion contributes less to the transi...

Scandinavian Journal of Gastroenterology, 2001

Tachykinins and acetylcholine are main physiological motility stimulators in the gut by their eff... more Tachykinins and acetylcholine are main physiological motility stimulators in the gut by their effects exerted through neurokinin and muscarinic receptors. Longitudinal and circular muscle strips from normal ileum and colon or corresponding tissues from patients with inflammatory bowel disease were studied in organ baths. Contractile responses to the tachykinins substance P, neurokinin A, neurokinin B and neuropeptide gamma and specific analogs for their respective receptors were compared to acetylcholine. Acetylcholine caused concentration-dependent phasic contractions in longitudinal and circular muscle of normal ileum and colon (both P < 0.01). In inflamed tissues, contractile responses were reduced to 17%-33% in ileum (P < 0.05) and 3%-26% in colon (P < 0.01). Both natural tachykinins and their specific analogs caused concentration-dependent phasic, tonic and rhythmic contractions (each P < 0.01). Neuropeptide gamma was most potent in contracting the ileum and colon, followed by neurokinin A, substance P and neurokinin B, let alone longitudinal muscle of the ileum where neuropeptide gamma and neurokinin A were equipotent. Of the tachykinin analogs, Nle10-NKA(4-10) was more potent than substance P methyl ester and senktide, indicating neurokinin 2 receptors are predominant for contractile effects of tachykinins. In inflamed tissues, contractile responses to tachykinins were reduced to 0%-42% in ileum (P < 0.05) and 0%-17% in colon (P < 0.01) compared to controls. In humans, tachykinins exert gut contractile effects, of similar strength as acetylcholine, predominantly through activation of neurokinin 2 receptors. These responses are greatly reduced in inflamed tissues of ulcerative colitis and Crohn disease.

Scandinavian Journal of Gastroenterology, 1985

The effect of peptide YY (PYY) on the myoelectric activity of the small intestine was studied in ... more The effect of peptide YY (PYY) on the myoelectric activity of the small intestine was studied in relation to the transit of a 51Cr marker solution in fasted conscious rats. The myoelectric activity was recorded by means of bipolar electrodes implanted at 5, 20, and 35 cm from the pylorus. The marker was administered in the duodenum immediately after an activity front of a migrating myoelectric complex (MMC) had passed the first recording site. Under control conditions, the propagation of one activity front over the three recording levels was accompanied by the propulsion of 90.2 +/- 11.4% of the total radioactivity as one portion distal to the third electrode site. The median peak of the radioactivity was recovered at a distance approximately twice that propagated by an activity front. Intravenous infusion of PYY (50 pmol X kg-1 X min-1) had no effect on the occurrence of the MMC in the duodenum but interrupted its distal propagation and almost totally abolished the spiking activity in the jejunum. In comparison with controls, the transport of the marker was significantly retarded, and the median peak of the radioactivity was recovered proximal to the third electrode site. The results indicate that the small-intestinal contents are propelled as one portion in front of a propagating activity front. The inhibition of the activity front by PYY may account for the delay in the transit of the small-intestinal contents.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal of Pharmacological and Toxicological Methods, 2006

IntroductionTo assure drug safety, the investigation of the relationship between plasma concentra... more IntroductionTo assure drug safety, the investigation of the relationship between plasma concentration and drug-induced prolongation of the QT interval of the ECG is a challenge in drug discovery. For this purpose, dofetilide was utilized to demonstrate the benefits of characterizing the complete time course of concentrations and effect in conscious beagle dogs in the assessment of drug safety.

Naunyn-Schmiedeberg's Archives of Pharmacology, 1986

Journal of Pharmacological and Toxicological Methods, 2011

The gastrointestinal (GI) tract is one of the target organs of adverse drug effects in different ... more The gastrointestinal (GI) tract is one of the target organs of adverse drug effects in different phases of drug development. This study aimed to investigate the feasibility of population pharmacokinetic modeling to quantify the rate of gastric emptying (GE) and small intestinal transit time (SITT) in response to drugs that affect GI motility in fed and fasted dogs. Paracetamol and sulfapyridine (sulfasalazine metabolite) pharmacokinetics were used as markers for GE and SITT, respectively. In two separate studies, under fed and fasted conditions, six male beagle dogs received a 15min intravenous infusion of vehicle, atropine (0.06mg/kg) or erythromycin (1mg/kg) followed by an intragastric administration of a mixture of paracetamol (24mg/kg) and sulfasalazine (20mg/kg). Food was given just before or at 6h after drug administration in the fed and fasted study, respectively. Blood samples were collected for analysis of paracetamol and sulfapyridine in plasma. Population pharmacokinetic analysis of paracetamol and sulfapyridine in plasma was used to determine the rate of GE and SITT. The quantitative parameter estimates demonstrated a detailed and significant influence of atropine, erythromycin and food on GE and SITT. Compared to fasted conditions food intake delayed GE in pharmacologically treated dogs and SITT was shortened after treatment with vehicle or erythromycin. Atropine substantially delayed GE in fed and fasted conditions but the effect on SITT was evident only under fed condition. Erythromycin, in contrast, increased GE only in fasted conditions, and generally delayed SITT. Population pharmacokinetic modeling of paracetamol and sulfapyridine provides a suitable preclinical non-invasive experimental method for quantification of drug- and food-induced changes in the rate of GE and SITT in conscious beagle dogs for use in safety evaluations to predict changes in GI transit and/or to explain the pharmacokinetic profile of drugs under development.

Journal of Pharmacological and Toxicological Methods, 2011

Journal of Pharmacological and Toxicological Methods, 2007

Drug-induced QT interval prolongation may lead to ventricular arrhythmias. The aim of the study w... more Drug-induced QT interval prolongation may lead to ventricular arrhythmias. The aim of the study was to optimize QT interval data processing to quantify drug-induced QT interval prolongation in the telemetry instrumented conscious dog model. The test substances cisapride, dofetilide, haloperidol, and terfenadine and corresponding vehicles were given to male and female beagle dogs during two consecutive 90-min intravenous infusions. Cardiovascular parameters were recorded for 24 h and exposure to the drugs was measured. The delayed response in the QT interval after an abrupt change in heart rate was investigated. Eight mathematical models to describe the QT interval-heart rate relationship were compared and different sets of covariates were used to quantify the drug-induced effect on the QT interval. After an abrupt decrease in heart rate, a 75% adaptation of the QT interval was reached after 54+/-9 s. A linear model was preferred to correct the drug-induced effect on the QT interval for heart rate, vehicle effect, serial correlation, plasma concentration and time of day. All test substances significantly prolonged the QT interval. To optimize the processing of QT interval data, the delay in QT interval response after an abrupt change in heart rate should be considered. The QT interval-heart rate relationship and vehicle response were individual-specific and corrections were therefore made individually. When estimating the drug-induced effect on the QT interval it is considered advantageous to use plasma concentration as a covariate, as well as adjusting for vehicle effect and serial correlation in measurements. The conscious dog model detected significant increases in the QT interval for all test substances investigated.

Journal of Pharmacological and Toxicological Methods, 2008

Annals of the New York Academy of Sciences, 1982

Thesis (doctoral)--Karolinska Institutet, 1985. Includes bibliographical references.

Handbook of Experimental Pharmacology, 2015

Although the basic structure of the gastrointestinal tract (GIT) is similar across species, there... more Although the basic structure of the gastrointestinal tract (GIT) is similar across species, there are significant differences in the anatomy, physiology, and biochemistry between humans and laboratory animals, which should be taken into account when conducting a gastrointestinal (GI) assessment. Historically, the percentage of cases of drug attrition associated with GI-related adverse effects is small; however, this incidence has increased over the last few years. Drug-related GI effects are very diverse, usually functional in nature, and not limited to a single pharmacological class. The most common GI signs are nausea and vomiting, diarrhea, constipation, and gastric ulceration. Despite being generally not life-threatening, they can greatly affect patient compliance and quality of life. There is therefore a real need for improved and/or more extensive GI screening of candidate drugs in preclinical development, which may help to better predict clinical effects. Models to identify drug effects on GI function cover GI motility, nausea and emesis liability, secretory function (mainly gastric secretion), and absorption aspects. Both in vitro and in vivo assessments are described in this chapter. Drug-induced effects on GI function can be assessed in stand-alone safety pharmacology studies or as endpoints integrated into toxicology studies. In silico approaches are also being developed, such as the gut-on-a-chip model, but await further optimization and validation before routine use in drug development. GI injuries are still in their infancy with regard to biomarkers, probably due to their greater diversity. Nevertheless, several potential blood, stool, and breath biomarkers have been investigated. However, additional validation studies are necessary to assess the relevance of these biomarkers and their predictive value for GI injuries.

Regulatory Peptides, 1984

The effect of i.v. infusions of bombesin and somatostatin, administered either separately or in c... more The effect of i.v. infusions of bombesin and somatostatin, administered either separately or in combination, on migrating myoelectric complexes (MMCs) in the small intestine were studied in conscious, fasted rats. The myoelectrical activity was recorded by means of three bipolar electrodes chronically implanted into the duodenum and jejunum. Infusion of bombesin (0.5, 0.9 and 3 pmol . kg-1 . min-1) interrupted the MMC and induced irregular spiking activity similar to that observed on feeding. Only after the highest dose a consistent inhibition of the MMCs and a significant increase (P less than 0.05) of the spiking activity were achieved at all recording levels. Somatostatin (90 pmol . kg-1 . min-1) did not interrupt the MMC, but reduced significantly the incidence of the activity fronts and spiking activity of the MMCs (P less than 0.05). The effects of bombesin (3 pmol . kg-1 . min-1) on the MMC pattern were inhibited by simultaneous infusion of somatostatin (P less than 0.05). In a second series of experiments, using anesthetized rats, infusion of bombesin (0.5 and 3 pmol . kg-1 . min-1) increased the plasma concentration of neurotensin- gastrin-like immunoreactivities in a dose-dependent manner. The results show that bombesin alters the myoelectrical activity of the small intestine from a fasting to a fed pattern. Since the effect of bombesin was inhibited by the hormone release inhibitor somatostatin, it is suggested that the effect of bombesin on MMC may be secondary to the release of gastrointestinal peptides, such as neurotensin or gastrin.

Journal of Pharmacological and Toxicological Methods, 2008

... Title. Correction of QT intervals in dogs with tachycardia. Challenge to atropin. View Full T... more ... Title. Correction of QT intervals in dogs with tachycardia. Challenge to atropin. View Full Text (Elsevier ScienceDirect user account required). Author(s). Pehrson, R., Forsberg, T., Al-Saffar, A.,. Journal. Journal of Pharmacological and Toxicological Methods. Vol. 58, No. ...

Acta Physiologica Scandinavica, 1983

The aim of the present study in the rat was to localize the gastrointestinal site(s) of NTLI rele... more The aim of the present study in the rat was to localize the gastrointestinal site(s) of NTLI release and to investigate the importance of bile and pancreatic juice for fat-induced NTLI release. Administration of Intralipid (2 ml) into the stomach and oleic acid (0.5 ml) into the duodenum increased the plasma concentration of NTLI (p-NTLI). The increase in p-NTLI levels occurred only when the jejunum and ileum were exposed to Intralipid but not when the exposure was limited to the stomach and duodenum. Exclusion of pancreatic juice significantly reduced the p-NTLI response and exclusion of both bile and pancreatic juice completely abolished the p-NTLI response to duodenally-administered oleic acid. The results indicate that neurotension is released by a direct luminal exposure of the neurotensin containing N-cells to fatty acids. It seems probable that fatty acids have to be transformed to a micellar form in order to release NTLI.

Acta Pharmacologica Sinica, 2007

1 The purpose of this study was to develop and validate an integrated pharmacokineticpharmacodyna... more 1 The purpose of this study was to develop and validate an integrated pharmacokineticpharmacodynamic model for the anti-lipolytic eects of the adenosine A 1 -receptor agonist N 6 -(psulphophenyl)adenosine (SPA). Tissue selectivity of SPA was investigated by quanti®cation of haemodynamic and anti-lipolytic eects in individual animals. 2 After intravenous infusion of SPA to conscious normotensive Wistar rats, arterial blood samples were drawn for determination of blood SPA concentrations, plasma non-esteri®ed fatty acid (NEFA) and b-hydroxybutyrate levels. Blood pressure and heart rate were monitored continuously. 3 The relationship between the SPA concentrations and the NEFA lowering eect was described by the indirect suppression model. Administration of SPA at dierent rates and doses (60 mg kg 71 in 5 min and 15 min, and 120 mg kg 71 in 60 min) led to uniform pharmacodynamic parameter estimates. The averaged parameters (mean+s.e., n=19) were E max : 780+2% (% change from baseline), EC 50 : 22+2 ng ml 71 , and Hill factor: 2.2+0.2. 4 In another group, given 400 mg kg 71 SPA in 15 min, pharmacodynamic parameters for both heart rate and anti-lipolytic eect were derived within the same animal. The reduction in heart rate was directly related to blood concentration on the basis of the sigmoidal E max model. SPA inhibited lipolysis at concentrations lower than those required for an eect on heart rate. The EC 50 values (mean+s.e., n=6) were 131+31 ng ml 71 and 20+3 ng ml 71 for heart rate and NEFA lowering eect, respectively. 5 In conclusion, the relationship between blood SPA concentrations and anti-lipolytic eect was adequately described by the indirect suppression model. For SPA a 6 fold dierence in potency was observed between the eects on heart rate and NEFAs, indicating some degree of tissue selectivity in vivo.

The paracetamol (PCM) and sulfapyridine (SP) double marker technique is based on combined gastric... more The paracetamol (PCM) and sulfapyridine (SP) double marker technique is based on combined gastric administration of PCM and sulfasalazine followed by plasma concentration measurements for PCM and SP. PCM is rapidly absorbed from the duodenum and can be regarded as a marker for gastric emptying (GE). Sulfasalazine is poorly absorbed from the small intestine but is extensively metabolized in the colon by bacteria into SP. As SP is only absorbed from the colon it serves as a marker for small intestinal transit time (SITT). The double marker method is used to identify and characterize effects on GE and SITT. The aim of the present investigation was to demonstrate how semi-mechanistic modeling of PCM and SP could facilitate characterization and the understanding of pharmacologically induced changes in GI transit under fed and fasting conditions. Two double marker validation studies were performed in dogs with erythromycin (1 mg/kg) and atropine (0.06 mg/kg), both of which have been descr...

Digestive diseases and sciences, 1997

The lipopolysaccharide (endotoxin) of gram-negative bacteria has systemic effects in animals and ... more The lipopolysaccharide (endotoxin) of gram-negative bacteria has systemic effects in animals and man. Our aim was to investigate the effects of E. coli lipopolysaccharide on motility and transit through the small intestine in rats and to analyze plasma and tissue concentrations of intestinal neuropeptides. When lipopolysaccharide (20-160 micrograms/kg) was administered intravenously, the migrating myoelectric complex was replaced by spike bursts accompanied by rapid transit. Tissue concentrations of substance P and neurokinin A decreased, while plasma levels of calcitonin gene-related peptide increased N omega-Nitro-L-arginine, N omega-L-arginine methyl ester, dexamethasone, or indomethacin prevented these changes in myoelectric activity and tissue contents of neuropeptides. All of these compounds, except indomethacin, prevented the increased rate of transit. Thus, lipopolysaccharide changes motility through the nitric oxide and arachidonic pathways, resulting in rapid transit throu...

Scandinavian journal of gastroenterology. Supplement, 1984

The physiological significance of neurotensin, with respect to gut motility in man, may be to med... more The physiological significance of neurotensin, with respect to gut motility in man, may be to mediate postprandial, fat-induced changes in the motility pattern of the gastrointestinal tract. There is strong experimental evidence that this effect of neurotensin is endocrine-mediated. The role of neurotensin as a paracrine hormone, neurotransmitter or neurocrine hormone remains to be determined.

Scandinavian journal of gastroenterology, 1984

The relation between the occurrence of the migrating myoelectric complexes (MMC) and the transit ... more The relation between the occurrence of the migrating myoelectric complexes (MMC) and the transit of small-intestinal contents was studied in fasted, conscious rats. MMC were monitored by means of three bipolar electrodes implanted along the small intestine 5, 20, and 35 cm distal to the pylorus. In the presence of an MMC, the radioactive marker was transported along the small intestine as one main peak and recovered aboral to the activity front. Intravenous infusion of bombesin, 3 pmol X kg-1 X min-1, disrupted the MMC and induced irregular spiking activity at all recording levels. Furthermore, during bombesin infusion the radioactive marker was propelled a considerable distance, although the transit was significantly retarded in comparison to that in the presence of an MMC (p less than 0.01). The results indicate that the small-intestinal contents are propelled aboral to an activity front. Continuous irregular spiking activity during bombesin infusion contributes less to the transi...

Scandinavian Journal of Gastroenterology, 2001

Tachykinins and acetylcholine are main physiological motility stimulators in the gut by their eff... more Tachykinins and acetylcholine are main physiological motility stimulators in the gut by their effects exerted through neurokinin and muscarinic receptors. Longitudinal and circular muscle strips from normal ileum and colon or corresponding tissues from patients with inflammatory bowel disease were studied in organ baths. Contractile responses to the tachykinins substance P, neurokinin A, neurokinin B and neuropeptide gamma and specific analogs for their respective receptors were compared to acetylcholine. Acetylcholine caused concentration-dependent phasic contractions in longitudinal and circular muscle of normal ileum and colon (both P < 0.01). In inflamed tissues, contractile responses were reduced to 17%-33% in ileum (P < 0.05) and 3%-26% in colon (P < 0.01). Both natural tachykinins and their specific analogs caused concentration-dependent phasic, tonic and rhythmic contractions (each P < 0.01). Neuropeptide gamma was most potent in contracting the ileum and colon, followed by neurokinin A, substance P and neurokinin B, let alone longitudinal muscle of the ileum where neuropeptide gamma and neurokinin A were equipotent. Of the tachykinin analogs, Nle10-NKA(4-10) was more potent than substance P methyl ester and senktide, indicating neurokinin 2 receptors are predominant for contractile effects of tachykinins. In inflamed tissues, contractile responses to tachykinins were reduced to 0%-42% in ileum (P < 0.05) and 0%-17% in colon (P < 0.01) compared to controls. In humans, tachykinins exert gut contractile effects, of similar strength as acetylcholine, predominantly through activation of neurokinin 2 receptors. These responses are greatly reduced in inflamed tissues of ulcerative colitis and Crohn disease.

Scandinavian Journal of Gastroenterology, 1985

The effect of peptide YY (PYY) on the myoelectric activity of the small intestine was studied in ... more The effect of peptide YY (PYY) on the myoelectric activity of the small intestine was studied in relation to the transit of a 51Cr marker solution in fasted conscious rats. The myoelectric activity was recorded by means of bipolar electrodes implanted at 5, 20, and 35 cm from the pylorus. The marker was administered in the duodenum immediately after an activity front of a migrating myoelectric complex (MMC) had passed the first recording site. Under control conditions, the propagation of one activity front over the three recording levels was accompanied by the propulsion of 90.2 +/- 11.4% of the total radioactivity as one portion distal to the third electrode site. The median peak of the radioactivity was recovered at a distance approximately twice that propagated by an activity front. Intravenous infusion of PYY (50 pmol X kg-1 X min-1) had no effect on the occurrence of the MMC in the duodenum but interrupted its distal propagation and almost totally abolished the spiking activity in the jejunum. In comparison with controls, the transport of the marker was significantly retarded, and the median peak of the radioactivity was recovered proximal to the third electrode site. The results indicate that the small-intestinal contents are propelled as one portion in front of a propagating activity front. The inhibition of the activity front by PYY may account for the delay in the transit of the small-intestinal contents.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal of Pharmacological and Toxicological Methods, 2006

IntroductionTo assure drug safety, the investigation of the relationship between plasma concentra... more IntroductionTo assure drug safety, the investigation of the relationship between plasma concentration and drug-induced prolongation of the QT interval of the ECG is a challenge in drug discovery. For this purpose, dofetilide was utilized to demonstrate the benefits of characterizing the complete time course of concentrations and effect in conscious beagle dogs in the assessment of drug safety.

Naunyn-Schmiedeberg's Archives of Pharmacology, 1986

Journal of Pharmacological and Toxicological Methods, 2011

The gastrointestinal (GI) tract is one of the target organs of adverse drug effects in different ... more The gastrointestinal (GI) tract is one of the target organs of adverse drug effects in different phases of drug development. This study aimed to investigate the feasibility of population pharmacokinetic modeling to quantify the rate of gastric emptying (GE) and small intestinal transit time (SITT) in response to drugs that affect GI motility in fed and fasted dogs. Paracetamol and sulfapyridine (sulfasalazine metabolite) pharmacokinetics were used as markers for GE and SITT, respectively. In two separate studies, under fed and fasted conditions, six male beagle dogs received a 15min intravenous infusion of vehicle, atropine (0.06mg/kg) or erythromycin (1mg/kg) followed by an intragastric administration of a mixture of paracetamol (24mg/kg) and sulfasalazine (20mg/kg). Food was given just before or at 6h after drug administration in the fed and fasted study, respectively. Blood samples were collected for analysis of paracetamol and sulfapyridine in plasma. Population pharmacokinetic analysis of paracetamol and sulfapyridine in plasma was used to determine the rate of GE and SITT. The quantitative parameter estimates demonstrated a detailed and significant influence of atropine, erythromycin and food on GE and SITT. Compared to fasted conditions food intake delayed GE in pharmacologically treated dogs and SITT was shortened after treatment with vehicle or erythromycin. Atropine substantially delayed GE in fed and fasted conditions but the effect on SITT was evident only under fed condition. Erythromycin, in contrast, increased GE only in fasted conditions, and generally delayed SITT. Population pharmacokinetic modeling of paracetamol and sulfapyridine provides a suitable preclinical non-invasive experimental method for quantification of drug- and food-induced changes in the rate of GE and SITT in conscious beagle dogs for use in safety evaluations to predict changes in GI transit and/or to explain the pharmacokinetic profile of drugs under development.

Journal of Pharmacological and Toxicological Methods, 2011

Journal of Pharmacological and Toxicological Methods, 2007

Drug-induced QT interval prolongation may lead to ventricular arrhythmias. The aim of the study w... more Drug-induced QT interval prolongation may lead to ventricular arrhythmias. The aim of the study was to optimize QT interval data processing to quantify drug-induced QT interval prolongation in the telemetry instrumented conscious dog model. The test substances cisapride, dofetilide, haloperidol, and terfenadine and corresponding vehicles were given to male and female beagle dogs during two consecutive 90-min intravenous infusions. Cardiovascular parameters were recorded for 24 h and exposure to the drugs was measured. The delayed response in the QT interval after an abrupt change in heart rate was investigated. Eight mathematical models to describe the QT interval-heart rate relationship were compared and different sets of covariates were used to quantify the drug-induced effect on the QT interval. After an abrupt decrease in heart rate, a 75% adaptation of the QT interval was reached after 54+/-9 s. A linear model was preferred to correct the drug-induced effect on the QT interval for heart rate, vehicle effect, serial correlation, plasma concentration and time of day. All test substances significantly prolonged the QT interval. To optimize the processing of QT interval data, the delay in QT interval response after an abrupt change in heart rate should be considered. The QT interval-heart rate relationship and vehicle response were individual-specific and corrections were therefore made individually. When estimating the drug-induced effect on the QT interval it is considered advantageous to use plasma concentration as a covariate, as well as adjusting for vehicle effect and serial correlation in measurements. The conscious dog model detected significant increases in the QT interval for all test substances investigated.

Journal of Pharmacological and Toxicological Methods, 2008