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Biomedical subjects

M G Hansen

Publications and source records attributed to M G Hansen.

13 recordsLinked to original sources
PubMed1994

Single-dose kinetics of clomipramine: relationship to the sparteine and S-mephenytoin oxidation polymorphisms.

The influence of the sparteine and the S-mephenytoin oxidation polymorphisms on the kinetics of clomipramine were investigated in 25 healthy volunteers: 10 extensive metabolizers of sparteine and mephenytoin (EMs/EMm), nine poor metabolizers of sparteine and extensive metabolizers of mephenytoin (PMs/EMm), five extensive metabolizers of sparteine and poor metabolizers of mephenytoin (EMs/PMm), and one poor metabolizer of sparteine and mephenytoin (PMs/PMm). A single oral dose of 100 mg clomipramine hydrochloride was given to each subject after an overnight fast. Serum and urine levels of clomipramine and its metabolites were monitored after 1, 2, 3, 4, 6, 8, 11, 14, 24, 36, 48, and 96 hours. Additional serum was monitored after 6, 9, 12, and 15 days in the poor metabolizers. 2-Hydroxyclomipramine was undetectable in most subjects before enzymatic hydrolysis of serum and urine. The total median clearance of clomipramine was 99 L.hr-1 (range, 68 to 210) in the EMs/EMm subjects, 56 L.hr-1 (range, 37 to 183) in the PMs/EMm subjects, 66 L.hr-1 (range, 37 to 89) in the EMs/PMm subjects, and 43 L.hr-1 in the PMs/PMm subject. It was significantly lower in PMs/EMm and EMs/PMm subjects compared with EMs/EMm subjects (p = 0.006 and 0.028, respectively; Mann-Whitney). In addition, the formation clearance of 2-hydroxyclomipramine and the hydroxylation indexes were significantly lower in PMs/EMm subjects, as was the demethylation index in EMs/PMm subjects compared with EMs/EMm subjects. Our data thus provide evidence that the 2- and 8-hydroxylation of clomipramine are catalyzed by CYP2D6 and that the N-demethylation is catalyzed in part by CYP2C.

Adult↗
PubMed1993

Pharmacokinetics of citalopram in relation to the sparteine and the mephenytoin oxidation polymorphisms.

The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of sparteine and mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.

Citalopram↗
PubMed1993

Citalopram: interaction studies with levomepromazine, imipramine, and lithium.

The pharmacokinetic interactions between the selective serotonin reuptake inhibitor citalopram, given as an oral dose of 40 mg/day for 10 days, and (1) levomepromazine (50 mg single oral dose), (2) imipramine (100 mg single oral dose), and (3) lithium (30 mmol/day orally for 5 days) were examined in three panels each of 8 healthy young male volunteers (age 20-31). All volunteers were classified as extensive metabolizers of sparteine and mephenytoin. Each subject completed three study phases--one with citalopram alone, one with one of the three other drugs, alone, and one with citalopram combined with the corresponding other drug. For citalopram and its metabolites, a non-enantioselective analytical method (high-performance liquid chromatography) was used. Only two statistically significant interactions were indicated. First, levomepromazine caused a 10-20% increase from the initial steady-state levels of the primary citalopram metabolite, desmethylcitalopram. Second, citalopram caused approximately 50% increase in the single-dose area under the serum concentration/time curve of desipramine (primary metabolite or imipramine) and a corresponding reduction in the level of the subsequently formed metabolite 2-hydroxydesipramine. These findings are in agreement with the recent observations that (1) the demethylation of desmethylcitalopram (to didesmethylcytalopram) is partly mediated via the sparteine/debrisoquine oxygenase (CYP2D6) and that levomepromazine is a potent inhibitor of CYP2D6, and (2) that desmethylcitalopram has a somewhat stronger affinity for CYP2D6 than desipramine, and therefore may inhibit the hydroxylation of desipramine, which is also a substrate of CYP2D6.

Adult↗
PubMed1991

[Excessive bile secretion in a patient with cirrhosis after cholecystectomy and choledochotomy].

The volume of bile collected from a choledochal stoma usually does not exceed 1,000 milliliters during 24 hours. A case of excessive output of bile (drainage of more than 2,000 milliliters in 24 hours) through a T-tube after cholecystectomy and choledochotomy is described. Biopsy of the liver revealed micronodular cirrhosis. The hypotheses and experimental studies concerning excessive biliary out-flow are mentioned. The conclusion of this case-report is that the T-tube can be removed, despite excessive output of bile, when the patient tolerates clamping of the tube without abdominal pain and when and external fistula has been formed.

Adult↗
PubMed1983

Colonic transport of water and electrolytes in a patient with secretory diarrhea due to collagenous colitis.

Whole colon perfusion studies and measurements of luminal prostaglandin E2 were carried out in a 41-year-old female with collagenous colitis to investigate pathophysiological mechanisms for the diarrhea. Biopsies of the colorectal mucosa had revealed a continuous 25- to 60-micron subepithelial collagenous layer, but normal junctional complexes and capillaries. When the patient fasted, the diarrhea persisted and fecal electrolytes, as estimated from the concentration of sodium, potassium, and their anions, accounted for all the osmolality (284 mosm/kg) of stool water, the pH of which was above 8.0. The lumen-negative electrical potential difference in the rectum was -64 mV vs -45 +/- 2 mV (mean +/- SEM) in healthy controls. Profuse secretion of fluid and electrolytes occurred during colonic perfusion with saline. Transport of sodium appeared to be passive with flux ratios equal to those predicted for passive sodium movements, while chloride transport against a steep electrical gradient indicated active secretion. Perfusion with an "ileal output"-like solution decreased fluid and electrolyte secretion, suggesting that bicarbonate, in addition to chloride, may be a major determinant of secretion rates. Since immunoreactive prostaglandin E2 levels following in vivo equilibrium dialysis of feces ranged from 555 to 650 pg/ml vs 55 to 235 pg/ml (99% confidence limits) in healthy controls, it is speculated that prostaglandins synthesized locally in response to mucosal hypoxia might be the mediators of anion secretion.

Adult↗
PubMed1983

Gastrin production following antrectomy. A study on the occurrence of gastrin-producing cells and the serum gastrin response to feeding.

Fifteen patients were studied 3 to 35 years after antrectomy, with a gastroduodenal (Billroth I (BI)) anastomosis in 8, and a gastrojejunal (Billroth II (BII)) anastomosis in 7. The investigations included gastric acid secretion, serum gastrin response to feeding and immunohistochemical search for gastrin-producing cells in gastric remnant mucosal biopsies. All of the patients had hypochlorhydria. The gastrin response to feeding was minimal. Apart from a significantly higher value of serum gastrin 3 hours post-prandial in BI operated as compared to BII operated patients, no greater differences were found in the gastrin production between the two groups of patients. No gastrin-producing cells could be identified in the gastric remnant, not even in areas of pseudopyloric metaplasia. It is concluded that the gastrin production following antrectomy is caused by extragastric G-cells; these cells are poorly stimulated by food, and do not respond to hypochlorhydria with hypergastrinaemia.

Aged↗