A paracetamol-pasta test for assessing gastric emptying in healthy and diabetic subjects.

Previous studies have shown that the relationship between gastrointestinal symptoms and gastric emptying is weak. Therefore the quantitative assessment of gastric emptying with a relatively simple, non-invasive test would be of considerable clinical value in insulin-treated diabetic patients to identify those with disturbed gastric emptying. The aim of this investigation was to evaluate the inter- and intra-subject variability of a paracetamol-pasta test in healthy subjects and in IDDM patients. Eighteen healthy subjects (8 women) with a mean age of 37 years (range 19-68) and 19 IDDM patients (10 women) with a mean age of 48 years (range 25-62) and mean duration of diabetes of 28 years (range 6-52) were studied on two occasions with an interval of 1 to 4 weeks. After an overnight fast the subjects ingested a standardized pasta meal mixed with 2 g paracetamol in a period of 15 min. Blood samples were drawn at regular intervals after meal intake and analysed for paracetamol (P) and blood glucose. The serum levels of P were significantly lower at 15 min in diabetic patients. The intra-subject coefficients of variation (CV%) of the areas under the serum paracetamol concentration-time curve (AUC) were almost identical in healthy and diabetic subjects, while the intra-subject CV of the P-Tmax was considerably lower in diabetic patients as well as markedly lower than the corresponding inter-subject CV. The inter-subject CVs of all parameters calculated were generally higher in diabetic patients. This study indicates that the assessment of paracetamol absorption kinetics during a paracetamol-pasta test is reproducible in healthy as well as in diabetic subjects. Diabetic patients with non-optimal glucose control and without a case history indicating gastroduodenal motor function disturbances achieve lower serum concentration of P at 15 min and generally display a higher inter-individual variability indicative of subclinical disturbances of gastric emptying in this group of patients.

Stereoselective disposition of mianserin is related to debrisoquin hydroxylation polymorphism.

The pharmacokinetics of mianserin and its main metabolite desmethylmianserin were studied in poor and extensive metabolizers of debrisoquin and of S-mephenytoin after a single oral dose of racemic mianserin. The debrisoquin metabolic ratio (MR) correlated significantly with area under the serum concentration-time curves (AUC) for (+/-)-mianserin and (+/-)-desmethylmianserin. Enantioselective high-performance liquid chromatographic analysis of mianserin showed that debrisoquin MR was related to AUC(0-12) for S(+)-mianserin (rs = 0.87; p = 0.001; n = 15) but not for R(-)-mianserin. The ratio between the AUC(0-12) for S(+)-mianserin and that for R(-)-mianserin was higher in poor metabolizers than in extensive metabolizers. Two extremely rapid extensive metabolizer subjects had the lowest mianserin S/R ratios. No differences in the pharmacokinetics of mianserin or desmethylmianserin were found between extensive metabolizers and poor metabolizers of S-mephenytoin. The study shows that the elimination of both mianserin and its main metabolite desmethylmianserin is dependent on CYP2D6 activity. Furthermore, the CYP2D6-dependent elimination of mianserin shows marked enantioselectivity for the more active S(+)-enantiomer of mianserin.

Importance of creatinine analyses of urine when screening for abused drugs.

We report here a simple method involving urine creatine measurements for testing authenticity and reducing false-negative results in urine testing for drugs of abuse. Urinary creatinine in consecutive patient samples (n = 176) ranged between 0.1 and 31.9 mmol/L (mean 9.8 +/- SD 6.2) and the osmolality in these urines ranged between 49 and 1183 mOsm/kg (mean 595 +/- SD 276). With other consecutive samples in which creatinine was (arbitrarily chosen) less than 4.3 mmol/L (n = 85), the correlation with osmolality was lower. In 10 randomly selected urine samples from different patients, all "clean" for all drugs of abuse in initial immunological drug testing with approved methodology (in which creatinine was less than 4.3 mmol/L and osmolality was less than 200 mOsm/kg), five patients turned out to be drug positive after a simple concentration by volume. In a formerly heavy smoker of cannabis, the excretion of cannabinoids and creatinine was monitored for 93 days. The substances showed very good correlation throughout this period (r = 0.93, P less than 0.001), whereas simple measurements of cannabinoid concentrations would have falsely indicated several relapses of cannabis abuse. Urine samples used in drug-abuse testing should be tested for creatinine; if creatinine is less than 4.0 mmol/L, negative results for drugs may not be valid.

[Interaction between drugs. A critical assessment of various controlling factors in relation to clinical significance--exemplified by cimetidine]. / Interaktion mellan läkemedel. En kritisk genomgång av några styrande faktorer i förhållande till klinisk betydelse--exemplet cimetidin.

Interactions between pharmaceutical preparations are common and can occur at almost every stage in a substance's metabolic clearance but frequently lack clinical significance. Different factors must be considered in the assessment of data on interactions. This article compares interactions between H2-antagonists from various aspects: the disposition of the study, the mechanism of operation, the pharmacokinetics and pharmaco-dynamics etc. Several pharmaceutical interactions are dose-related so that the questions of equipotent dosage, the length of the period of treatment etc are crucial. The principal interaction mechanism for this group of drugs pertains to absorption, interference with the oxidative metabolism and excretion via the kidneys. Important measures to avoid interaction problems are individualization of the dose (lower dose = less risk), scrupulous clinical observation, and determination of the concentration in the blood of the drug concerned, if an analytical method exists. Under these circumstances any of the H2 antagonists may be used.

The pharmacokinetics of cotinine in plasma and saliva from non-smoking healthy volunteers.

Cotinine is a major metabolite of nicotine in man. Its disposition kinetics has been followed in plasma and saliva from nine nonsmokers, 23 to 56 years of age. Cotinine 5, 10 and 20 mg was given intravenously and orally to each subject, and plasma, saliva and urine samples were collected for 96 h. The kinetics of cotinine was best described by a multicompartment model with three distinct phases both in plasma and saliva. Regardless of the mode of administration, there was no indication of dose-dependent kinetics. Mean total plasma clearance was 63.8 ml.h-1.kg-1 and mean renal clearance was 4.7 ml.h-1.kg-1, i.e. only 10% of the dose was excreted unchanged in the urine. The volume of distribution, as calculated from the plasma curves, was slightly greater than the body weight, 1.1 l.kg-1. The concentration of cotinine was 20 to 40% higher in unstimulated mixed saliva than in plasma during the absorption, distribution and elimination phases. As the clearance and distribution values in saliva were directly proportional to the corresponding values in plasma, similar terminal half-life values were obtained in the two body fluids, 15.5 and 16.8 h for plasma and saliva, respectively. Thus the kinetics of cotinine is linear after intravenous and after oral dosing, and salivary concentrations give the same information about cotinine disposition in the body as do plasma concentrations.

Lithium and renal function in relation to concomitant theory.

Two hundred and fourteen patients (99 men, 115 women, age 21-87 years) were treated with lithium during the period 1963-1984 at the Psychiatric Unit, Danderyd Hospital. The patients were diagnosed as having bipolar depression (97), unipolar depression (54), cycloid psychosis (21), schizoaffective psychosis and depressive neurosis (42). Sixty patients were treated with lithium salt only, 73 patients received neuroleptic drugs in addition to lithium and 51 antidepressant drugs. Sixteen patients were treated with a combination of neuroleptic drugs, antidepressant drugs and lithium. Fourteen patients were treated with lithium and benzodiazepines. The aim of this retrospective lithium study was to examine the renal function in these different treatment groups. The results show that patients treated with a lithium salt and neuroleptic drugs have significantly lower urinary osmolality than those treated with a lithium salt only. Also tricyclic antidepressants in combination with a lithium salt appear to have an influence on renal function. The duration of concomitant therapy seems to be of importance for the effect on renal function. Eleven patients with the lowest osmolality values were investigated at the Renal Unit, Danderyd Hospital, but in no case was it necessary to withdraw the lithium treatment.

Pharmacokinetics of bolus intravenous and oral doses of L-carnitine in healthy subjects.

The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 and 6 g was studied in 6 healthy subjects on a low-carnitine diet. Carnitine was more rapidly eliminated from plasma after the 6 g dose. Comparing the doses, the t1/2 beta of the elimination phase (beta) was 6.5 h vs 3.9 h, the elimination constant 0.40 vs 0.50 h-1 and the plasma carnitine clearance was 5.4 vs 6.11.h-1 for the 2 g and 6 g doses, respectively, showing dose-related elimination. Saturable kinetics were not found. The apparent volumes of distribution after the two doses were not significantly different and were of the same order as the total body water. Urinary recoveries of the 2 g and 6 g doses were 70% and 82%, respectively, during the first 24 h. Following the oral doses, there was no significant difference between the areas under the plasma carnitine concentration-time curves. Urinary recovery was 8% and 4% for the 2 g and 6 g doses during the first 24 h. Oral bioavailability was 16% for the 2 g dose and 5% for the 6 g dose. The results suggest that the mucosal absorption of carnitine was already saturated by the 2 g dose.

Pharmacokinetics of intravenous and oral bolus doses of L-carnitine in healthy subjects.

The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 g and 6 g has been investigated in 6 healthy subjects on a low carnitine diet. Carnitine was more rapidly eliminated from plasma after the higher dose. Comparing the 2-g and 6-g doses, the t1/2 beta of the elimination phase (beta) was 6.5 h vs 3.9 h, the elimination constant was 0.40 vs 0.50 h-1 and the plasma carnitine clearance was 5.4 vs 6.1 1 x h-1 (p less than 0.025), thus showing dose-related elimination. Saturable kinetics was not found in the range of doses given. The apparent volumes of distribution after the two doses were not significantly different and they were of the same order as the total body water. Urinary recoveries after the 2-g and 6-g doses were 70% and 82% during the first 24 h, respectively. Following the two oral dosing, there was no significant difference in AUCs of plasma carnitine. Urinary recoveries were 8% and 4% for the 2-g and 6-g doses during the first 24 h. The oral bioavailability of the 2-g dose was 16% and of the 6 h dose 5%. The results suggest that the mucosal absorption of carnitine is already saturated at the 2-g dose.

A long lasting gastrin response to apomorphine revealed by inhibitors of gastric acid secretion.

Gastrin levels, in the peripheral venous blood of conscious dogs treated with apomorphine (0.05 mg/kg IV), were analysed with a radioimmunoassay. Pretreatment (30 min) with the gastric acid inhibitors cimetidine, ranitidine (H2 receptor antagonists, 4 mg/kg and 1 mg/kg respectively) or omeprazole (H+-K+ ATPase inhibitor, 1.6 mg/kg) prolonged the elevation of gastrin levels occurring in response to an administration of apomorphine. Haloperidol (0.1 mg/kg), but not the peripheral dopamine receptor antagonist domperidone (0.2 mg/kg), abolished the enhanced gastrin response to apomorphine occurring after pretreatment with cimetidine. Cimetidine did not increase the gastrin response to apomorphine in vagotomized dogs. The results are interpreted in terms of an additive gastrin response to apomorphine (different from the short lasting initial peak previously described) which is vagally mediated and inhibited by the gastric acid.

Endocrine cells in the human colorectal mucosa: immunocytochemical observations on patients with prolapse or internal procidentia of the rectum.

We have examined the occurrence and distribution of endocrine cells storing serotonin and the regulatory peptides somatostatin, glicentin, peptide YY in rectal mucosa on 16 patients with prolapse or intussusception of the rectum. There were no significant differences compared with normal rectal mucosa. Our results do not support the assumption that these endocrine cells of the rectum are involved in the pathophysiology of rectal prolapse.

Single-dose kinetics and bioavailability of sodium-hydrogen divalproate.

Sodium-hydrogen divalproate (SHD) is a new chemical entity that quickly dissociates into valproic acid (VPA) and sodium valproate in water and is absorbed as VPA from the gastrointestinal tract. SHD is formulated as an enteric-coated tablet and may also result in less gastrointestinal irritation than other preparations of VPA. The bioavailability of valproate from SHD enteric-coated tablets (Epival, Abbott-50711) and from sodium valproate enteric-coated tablets (Ergenyl) was compared in a single-dose, double-blind, crossover study. Fourteen healthy volunteers (mean age 28.7 years) participated. A single oral dose of 250 mg SHD (assayed potency 249.3 mg VPA) or 300 mg sodium valproate (assayed potency 251.1 mg VPA) was given to each volunteer. Blood samples were collected intermittently up to 48 h and VPA in serum was assayed by gas chromatography. The areas under the serum concentration-time curves (AUC0----infinity) did not show any statistically significant difference (2,925.0 +/- 189.1 versus 2,816.2 +/- 162.2 h X mumol/L) between SHD and sodium valproate. The elimination parameters for SHD were t1/2 = 12.6 +/- 0.7 h and CLs = 0.008 +/- 0.0005 L/kg/h. Vd,area was 0.146 +/- 0.004 L/kg. Data for sodium valproate were not significantly different. Thus, the extent of bioavailability and the single-dose kinetics of SHD and sodium valproate are similar with the exception of a more rapid absorption (Tmax 2.37 versus 3.23 h) and a higher concentration (Cmax 192 versus 176 mumol/L) for SHD. Both of these differences were statistically significant (p less than 0.01).

Release of VIP-like immunoreactivity in response to dopamine agonists, insulin hypoglycemia and feeding in conscious dogs.

VIP levels were measured by radioimmunoassay in peripheral venous blood of conscious dogs. Bolus injections of the dopamine agonists apomorphine, 0.05 mg/kg, and bromocriptine, 0.2 mg/kg, were found to increase VIP levels from approximately 5 pmol/l to 150 pmol/l. The release responses were abolished by pretreatment with dopamine antagonists (haloperidol 0.1 mg/kg or halopemid 0.1 mg/kg) and by hexamethonium (1 mg/kg) a blocker of ganglionic transmission. Vagotomy did not inhibit the dopamine agonist induced output of VIP. Vagal activation by means of feeding or insulin hypoglycemia caused only minor rises of VIP levels (5-10 pmol/l). It is concluded that dopamine agonists stimulate the release of VIP from populations of neurons other than those affected by vagal and sympathetic activation. Possible sites of action for the VIP releasing effect exerted by dopamine agonists are discussed. Furthermore, it is suggested that some of the peripheral effects exerted by dopaminergic drugs are exerted via a previous release of VIP.

Phenytoin excretion in human breast milk and plasma levels in nursed infants.

Phenytoin excretion into human breast milk was studied in six nursing women with epilepsy. The average ratio between the areas under the plasma (and milk) concentration versus time curves (AUC) was 0.13. There was a good (r = 0.97) correlation between the mean plasma and milk concentrations of phenytoin, and an even better relation (r = 0.99) between the AUC for phenytoin in plasma and the mean milk concentration. The ratio between unconjugated and conjugated 4-OH-phenytoin (the main metabolite) in plasma was 0.08-0.09. The corresponding ratio in milk was considerably higher. The present data do not argue against breast feeding during phenytoin therapy, not even when weighed against the potential risks for toxicity of the parent compound. Only two of six infants had a measurable, yet very low plasma concentration of phenytoin. The calculated body weight--related doses of phenytoin secreted into milk will be less than 5% of the dose to infants and small children.