Potassium balance in piretanide and digoxin treatment.

Piretanide, a new potent diuretic, was given to 18 healthy male subjects to determine its effect on serum, total body (TBK), and red cell potassium (RCP). TBK and RCP were measured before treatment to establish baseline values, after which all subjects received 6 mg piretanide a day for 14 days. After this period subjects were divided into two groups; group 1 received 6 mg/day piretanide for 14 more days and group 2 received the same dose of piretanide with 0.5 mg digoxin daily during the remaining 14 days. All treatments were terminated after 28 days, but subjects remained under observation for another 14 days. Serum potassium, TBK, and RCP were measured weekly during the 42-day period. Piretanide in a dose of 6 mg daily for a period of 6 wk did not induce a fall in serum potassium, TBK, or RCP. The addition of digoxin for 2 wk after piretanide alone for 2 wk did not decrease serum potassium and TBK, but RCP fell under the influence of piretanide with digoxin.

Effects of pentoxifylline on red blood cell deformability and blood viscosity under hyperosmolar conditions.

Using a hyperosmolar erythrocyte model, the authors studied the effect of changes in red cell deformability on whole blood viscosity and investigated the possibility of using pentoxifylline to modify red cell deformability and whole blood viscosity. In vitro studies reveal a significant correlation between the two parameters in as much as they are inversely proportionate, i.e. viscosity increases as red cell deformability decreases and vice versa. Addition of pentoxyfylline improves impaired red cell deformability under hyperosmolar conditions and simultaneously produces a reduction in whole blood viscosity.

Kinetics of piretanide tablets, penbutolol tablets and the fixed combination of both drugs in healthy male subjects after a single oral dose.

In an open-labelled cross-over study, ten healthy males received an oral dose of piretanide (6 mg tablet), penbutolol (40 mg film-coated tablet) or the fixed dose combination (film-coated tablet). Serum pharmacokinetics and 48 h urinary excretion of each drug were determined for the three dose regimens. The serum pharmacokinetics and excretion of penbutolol were unchanged in combination with piretanide. In combination with penbutolol the maximum serum concentration (Cmax) of piretanide was lowered by 40% (p less than 0.05) and time to reach Cmax delayed from 1.0 h to 1.6 h (p less than 0.05). However, areas under the serum concentration-time curves over 12 h and excretion of piretanide were unchanged, and its diuretic effect was undiminished. Thus the bioavailability of piretanide was unaffected by combination with penbutolol. The above changes in the pharmacokinetics of piretanide were explained entirely by differences in dissolution of the conventional and film-coated tablets. The drugs were safe and well tolerated.

Kinetics of piretanide absorption from the gastrointestinal tract.

In a recent report, it was shown that the loop diuretic piretanide is rapidly absorbed after placement of a piretanide solution in the duodenum, while the rate of absorption is definitely slower when the drug is instilled into the ascending colon (5). When piretanide is instilled into the stomach, the absorption process does not differ significantly from that after placement in the duodenum, neither with respect to amount nor rate (5). However, it was not clear from this study whether piretanide is directly absorbed from the stomach or rapidly released into the duodenum. In a study with five volunteers piretanide was instilled into the stomach via a gastroscope. The volunteers took part in two trial phases in a randomized cross-over design: in one phase the administration of 6 mg piretanide was preceded by intravenous administration of 40 mg hyoscine-N-butylbromide (HNB) to immobilize the stomach while in the alternative phase this coadministration of HNB was omitted. Furthermore, the volunteers were lying on their left side to avoid the gastric fluid leaking out into the intestine by gravity. From the concentration-time-curves monitored it can be concluded that piretanide is absorbed directly from the stomach for almost all subjects but with different rates. The rate of absorption increases clearly when the immobilizing effect of HNB disappears. It is most probable that returning peristaltic waves and succeeding gastric emptying results in enhanced absorption from the upper intestinal tract. Furthermore, a pharmacokinetic model which takes into account the differences in the rate of absorption along the gastrointestinal tract was adjusted to the data.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastrointestinal clinical pharmacology of peppermint oil.

In nine studies, 269 healthy subjects or patients underwent exposure to peppermint oil (PO) either by topical intraluminal (stomach or colon) or oral administration by single doses or 2 weeks treatment (n = 19). Methods used to detect effects were oro-cecal transit time by hydrogen expiration, total gastrointestinal transit time by carmine red method, gastric emptying time by radiolabelled test meal or sonography, direct observation of colonic motility or indirect recording through pressure changes or relieve of colonic spasms during barium enema examination. The dose range covered in single dose studies is 0.1-0.24ml of PO/subject. With one exception, which show an unexplained potentiation of neostigmine stimulated colon activity, all other studies result in effects, indicating a substantial spasmolytic effect of PO of the smooth muscles of the gastrointestinal tract. Pharmacokinetic studies reveal that fractionated urinary recovery of menthol is dependent on the kind of formulation used for the application of PO. Optimal pH triggered enteric coated formulations start releasing PO in the small intestine extending release over 10-12 h thus providing PO to the target organ in irritable bowel syndrome, i.e. the colon. The hypothesis is supported by anecdotal observations in patients with achlorhydria or ileostoma, respectively.

Peppermint oil in irritable bowel syndrome.

In a literature search 16 clinical trials investigating 180-200 mg enteric-coated peppermint oil (PO) in irritable bowel syndrome (IBS) or recurrent abdominal pain in children (1 study) with 651 patients enrolled were identified. Nine out of 16 studies were randomized double blind cross over trials with (n = 5) or without (n = 4) run in and/or wash out periods, five had a randomized double blind parallel group design and two were open labeled studies. Placebo served in 12 and anticholinergics in three studies as comparator. Eight out of 12 placebo controlled studies show statistically significant effects in favor of PO. Average response rates in terms of "overall success" are 58% (range 39-79%) for PO and 29% (range 10-52%) for placebo. The three studies versus smooth muscle relaxants did not show differences between treatments hinting for equivalence of treatments. Adverse events reported were generally mild and transient, but very specific. PO caused the typical GI effects like heartburn and anal/perianal burning or discomfort sensations, whereas the anticholinergics caused dry mouth and blurred vision. Anticholinergics and 5HT3/4-ant/agonists do not offer superior improvement rates, placebo responses cover the range as in PO trials. Taking into account the currently available drug treatments for IBS PO (1-2 capsules t.i.d. over 24 weeks) may be the drug of first choice in IBS patients with non-serious constipation or diarrhea to alleviate general symptoms and to improve quality of life.

Pharmacology and preclinical pharmacokinetics of peppermint oil.

The principal pharmacodynamic effect of peppermint oil relevant to the gastrointestinal tract is a dose-related antispasmodic effect on the smooth musculature due to the interference of menthol with the movement of calcium across the cell membrane. The choleretic and antifoaming effects of peppermint oil may play an additional role in medicinal use. Peppermint oil is relatively rapidly absorbed after oral administration and eliminated mainly via the bile. The major biliary metabolite is menthol glucuronide, which undergoes enterohepatic circulation. The urinary metabolites result from hydroxylation at the C-7 methyl group at C-8 and C-9 of the isopropyl moiety, forming a series of mono- and dihydroxymenthols and carboxylic acids, some of which are excreted in part as glucuronic acid conjugates. Studies with tritiated I-menthol in rats indicated about equal excretion in feces and urine. The main metabolite indentified was menthol-glucuronide. Additional metabolites are mono- or di-hydroxylated menthol derivatives.

Decrease in whole blood viscosity in alloxan diabetic rabbits.

Whole blood and plasma viscosity of normal and alloxan diabetic rabbits were measured by means of cone in cone viscosimeters at different shear rates. Blood behaves like a non-Newtonian fluid, i.e. the viscosity is shear rate-dependent whereas plasma viscosity remains constant over the shear rate range employed, i.e. behaves like a Newtonian fluid. Blood viscosity was found to be statistically significantly decreased in the alloxan diabetic group in comparison to the control group. The decrease is attributed to a slight decrease in mean hematocrit and mean plasma viscosity of the diabetic animals. The possible mechanisms of these changes are discussed.

Biorhythm in the renal excretion of electrolytes and uric acid in healthy subjects.

The same 8 subjects were investigated twice within 4 months with regard to variations in the renal clearance of uric acid, creatinine, sodium, potassium, chloride and osmolarity. After a 48-hour stabilization period, clearance values were determined at 2-hourly intervals for 12 hours. Food and fluid intake remained the same for the duration of the studies. The calculation of excretory fractions was based on creatinine clearance as an approximate of glomerular filtration rate. With the exception of creatinine clearance, all the variations tended to decrease during the morning and to exhibit distinct increases in the early afternoon. The maximal excretion fraction coincided with maximal clearance values. The following minimal and maximal clearance values were recorded: uric aicd 4,7-12,7 ml/min; creatinine 131-179 ml/min; Na+ 1,1-2,9 ml/min; K+ 6,6-16,5 ml/min; Cl- 1,4-3,5 ml/min; osmolarity 2,6-3,9 ml/min. The excretion fractions varied from 3,3 to 8,0% (uric acid); 0,7 to 1,8% (Na+); 5,4 to 1,08% (K+); 1,0 to 2,2% (Cl-) and 1,7 to 2,3% (osmolarity). The results of this investigation strongly suggest that clinical trials designed to evaluate the influence of drugs on renal clearances should not be conducted without an appropriate control phase.

Erythrocyte deformability in a red cell ageing model.

The authors studied the effect of a period of storage on erythrocyte deformability in blood samples collected from 31 healthy subjects. A significant reduction in erythrocyte deformability was recorded over the course of time. The study was designed to determine whether pentoxifylline produces a dose-dependent increase in erythrocyte deformability in red cells from ageing blood. The effect of theophylline and prednisolone on this parameter was also studied. A dose-dependent increase in erythrocyte deformability was established for pentoxifylline and was measurable immediately after addition of the substance. Theophylline increased erythrocyte deformability but not to a degree which differed significantly from the controls. Prednisolone elicited a slight reduction in erythrocyte deformability, but again the change was not significant by comparison with the controls. None of the substances brought about any change in the rate of red cell ageing.

Red blood cell aging as a model to influence pharmacologically the red cell filterability.

A method to filter whole blood through 5-micron filters at a pressure of 20 cm column of water and the use of aging red cells as a reproducible procedure to generate rigidified cells is described. The system is sensitive enough to evaluate in pharmacologic screening possible influences of chemical agents on red cell deformability. Investigations with the methylxanthine derivates pentoxifylline and theophylline, the beta-blocker penbutolol and prednisolone, revealed that only the first compound has a dose-dependent effect on red deformability.

The absorption of piretanide from the gastro-intestinal tract is site-dependent.

The absorption of piretanide was investigated after placing the drug in the stomach, duodenum and ascending colon under visual control. The relative amounts absorbed and the rates of absorption were estimated from the area under the curve and the total mean time, respectively. Similar amounts of piretanide were absorbed and at almost the same rate after placement in the stomach and duodenum; the area under the curve for the stomach was 250 ng h/ml and for the duodenum 243 ng h/ml, the mean absorption times being 1.97 h and 1.51 h respectively. A marked difference was observed in the rate of from the ascending colon; the area amounted to 66 ng h/ml and the mean time to 3.99 h. Although area values for the colon were significantly different from those observed with the stomach and duodenum, it must be emphasised that the amount absorbed depends on the time the drug is in contact with the absorbing surface. There is discussion of whether the differences in absorption between the duodenum and colon can be explained by the physico-chemical properties of the drug alone, or whether the results reflect a saturable transport mechanism.