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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.

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.

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.

The influence of 5,6-trans-25-hydroxycholecalciferol on renal osteopathy was investigated in a total of 132 patients in 26 dialysis centres. Various doses were used, the average being 4000-6000 IU/day. In 32 patients a daily dose of 6000-9000 IU was used. The average individual duration of treatment was 276 days with a maximum of 910 days. Histologically there was an improvement in the renal osteopathy in 55.9% of evaluable cases (n = 34) and in 25.3% there was no deterioration. Radiographically these results were found in 21% and in 70.5% of evaluable cases (n = 105). Serum calcium increased in 46.6% of cases (n = 131), remained the same in 32.8% and decreased in 20.6%. The changes in alkaline phosphatase were similar : it dropped in 42.1% of patients, remained the same in 28.1% and rose in 29.8%. Immunoreactive parathormone which was invariably raised at the beginning of treatment (n = 36), fell in 25.0%, remained the same in 44.4% and rose further in 30.6%. The clinical symptoms of renal osteopathy which had been present in 57 patients improved in 51.0%, remained the same in 46.0% and deteriorated in 3.0%. Signs of intolerance and side effects were rare. Severe hypercalcaemia did not occur.

Investigations have been performed on the metabolism and organ distribution of 5,6-trans-25(OD)D-3, which represents an analog of vitamin D-3 being active in uremia. This analog is rapidly metabolized into at least two more metabolites. The main storage organ for this compound seems to be fat, whereas liver and intestinal mucosa showed at 24 hrs the highest concentration of polar metabolites. In contrast to 25(OH)D-3 5,6-trans-25(OH)D-3 is much less absorbed from the intestinal tract, which should be considered if this compound is applied for treatment of uremic bone diseases.

Es werden die Moglichkeiten der Messung der Erythrozytenverformbarkeit dargestellt und eigene Untersuchungen mit einer Methode beschrieben, welche die Erythrozytenalterung als Modell fur eine physiologische Reduzierung der Erythrozytenverformbarkeit benutzt. Die Messung dieser Grose erfolgt in Vollblut mittels Filtration durch Filter mit Poren von 5 µm. Das Erythrozytenalterungsmodell und die Methode zur Messung der Erythrozytenverformbarkeit eignet sich fur die routinemasige Prufung, ob chemische Substanzen die Erythrozytenverformbarkeit beeinflussen. In zwei Untersuchungsserien wurden Pentoxifyllin in Konzentrationen von 10 µg und 20 µg/ml Blut sowie Theophyllin in einer Konzentration von 96,6 µg/ml Blut und Prednisolon in einer Konzentration von 20 µg/ml Blut untersucht. Fur Pentoxifyllin fand sich eine dosisabhangige Erhohung der Erythrozytenverformbarkeit, unter Theophyllin und Prednisolon fanden sich keine signifikanten Anderungen gegenuber der Kontrolle. Der Effekt von Pentoxifyllin ist wahrscheinlich in einer Erhohung des erythrozytaren ATP-Gehaltes begrundet. Rasterelektronenmikroskopische Untersuchungen zeigen, das die morphologische Struktur der auseren Erythrozytenmembran durch Pentoxifyllin nicht beeinflust wird.

In a study of eight volunteers and six patients, glibenclamide was placed at different sites of the gastro-intestinal tract under visual control. The dose was instilled once into the stomach and once into the duodenum of the eight volunteers in a randomized crossover design. The six patients underwent diagnostic colonoscopy, and the dose was placed into the ascending colon if pathological findings were not present. The area under the concentration-time curve, completed by extrapolation, and the mean residence time of the drug in the body were calculated. These pharmacokinetic characteristics were examined using a Jonckheere test for ordered alternatives and a Wilcoxon signed rank pair test. The means of the areas under the curve were 477 +/- 131 ng . h ml-1 for the stomach, 475 +/- 142 ng . h ml-1 for the duodenum and 486 +/- 301 ng . h ml-1 for the colon. The mean residence time changed from 2.67 +/- 0.35 h for the stomach to 2.42 +/- 0.48 h for the duodenum and 3.55 +/- 0.68 h for the colon. These results indicate that although glibenclamide is absorbed from all three sites of the gastro-intestinal tract to the same extent, the rates of absorption are different. It is discussed whether these findings really confirm the pH-partition hypothesis in drug absorption. Since glibenclamide--a weak acid--has a pK-value of about 6.5, these data seem to confirm the pH-partition hypothesis of drug absorption.

Drug elimination by extracorporeal methods (hemodialysis, hemoperfusion, hemofiltration, plasmapheresis) was investigated in an ex vivo model using banked blood. The drugs (cefotaxime, glibenclamide

A method to filter whole blood through 5-µm 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 cell deformability.

Mittels einer Filtrationstechnik fur Vollblut mit Filtern mit einem Porendurchmesser von 5 µm wurde die Erythrozytenverformbarkeit von Blutkonserven uber einen Zeitraum von 6 Tagen untersucht. Innerhalb von 12 Stunden nimmt die Filtrabilitat von Vollblut aus Blutkonserven um ca. 50% ab, nach 6 Tagen betragt der Verlust an Filtrabilitat ca. 98%. Der Zusatz von Pentoxifyllin zu alternden Blutkonserven (20 µg/ml Blut) verbessert die Filtrabilitat wieder, wobei der Anstieg der Erythrozytenverformbarkeit statistisch signifikant wird, wenn die Blutproben, versetzt mit Pentoxifyllin, fur 2.5 Stunden bei 37°C inkubiert werden. Die Ursache dieses Effektes wird in einer Zunahme des erythrozytaren ATP-Gehaltes vermutet. Die Messung der Erythrozytenverformbarkeit bei 29 klinisch gesunden Probanden unter Berucksichtigung der Risikofaktoren Zigarettenrauchen und orale Kontrazeptiva ergab, das mannliche Raucher eine signifikant niedrigere Erythrozytenverformbarkeit haben (p

Suspensions of Forskolin in concentrations of 0.3; 0.6; and 1.0% decreased effectively the intraocular pressure of healthy subjects when instillated in the conjunctival sac. The suspensions were compared with placebo in double blind studies. The maximum effect was reached 3 hours after application of the 0.3% (22.8%) and 0.6% (27.8%) suspensions and 4 hours after the 1.0% (26.5%) suspension. The higher concentrations decreased the intraocular pressure to the same extent as the lowest concentration but the effect lasted longer: 4 hours after instillation of the 0.3% suspension, 5 hours after instillation of the 0.6% suspension and 7 hours after the 1.0% suspension. The suspensions were well tolerated. Subjective sensations like burning, itching and augmentated lacrimation were observed only in a minor amount and for a short period of time.

SummaryUsing a filtration technique for whole blood incorporating filters with a pore diameter of 5 pm, red cell deformability in banked blood was measured over a 6-day period. Whole blood filterability in banked blood fell by approximately 50% within 12 hours, the loss of filterability after 6 days being approximately 98%. The addition of pentoxifylline to ageing banked blood (20 μg pentoxifylline/ml blood) improved filterability, the increase in red cell deformability being statistically significant when blood samples were mixed with pentoxifylline and incubated for 2 1/2 hours at 37°C. This effect is attributed to an increase in erythrocyte ATP levels. Measurement of red cell deformability in 29 clinically healthy subjects, taking into account the risk factors ‘cigarette smoking’ and ‘oral contraceptives’, revealed a significant reduction in red cell deformability in male smokers by comparison with male non-smokers (p < 0.001). Similarly, red cell deformability in all male and female smokers was reduce...

Investigations were performed in order to test the biological effectiveness of 5,6-trans-25-hydroxycholecalciferol in patients suffering from terminal renal failure. All patients received for six days a daily i.v. injection of 100 U of this compound: The absorption of47calcium increased in four of five patients, the serum calcium level rose in all. The data suggest that 5,6-trans-25-hydroxycholecalciferol may be useful in the treatment of uremic bone disease, especially because this compound has little, if any, activity in stimulating the mobilization of calcium from the bone.

Twelve healthy males participated in a trial to determine whether furosemide diuresis and its effects on electrolyte excretion patterns, aldosterone concentrations and renin activity are subject to diurnal variations. Six treatments were give: placebo at 07h00, 13h00 and 19h00 and furosemide 40 mg at 07h00, 13h00 and 19h00. Each subject participated in six phases. It was found that the time of administration of furosemide does not affect the effect of the drug on sodium and potassium excretion and diuresis. There is a tendency for furosemide to elevate serum aldosterone levels and renin activity regardless of the time of administration.

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.

Suspensions of Forskolin in concentrations of 0.3; 0.6; and 1.0% decreased effectively the intraocular pressure of healthy subjects when instillated in the conjunctival sac. The suspensions were compared with placebo in double blind studies. The maximum effect was reached 3 hours after application of the 0.3% (22.8%) and 0.6% (27.8%) suspensions and 4 hours after the 1.0% (26.5%) suspension. The higher concentrations decreased the intraocular pressure to the same extent as the lowest concentration but the effect lasted longer: 4 hours after instillation of the 0.3% suspension, 5 hours after instillation of the 0.6% suspension and 7 hours after the 1.0% suspension. The suspensions were well tolerated. Subjective sensations like burning, itching and augmentated lacrimation were observed only in a minor amount and for a short period of time.

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.

Six healthy male volunteers participated in a double-blind cross-over study in which 12,5 mg, 25 mg, or 50 mg tendamistate (HOE 467), an alpha-amylase inactivator, or placebo were administered with 100 g maize meal, which contains 85,5 g pure starch. Serial blood specimens for measurement of plasma glucose concentrations, which served as a criterion of starch absorption, were taken up to 3 hours after each starch meal, and side-effects were recorded. The administration of HOE 467 with a starch meal resulted in a significant inhibition of starch absorption. Side-effects were not severe. Flatulence occurred in the placebo phase as well as after administration of the active drug. Loose stools were reported by 1 subject after 25 mg tendamistate.

Twelve healthy male volunteers participated in an open cross-over study designed to test whether two fixed-dose combination formulations of penbutolol (40 mg) and furosemide (20 mg), an ordinary and a film-coated tablet, are bio-equivalent. Penbutolol capsules (40 mg) and 20 mg furosemide tablets (Lasix; Hoechst) served as reference formulations. The maximum concentration of furosemide was significantly depressed in the case of fixed-dose combinations, reflecting a possible pharmacokinetic interaction between penbutolol and furosemide. However, the area under the concentration versus time curve for furosemide and its cumulative urinary excretion and diuretic effect were not influenced by penbutolol. On the basis of plasma concentration versus time data and urinary parameters, the two fixed-dose formulations are bio-equivalent.

Erythrocyte flexibility was tested in 29 healthy subjects, using whole-blood filtration through membrane filters with 5 micron pores, special attention being given to cigarette smoking and oral contraceptives as risk factors. Red cell flexibility was significantly reduced in male smokers compared with non-smokers (P is less than 0.0001), and in all male and female smokers (P is less than 0.05) An influence of oral contraceptives to erythrocyte flexibility could not be found. Reduced erythrocyte flexibility in smokers as a factor contributing to an abnormal microcirculation and to the development of arterial occlusive disease is discussed.14 men, aged 20-57, and 15 women, aged 18-57, were tested for erythrocyte flexibility (e.r.) by filtering whole blood samples through membrane filters with 5 micrometer pores. The data were analyzed to determine the effect of cigarette smoking and oral contraceptive use on e.r. Male smokers showed significantly lower e.r. than male non-smokers (p .001) and all male and female smokers had a significantly lower e.r. than non-smokers (p .05). No relationship between oral contraceptive use and e.r. could be ascertained. Reduced e.r. could cause disturbances in the microcirculation, which in turn could lead to arteriosclerosis and other arterial occlusive diseases.

Penbutolol, a new beta-adrenoceptor blocker, was found to increase the glomerular filtration rate (GFR) significantly (16%) relative to placebo when administered orally in a dose of 40 mg daily for 7 consecutive days to healthy males. Measurements were performed after the seventh dose. In contrast, a single acute intravenous dose of penbutolol 4 mg did not influence the GFR, which was determined by means of a gamma counter after intravenous injection of technetium-99m diethylenetriaminepenta-acetic acid. Since penbutolol possesses moderate beta-adrenomimetic activity, it is postulated that the observed increase in the GFR after oral penbutolol could be due to increased cardiac output at rest.

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.

Ten hypertensive patients completed a trial lasting 12 weeks to measure the effect of long-term treatment with piretanide, a new, powerful 'loop' diuretic, on total body potassium (TBK). After 2 weeks of placebo treatment, they received 6 mg piretanide twice daily. This dose was increased to 6 mg 3 times a day if blood pressure was not satisfactorily lowered after 4 weeks. Blood pressure and plasma potassium levels were measured weekly. The TBK was measured fortnightly. In this study potassium balance was not significantly affected by the administration of piretanide.

Ten volunteers participated in a study comparing the effects on renal enzymes of multiple oral doses of aspirin relative to no treatment. The total urinary output was collected daily for 21 days from all subjects. The first 7 days were treatment-free. During the second 7-day period the subjects received aspirin 1500 mg 3 times daily. This was followed by another treatment-free period of 7 days. The activity of the enzymes alanine aminopeptidase and N-acetyl-beta-glucosaminidase were determined in each daily urine specimen. Statistical analysis revealed that aspirin significantly increased the output of both enzymes.

Possible nephrotoxicity of a drug has to be established in the very early phases of its development. Nephrotoxicity is predominantly manifested in the tubular system and only becomes clinically evident when damage has reached a relatively advanced stage. It is therefore necessary to look for variables which would allow an early detection of pathological changes within the kidney. Mondorf et al. [1] have shown that alanine-aminopeptidase (AAP) is a marker of tubular damage. This enzyme was shown to be released from the brush border cells of the kidney. After treatment with cephalosporines these authors have shown increases of AAP excretion and they therefore advised that AAP should be measured during treatment with drugs like cephalosporines which act on the proximal tubule.

Tolbutamide is known to bind highly to serum proteins. Quite different values have, however, been reported for binding, ranging from 80 to 99 percent. In this study, in vivo and in vitro binding of increasing concentrations of tolbutamide to human serum proteins were evaluated. In vitro studies were done serum from three healthy males and for in vivo studies serum samples from eight healthy males who had received 1,000 mg tolbutamide were used. Protein binding was determined by equilibrium dialysis, using DIANORM system. Tolbutamide concentrations were determined by HPLC method of Uihlein and Hack. The results suggest that there is an increase in percent tolbutamide bound with increasing concentrations of tolbutamide. Generally, an inverse relationship between the total concentration of a drug in serum and its bound fraction is observed. Our findings seem to be contrary to this, at least within the concentration range studied. There exist at least two binding sites on albumin with different affinities for tolbutamide and most probably, at low concentrations, the drug binds mainly to the high affinity sites, whereas at higher concentrations additional drug will bind to the lower affinity sites leading to the observed increase in fraction bound with concentration. In conclusion it may be said that serum protein binding is a much more complicated phenomenon than generally stated and that the normal observations are only true for some ideal compounds where only one site of adsorption has to be taken into account.

Tendamistate (HOE 467) is an alpha-amylase inactivator. Doses of 100 and 200 mg and a placebo were administered to 6 volunteers in order to investigate the effect of the drug on plasma glucose levels after a bread meal. Each subject participated in three phases, in each of which they received a meal consisting of 200 g white bread together with either placebo or tendamistate 100 or 200 mg. Serial blood specimens for plasma glucose determinations were taken up to 3 hours after the meal. Plasma glucose concentrations served as a criterion of starch absorption. Side-effects (flatulence and/or diarrhoea) were reported after each of the three treatments. The administration of tendamistate together with the bread meal resulted in significant inhibition of starch absorption.

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.

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 pentoxifylline improves impaired red cell deformability under hyperosmolar conditions and simultaneously produces a reduction in whole blood viscosity.

A dose of 400 mg tendamistate or a placebo was given to 10 volunteers in order to investigate its effects on plasma glucose, free fatty acid and triglyceride levels after a porridge meal. Each subject participated in two phases, in each of which they ate porridge prepared from 100 g maize meal together with either placebo or tendamistate 400 mg. Serial blood specimens for plasma glucose determinations were taken up to 3 hours after the meal, and those for free fatty acid and triglyceride determinations up to 14 hours after the meal. Side-effects (flatulence and bulky stools) were not severe and were reported after both treatments. Tendamistate administration significantly attenuated postprandial glycaemia; it had no effect on postprandial triglyceride levels and was associated with a reduction in free fatty acid levels.

Nine volunteers participated in a double-blind, cross-over study to compare the effects of tendamistate (HOE 467), guar and placebo on starch metabolism. In each phase of the trial they received a maize-meal porridge breakfast. They either received 5 g guar granules before the porridge or 100 mg tendamistate mixed with the porridge, or porridge alone. Sequential plasma glucose concentrations served as a criterion of starch digestion. The area under the plasma glucose curve and maximal glucose concentrations after administration of tendamistate with the starch were significantly lower (P less than 0,05) than after guar and placebo. No significant differences were found between placebo and guar. We concluded that tendamistate effectively attenuates starch digestion and is superior to guar in reducing postprandial glycaemia.

The influence of 5,6-trans-25-hydroxycholecalciferol on renal osteopathy was investigated in a total of 132 patients in 26 dialysis centres. Various doses were used, the average being 4000-6000 IU/day. In 32 patients a daily dose of 6000-9000 IU was used. The average individual duration of treatment was 276 days with a maximum of 910 days. Histologically there was an improvement in the renal osteopathy in 55.9% of evaluable cases (n = 34) and in 25.3% there was no deterioration. Radiographically these results were found in 21% and in 70.5% of evaluable cases (n = 105). Serum calcium increased in 46.6% of cases (n = 131), remained the same in 32.8% and decreased in 20.6%. The changes in alkaline phosphatase were similar : it dropped in 42.1% of patients, remained the same in 28.1% and rose in 29.8%. Immunoreactive parathormone which was invariably raised at the beginning of treatment (n = 36), fell in 25.0%, remained the same in 44.4% and rose further in 30.6%. The clinical symptoms of renal osteopathy which had been present in 57 patients improved in 51.0%, remained the same in 46.0% and deteriorated in 3.0%. Signs of intolerance and side effects were rare. Severe hypercalcaemia did not occur.

Drug absorption after oral administration — the most convenient and popular way of applying a drug - takes place in both the stomach and the small intestine. Little is known about the absorption characteristics of the colon.