Biomedical subjects

H Osswald

Publications and source records attributed to H Osswald.

At least 19 recordsLinked to original sources

PubMed1995

Complete reversion and prevention of rectal adenomas in colectomized patients with familial adenomatous polyposis by rectal low-dose sulindac maintenance treatment. Advantages of a low-dose nonsteroidal anti-inflammatory drug regimen in reversing adenomas exceeding 33 months.

PURPOSE: This nonrandomized, controlled Phase II pilot study aims at the lowest effective dose of rectally applied sulindac to achieve and maintain adenoma reversion in colectomized patients with familial adenomatous polyposis (FAP). METHODS: The study group (n = 15) underwent proctoscopic and laboratory follow-up for polyp reversion every 6 to 12 weeks. Polyp reversion was followed by dose reduction in predefined steps. Proliferating cell nuclear antigen/cyclin (PCNA) and KI-67 proliferation indices (PI) were performed by point counting. Prostaglandin (PG)E2 and PGF2 alpha were quantified by time-resolved competitive fluorescence immunoassay. RESULTS: All patients responded to therapy within 6 to 24 weeks. Sixty and 87 percent of patients achieved complete adenoma reversion after 48 weeks at 53 and 67 mg of sulindac per day per patient on average, respectively. Reversion was evident compared with the control group. Dose reduction by one-sixth to one-eighth of the usual oral dose was significant (Mann's trend test, P < 0.05). PCNA and KI-67 PIs of adenomatous and flat mucosa were significantly reduced (Wilcoxon's test, P < 0.05). Correlation of PCNA and KI-67 PIs indicate similar reaction of different tissue structures (Spearman's rank correlation test, P < 0.01). Nonsteroidal anti-inflammatory drug-induced redifferentiation from high-grade to low-grade dysplasia occurred in all but two patients. Tissue-PGE2 levels were greatly reduced. Unwanted, curable side effects were rare (gastritis, n = 2), and laboratory controls are within detection limits. CONCLUSIONS: Low-dose rectal sulindac maintenance therapy is highly effective in achieving complete adenoma reversion without relapse in 87 percent of patients after 33 months. Rectal FAP phenotype should be crucial for the surgical decision. Colectomy with ileorectal anastomosis and regular chemoprevention might proceed to be a promising alternative to pouch procedures. Chemoprevention with lower incidence of FAP-related tumors via dysplasia reversion may be possible in the future.

Adenomatous Polyposis Coli↗

PubMed1995

The pharmacological basis for the combination of calcium channel antagonists and angiotensin converting enzyme inhibitors in the treatment of hypertension.

IMPROVING THE TREATMENT OF HYPERTENSION: The results of basic and clinical research in hypertension over the last 30 years have shown that this disease cannot be treated merely by inducing vasodilation and a fall in blood pressure. The development of high blood pressure is associated with changes in carbohydrate and lipid metabolism and with the development of organ damage, mainly of the heart and kidneys. It is now clear that different elements of blood pressure control mechanisms can lead to hypertension, emphasizing the need to select the appropriate type of hypertensive drug in treating different patients. COMBINATION OF CALCIUM CHANNEL ANTAGONISTS AND ANGIOTENSIN CONVERTING ENZYME (ACE) INHIBITORS: Calcium channel antagonists and ACE inhibitors have synergistic effects on sodium and fluid balance and on the renin-angiotensin-aldosterone system. Thus a combination of these two antihypertensive drug classes is likely to be beneficial in certain subgroups of patients with hypertension. Large clinical trials are needed to determine whether this is indeed the case.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Increased sensitivity of the renal vasculature to adenosine in streptozotocin-induced diabetes mellitus rats.

Adenosine (ADO) has been implicated as a pathophysiological factor in contrast media (CM)-induced acute renal failure, which has been encountered more often in patients with diabetes and impaired renal function. Therefore, we studied the renal vascular response to exogenous and endogenous ADO in streptozotocin-induced diabetic rats. We found that exogenous ADO (0.01-100 nmol), injected into the abdominal aorta, decreased renal blood flow (RBF) in a dose-dependent manner. The dose-response curve was shifted to the left by factor 30 in diabetic, compared with nondiabetic rats rats. Renal vascular response to endogenous ADO, assessed by postocclusive reduction of RBF after a 30-s renal artery occlusion, was significantly enhanced (P < 0.001) in diabetic rats (75.6 +/- 3.9%) compared with nondiabetic rats (36.5 +/- 2%). ADO A1-receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine attenuated exogenous and endogenous ADO-induced renal vasoconstriction in both groups. We conclude that the ADO A1-receptor signal-transduction chain is altered in diabetic animals and that the enhanced vasoconstrictive action of ADO could be involved in the kidney pathophysiology of diabetes mellitus.

Adenosine↗

PubMed1995

Therapeutic use of theophylline to antagonize renal effects of adenosine.

Experiments in laboratory animals clearly show that adenosine acts as a vasoconstrictive metabolite in the kidney. Adenosine receptor antagonists like theophylline can inhibit renal vasoconstriction in response to exogenous and endogenous adenosine. Based on these findings a number of experiments have been performed to test whether the vasoconstrictive action of adenosine in the kidney might be important also in pathophysiological states. In various animal models theophylline and other methylxanthine derivatives have been successfully employed to improve renal function after induction of acute renal failure. Clinical implications of these experimental findings comprise the prevention of acute renal failure following the administration of radio contrast media by theophylline. Another therapeutic aspect derives from experimental and clinical data showing that theophylline controls erythropoietin production in erythrocytosis after renal transplantation.

Acute Kidney Injury↗

PubMed1994

Renal response to amino acid infusion in rats: effect of dopamine receptor antagonists and benserazide.

Previously, we have found that feeding is a dominant factor controlling urinary dopamine excretion (UDA) in conscious rats (Mühlbauer and Osswald 1992). Since the renal response to feeding is also characterized by an increase in glomerular filtration rate (GFR), we wanted to investigate in a first step whether the feeding-induced elevations of GFR and UDA could be causally related phenomena. Therefore, we studied the influence of dopamine synthesis and dopamine receptor blockade on the renal response to amino acid infusion (AA) in thiopental anesthetized rats. AA infusion (n = 7) increased GFR by 33 +/- 7% (P < 0.001) and UDA by 87 +/- 19% (P < 0.001). In the presence of benserazide (BZD, n = 5), an inhibitor of dopamine synthesis, infused i.v. at a dose of 30 micrograms/min/kg, UDA was suppressed to values below detection limit and the AA-induced GFR increase was abolished. Continuous intravenous infusion of the DA1 receptor antagonist SCH 23390 (SCH, n = 7) in a dose of 4.0 micrograms/kg/min did not prevent the AA-induced increase in GFR (33 +/- 3%, P < 0.001) and UDA (97 +/- 12%, P < 0.001). In contrast, S-sulpiride (SUL), a specific DA2 receptor antagonist, infused continuously i.v. in a dose of 5 micrograms/kg/min, completely abolished the AA-induced GFR increase, while UDA was increased 1.6-fold (P < 0.01). Like BZD, both dopamine receptor antagonists did not affect renal sodium excretion substantially. Our results suggest, that endogenous dopamine could act as a mediator in the renal response to amino acid infusion in the rat, most likely by activation of DA2 receptors.

Amino Acids↗

PubMed1994

Dipyridamole prevents diabetes-induced alterations of kidney function in rats.

One possible factor for glomerular hyperfiltration in early diabetes could be a deficiency of renal vasoconstrictive mechanisms. Dipyridamole (DIP) inhibits cellular uptake of adenosine thereby increasing interstitial adenosine concentration. The effect of DIP on tubuloglomerular feedback (TGF) and on urinary protein excretion (UPE), glomerular filtration rate (GFR), and kidney weight was studied in early diabetes in rats. One day after onset of streptozotocin (STZ)-induced insulin-dependent diabetes mellitus (IDDM) daily treatment with DIP (50 mg/100 g twice a day via a gastric tube) was started in one group (STZ-DIP) and with vehicle alone in another group (STZ). Rats were housed in metabolic cages for 24 h to measure UPE 7, 14, and 21 days after STZ-injection. Non-diabetic animals, also receiving vehicle, served as controls (CON). While 7, 14, and 21 days after STZ-injection UPE was enhanced by 88, 123, and 153% in the STZ-group (n = 5) as compared to the CON-group (n = 6), the increase in UPE in the STZ-DIP-group (n = 5) was reduced by 82, 66, and 60%, respectively. Subsequently these diabetic rats were prepared for clearance and micropuncture study. Weight-matched (wm) non-diabetic rats served as controls (CONwm). TGF activity was assessed as the difference between stop flow pressures (delta SFP) in the early proximal tubule at 0 and 50 nl/min perfusion rates of Henle's loop. delta SFP was 8.8 +/- 0.7 mmHg (mean +/- SEM) in the CONwm-group (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

PubMed1994

Reduction of vitamin D induced stone formation by calcium.

Investigations were carried out as to whether cytoprotective agents such as calcium antagonists can influence vitamin D induced nephrolithiasis. Increased vitamin D levels are found in 10-30% of all calcium oxalate stone formers. Male rats were assigned to one of the following groups: (1) 1,25-dihydroxycholecalciferol (DHCC) (n = 8), (2) 1,25-DHCC + calcium antagonist Goe 6070 (a new 1,4-dihydronaphthyridine, Goedecke, Berlin) (n = 8), or (3) control (n = 8). 1,25-DHCC was administered for 6 days (120 pmol/24 h s.c.), Goe 6070 (1 mg/kg/24 h) by gavage. Clearance studies were performed on day 6. Kidneys were taken for histological examination and determination of calcium tissue content. 1,25-DHCC induced substantial concrement formation, which could be significantly limited by Goe 6070. The calcium tissue content was also reduced (0.17 vs. 0.04 mg/100 mg dry weight). 1,25-DHCC induced a dramatic fall in the glomerular filtration rate (GFR) (3.84 ml/min per kilogram). This reduction could be almost completely inhibited by the concomitant application of Goe 6070 (9.4 ml/min per kilogram; control 10.7 ml/min per kilogram). Goe 6070 did not influence the calcium handling. The results demonstrate a protective effect of Goe 6070 on vitamin D induced nephrolithias. The histological pattern (intracellular and membrane-bound concretions) and the fact that biochemical parameters were not influenced significantly by Goe 6070 indicate that cellular proceses are important for 1,25-DHCC-induced nephrolithiasis.

Animals↗

PubMed1994

Influence of cisplatinum and 5-fluorouracil on the oral mucosa.

In a prospective study we examined the effect of preoperative chemotherapy with cisplatinum and 5-fluorouracil (5FU) in 40 patients with a carcinoma of the oral cavity. Histopathological grading, cell kinetic and immuno-histochemical parameters of the mucosa were determined at two different locations. Prior to therapy histological dysplasias "close" to the tumour were observed in the mucosa of 75% of the patients. Dysplastic changes of the mucosa "far" from the tumour were also found in more than one third of the patients. Our results show that more advanced dysplasias improve under the influence of preoperative systemic chemotherapy only temporarily. Moreover, new dysplasias which appeared during chemotherapy and persisted after its termination are probably induced.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1994

Adenosine antagonist theophylline prevents the reduction of glomerular filtration rate after contrast media application.

Radiographic contrast media (CM) can induce renal failure and this may serve as an experimental model of acute renal failure (ARF). One vasoactive factor likely to be involved in ARF is adenosine. In a double-blind, placebo-controlled study we investigated the effect of theophylline (TP), an adenosine receptor antagonist, regarding changes in renal hemodynamics induced by CM. Thirty-nine patients who received 100 ml of a non-ionic low osmolar CM (iopromide) were studied for changes in GFR and RPF by continuous inulin and PAH clearance before and until four hours after CM application. Forty-five minutes before the application of CM, patients were randomized and received either theophylline (5 mg/kg body wt) or the vehicle and placebo (saline) intravenously in a blinded manner. We additionally measured the creatinine clearance on the day before and two days after CM application. Sodium excretion, N-acetyl-beta-glucosaminidase (NAG) excretion, plasma renin activity (PRA) and aldosterone levels were also measured before and after CM application. Theophylline levels were within the therapeutic range in patients of the theophylline group during and four hours after CM application (59.0 +/- 10.6 mumol/liter and 40.1 +/- 10.9 mumol/liter). GFR, measured by inulin clearance significantly declined under CM application in patients without TP application (N = 19; 88 +/- 40 to 75 +/- 32 ml/min/1.72 m2; P < 0.01). In the group of patients receiving theophylline (N = 18) the GFR remained constant (75 +/- 26 vs. 78 +/- 33 ml/min/1.72 m2).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗

PubMed1994

Feeding-induced increase in urinary dopamine excretion is independent of renal innervation and sodium intake.

Food intake increases urinary dopamine excretion. To investigate the role of renal nerve activity in this renal response to feeding, we studied urinary dopamine excretion after chronic bilateral renal denervation (DNX, n = 8) in male Sprague-Dawley rats. Controls were sham operated (CON, n = 6). In a paired crossover design, animals were studied both in fed and fasted state. Time course measurements of renal tissue norepinephrine (NE) content in a third group of DNX rats showed a decrease by 90% not earlier than 18 h post-DNX, remaining to be reduced to this level until day 11. Renal NE content in DNX animals was measured at the end of the study to confirm complete denervation. In 24-h urine, collected from fed and fasted conscious CON and DNX rats in metabolic cages, concentrations of dopamine and sodium were measured during two different sodium intake regimens, i.e., tap water and 1 g/dl NaCl as drinking water. No influence of renal innervation on urinary dopamine could be observed in fed and fasted animals. The marked changes in urinary volume and sodium output due to the different sodium regimens were not paralleled by urinary dopamine excretion. However, urinary dopamine was increased 2.1- to 2.4-fold (P < 0.01) because of feeding in all groups, independent of sodium balance and renal innervation. We conclude that in conscious rats both basal urinary dopamine excretion and its marked increase in response to feeding are independent of sodium balance and of renal nerve activity.

Animals↗

PubMed1994

[Acute noninflammatory renal failure. New pathogenetic aspects in light of findings obtained in autopsy and biopsy of kidneys].

Thorough studies of kidney specimens obtained at autopsy or by renal biopsy revealed, that in noninflammatory acute renal failure oliguria/anuria is caused by increased activation o the renal renin-angiotensin system and increased generation of adenosine. At the polyuric phase moderately increased adenosine in kidney tissue seems to be the main factor responsible for decreased glomerular filtration.

Acute Kidney Injury↗

PubMed1994

[Effect of a cisplatin-5-fluorouracil combination chemotherapy on malignant transformation of the epithelium of mouth mucosa].

In a prospective study we examined the effect of preoperative chemotherapy with cisplatinum and 5-fluorouracil (5-FU) in 40 patients with advanced carcinoma of the oral cavity. Histopathologic grading, cell kinetics and immunohistochemical parameters of the mucosa were determined at two different locations. Prior to therapy, histologic dysplasias in the mucosa "close" to the tumor were observed in 75 percent of the patients. Dysplastic changes of the mucosa "far" from tumor were also found in more than one-third of the patients. Our results show that more advanced dysplasias improve only temporarily under the influence of preoperative systemic chemotherapy. Moreover, new dysplasias appearing during chemotherapy and persisting after its termination are probably induced. The results point to a possible carcinogenic potential of the combined chemotherapy schema used.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1994

Neuromodulatory effects of the renin-angiotensin system on the cat electroretinogram.

PURPOSE: Angiotensin-converting-enzyme (ACE) catalyses the formation of angiotensin II (ANGII), which presumably acts as a central neurotransmitter/modulator. ANGII-related effects have also been observed in the retina. Present in vivo experiments were designed to investigate further ANGII-related effects on retinal neuromodulation. METHODS: In 12 anesthetized cats, electroretinographic measurements were carried out in the dark-adapted state using corneal contact lens electrodes and a Ganzfeld stimulator. Quinapril was used to inhibit ACE. RESULTS: Reducing ANGII-concentration increased sensitivity (0.5 log units) and gain (50%) of the rod b-wave amplitude. The b-wave implicit time was stimulus dependent, shortening at high intensities. The scotopic threshold response and the oscillatory potentials were also influenced by ACE inhibition. However, a-wave and 30 Hz flicker remained unaffected. Effects of Quinapril on ERG-amplitudes were reversed by subsequent ANGII administration, except for the implicit time of the b-wave and scotopic threshold response. CONCLUSIONS: Although these results are accompanied by alterations in systemic blood pressure, several findings support the evidence that the renin-angiotensin system might have a neurophysiologic effect on retinal neurons outside the vascular system. These results are in accordance with immunohistochemical data found by others that point to angiotensinergic cell involvement and thereby further support the concept of angiotensinergic processes in the inner retina from a functional point of view.

Angiotensin II↗

PubMed1993

The NSAID sulindac reverses rectal adenomas in colectomized patients with familial adenomatous polyposis: clinical results of a dose-finding study on rectal sulindac administration.

After colectomy with ileorectal anastomosis (IRA) for treatment of familial adenomatous polyposis (FAP), the rectal mucosa remains, with the risk of malignant change. Locoregional (rectal) sulindac has been applied, with initial higher-dose therapy and subsequent low-dose maintenance therapy to minimise side-effects. The dose-finding study with sulindac suppositories started with a dose of 300 mg sulindac daily per patient over 6 weeks. Depending on proctoscopical evaluation of regression of polyposis, sulindac doses were reduced in predefined steps. Ten of 15 patients developed a complete remission following 42 weeks of treatment, while the rest had partial remission. Responses were recorded 6-24 weeks after beginning sulindac treatment. After 36 weeks, 13/15 patients received 25-50 mg sulindac daily. An increase in the number of partial remissions after 42 weeks of treatment at doses of 100 mg sulindac daily may indicate the first approach to a reduced dose between 100 mg to 25 mg sulindac daily, but may also point to the importance of long-term treatment rather than dose-intense therapy.

Adenomatous Polyposis Coli↗

PubMed1993

Fate of circulating oxalate in rats.

The pharmacokinetics of oxalate were studied in normal and nephrectomized rats with the use of radioisotope-labelled oxalate. The disappearance of [14C]oxalate from the plasma was analyzed with a two-compartment open model. The pharmacokinetic parameters of oxalate were compared with those for inulin. In normal rats, the plasma half-life of the elimination of oxalate was 0.33 +/- 0.06 h and that for inulin was 0.26 +/- 0.05 h (n = 10, mean +/- SD). The volume of distribution for oxalate was 56.7 +/- 6.80 and that for inulin 34.0 +/- 4.79 ml/100 g body weight, indicating that oxalate has access to additional compartments besides the extracellular volume. The total clearance of oxalate was 1.2 times higher than that for inulin. In nephrectomized rats, however, the plasma half-life of the elimination of oxalate was 1.85 +/- 0.34 h (n = 7, mean +/- SD) and that for inulin was 4.26 +/- 0.78 h. The total clearance of oxalate was 177 +/- 29 and that for inulin was 30 +/- 5 microliters/min/100 g body weight. In order to identify the extrarenal elimination route of oxalate, the bile of nephrectomized rats was collected. The hepatic clearance of oxalate was 31.2 +/- 2.7 microliters/min/100 g body weight. The biliary excretion of oxalate accounts for 17.6% of the total clearance in nephrectomized rats. Thus, other elimination processes of oxalate besides renal and hepatic clearance take place.

Animals↗

PubMed1993

[Hypernatremia and kidney function].

Hypernatremia is caused by a water deficit. Cases with hypernatremia and dehydration appear to cluster among children and the elderly with alterations in the level of consciousness thus with no independent access to water. In general, central nervous symptoms prevail. However, thorough examination reveals impaired renal function in many such cases. Animal experiments have shown that rapid increases of the sodium concentration in the renal artery will cause a reduction of renal blood flow (RBF), glomerular filtration rate (GFR) and inhibition of renin secretion, particularly during states of sodium chloride or volume depletion (i.e. with high plasma renin activity). In any other organ hypernatremia leads to vasodilation. The kidney, however, responds with vasoconstriction which can be reversed by the adenosine antagonist theophylline. This finding led to the hypothesis that adenosine mediates the renal response to hypernatremia. Adenosine is generated by the tubules at a higher rate when the kidney is forced to reabsorb large amounts of sodium. In this concept adenosine links metabolic processes of sodium reabsorption with the regulation of organ blood flow causing vasoconstriction via adenosine receptors on the vasa afferentia. This mechanism can explain impaired renal function during acute hypernatremia. It is concluded from experimental evidence that-apart from other therapeutic measures-the recovery of impaired renal function can be improved by administration of the adenosine antagonist theophylline.

Acute Kidney Injury↗

PubMed1993

[Renal effects of adenosine: possible consequences for kidney transplantation].

This review summarizes in the first part the action of adenosine on the kidney. In the second part we discuss the pathophysiological consequences and the possibilities of a pharmacological intervention to improve impaired kidney function. Adenosine causes vasoconstriction in the kidney and reduces glomerular filtration rate (GFR). This action is enhanced in proportion to elevated plasma renin activity. Chronic elevation of ureteral pressure enhances and reduction of renal perfusion pressure attenuates adenosine-induced vasoconstriction. From the kidney-specific relationship between renal blood flow and tubular electrolyte transport the concept is developed which ascribes adenosine a role of a mediator that is essentially contributing to the homeostatic regulation of kidney function. The accumulation of adenosine in the kidney tissue after ischemia or after administration of nephrotoxic substances led to the hypothesis that adenosine is an important intrarenal factor in the pathogenesis of acute renal failure. The possibility to antagonize adenosine actions in the kidney with theophylline was used successfully in a number of experimental studies in acute renal failure and most recently in a study in humans after contrast media administration. Adenosine actions mediated via membrane receptors must be separated from adenosine actions in the cell to increase ATP tissue content. The concept of the "University of Wisconsin" (UW) solution to improve the energy state of the tubular cells appears to be successful, however, we propose that the potential dangerous adenosine actions in the kidney, especially during the reperfusion phase may be antagonized by the administration of theophylline.

Acute Kidney Injury↗

PubMed1992

Feeding but not salt loading is the dominant factor controlling urinary dopamine excretion in conscious rats.

We studied urinary dopamine excretion in three different groups of rats after the following treatment regimens: normal chow and tap water (controls, CON), normal chow and 1% NaCl as drinking water (high salt, HS), and chow with low sodium content plus tap water (low salt, LS). On days 5 and 7 of the respective dietary treatment, rats were placed in metabolic cages. Using a cross over design, chow was given (fed) or withheld (fasted). Urine was collected for 24 h and analyzed for sodium, creatinine, and dopamine. Urinary dopamine excretion did not change in proportion to large differences in sodium excretion in fasted animals. Sodium excretion was enhanced (45%) due to feeding only in the CON group but not in HS and LS rats. However, there was a striking increase in renal dopamine excretion in fed compared to fasted animals, irrespective of their sodium diet: 2.5-fold in CON, 2-fold in HS, and 1.8-fold in LS rats. Urinary creatinine excretion was significantly elevated during the feeding condition compared to fasted animals in all treatment groups. Our results demonstrate that urinary dopamine excretion is dominantly influenced by feeding but not by oral sodium intake in conscious rats. We conclude that 1) the dietary state of the animals should be controlled in experiments on renal dopamine production, 2) renally formed dopamine could be involved in the functional response of the kidney to oral food intake.

Animals↗