The effect of pentosan polysulphate (SP54) on the fibrinolytic enzyme system. An experimental animal study

Pentosan polysulphate (SP54) causes a transient increase in blood fibrinolysis in conscious and anaesthetized rats. Postoperative "fibrinolytic shutdown" was prevented by a dose of 2 mg/kg body weight but there appeared to be no dose-response relationship with higher doses. Fibrinolysis was also measured in conscious unstressed animals using an indwelling jugular cannula. The venous response to SP54 in these animals was substantially higher than the arterial response. Experiments with an inferior vena cava model of thrombosis suggest that a single dose of 10 mg/kg pentosan polysulphate given 90 min after thrombus formation is sufficient to achieve thrombolysis. This effect was more marked if the animals were given multiple doses over 24 to 48 hours.     

The effect of pentosan polysulphate (SP54) on the human fibrinolytic system

In human volunteers the oral and subcutaneous (s.c.) administration of SP54 enhanced the fibrinolytic potential of plasma. When the effect was compared between exercise and s.c. administration of SP54 the latter was found to "peak" at about 3 hours and to have a more sustained effect than the exercise. Oral versus s.c. administration suggests that only about 10% of the SP54 reaches the circulation by the oral route. However, repeat SP54 oral dosage did not elicit any resistance to the daily response over a period of five days and suggests that the volunteers used in this study tolerated repeated use of the drug with no ill-effects. The source of the fibrinolytic enhancement is as yet not fully explained and a hypothesis is presented which suggests that very small elevations of t-PA in plasma can affect the fibrinolytic potential in the presence of forming fibrin but may remain undetected by conventional immunometric assays.     

Treatment of Congestive Heart Failure with Triamterene

Triamterene, a newer oral diuretic, was administered to nine hospitalized patients with congestive heart failure for an average of 15 days, and to 22 ambulatory patients for a period of three to 11 months. The daily dosage of triamterene ranged from 50 to 250 mg., but usually 100-200 mg. was administered daily in two divided doses, with or without the addition of 50 mg. of hydrochlorothiazide daily.Triamterene is a safe and effective diuretic at doses of 100-200 mg. daily and no drug tolerance develops with long-term therapy. However, when used alone, it is not as effective as hydrochlorothiazide, but in combination with the latter drug the resultant diuresis is unsurpassed by any other oral diuretic therapy that we have used to date.Triamterene itself does not produce kaliuresis and it blocks thiazide-induced kaliuresis. Serum uric acid levels may rise slightly, but no clinical gout was seen in this study.     

In vivo cytogenetic activity of diphenylhydantoin in mice.

Diphenylhydantoin was tested in vivo in mice using a variety of cytogenetic endpoints to evaluate its genotoxicity. Injected doses of 125, 250 and 500 mg/kg failed to increase the number of chromosome aberrations in marrow cells at 17 h post-treatment, and 37.5, 75 and 150 mg/kg doses were likewise ineffective at 36 h. SCEs were significantly increased by doses of 125 mg/kg (but not 250 mg) after 23 h and modestly, in relation to dose, at 42 h. No increase in the number of micronuclei among marrow PCEs was seen following single i.v. injections ranging from 0.1 to 20 mg/kg. Three daily i.p. injections of doses up to 70 mg/kg also failed to increase the number of micronuclei in either marrow or peripheral blood PCEs. Some cytotoxic effect was evident following relatively high doses.     

In vivo cytogenetic activity of diphenylhydantoin in mice

Diphenylhydantoin was tested in vivo in mice using a variety of cytogenetic endpoints to evaluate its genotoxicity. Injected doses of 125, 250 and 500 mg/kg failed to increase the number of chromosome aberrations in marrow cells at 17 h post-treatment, and 37.5, 75 and 150 mg/kg doses were likewise ineffective at 36 h. SCEs were significantly increased by doses of 125 mg/kg (but not 250 mg) after 23 h and modestly, in relation to dose, at 42 h. No increase in the number of micronuclei among marrow PCEs was seen following single i.v injections ranging from 0.1 to 20 mg/kg. Three daily i.p. injections of doses up to 70 mg/kg also failed to increase the number of micronuclei in either marrow or peripheral blood PCEs. Some cytotoxic effect was evident following relatively high doses.     

Effect of parenterally injected benzimidazole compounds on Echinococcus multilocularis and Taenia crassiceps metacestodes in laboratory animals.

In mice infected with metacestodes of Taenia crassiceps, the following compounds were at least partially effective when injected intraperitoneally at the dosage indicated: cambendazole (500 mg/kg), mebendazole (6.25 mg/kg), oxibendazole (500 mg/kg), 5-benzamido-2(4-thiazolyl)benzimidazole (500 mg/kg), 2-carboethoxyamino benzimidazole (125 mg/kg), and 2-carbomethoxyamino benzimidazole (500 mg/kg). The following were inactive at the dosage indicated: parbendazole (500 mg/kg), thiabendazole (1,000 mg/kg), and fenbendazole (1,000 mg/kg). Mebendazole, which showed some activity at 6.25 mg/kg, was highly active as a single intraperitoneal dose at 25 mg/kg. When injected subcutaneously, mebendazole was much less active than when given intraperitoneally. In mice infected with metacestodes of Echinococcus multilocularis, intraperitoneal injection of mebendazole at 75 to 150 mg/kg, daily for 3 days, was highly effective (95 to 100% reduction in cyst mass). In contrast, oral administration at 1,000 mg/kg, daily for 3 days, was only partially effective. The drug was also effective when given intraperitoneally to infected cotton rats. A water-soluble benzimidazole, carboxymethyleneamino cambendazole, was approximately 50% effective in mice when injected daily for 3 days at a dosage of 75 or 150 mg/kg. The results suggest that, in metacestode infections of medical importance, it may be possible to kill the parasite by delivering a drug to its immediate vicinity, and so to reduce the required dosage with respect to the host.     

Early postoperative substitution procedure of the antioxidant ascorbic acid

BACKGROUND: Postoperatively reduced concentration of ascorbic acid (AA) in plasma (< or =45.5 micromol/l (< or =800 microg/dl)) is commonly interpreted as increased metabolic requirements, but it is not shown yet that the patient benefits from a substitution toward normal levels of AA. This is due to the missing knowledge on how to substitute AA effectively to normal plasma values in postoperative patients. Therefore, a postoperative AA substitution procedure "overnight" to normal values in plasma was investigated on a postoperative intensive care unit (ICU) in a university hospital. MATERIAL AND METHODS: Fifty-seven operated patients were randomly assigned to a control- or intervention group (CG and IG, respectively). In all patients, the AA plasma concentration was analysed preoperatively and on the first three postoperative days. Patients of the IG received AA intravenously up to four times within 12 h depending upon the initial AA concentration (<34.1 micromol/l (4x500 mg AA); < or =56.8 micromol/l (2x500 mg AA); < or =68.2 micromol/l (1x500 mg AA)). RESULTS: The preoperative and early postoperative AA values did not differ between the groups. On the first postoperative day in both groups the plasma concentration was lowered (< or =45.5 micromol/l) in 23 of all patients (CG: 85.18%; IG: 82.14%). In the IG, the dosage regime increased the AA plasma concentration to > or =45.5 micromol/l in 26 of 28 (92.86%) patients overnight. CONCLUSION: The investigated substitution procedure is sufficient to increase AA plasma concentration overnight to normal or high normal values in postoperative ICU patients.     

Comparison of urinary creatine with other biomarkers for the detection of 2-methoxyethanol-induced testicular damage

This study has compared different biomarkers of testicular damage, in particular evaluating urinary creatine as a non-invasive marker. Male rats were exposed to various doses of 2-methoxyethanol, a known testicular toxicant. Pathological damage, testis weight, urinary creatine and creatinine, serum lactate dehydrogenase, isozyme C4 (LDH-C4), and serum testosterone were determined. 2-Methoxyethanol caused dose-dependent pathological damage to the testes which was detectable at the lowest dose (100 mg kg^-1). Urinary creatine excretion was significantly raised at all doses but testis weight was only significantly decreased at the highest two doses (500, 750 mg kg^-1). Serum testosterone was only significantly decreased at 500 mg kg^-1 and LDH-C4 was not significantly increased at any dose. Therefore urinary creatine was the most sensitive marker of 2-methoxethanol-induced testicular damage and dysfunction.     

Clinical studies on the fibrinolytic action of pentosan polysulfate

The influence on fibrinolysis of the heparin-like substance Polyanion SP 54 is described. In vitro tests showed an increase of fibrinolysis by activation of the endogenous pathway via factor XII and prekallikrein. In vivo an increase of the availability of tissue plasminogen activator was assumed in addition. When different ways of administration of Polyanion SP 54 were tested an enhancement of fibrinolysis was also found after oral application of the substance. In a long term test the stimulation of fibrinolysis after oral therapy did not diminish within 12 months. A trial on patients with cerebral ischemic attacks and diminished fibrinolysis is not yet concluded but permits the assumption of a considerable diminution of ischemic attacks during therapeutic use of Polyanion SP 54.     

Distinct responses of basal ganglia substance P systems to low and high doses of methamphetamine

Substance P (SP) is a neuropeptide closely associated with basal ganglia dopaminergic neurons. Because some neuropeptide systems in the basal ganglia (i.e. neurotensin and metenkephalin) are differentially affected by treatment with low or high doses of methamphetamine, we determined if basal ganglia SP pathways were also differentially influenced in a dose-dependent manner by this psychostimulant. Employing in vivo microdialysis, it was observed that the low dose (0.5 mg/kg) of methamphetamine increased the extracellular concentration of SP in the substantia nigra, but not in globus pallidus or striatum. In contrast, the high dose (10 mg/kg) of methamphetamine did not increase extracellular SP content in any of these structures. The effect of the low-dose methamphetamine treatment on nigral extracellular SP levels was blocked by pre-treatment with either a D1 or D2 antagonist. In addition, 12 h after similar methamphetamine treatments, a dose-dependent differential response in SP tissue levels occurred in some of the regions examined. When these changes occurred, the low dose of methamphetamine usually reduced, whereas the high dose increased, SP tissue content. This study demonstrated opposite responses of the basal ganglia SP system to low and high doses of methamphetamine and suggested that a combination of dopamine D1 and D2 receptor activity contributed to these effects.     

Reevaluation of the Cottbus Reinfarction Study with 30 mg aspirin per day 4 years after the end of the study

Four to 6 years after the end of the Cottbus Reinfarction Study with 30, 60 and 1000 mg/day aspirin, the survivors (72% of the patients) were reevaluated under standardized conditions at the district hospital. Nearly all patients (82%) of the former 30 mg group took further on 30 mg aspirin daily whereas of the former 1000 mg group only 20% continued to take doses higher than 500 mg aspirin. Forty-five percent changed to very low doses. Whereas the death rate was nearly the same in all three former dosage groups the total reinfarction rate was higher (22.5%) in the previous 1000 mg group in comparison to the 30 mg group (17.4%, p less than 0.05). The non-fatal reinfarction rate was by 50% lower in the former 30 mg group compared with the previous 1000 mg group. In the age group 50-59 a 8.6% non-fatal reinfarction rate is contrasted to 1.7% reinfarctions in patients of the former 30 mg group (p less than 0.01). The risk factors were not significantly different in the three groups.     

Comparison of urinary creatine with other biomarkers for the detection of 2-methoxyethanol-induced testicular damage

Abstract

This study has compared different biomarkers of testicular damage, in particular evaluating urinary creatine as a non-invasive marker. Male rats were exposed to various doses of 2-methoxyethanol, a known testicular toxicant. Pathological damage, testis weight, urinary creatine and creatinine, serum lactate dehydrogenase, isozyme C4 (LDH-C4), and serum testosterone were determined. 2-Methoxyethanol caused dose-dependent pathological damage to the testes which was detectable at the lowest dose (100 mg kg^?1). Urinary creatine excretion was significantly raised at all doses but testis weight was only significantly decreased at the highest two doses (500, 750 mg kg^?1). Serum testosterone was only significantly decreased at 500 mg kg^?1 and LDH-C4 was not significantly increased at any dose. Therefore urinary creatine was the most sensitive marker of 2-methoxethanol-induced testicular damage and dysfunction.     

Effect of dose escalation of a monoclonal anti-CEA IgG on tumour localisation and tissue distribution in nude mice xenografted with human colon carcinoma

Summary A monoclonal anti-CEA antibody (1H12) has been examined for the effect of dosage on tumour localisation in immunodeprived mice xenografted with human colon carcinoma. Increased doses produced a linear rise in the absolute concentration found in the tumour but this was found to depend on tumour size, with the smaller tumours (mean weight 44 mg) accumulating significantly more antibody compared to larger tumours (mean weight 146 mg). With the smallest tumour (18 mg), in which saturation was achieved, a 500 g dose produced a concentration in tumour of 60 g/g. In the larger tumours a dose of 256 g produced a mean concentration of 5.2 g/g. Prolonged retention of 1H12 by tumour up to 8 days, observed at doses of 4, 128 and 256 g, indicated that the dynamics of localisation is unaffected by dosage.Increased doses of ¹²⁵I-1H12 caused an increase in the levels of radioactivity associated with all normal tissues studied. Thus at 8 days after injection an increase from 4 to 128 g produced 50% and 42% declines in the tumour to blood and liver ratios, respectively. Cumulative localisation of 1H12 in tumour, from 4 h to 8 days, relative to normal tissue clearance was diminished on increasing dosage. This study shows that attempted therapy with escalated amounts of intact antibody is likely to be limited by a protracted excretory process and measures aimed at accelerating circulatory clearance are necessary.     

Influence of substance P on the behavioral changes induced by haloperidol in rats

Locomotor activity and grooming behavior of rats were recorded for a period of 30 min following intraventricular injections of substance P(SP) in doses of 0.60 and 2.50 microgram/rat. The lower dose of the peptide significantly increased locomotion for 10 min and time spent grooming for 25 min. The effects of the same two doses of SP on the hypokinesia induced by various pharmacological treatments modifying catecholaminergic systems were then examined. SP did not affect the behavioral depression produced by alpha-methyl-para-tyrosine (250 mg/kg), FLA-63 (25 mg/kg) and phenoxybenzamine (20 mg/kg). However, SP, in dose of 0.60 microgram/rat, systematically reversed the decrease in locomotor activity induced by a relatively small dose of haloperidol, 0.1 mg/kg. The dame dose of the peptide significantly counteracted the rigidity but not the hypokinesia and catalepsy resulting from the previous administration of a higher dose of haloperidol, 3 mg/kg. The results support the hypothesis that SP may exert direct or indirect function in motor behavior, possible via a modulatory action on brain dopaminergic systems.     

Streptozotocin diabetes in juvenile pigs. Evaluation of an experimental model

Spontaneous diabetes in the domestic pig, an animal suitable for metabolic and endocrine studies and for experimental surgery, is extremely rare. In this study we have compared the diabetogenic response of various doses of streptozotocin in comparison to surgically induced diabetes. Streptozotocin in a low dose, 35 mg/kg body weight did not influence glucose metabolism while an intermediate dose, 85 mg/kg, resulted in a transient diabetic reaction. Streptozotocin, 100-150 mg/kg body weight, caused a complete and permanent diabetes. Animals made diabetic by means of pancreatectomy did not survive more than 10 days due to their poor general condition and diabetes. Streptozotocin induced diabetic animals survived with insulin treatment up to seven months. The results show that juvenile pigs made diabetic with 100-150 mg/kg body weight of streptozotocin may be useful in experimental work on glucose-, insulin- and C-peptide-metabolism in a large animal. Therefore it is potentially useful in pancreatic transplantation research.     

Plasma lidocaine levels during augmentation mammaplasty and suction-assisted lipectomy

Many plastic surgical procedures are dependent on or aided by the use of local anesthetics. Drug toxicity, although uncommon, is the most feared complication of this technique. There are multiple factors that lead to varying drug levels. These include drug concentration, speed of injection, rate of degradation, total dosage, site of injection or application, rate of administration, and the adjunctive use of vasoconstrictors. This study evaluates the use of subcutaneously injected lidocaine in patients undergoing suction-assisted lipectomy and augmentation mammaplasty. Lidocaine in the concentration of 0.5% containing either 1:100,000 or 1:200,000 epinephrine was used in doses up to 500 mg. Serial lidocaine levels were then obtained up to 1 1/2 hours after injection utilizing two different assay techniques. Our findings demonstrate consistently nondectable serum lidocaine levels despite the use of doses in excess of recommended "safe" amounts. This suggests that under specific circumstances and with certain operative procedures, lidocaine dosing can be liberalized.     

Quantitative analysis of a polysulfated xylan (SP54) in urine using gas-liquid chromatography

A sensitive analytical method for the quantitation of a polysulfated xylan (SP54) in urine has been developed. SP54 and urinary glycosaminoglycans have been isolated from urine using cetylpyridinium chloride. This method removes all glycosaminoglycans with molecular weights less than 3000 Da. Following isolation, SP54 and urinary glycosaminoglycans have been selectively hydrolyzed under conditions (0.5 M HCl/105 degrees C/30 min) which produce an efficient yield of xylose from SP54 but not from the glycosaminoglycans. Xylose derived from SP54 has subsequently been determined using gas-liquid chromatography. Levels of SP54 down to 10 micrograms/ml have been determined using this technique.     

Deoxycholate-treated, nontoxic, whole-cell vaccine protective against experimental salmonellosis of mice

A vaccine prepared from the residue after extraction of whole cells of Salmonella typhimurium with 2% sodium deoxycholate proved to be nontoxic and highly immunogenic. The material was not lethal for mice at 6.0 mg and was essentially nontoxic in rabbit skin, whereas endotoxic activity was found in the dialyzed extract. A high dosage, above 2.0 mg, was less protective than lower doses, indicating a degree of "immunologic paralysis." Three inoculations of low doses, 0.25 mg each, induced protection against death and tissue infection in animals challenged with 2,000 ld(50) of virulent homologous S. typhimurium and against death, but not against tissue infection, after heterologous challenge with S. enteritidis. Residues of purified cell walls were as effective as residues of whole cells, indicating that the immunizing antigen(s) resided in the cell wall.     

IL-18 levels and the outcome of innate immune response to lipopolysaccharide: importance of a positive feedback loop with caspase-1 in IL-18 expression

LPS enhanced antibacterial host defenses (ABHD) when given at low (75 micro g) doses (16 of 19 mice survived 3x LD(50) Escherichia coli vs 3 of 19 LPS-naive mice; p = 0.0001), but induced lethal inflammation at high (500 micro g) doses (5 of 5 died). Differences in the cytokine profiles induced by these LPS doses may provide insight into the mechanism(s) of transition from beneficial to lethal LPS responses. The 75 micro g LPS induced 5.9 +/- 0.9 ng/ml serum IL-18 at 8 h, which decreased to 2.3 +/- 0.4 ng/ml by 24 h, whereas 500 micro g LPS induced 11.1 +/- 1.6 ng/ml serum IL-18 levels at 8 h, which increased until death. Compared with 75 micro g, higher but sublethal (150 micro g) doses of LPS induced greater serum IL-18 levels and less effectively induced ABHD (3 of 8 survived). Reduction of serum IL-18 with neutralizing Ab improved the ABHD induced by 150 micro g, but reduced that produced by 75 micro g LPS, suggesting an optimal range of serum IL-18 level was essential for efficient ABHD. Increased expression of caspase-1 mRNA in response to the higher IL-18 levels induced at the 150 and 500 micro g, but not at the 75 micro g doses of LPS may represent a positive feedback regulatory loop leading to sustained serum IL-18 levels. We conclude that the regulation of serum IL-18 expression is critical to the outcome of innate immune responses to LPS.