Long-term effects of St. John's wort and hypericin on monoamine levels in rat hypothalamus and hippocampus

Hypericum perforatum L. (St. John’s wort) is one of the leading psychotherapeutic phytomedicines and, because of this, great effort has been devoted to clarifying its mechanism of action. Chronic effects of St. John’s wort and hypericin, one of its major active compounds, on regional brain amine metabolism have not been reported yet. We used a high-performance liquid chromatography system to examine the effects of short-term (2 weeks) and long-term (8 weeks) administration of imipramine, Hypericum extract or hypericin on regional levels of serotonin (5-HT), norepinephrine, dopamine and their metabolites in the rat brain. We focused our interest on the hypothalamus and hippocampus, as these brain regions are thought to be involved in antidepressant drug action. Imipramine (15 mg/kg, p.o.), Hypericum extract (500 mg/kg, p.o.), and hypericin (0.2 mg/kg, p.o.) given daily for 8 weeks significantly increased 5-HT levels in the hypothalamus (P<0.05). The 5-HT turnover was significantly lowered in both brain regions after 8 weeks of daily treatment with the Hypericum extract (both P<0.05). Consistent changes in catecholamine levels were only detected in hypothalamic tissues after long-term treatment. Comparable to imipramine, Hypericum extract as well as hypericin significantly decreased 3,4-dihydroxyphenylacetic acid and homovanillic acid levels in the hypothalamus (P<0.01). Our data clearly show that long-term, but not short-term administration of St. John’s wort and its active constituent hypericin modify levels of neurotransmitters in brain regions involved in the pathophysiology of depression.     

Once-A-Day therapy for sinusitis: A comparison study of cefixime and amoxicillin

The efficacy and safety of a once-a-day antibiotic in the treatment of sinusitis was studied. Two randomly assigned groups were treated with either once-a-day cefixime, a third generation cephalosporin, or amoxicillin three times a day. One hundred and fourteen patients were evaluated with antral punctures, microbiologic evaluation, and radiographic studies. Cultures revealed 40% gram-negative organisms, 48% gram-positive, and 12% anaerobes. The most common bacteria were Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus and viridans group streptococci. Ninety-four percent of the cefixime group were cured compared with 96% of the amoxicillin group. Staphylococcus resistance was a problem in both groups, necessitating an occasional change to amoxicillin-clavulanate potassium in the amoxicillin group. Once-a-day antibiotics offer the potential for improved compliance in the treatment of sinusitis. Cefixime offers an additional benefit of covering β-lactamase producing strains of bacteria which are increasing in incidence and resistant to many penicillins.     

Anticancer efficacy of the irreversible EGFr tyrosine kinase inhibitor PD 0169414 against human tumor xenografts

Purpose: The involvement of the EGF receptor (EGFr) family of receptors in cancers suggests that a selective inhibitor of the tyrosine kinase activity of the EGFr family could have a therapeutic effect. PD 0169414, an anilinoquinazoline, is a potent irreversible inhibitor of the EGFr family tyrosine kinase activity with IC₅₀ values of 0.42 nM against the isolated EGF receptor, and 4.7 nM and 22 nM against EGF- and heregulin-mediated receptor phosphorylation in A431 and MDA-MB-453 cells, respectively. Methods and Results: Oral administration of 260 mg/kg per day PD 0169414 for 15 days to animals bearing advanced-stage A431 epidermoid carcinoma produced a 28.2-day delay in tumor growth and resulted in three complete and three partial tumor regressions in six animals. Toxicity at this dose level was limited to <6% loss of initial body weight. Doses of 160 and 100 mg/kg per day produced tumor growth delays of 29.5 and 20.9 days and two and one complete regressions in six animals, respectively. Subcutaneous, intraperitoneal, and oral routes of administration have also shown in vivo antitumor activity of PD 0169414 in a panel of human tumor xenografts. Responsive tumor lines include A431 (human epidermoid carcinoma), H125 (NSCL carcinoma), MCF-7 and UISO-BCA1 (human breast carcinoma), and SK-OV-03 (human ovarian carcinoma). The therapeutic effect ranged from delayed tumor growth (6.4 days delayed tumor growth for 14 days of treatment) to tumor regressions (32.2 days delayed tumor growth and five partial regressions in six animals) in these model systems. Conclusion: PD 0169414 is a specific, irreversible inhibitor of EGFr family tyrosine kinases with significant in vivo activity against a variety of relevant human tumor xenografts. Received: 19 May 1999 / Accepted: 11 August 1999     

Effect of simvastatin on qualitative and quantitative changes of lipoprotein metabolism in CAPD patients.

The efficacy of simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase, was investigated in 12 patients treated with continuous ambulatory peritoneal dialysis (CAPD), displaying hypercholesterolemia and moderate hypertriglyceridemia. After a 4-week placebo period, simvastatin was administered in increasing doses over a period of 3 months (1st month 10 mg; 2nd month 20 mg and 3rd month 40 mg day-1). Simvastatin reduced total serum cholesterol (300.0 +/- 15.5 vs. 193.0 +/- 8.0; -35%), LDL cholesterol (203.8 +/- 13.0 vs. 104.7 +/- 6.0; -48.0%) as well as apolipoprotein B (132.3 +/- 6.6 vs. 77.8 +/- 2.7 mg/dl; -40%). Furthermore, the ratio of LDL apo B/LDL cholesterol increased significantly (0.55 +/- 0.016 vs. 0.64 +/- 0.027). Another remarkable effect was the reduction of cholesterol concentration in VLDL (47.8 +/- 5.6 vs. 30.4 +/- 5.2; -35%). Therefore, the ratio of triglycerides/cholesterol in VLDL increased (3.57 +/- 0.3 vs. 4.28 +/- 0.29), indicating VLDL formation poor in cholesterol and rich in triglycerides. However, HDL cholesterol increased significantly from 48.6 +/- 4.4 to 57.9 +/- 5.3 mg/dl (23%). Lipoprotein(a) levels were increased as compared to controls (420 +/- 73 vs. 145 +/- 26 U/l), but were not influenced significantly by simvastatin treatment (539 +/- 99 U/l, 3rd month). No evidence for notable clinical side effects and laboratory abnormalities were reported. Measurement of simvastatin plasma levels 12 h after drug administration (single dose 40 mg) showed no detectable plasma values. At present, it appears that CAPD patients with high serum cholesterol are good candidates for the treatment with HMG-CoA reductase inhibitors.     

Effects of lipoprotein(a) on mesangial cell proliferation and viability

BACKGROUND: Lipoprotein abnormalities are considered to accelerate glomerularinjury in various forms of renal disease, probably by affectingmesangial proliferation. Serum levels of the atherogenic Lipoprotein(a)(Lp(a)) are elevated in patients with nephrotic syndrome andLp(a) deposits have been identified in diseased glomeruli. Sofar, the influence of Lp(a) on mesangial cell function has notbeen defined. METHODS: The influence of Lp(a) on mesangial cell proliferation was assessedin a rat mesangial cell culture model by direct measurementof cell growth as well as analysis of DNA-synthesis and mRNAlevels of c-fos and c-myc, two growth-associated ‘immediateearly response genes’. RESULTS: Lp(a) triggered a biphasic response on DNA synthesis: ³H-thymidineuptake was increased when cells were incubated with Lp(a) (2.5–10µg/ml) for 24 h. The response was dose dependent, a maximaleffect was seen for Lp(a) 5 µg/ml. The stimulatory propertiesof Lp(a) were comparable to 10% fetal calf serum (FCS). No additiveeffect of 10% FCS and Lp(a) on DNA synthesis was observed. Cellproliferation was moderately stimulated (120±9% of control)by low levels of Lp(a) in the presence of small amounts of FCS.Messanger RNA levels for c-fos and c-myc were upregulated asearly as 15 min after incubation with Lp(a) 5 µg/ml, amaximum response was observed after 30 and 240 min respectively.Stimulation of DNA synthesis was partly blunted when cells wereincubated with Lp(a) in the presence of catalase 100 U/ml andsuperoxide dismutase 10^–7M (SOD) but not in the presenceof SOD alone. Lp(a) in concentrations above 10 µg/ml depressedDNA-synthesis and elicted signs of cytotoxicity. The cytotoxiceffects of Lp(a) were not blunted by oxygen radical scavengers.The stimulatory and cytotoxic effects of Lp(a) were not restrictedto a specific isoform. CONCLUSION: Low concentrations of Lp(a) stimulated growth of mesangial cells,whereas higher concentrations had antiproliferative or toxiceffects. The stimulation of mesangial cell proliferation aswell as the cytotoxic effects causes by Lp(a) are both likelyto have a negative impact on the course of renal disease.     

Neue Bücher

International Journal of Public Health -     

Comparative studies of radioisotope uroflowmetry (author's transl)]

Radioisotope uroflowmetry allows continuous recording of urinary stream with determination of maximum and mean urine flow rate, duration of voiding and residual urine without urethral catheterisation. By the aid of twenty simulated tests and nine examinated patients the precision of this method was investigated by comparing our results with the findings of simultaneously recorded mictiographic measurement. The flow curves and the maximum flow rate show a high correlation.     

The use of dynamic models to study the role of calcium in the oxytocin-induced contractions of the uterus.

The question as to whether calcium can be considered to be a mediator of oxytocin-induced myometrial contraction has been investigated. Assuming that the contraction is linearly proportional to the myoplasmic calcium concentration, several possible molecular mechanisms leading to its increase (calcium release from the cell membrane, acceleration of calcium transport from extracellular space by a 'gate' mechanism, release from intracellular organelles, blockade of calcium pumps) were modelled on an analog computer. The oxytocin intervention in the calcium distribution was mimicked by a discontinuous change of the appropriate rate constants. The computed transient simulating the myoplasmic calcium concentration was then compared with an experimental time profile of uterine tension. The result of screening the models shows that oxytocin must act predominantly via release of calcium bound to the cell membrane. A quantitative comparison, however, requires that the kinetics of oxytocin distribution in myometrium also be considered in the model. The problem treated in this paper demonstrates the possibilities and limitations of a screening procedure based upon direct comparison of time profiles of experimental processes with several computed model alternatives.