Gender has an important influence on blood pressure, with premenopausal women having a lower arterial blood pressure than age-matched men. Compared with premenopausal women, postmenopausal women have higher blood pressures, suggesting that ovarian hormones may modulate blood pressure. However, whether sex hormones are responsible for the observed gender-associated differences in arterial blood pressure and whether ovarian hormones account for differences in blood pressure in premenopausal versus postmenopausal women remains unclear. In this review, we provide a discussion of the potential blood pressure regulating effects of female and male sex hormones, as well as the cellular, biochemical and molecular mechanisms by which sex hormones may modify the effects of hypertension on the cardiovascular system.

This review sought to examine the rationale for selecting an oral micronized progesterone formulation rather than a synthetic progestin for some of the main indications for progestogens. Unopposed estrogen use is associated with a high risk (relative risk, 2.1 to 5.7) of endometrial hyperplasia and adenocarcinoma, and it has been understood for some time that a progestogen must be added for at least 10 to 14 days per month to prevent these effects. However, the most commonly used synthetic progestins, norethisterone and medroxyprogesterone acetate, have been associated with metabolic and vascular side effects (eg, suppression of the vasodilating effect of estrogens) in both experimental and human controlled studies. All comparative studies to date conclude that the side effects of synthetic progestins can be minimized or eliminated through the use of natural progesterone, which is identical to the steroid produced by the corpus luteum. The inconvenience associated with the use of injectable, rectal, or vaginal formulations of natural progesterone can be circumvented by using orally administered micronized progesterone. The bioavailability of micronized progesterone is similar to that of other natural steroids, and interindividual and intraindividual variability of area under the curve is similar to that seen with synthetic progestins. A clear dose-ranging effect has been demonstrated, and long-term protection of the endometrium has been established. Micronized progesterone has been used widely in Europe since 1980 at dosages ranging from 300 mg/d (taken at bedtime) 10 days a month for women wishing regular monthly bleeding to 200 mg 14 days a month or 100 mg 25 days a month for women willing to remain amenorrheic. This therapy is well tolerated, with the only specific side effect being mild and transient drowsiness, an effect minimized by taking the drug at bedtime. The prospective, comparative Postmenopausal Estrogens/Progestin Intervention trial has recommended oral micronized progesterone as the first choice for opposing estrogen therapy in nonhysterectomized postmenopausal women.

1. Oral micronized progesterone (P) is proposed for the treatment of certain endocrine gynaecological disorders. To examine the effects of P on performance and mood, a randomized, placebo-controlled study of 24 healthy females ages 18-24 years on low-dose oral contraceptives was conducted. 2. Subjects were admitted to the Clinical Research Center on four occasions and received single doses of oral P (300, 600, 1200 mg) or placebo. Blood sampling, psychometric tests and mood scales were administered at baseline and at hourly intervals for 6 h. 3. P doses produced significant dose-related but highly variable increases in plasma P concentrations. Fatigue increased with P doses, although few subjects were objectively drowsy. Very high peak plasma P concentrations, achieved by some subjects at the 1200 mg dose, were associated with decreased information processing and verbal memory function as well as fatigue. 4. We conclude that oral P can safely be prescribed at higher than previously-reported doses, based on evidence of transient behavioural effects only at the highest doses in some subjects who achieved high plasma P concentrations.

The effects of substituted catechols (3-methylcatechol, 4-methylcatechol, 4-nitrocatechol, and guaiacol) and trihydroxybenzenes (pyrogallol, propyl gallate, 1,2,4-trihydroxybenzene, and 1,3,5-trihydroxybenzene) on the synthesis of prostaglandin (PG)E2 and leukotriene (LT)B4 were tested in human A23187-stimulated polymorphonuclear leukocytes. The effects were related to their peroxyl-radical-scavenging (antioxidant), superoxide-scavenging (antioxidant), and superoxide-generating (prooxidant) properties. In general, compounds with hydroxyl groups in the ortho position increased PGE2/LTB4 ratio, and compounds with hydroxyl groups in the meta position decreased PGE2/LTB4 ratio. Catechols, which have hydroxyl groups in the ortho position, were the most potent peroxyl radical and superoxide anion scavengers. Trihydroxybenzenes (pyrogallol, 1,2,4-trihydroxybenzene, and 1,3,5-trihydroxybenzene) generated superoxide, whereas dihydroxybenzenes did not. Thus, the positions and number of hydroxyl groups seem to be the most important properties determining the action of phenolic compounds on PGE2/LTB4 ratio and their antioxidant/prooxidant activities.

1. The study was designed to test the hypothesis that nitric oxide (NO)-releasing compounds increase guanosine 3':5'-cyclic monophosphate (cyclic GMP) production in human polymorphonuclear leucocytes (PMNs) and concomitantly inhibit PMN functions, i.e. leukotriene B4 (LTB4) synthesis, degranulation, chemotaxis and superoxide anion (O2-) release. The effects of two new NO-releasing compounds, GEA 3162 and GEA 5024 were compared to 3-morpholino-sydnonimine (SIN-1) and S-nitroso-N-acetyl-penicillamine (SNAP). 2. GEA 3162 and GEA 5024 (1-100 microM) inhibited Ca ionophore A23187-induced LTB4 and beta-glucuronidase release, chemotactic peptide FMLP-induced chemotaxis and opsonized zymosan-triggered chemiluminescence dose-dependently in human PMNs. SIN-1 and SNAP were weaker inhibitors. 3. Cellular cyclic GMP production was increased after exposure to NO-donors concomitantly with the inhibition of PMN functions. No alterations in the levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) were detected. 4. The results suggest that NO, possibly through increased cyclic GMP, inhibits the activation of human PMNs and may thus act as a local modulator in inflammatory processes.

We have shown earlier that catecholamines have opposite regulative effects on prostaglandin (PG)E2 and leukotriene (LT)B4 formation with a receptor-independent mechanism in human polymorphonuclear leukocytes (PMNs) and whole blood. To shed further light on the mechanisms involved and structure-action relationship, we tested the effects of phenols (catechol, hydroquinone, phenol, and resorcinol) on the synthesis of PGE2 and LTB4 in human A23187-stimulated PMNs. To study the mechanism of how phenols influence PGE2 and LTB4 synthesis, their peroxyl radical-scavenging properties were analyzed. In general, low concentrations of phenols stimulated (catechol > hydroquinone >> phenol) and high concentrations inhibited (resorcinol > catechol > hydroquinone > phenol) PGE2 formation. Resorcinol was different from the other phenols: It did not stimulate PGE2 synthesis at all, but it was effective inhibitor at high concentrations. Phenols had only an inhibitory effect on LTB4 formation (catechol = hydroquinone >> phenol > resorcinol). The order of both stochiometric factors and reactivities of phenols for scavenging peroxyl radicals was catechol > hydroquinone > resorcinol >> phenol. According to these results, phenols having hydroxyl groups in ortho- or paraposition have the greatest stimulative effect on PGE2 synthesis, the highest inhibitory action on LTB4 synthesis, and are good antioxidants. Resorcinol, having hydroxyl groups in the metaposition, behaves differently. It neither stimulates PGE2 nor inhibits LTB4 formation, but it is the most potent inhibitor of PGE2 formation. In spite of resorcinol's two hydroxyl groups, it mimics as an antioxidant phenol more than catechol and hydroquinone.

Indicators of cardiovascular strain were studied in 12 healthy young men under the influence of drugs affecting the autonomic nervous system during the course of taking a sauna bath. There were four bath sessions: one without a drug (control) and three with drug pretreatment (Atenolol 50 mg or Scopolamine 0.3 mg or their combination taken orally 2 h before the bath). The time spent in the hot room depended on the subjective rating of heat stress. Its mean duration at a temperature of 88 degrees C (dry bulb) was 22 (range 14-33) min and did not differ significantly among the sessions. In the Atenolol experiment the mean resting heart rate before the bath was significantly lower (P < 0.001, ANOVA of repeated measures) than in the other experiments. The increase in heart rate per minute of heat exposure was significantly lower (P < 0.001) in the Atenolol experiment and higher (P = 0.017) in the Scopolamine experiment than in the other experiments. The systolic blood pressure increased more slowly (P = 0.004) and the diastolic pressure decreased less (P = 0.02) in the Atenolol experiment than in the other experiments. Heart rate and blood pressure returned to their initial levels during the 30-min recovery after the heat exposure. The plasma noradrenaline concentrations increased approximately twofold during all of the bath sessions, whereas the plasma adrenaline and serum thromboxane B2 concentrations showed no consistent alterations. A small oral dose of Scopolamine alone or in combination with Atenolol produced no marked cardiovascular strain in healthy men during a sauna bath.

We have previously demonstrated that adrenaline infusion increases the thromboxane/leukotriene (TX/LT) ratio in whole blood in healthy volunteers. The aim of the present study was to see whether other catecholamines--noradrenaline and dopamine--are also capable of modulating arachidonic acid (AA) metabolism in man. Low doses of noradrenaline (0.025 microgram/kg/min) and dopamine (3.0 micrograms/kg/min), which did not change hemodynamics, were infused for 60 min into healthy male volunteers. Both dopamine and noradrenaline decreased TX synthesis stimulated by spontaneous clotting, but no remarkable effect was seen when calcium ionophore A23187 was used as a stimulus. Dopamine but not noradrenaline increased prostaglandin E2 (PGE2) synthesis in A23187-stimulated whole blood. They both marginally decreased LTB4 formation in A23187-stimulated whole blood. The findings indicate that not only adrenaline but also noradrenaline and dopamine modulate AA metabolism in man.

Mesoionic oxatriazole derivatives were synthetized by GEA LTD1. The GEA compounds (GEAC) constitute a new class of NO-donors, some of which stimulate selectively guanylate cyclase abiding either platelets or leukocytes or lung tissues. In consequence, some of GEAC are potent anti-platelet, fibrinolytic, thrombolytic or broncholytic agents, both in vitro and in vivo. GEAC synergize with prostacyclin in their thrombolytic actions. They also suppress the release of histamine and leukotriene B4, and prevent degranulation of granulocytes. Methylene blue reduces, and zaprinast augments their pharmacological effects. It is suggested that within a series of the newly synthetized GEA compounds there are likely to be found potential candidates for treating either thrombotic or asthmatic disorders.

It has been suggested that cyclic nucleotides (cAMP and cGMP) participate in the regulation of cardiac contractility and glycolysis. In the present study, this possible involvement was examined in spontaneously beating rat atria during hypoxia (50% oxygen saturation). Thirty seconds after reduction of high oxygen saturation (HiOxSa) in the incubation medium, the contraction amplitude declined to 50% of the initial level. The decline was partly antagonized by norepinephrine (NE) or hypercalcemia. The cAMP level remained unchanged during hypoxia, but the cGMP content gradually increased. Paradoxically, the production of lactate decreased after 30 sec of hypoxia but had increased by 2 min, when depletion of creatine phosphate and ATP stores was also initiated. Sodium nitroprusside (nitroprusside) and NE elevated the cGMP and cAMP, respectively, in both HiOxSa and hypoxia. Nitroprusside and NE also showed a positive inotropic effect in HiOxSa. Verapamil decreased contractility without changing the levels of cAMP or cGMP. In HiOxSa, both nitroprusside and verapamil decreased lactate production but were not able to resist the increase in atrial lactate level brought about by NE. In hypercalcemia the amplitude increased, but lactate production was slightly reduced in HiOxSa. Between 5 and 10 min of hypoxia, 45Ca uptake was reduced to about one-third of that in the control. It is suggested that lack of oxygen has direct and parallel effects on the sarcolemma and the mitochondria. The former induces deterioration of contractility, the latter termination of aerobic energy production. Cyclic nucleotides are not involved in either of these phenomena. However, at a low rate of anaerobic glycolysis, e.g., in HiOxSa or at the very early stage of hypoxia, cGMP could inhibit and cAMP accelerate lactate production.

The effects of 8-bromo-cGMP on tissue lactate and NADH levels were studied under conditions of high oxygen saturation (95-100%) and hypoxia (50%) in spontaneously beating rat atria. The induction of hypoxia caused a rapid decline in contractility with a simultaneous increase in tissue lactate and NADH. 8-bromo-cGMP (10(-4) mol/l) prevented the accumulation of lactate occurring during hypoxia. It also lowered the level of lactate during high oxygen saturation. Furthermore, 8-bromo-cGMP inhibited the hypoxia-induced increase in NADH and lowered the level of NADH in high oxygen saturation. 8-bromo-cGMP did not affect contractility or heart rate during hypoxia. It is concluded that cGMP may influence the redox-state and metabolism in a direction which is beneficial for the hypoxic myocyte. It is also suggested that antianginal nitro compounds which enhance the level of cGMP might exert an effect similar to that of 8-bromo-cGMP.

The alkaloid, rhynchophylline (RHY), from the stems and hooks of Uncaria rhynchophylla was revealed in recent years to have protective effect on neuronal damage. The present research was carried out to investigate the in vivo metabolism of this bioactive alkaloid. After administering RHY to rats, LC-MS detected RHY in plasma, bile, brain, urine and feces, the glucuronides, 11-hydroxyrhynchophylline 11-O-beta-D-glucuronide (M1) and 10-hydroxyrhynchophylline 10-O-beta-D-glucuronide (M2) in bile, and 11-hydroxyrhynchophylline (M3) and 10-hydroxyrhynchophylline (M4) in urine and feces. Within 24 h, 78.0% of RHY was excreted into the feces and 12.6% into the urine of rats after oral administration of 37.5 mg/kg. Monitoring by LC-MS showed that 9.4% of RHY was metabolized to M3 and M4 in a ratio of about 1 : 1. RHY was also detected in the brain (0.650 ng/g) at 3 h after oral administration of the same dose. Cytochrome P450 (CYP) in rat liver microsomes played a key role in RHY hydroxylation. Specific inhibition of CYP isozymes indicated that CYP2D, CYP1A1/2 and CYP2C participated in RHY hydroxylation, but not CYP3A.

The efficacy of anaesthetic premedication has been assessed using sedative scores or a visual analogue scale. However, in both it may be difficult to exclude evaluators' subjectivity or a placebo effect. Plasma concentration of catecholamines may also be useful for the assessment of patient anxiety. Recently bispectral electro-encephalographic analysis has been developed, and the bispectral index monitor has been reported to give measurements which correlate well with the depth of sedation. In the present study, we have examined the relation between bispectral index values and plasma catecholamine concentrations after oral diazepam premedication. Twenty-eight patients scheduled for elective surgery were randomly assigned to one of two groups: diazepam premedication group (group D(+), n = 14) and no premedication group (group D(-), n = 14). The patients were premedicated orally with diazepam 10 mg and roxatidine 75 mg in group D(+), and with roxatidine 75 mg only in group D(-) 90 min before arrival in the operating theatre. After patients arrived in the operating theatre, the bispectral index monitor was applied. Venous blood samples (6 mL) were collected in the case of patients in group D(+) for the measurement of plasma catecholamines levels using high-performance liquid chromatography. The bispectral index level (mean +/- SD) in group D(+): 93.5 +/- 773.5 was significantly lower than that in group D(-): 96.1 +/- 1.8 (P < 0.05). There was a significant correlation between bispectral index and plasma norepinephrine levels (r = 0.567, P < 0.05). The present study suggests that the bispectral index monitor may detect the effect of oral diazepam premedication.

The purpose of this study was to determine disorders in the metabolism of the essential elements (Ca, Fe, Cu, and Zn) in some tissues of rats, as well as to detect the dynamics of urinary excretion of these metals after oral administration of 20 mgAl/kg every day for 8 wk. The elements were determined in brain, kidneys, blood, and urine of the animals in 1st, 2nd, 3rd, 4th, and 8th wk after the exposure to AlCl3. After the 1st wk of aluminium administration, we observed increase of Ca and a decrease of Fe in blood. In brain Ca, Fe, and Cu concentrations were significantly higher in Al-treated rats than in controls after 8-wk exposure. The concentration changes of the essential metals in the tissue were accompanied by increase of the Ca, Fe, and Zn urinary excretion. We assume that the increase in urinary excretion of Ca and the decrease of Fe in the blood may be sensitive indicators of oral aluminium administration.

1. After intravenous administration of the non-nutritive sweetener, saccharin (10 mg/kg), to normal volunteers; the plasma concentration--time curve fitted a two-compartment open model with a terminal half-life of 70 min. Renal clearance was high and the dose was recovered quantitatively in the urine. The elimination rate and clearance were decreased significantly by concurrent probenecid administration. 2. After oral administration (2 g) more complex and variable plasma concentration--time curves were obtained and these were reflected in the urinary excretion of saccharin. The fraction absorbed was about 0.85 as determined by the recovery in urine and the area under the plasma concentration--time curves. 3. No indication of saturation of renal elimination was found after oral or intravenous doses that were many times the average daily intake.

Secnidazole, a derivative of 5-nitro imidazole exhibits trichomonacid, amoebicid and antimicrobial properties; it has been studied in view of its biological fate in healthy volunteers (man and woman) comparatively with tinidazole. Both products were administered orally to the same volunteers at the single dose level of 2 g. The seric concentrations and the pharmacokinetic profile were determined up to the 72nd hour after drug administration. The whole urinary excretion (unchanged product + metabolites) during the same period was determined in percent of the administered dose level. Secnidazole is particularly different from tinidazole owing to its slower blood clearance. The apparent average half-life in the ten volunteers (5 men and 5 women) is about 17 hours for secnidazole and 13 hours for tinidazole. However, for both drugs, a difference between men and women was demonstrated: in female volunteers, the decrease in blood concentrations occurs a little quicker than in male volunteers. Regarding urinary excretion, it is also a little greater in female volunteers than in male volunteers.

A study of blood and urinary clearance of prednisone after ingestion of a 25 mg/m2 body surface test-dose, at 8 AM, was undertaken in 20 children treated for 18 months with prednisone after renal transplant. Results show important variability between patients: the elimination half life was 2.70 +/- 0.78 hr.; Tmax time to reach Cmax was 2.10 +/- 1.08 hr.; Maximal concentration (Cmax) was 474 +/- 153 ng/ml. With respect to the dose of steroid administered, the urinary excretion of corticosteroids: 17-hydroxycorticosteroids was 12.9 +/- 7.4% and that of unchanged prednisolone 2.8 +/- 3.1%. This level was essentially achieved in the 6 first hours: 55.4 +/- 16.2% for 17-OH steroids and 87.2 +/- 14.3% for prednisolone. Two points emerge from this study:(a) Renal failure slows urinary excretion of prednisone and its metabolites, making a reduction in the doses of corticosteroids necessary at certain doses.(b) The association prednisone-phenobarbital changes the blood kinetics (excretion is faster) without a clear change in 17-OH steroid and prednisolone urinary excretion. It is associated with a decrease in graft tolerance. The kinetic changes do not seem to be the only factors implicated in the decreased therapeutic response.

The effects of erythromycin on the immune system have been studied in healthy volunteers and patients suffering from chronic bronchopneumonial diseases, by means of the following assays: phagocytosis, natural killer activity and superoxide anion production. The tests were performed before and after oral administration of 1 g of erythromycin. The findings suggest that erythromycin enhances phagocytosis by means of increasing ingestion of microorganisms, superoxide anion (O2-) production as well as natural killer activity. Under the experimental conditions described these effects appear 4-6 h after drug intake and reach their maximum around the 8th hour.

1. Stereoselective metabolic disposition of ofloxacin (OFLX) was studied in rats after oral administration of S-(-)-14C-OFLX and R-(+)-14C-OFLX at a dose of 20 mg/kg. 2. Radioactivity of the S-(-)-isomer was eliminated from blood much faster than that of the R-(+)-isomer. Marked differences in pharmacokinetic parameters exist between the enantiomers; the half life and AUC values of R-(+)-OFLX were greater than those of S-(-)-OFLX. Enantiomeric differences were also seen in the excretion of radioactivity, especially in biliary excretion. 3. 31.3 and 7.4% dose were excreted in the 8 h bile as ester glucuronides after oral administration of S-(-)- and R-(+)-OFLX, respectively. The enantiomeric difference in biliary excretion may be caused by stereoselective glucuronidation of S-(-)-OFLX to the ester glucuronide. 4. The metabolite pattern in serum and urine showed that the ester glucuronide of S-(-)-OFLX was more predominant than that of R-(+)-OFLX. 5. The stereoselective ester glucuronidation of the S-(-)-isomer in rats may induce significant differences in the pharmacokinetic parameters of S-(-)- and R-(+)-OFLX.

The excretion of 3-mercaptolactate-cysteine mixed disulfide [S-(2-hydroxy-2-carboxyethylthio)-L-cysteine, HCETC], sulfate and taurine in the urine of normal adults was investigated before and after oral administration of L-cysteine and related sulfur-containing amino acids. Before the loading of amino acids, the excretion (mean +/- SD) per kg of body weight per day of HCETC, free sulfate and taurine was 0.096 +/- 0.042, 305.7 +/- 66.1 and 31.9 +/- 8.7 mumols, respectively. After the loading of L-cysteine (800 mumols/kg of body weight), the average excretion in the 24-h urine of HCETC increased 2-fold and that of taurine increased 1.6-fold. The average excretion of free sulfate after the L-cysteine loading was 989.4 +/- 145.1 and 388.8 +/- 51.6 mumols/kg per day in the first and second 24-h urine, respectively, indicating that the sulfur corresponding to 85% of the L-cysteine loaded was excreted as free sulfate in 24 h. Administration of L-cystine (400 mumols/kg) resulted in similar results. The increase in HCETC after L-cysteine or L-cystine administration indicates that L-cysteine is metabolized in part through the transamination pathway (3-mercaptopyruvate pathway) and that an equilibrium exists between the intake and excretion of sulfur in humans.

1. Urinary metabolites of methylephedrine and their excretion after oral administration to rat and human volunteers have been studied. 2. The unchanged drug, ephedrine, norephedrine, their aromatic hydroxylated compounds and methylephedrine N-oxide were found in rat urine. The same metabolites, except the p-hydroxylated metabolites, were detected in human urine. The most abundant metabolite in rat urine was methylephedrine N-oxide, and in human urine was the unchanged drug. 3. Metabolites excreted in three days after administration of the drug to rat amounted to about 54% of the dose and those after administration to man, 70-72%.