Pharmacokinetics of natural progesterone administered in the form of a vaginal tablet.

Our study was conducted to assess the pharmacokinetics of natural progesterone administered in the novel formula of an effervescent vaginal tablet. Fifty post-menopausal women, with a median age of 43.5 years (range 28-55), volunteered to participate in the research. All women discontinued their hormonal replacement therapy 1 month prior to the study. The pharmacokinetics of 50 and 100 mg of progesterone administered as a vaginal tablet were evaluated. After the initial administration of 50 mg or 100 mg, a mean serum Cmax of 20.43 +/- 8.01 nmol/l and 31.61 +/- 12.62 nmol/l (P < 0.0004) was reached at a Tmax of 6.1 +/- 2.63 and 6.4 +/- 3.35 h respectively. The terminal half-life was 13.18 +/- 1.3 and 13.7 +/- 1.05 h respectively. Continuous use of the 100-mg tablet resulted in a mean serum progesterone concentration of 26.08 +/- 13.96 nmol/l and 21.42 +/- 16.32 nmol/l after 14 and 30 days respectively. Women >40 years were found to have a significantly lower Tmax compared to younger women (P = 0.02). The continuous use of vaginal progesterone did not influence the hormonal, liver or lipid profiles evaluated. Only three (6%) women suffered from mild vaginal irritation. Natural progesterone given as a vaginal tablet is well tolerated, safe and an easily administered treatment. Even in a non-oestrogenized vagina the absorption was efficient and the 100 mg dosage resulted in adequate serum progesterone concentrations.

Relationship between routine hematological parameters, serum IL-3, IL-6 and erythropoietin and mild anemia and degree of function in the elderly.

To investigate the influence of functioning on unexplained senile anemia, we measured commonly used hematological parameters (serum iron, transferrin, iron saturation and ferritin) in addition to specific erythropoietic factors, such as interleukin-3 (IL-3), interleukin-6 (IL-6), and erythropoietin (EPO) in 48 elderly subjects aged 65-90 years. The subjects were divided into 3 groups: 1) 17 patients with unexplained mild anemia; 2) 17 non-anemic patients with newly acquired stroke and who previously were functionally active; 3) 14 functionally active patients with no major disease who served as controls. Anemia was defined as hemoglobin (Hb) values under 12.0 g/dL. The degree of functional ability was defined and scored by the "functional independence measure" (FIM) test. Data are presented as mean values +/- SD. The results revealed a correlation between the functional state and levels of Hb, iron and transferrin with unchanged iron saturation. Patients in the mild anemia group were found to be functionally declined (FIM = 57 +/- 19.4) with the relatively lowest mean iron (75.1 +/- 17 micrograms/dL) and transferrin levels (243 +/- 42.6 micrograms/dL). The stroke group (FIM = 62 +/- 17.7) had intermediate levels of iron (85.4 +/- 20.3 micrograms/dL) and transferrin (245 +/- 45.2), and with the continuation of the declined functional state the Hb level decreased significantly (13.7 +/- 0.9 to 12.0 +/- 1.0 g/dL, p < 0.001). The highest mean values of iron (102 +/- 27.9 micrograms/dL) and transferrin (322 +/- 42.7 micrograms/dL) were found in the control group (FIM = 122.7 +/- 5.8). The ferritin levels showed an opposite trend. IL-3 values were undetectable in the anemic and control groups, and were elevated in some patients in the stroke group. The lowest IL-6 level was observed in the anemic group, and the highest in the control group. Serial IL-6 assays in the stroke group showed an upward trend. Erythropoietin levels in all groups showed no difference.

The effect of heat exposure on performance of and recovery from high-intensity, intermittent exercise.

Environmental heat is known to hamper aerobic performance. The purpose of this study was to examine the effect of heat on the performance of anaerobic exercise and the recovery from such exercise. Eleven trained men underwent two identical exercise-recovery protocols in neutral (22 degrees C, N) and hot (35 degrees C, H) conditions, in a cross-balanced order. Exercise consisted of a series of five 15 s bouts separated by 30 s of active recovery between bouts. The 60 min resting recovery was evaluated with a subsequent exercise series. Subjects were kept euhydrated with water. Peak power developed in the initial exercise series was higher in H compared with N (720 +/- 80 vs 664 +/- 74 W, respectively, p < 0.05). In the second series of exercise, peak power slightly improved in N but decreased in H (6.1 vs -4.1 %, respectively). Mean power was higher in the initial exercise series in H compared with N (636 +/- 83 vs 584 +/- 60 W, respectively, p < 0.05). No significant change occurred in the subsequent series of exercise. There was no difference in peak lactate following the initial series, nor in the decrease of lactate during recovery between the two conditions. Likewise, there were no differences in the changes in electrolyte concentrations and serum osmolality during recovery. VO2 and heart rate decreased following exercise in a similar manner in the two conditions. Rectal temperature increased similarly but remained elevated during H compared with N (p<0.05). In conclusion, the results of this study suggest that heat exposure may improve anaerobic performance but does not appear to affect the physiological responses during 60 min of recovery. Future research should examine the effect of more extreme heat stress, as well as shorter recovery periods.

The effect of environmental temperature on testosterone and cortisol responses to high intensity, intermittent exercise in humans.

The purpose of this study was to examine the testosterone, cortisol, and the molar ratio of testosterone to cortisol (T:C) blood concentration responses to intermittent, high intensity exercise in the heat. Eight active men [mean age 25 (SD 3) years, mass 71.1 (SD 5.5) kg, height 175.9 (SD 4.4) cm] performed two series of five 15-s Wingate anaerobic power tests in both hot (H, 35 degrees C) and thermoneutral (TN, 22 degrees C) environments. Each period of exercise was separated by 30-s of active recovery. Each series was separated by 60 min of passive recovery. Blood samples were obtained before (PRE), immediately post (IP), and 5(5R), 10(10R), 15(15R), 30(30R), 45(45R), and 60(60R) min following exercise. Peak power was significantly higher, during the first series of exercise, in the H compared to TN. No significant differences were seen in any of the variables between the first and second series of exercise in either environmental condition. Furthermore, no significant differences between these conditions were observed in heart rate, blood lactic acid concentration, or rectal temperature. A significant decrease in cortisol concentration was observed between PRE and IP, during both conditions. However, no significant interactions between TN or H were seen. No change from PRE was observed in testosterone or T:C during either TN or H. It would appear that testosterone and cortisol respond similarly to repeated periods of short duration high intensity exercise, in either thermoneutral or moderately hot environments.

Recombinant human erythropoietin in the treatment of multiple myeloma-associated anemia.

UNLABELLED: Multiple myeloma (MM) is commonly associated with anemia. Several causes have been implicated but inadequate erythropoietin (Epo) production appears to be important. This single-institute open-label, non-comparative clinical trial was undertaken in order to evaluate serum Epo levels in patients with MM and to study the efficacy and toxicity of recombinant human Epo (rHuEpo) in the treatment of MM-associated anemia. MM patients with a baseline hemoglobin (Hb) level of < 11 g/dl received rHuEpo 150 U/kg 3 times/week subcutaneously, with a possible dose increase to 300 U/kg if no response was observed after 4 weeks. The study was designed for 12 weeks, although some responders continued rHuEpo. The study endpoints were determined by an increase in Hb and a decrease in blood transfusion requirements (BTR). Seventeen patients were enrolled in the study. The median serum Epo level was 150 mU/ml (range 11-232). Four patients did not complete the study for reasons unrelated to rHuEpo, but to their underlying MM. Twelve patients (70.6%) responded with an increase in their Hb levels. One patient (5.9%) responded partially. The median Hb level rose from 9.4 g/dl (range 7.3-10.7) at study commencement to 12.5 g/dl (range 9.0-15.2). Six of the 11 patients who were transfusion dependent enjoyed a complete abolition of BTR. The response was also interpreted as an improved quality of life: 3 patients reported a decrease of 1 level in their WHO performance status (PS) score; in 8 patients, the PS declined by 2 grades and 1 patient enjoyed PS reduction by 4 scores. Six patients continue to receive rHuEpo up to 18 months, with a good response and a smaller maintenance dose. Four patients reported flu-like symptoms, 2 suffered from a local irritation and 1 experienced a transient controlled elevation of blood pressure. SUMMARY: (1) Pretreatment endogenous serum Epo levels were relatively low in all patients studied with MM-associated anemia; (2) rHuEpo was well tolerated in these patients; (3) rHuEpo was highly effective in the treatment of anemia in MM, and (4) the response to rHuEpo is characterized by an increase in Hb levels, a reduction in BTR and an improvement in the WHO PS score.

Increased creatine kinase brain isoenzyme concentration in cerebrospinal fluid with meningitis.

CPK-BB (CK-BB) isoenzyme is an intracellular enzyme released in various neurologic conditions, including central nervous system (CNS) infections. Activity of CK-BB in cerebrospinal fluid (CSF) was determined in 80 children by electrophoresis and densitometry. The possible correlation between CNS infection and CK concentrations was assessed. Significantly elevated concentrations of CK activity (P < 0.01) in the CSF were found in children with bacterial meningitis as compared with children with either aseptic meningitis or normal CSF findings. The data suggest the possibility of utilizing CSF CK activity to differentiate between bacterial and viral meningitis in situations where a routine CSF examination is inconclusive.

Pseudohyperphosphataemia incidence in an automatic analyzer.

A routine blood analysis, using the Hitachi 717 analyser, of an asymptomatic patient with multiple myeloma revealed a phosphate concentration of 6.2 mmol/l (reference range 0.8-1.4 mmol/l). There was no clinical or biochemical evidence for secondary hyperphosphataemia. Two additional myeloma patients with a normal renal function were found to have serum phosphate concentrations of 5 and 4.7 mmol/l. Globulin-depleted sera of these patients were found to have phosphate levels within the normal range as assayed by a Hitachi 717. All these patients were found to have normal inorganic phosphate levels when a SMAC autoanalyser was used, thus indicating spurious readings by the Hitachi 717. The incidence of pseudohyperphosphataemia in 298 patients with normal renal function and hyperglobulinaemia was 8%. To test the direct effect of globulin on phosphate analysis by the Hitachi 717, globulin was precipitated from serum of myeloma and non-myeloma patients by ammonium sulphate. The analysed data showed a positive correlation between globulin concentration and the spurious phosphate levels. Furthermore, even when inorganic phosphate was completely removed from the tested samples, spurious phosphate readings were detected in the presence of globulins from either myeloma or non-myeloma patients by Hitachi 717. It can be concluded that the ammonium molybdate method for determining inorganic phosphate in the Hitachi 717 gives spuriously high phosphate levels in the presence of a high serum globulin concentration.

Reexamination of Stewart's quantitative analysis of acid-base status.

To provide experimental verification to Stewart's quantitative approach to acid-base analysis, the effects of acute maximal treadmill exercise (VO2max test) on venous acid base status were studied in 17 male subjects aged 18-23 yr. Venous CO2 tension (PCO2) total plasma proteins ([PTOT]), [H+], and concentrations of strong ions [( Na+], [K+], [Cl-] and lactate ion concentration ([La-]) were measured before and within 1 min post-exercise. Mean post-exercise PCO2, [PTOT], [K+], and [La-] were significantly higher than the corresponding pre-exercise values (P less than 0.05), there was a strong tendency for a significant change in [Na+] (P less than 0.056), and no changes were found in [Cl-]. Changes in venous acid-base status were analyzed quantitatively by applying relevant physicochemical theory. Altered values measured in the independent variables ([PTOT], PCO2, and net strong ion difference, [SID]) were used to calculate the corresponding changes in the dependent quantities. Comparison of individual measured and calculated values for the only one of these that is normally measured, ([H+]), yielded the theoretically expected agreement. PCO2 and [SID] changes accounted for most [H+] changes. These results demonstrate the usefulness of the quantitative approach (i.e., [H+]-PCO2 diagram) in the analysis and in understanding of plasma acid base changes with exercise and in clinical situations.

Effect of an iron supplement on body iron status and aerobic capacity of young training women.

Serum iron deficiency has a high incidence in female athletes. We investigated the effects of a daily oral iron supplement, (160 mg) administered during an intensive 7-week physical training programme, on body iron status, and the maximal aerobic capacity (VO2max) of 13 women (group A) compared to 15 who took a placebo (group B). The subjects were 19 years old. Blood samples were obtained before training began and on days 1, 7, 21 and 42 of training. They were analysed for packed cell volume (PVC) and for haemoglobin (Hb), 2,3-diphosphoglycerate (2,3-DPG), haptoglobin, iron and ferritin concentrations. The VO2max was measured on days 0, 21 and 42 of training. Following 21 days of training Hb, PCV and ferritin were significantly higher (P less than or equal to 0.01) in group A compared to group B. Over the training period Hb rose by 9.3% and 2.4% in groups A and B, respectively. At the end of training 66% of group B exhibited ferritin concentrations below 10 ng.ml-1, while none of group A had such low values. Mean VO2max of group A had increased by 7.5% following 21 days of training (P less than or equal to 0.01) and by 15.3% after 42 days. No appreciable increase in VO2max had occurred in group B by day 21 (significantly lower than VO2max of group A; P less than or equal to 0.05), however by day 42 it had increased by 14.3% (P less than or equal to 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma-cortisol levels in experimental heatstroke in dogs.

The effect of external heat-load, exercise and dehydration on dynamic changes in plasma cortisol during the development of heatstroke was investigated. Thirty-three unanesthetized dogs were tested under two sets of climatic conditions: comfort conditions and hot-dry climatic conditions, half of them while exercising. Half of the dogs in each group were rehydrated. None of the dogs that were investigated at room temperature suffered heatstroke. Of the dogs exposed to high ambient temperature, all of the exercising, as well as five out of six non-hydrated dogs and one rehydrated non-exercising dog suffered heatstroke. Significant dehydration (6%-7% of body weight), occurred only under high ambient temperature. Plasma cortisol levels of all dogs that suffered heatstroke rose conspicuously for at least 5 h and returned to normal levels 24 h later. Cortisol levels of dogs who did not experience heatstroke remained within the normal range. Cortisol levels correlated with the severity of the stress leading to heatstroke. High and rising levels of cortisol, several hours after body temperature returns to normal, may support the diagnosis of heatstroke.

Predicting genotypes at loci for autosomal recessive disorders using linked genetic markers: application to Wilson's disease.

Recently, the Wilson's disease locus (WND) has been mapped to the long arm of chromosome 13. We have analyzed segregation of several chromosome 13 markers flanking the WND locus and used multipoint linkage analysis to determine the most likely WND genotype of each of 57 unaffected individuals in 5 Wilson's disease families. Approximately 46% of these could be classified as carrier (heterozygote), homozygous normal, or homozygous affected (not yet symptomatic) with a probability of at least 90%, while 77% could be classified with a probability of at least 80%. Our results demonstrate that even though there is a significant decrease on average in serum copper concentration in Wilson's disease heterozygotes compared to normal homozygotes, other sources of variation in serum copper concentration are much greater and preclude use of serum copper to detect heterozygotes for Wilson's disease. Subsequent analyses showed that a familial component, independent of WND genotype, is the major factor accounting for variation in ceruloplasmin levels among unaffected individuals; age is another factor accounting for more variation in copper levels among unaffected individuals than WND genotype.

X-ray microanalysis of the element content in the hearts of mice treated with digoxin.

The element content was detected by X-ray microanalysis in the hearts of mice treated with daily doses of 0.075 microgram digoxin for 12 days and compared with that of controls. Statistically significant differences were found for K and S, which were lower, and for P, which was higher following treatment with digoxin. In the sera of the treated mice Mg was slightly lower, whereas Ca and K levels were found to be elevated in comparison with those of nontreated animals. A possible explanation for these findings is discussed.

Iron deficiency caused by 7 weeks of intensive physical exercise.

The present study was designed to evaluate the effect of an intensive physical training program involving both isometric and isotonic activities on the body iron status of 8 females and 11 males (age 20 +/- 1 year). The training was carried out over a 7 week period and included 8 h of varying physical activities each day. Venous blood samples were obtained from the subjects prior to the beginning of the training, on day 2 and in weeks 2, 4, 6 and 7 of the program. Blood samples were analyzed for iron, ferritin and hemoglobin (Hb) concentrations, total iron binding capacity (TIBC) and red blood cell count (RBC). Iron levels of males and females decreased 65% after 2 weeks of training (p less than 0.001). At the end of the training program 5 males and 6 females had lower than normal iron values (less than 13.4 mumol.l-1). TIBC increased 25% in women and 18% in men following 2 and 4 weeks of training (p less than 0.001) and remained at this elevated level throughout the training period. Ferritin levels decreased 50% in both sexes after 4 weeks of exercise (p less than 0.05) and remained at this level until the end of the training. Hb and RBC decreased 8-10% in both sexes during the training period. In two of the women anemia occurred after 4 weeks of training. The development of latent iron deficiency in a substantial number of participants after a relatively short period of training is uncommon and may reflect the high intensity of exercise required in this program.(ABSTRACT TRUNCATED AT 250 WORDS)

Increase in rat intestinal permeability to endotoxin during hyperthermia.

Victims of heat stroke exhibit several clinical features which are also encountered in endotoxaemia. In order to investigate these similarities hyperthermic rats were used to explore the possibility that high body temperature results in increased permeability of intestinal wall to endotoxin. 125I endotoxin was introduced into intestinal segments taken from non-heat exposed rats. The segments were then incubated at 37 degrees C or 45 degrees C. Intestinal segments from heat stressed rats were similarly prepared and incubated at 37 degrees C. Leakage of endotoxin from segments taken from heat stressed rats was three times greater than from those from non-heat stressed rats, as were the segments from non-heat stressed rats which were incubated at 45 degrees C. These results indicate that the intestinal membrane is damaged by heat and that an increase in outward leakage of microbial endotoxins from the gut then occurs. This might contribute to the pathophysiological picture of heatstroke.

Effects of salt loading during exercise in a hot dry climate.

Strenuous work or sports activities in a hot environment can cause significant fluid and salt losses due to excessive sweating. Fluid replacement is commonly accepted to be beneficial, but controversy surrounds the necessity of adding salt to the dietary intake in hot climates. Five healthy young men participated in a self-controlled experiment designed to investigate the effects of salt loading on acclimatized people exercising under controlled laboratory conditions. The additional salt ingestion was found to cause an increase in body weight, rectal temperature, heart rate, urinary sodium and potassium concentrations and in the total amounts of sodium and chloride excreted in urine during the exercise. Furthermore, it decreased plasma aldosterone level and sweat chloride excretion, but did not affect fluid intake, urine output, sweat rate, skin temperature, excretion of sodium and potassium in sweat or urinary potassium content and chloride concentration. Neither did the additional salt intake affect plasma electrolyte levels, renin activity or acid base balance. It is concluded that acclimatized people living in a hot dry climate need no supplementary salt to their daily dietary intake while engaging in physical exercise or sports activities up to two hours a day. Salt loading has no beneficial effects in these conditions and may even be hazardous.

Assignment of the gene for Wilson disease to chromosome 13: linkage to the esterase D locus.

Wilson disease (WD) is an autosomal recessively inherited disorder of copper metabolism for which the basic defect is still unknown. Twenty-seven autosomal markers were investigated for linkage in a large inbred kindred with affected individuals in two generations. Also, serum copper and ceruloplasmin were measured on all available members. Close linkage (theta = 0.06) with a logarithm of odds (lod) score of 3.21 was found between the gene for WD and the esterase D locus. Efficient detection of linkage was made possible by the use of a multisibship inbred pedigree. The discovery of a polymorphic marker genetically linked to the WD locus has profound implications both for investigation of the primary gene defect and for clinical services.

Temporary heat intolerance in a heatstroke patient.

A case history of recurrent heatstroke is presented. The first heatstroke was incurred during strenuous exercise following acute gastroenteritis; the second heatstroke happened 1 month later during a march in hot climatic conditions. Two heat tolerance tests were performed. On the first, 1 month after the second incidence, an intolerance to heat was observed which, on the second test 5 months after the incidence, had disappeared. It is proposed that acute intercurrent illness and heatstroke in itself cause temporary susceptibility to exercise in heat, and that every heatstroke patient should be examined to determine the efficiency of his thermoregulatory mechanisms.

The energy cost of walking and running with and without a backpack load.

The effect of backpack load (20 kg) on oxygen consumption while walking and running at different speeds was investigated. Fifteen males walked an ran (with and without load) up a 5% sloped treadmill at 6.4, 7.2, 8.0, 9.6, and 11.2 km/h (4, 4.5, 5, 6, and 7 mph). While walking VO2 rose at a rate of 0.6 (l/min)/(km/h) and while running 0.3 (l/min)/(km/h). The mean oxygen consumption at the various speeds was 28.65, 33.78, 40.64, 46.84, 54.48 ml O2/kg BW/min, respectively, for the whole group without load and 26.52, 32.26, 38.28, 44.26, 48.16, respectively, with load. The breaking point between walking and running was at about 8.2 km/h. Carrying the load increased VO2 at a constant rate, and induced a breaking point between walking and running at a significantly lower speed for the smaller subjects than for the more robust ones. The results indicate that for certain tasks involving endurance and heavy load carriage, people should be selected according to criteria which integrate aerobic capacity and anthropometrical features.

Dynamic changes in acid base balance during heatstroke in dogs.

The dynamic changes in acid base balance and respiratory metabolism during the development of heatstroke in dogs were studied. Three groups of five unanesthetized dogs each were exposed to different climatic conditions while at rest: A) 24 degrees C, 50% relative humidity (RH); B) 35 degrees C, 35% RH, and C) 45 degrees C , 25% RH. These conditions were maintained for 4 h or until the dogs collapsed. The heatstroke dogs were cooled in tap water bathes and were observed for another 4 h. Dogs of groups A and B did not show any notable changes in rectal temperature (Tre) and acid base balance. All dogs in group C developed heatstroke. Their peak mean Tre (44.1 degrees C) was reached after a mean of 111 min of exposure, with respiratory alkalosis followed by increasingly severe metabolic acidosis above Tre of 42 degrees C. At peak Tre mean arterial pH was 7.26. Acidosis increased (pHa = 7.17) following cooling, as panting subsided. At Tre above 42 degrees C blood lactate increased and bicarbonate decreased significantly, attaining mean values of 58 mg% and 8 mEq/l, respectively. Bicarbonate changes correlated linearly with lactate changes. During recovery lactate decreased and blood pH increased approximating normal by the end of the experiment. The results illustrate the body's ability to spontaneously correct arterial pH without therapeutic means.

Orthostatic responses in heat tolerant and intolerant subjects compared by three different methods.

The orthostatic responses of 10 heat tolerant and five intolerant subjects were evaluated by three different test methods--standing, head-up tilt (HUT), and head-up tilt after prolonged exercise (HUTPE)--in a hot environment of 40 degrees C, 40% RH. No difference was found within the normal group between responses in the standing and HUT test. In the HUTPE test, orthostatic responses were inadequate and 5 of 10 subjects fainted. The heat intolerant subjects reacted to all three tests similarly to the normal group, though their heart rate was higher and 3 out of 5 fainted at an earlier phase in the HUTPE test.