RESUMO
Phosphorylation sites in members of the protein kinase A (PKA), PKG, and PKC kinase subfamily are conserved. Thus, the PKB kinase PDK1 may be responsible for the phosphorylation of PKC isotypes. PDK1 phosphorylated the activation loop sites of PKCzeta and PKCdelta in vitro and in a phosphoinositide 3-kinase (PI 3-kinase)-dependent manner in vivo in human embryonic kidney (293) cells. All members of the PKC family tested formed complexes with PDK1. PDK1-dependent phosphorylation of PKCdelta in vitro was stimulated by combined PKC and PDK1 activators. The activation loop phosphorylation of PKCdelta in response to serum stimulation of cells was PI 3-kinase-dependent and was enhanced by PDK1 coexpression.
Assuntos
Isoenzimas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteína Quinase C/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Sítios de Ligação , Linhagem Celular , Cromonas/farmacologia , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Humanos , Morfolinas/farmacologia , Fosfatidilcolinas/farmacologia , Fosfatos de Fosfatidilinositol , Fosfatidilserinas/farmacologia , Fosforilação , Proteína Quinase C beta , Proteínas Recombinantes/metabolismo , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
BACKGROUND: The protein kinase C (PKC) family has been implicated in the control of many cellular functions. Although PKC isotypes are characterized by their allosteric activation, phosphorylation also plays a key role in controlling activity. In classical PKC isotypes, one of the three critical sites is a carboxy-terminal hydrophobic site also conserved in other AGC kinase subfamily members. Although this site is crucial to the control of this class of enzymes, the upstream kinase(s) has not been identified. RESULTS: A membrane-associated kinase activity that phosphorylates the hydrophobic site in PKCalpha was detected. This activity was suppressed when cells were pretreated with the immunosuppresant drug rapamycin or the phosphoinositide (Pl) 3-kinase inhibitor LY294002. These pretreatments also blocked specifically the serum-induced phosphorylation of the hydrophobic site in PKCdelta in vivo. The most highly purified hydrophobic site kinase preparations ( approximately 10,000-fold) reacted with antibodies to PKCzeta/iota. Consistent with this, rapamycin and LY294002 reduced the recovery of PKCzeta from the membrane fraction of transfected cells. An activated mutant of PKCzeta, but not wild-type PKCzeta, induced phosphorylation of the PKCdelta hydrophobic site in a rapamycin-independent manner, whereas a kinase-dead PKCzeta mutant suppressed this serum-induced phosphorylation. The immunopurified, activated mutant of PKCzeta could phosphorylate the PKCdelta hydrophobic site in vitro, whereas wild-type PKCzeta could not. CONCLUSIONS: PKCzeta is identified as a component of the upstream kinase responsible for the phosphorylation of the PKCdelta hydrophobic site in vitro and in vivo. PKCzeta can therefore control the phosphorylation of this PKCdelta site, antagonizing a rapamycin-sensitive pathway.
Assuntos
Proteína Quinase C/metabolismo , Sirolimo/farmacologia , Animais , Sítios de Ligação , Linhagem Celular , Cromonas/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Proteína Quinase C/química , Ratos , Serina/metabolismo , Especificidade por SubstratoRESUMO
The role of various pressor factors and cardiovascular responsiveness to norepinephrine or angiotensin II in the pathogenesis of borderline hypertension was evaluated. Exchangeable body sodium, blood volume, plasma renin activity, norepinephrine or dopamine levels, and norepinephrine or epinephrine excretion rates were similar between 24 patients with borderline hypertension (mean age 34 +/- 4 (SEM) years and 22 normal subjects matched for age; the patients had a slight increase in supine plasma epinephrine. Pressor doses of norepinephrine or angiotensin II were significantly lower (p less than 0.01 and 0.001, respectively) in the borderline hypertensive group. These findings suggest that borderline hypertension may be maintained by inappropriately increased cardiovascular response to norepinephrine and angiotensin II in the presence of normal sympathetic and renin activity and a normal body sodium-volume state.
Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Hipertensão/fisiopatologia , Adulto , Aldosterona/sangue , Angiotensina II/farmacologia , Volume Sanguíneo , Peso Corporal , Dopamina/sangue , Feminino , Humanos , Masculino , Norepinefrina/sangue , Norepinefrina/urina , Potássio/sangue , Potássio/urina , Pulso Arterial , Renina/sangue , Sódio/sangue , Sódio/urinaRESUMO
The pathogenic role of the sympathetic system in essential hypertension was evaluated by combined analysis of plasma catecholamine levels and the pressor sensitivity to endogenous norepinephrine. The latter was estimated indirectly by the ratio between changes in blood pressure and those in plasma norepinephrine after adrenergic neuronal blockage with debrisoquine (given orally for 6 weeks). Normal subjects and patients with borderline or established essential hypertension had comparable pretreatment levels of plasma norepinephrine and epinephrine. Debrisoquine lowered plasma norepinephrine by a similar degree (almost 50%) in these three groups; in contrast, blood pressure decreased only slightly in normal or borderline hypertensive subjects [-3.4 +/- 3.2% and -5.4 +/- 1.6% (SE), respectively] but fell significantly more (P less than 0.005) in patients with established essential hypertension (-20.7 +/- 3.9%). The ratio between percentile changes in blood pressure and those in endogenous norepinephrine levels was comparable in normal and borderline hypertensive subjects (0.03 +/- 0.08 and 0.17 +/- 0.04, respectively), but increased (P less than 0.001) in established essential hypertension (0.62 +/- 0.11). This suggests that essential hypertension may be maintained, at least partly, by the inappropriate association of normal plasma norepinephrine levels with increased norepinephrine pressor sensitivity.
Assuntos
Pressão Sanguínea , Hipertensão/sangue , Norepinefrina/sangue , Debrisoquina/uso terapêutico , Humanos , Hipertensão/tratamento farmacológico , Renina/sangueRESUMO
OBJECTIVE: To investigate the effects of grapefruit juice on the pharmacokinetics and dynamics of midazolam. METHODS: Eight healthy male subjects participated in this open crossover study. Intravenous (5 mg) or oral (15 mg) midazolam was administered after pretreatment with water or grapefruit juice. We measured the pharmacokinetics and pharmacodynamics (reaction time, Digit Symbol Substitution Test [DSST], general impression judged by the investigators, and drug effect judged by the subjects) of midazolam and the pharmacokinetics of alpha-hydroxymidazolam. RESULTS: In comparison to water, pretreatment with grapefruit juice did not change the pharmacokinetics or pharmacodynamics of intravenous midazolam. After oral administration, pretreatment with grapefruit juice led to a 56% increase in peak plasma concentration (Cmax), a 79% increase in time to reach Cmax (tmax), and a 52% increase in the area under the plasma concentration-time curve (AUC) of midazolam, which was associated with an increase in the bioavailability from 24% +/- 3% (water) to 35% +/- 3% (Grapefruit juice; mean +/- SEM, p < 0.01) After oral administration of midazolam, pretreatment with grapefruit juice was associated with a 105% increase in tmax and with a 30% increase in the AUC of alpha-hydroxymidazolam. For oral midazolam, pretreatment with grapefruit juice led to significant increases in tmax for all dynamic parameters and in the AUC values for the reaction time and DSST, whereas the maximal dynamic effects remained unchanged. CONCLUSIONS: Pretreatment with grapefruit juice is associated with increased bioavailability and changes in the pharmacodynamics of midazolam that may be clinically important, particularly in patients with other causes for increased midazolam bioavailability such as advanced age, cirrhosis of the liver, and administration of other inhibitors of cytochrome P450.
Assuntos
Bebidas , Citrus , Interações Alimento-Droga , Midazolam/farmacologia , Midazolam/farmacocinética , Administração Oral , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Humanos , Injeções Intravenosas , Masculino , Midazolam/metabolismoRESUMO
The kinetics of ceftriaxone, a cephalosporin, was studied in six healthy subjects who received bolus injections of 150, 500, and 1,500 mg intravenously in a random crossover fashion. Although total drug concentration time profiles after all doses could be described by biexponential equation, simple compartment analysis was inappropriate because a disproportional increase in the area under the total drug concentration time curves occurred with dose. This resulted in a dose-dependent increase in total systemic clearance (ClTS) from 9.7 ml/min at the 150-mg dose to 13 ml/min at the 1500-mg dose. The dose-dependent changes in ClTS could be explained in terms of the concentration-dependent plasma protein binding of ceftriaxone (fplasma ranging from 0.04 to 0.167), because the area under the free drug concentration time curves (AUCFO-infinity) increased proportionately to dose. Mean total clearance with reference to free (unbound) ceftriaxone (ClFS) was constant at 255 ml/min. Calculated mean renal clearance with reference to free ceftriaxone (ClFR) was 173 ml/min, or slightly more than the average glomerular filtration rate in humans. Mean plasma ceftriaxone t1/2 was not influenced by dose and averaged 8 hr. This biological t1/2 is by far the longest ever for a cephalosporin in healthy subjects.
Assuntos
Cefalosporinas/sangue , Adulto , Proteínas Sanguíneas/metabolismo , Ceftriaxona , Cefalosporinas/urina , Relação Dose-Resposta a Droga , Humanos , Rim/metabolismo , Cinética , Masculino , Modelos Biológicos , Ligação ProteicaRESUMO
Interrelations among blood pressure, circulatory volume, plasma renin activity (PRA) and urinary catecholamine excretion rates were studied in normal subjects and in patients with benign essential hypertension. Mean plasma or blood volumes related to lean body mass, products of blood volume and the logarithm of PRA, and catecholamine excretion rates did not differ significantly between normal and hypertensive subjects. In both normal subjects and hypertensive patients, blood pressure levels correlated positively with the noradrenaline excretion rate (r = 0.40 and 0.36, respectively; p less than 0.025) but not with adrenaline excretion, circulatory volume or the volume-renin product. The logarithm of PRA correlated inversely with mean blood pressure in normal subjects (r = 0.40; p less than 0.001) but not in hypertensive patients; however, there was no convincing evidence for an inappropriate blood pressure-PRA relationship as a prominent feature in the hypertensive patients. PRA did not correlate with blood volume. Patients with low PRA relative to sodium excretion (21 per cent of hypertensive population) were consistently normovolemic, but they tended to be older and excreted less (p less than 0.025) adrenaline than patients with normal or high PRA. The patient subgroup with high PRA relative to sodium excretion (11 per cent of population) was hypovolemic (p less than 0.02); despite this, urinary sodium output was high (172 +/- 64 meq/24 hours). These data reveal no evidence for major roles of PRA, circulatory volume and free peripheral catecholamines in the maintenance of benign essential hypertension. Essential hypertension with low PRA is usually not a hypervolemic state, but it may reflect diminished adrenergic activity, factors associated with aging and effects of a high systemic pressure. High PRA in benign essential hypertension may be at least partly a consequence of hypovolemia resulting from high blood pressure-induced sodium diuresis.
Assuntos
Pressão Sanguínea , Volume Sanguíneo , Catecolaminas/urina , Hipertensão/metabolismo , Renina/sangue , Adulto , Composição Corporal , Estatura , Creatinina/urina , Epinefrina/metabolismo , Humanos , Pessoa de Meia-Idade , Sódio/urinaRESUMO
Ketanserin is a selective serotonin-S2 receptor antagonist with alpha 1-adrenoceptor inhibiting activity. The relative contribution of the latter mechanism to antihypertensive efficacy was studied in a group comprising eight normal subjects, 10 patients with essential hypertension and eight diabetics with arterial hypertension. Ketanserin treatment administered over a period of 8 weeks, decreased arterial pressure in patients with essential hypertension and, to a lesser extent, in diabetics, but not in normal subjects. In all three groups, exchangeable sodium, blood volume, the activity of the adrenergic and renin-angiotensin-aldosterone systems and the pressor responsiveness to norepinephrine (NE) or angiotensin II (Ang II) were unaltered, while the pressor reactivity to phenylephrine showed a significant decrease in normal subjects only. This suggests that the antihypertensive mechanism of ketanserin does not involve a modification of the physiological relationship between endogenous noradrenergic and pressor reactivity to NE. Moreover, ketanserin does not interfere with Ang II-dependent mechanisms.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Angiopatias Diabéticas/tratamento farmacológico , Hipertensão/tratamento farmacológico , Ketanserina/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/fisiologia , Sistema Renina-Angiotensina , Fatores de TempoRESUMO
Diabetes-associated hypertension is accompanied by high levels of body sodium and cardiovascular hyper-reactivity to noradrenaline. Captopril, a promising drug for the treatment of hypertension in diabetics, may influence sodium metabolism and adrenergic pathways. This possibility was investigated in 11 patients with non-azotaemic diabetes mellitus and hypertension, studied after a 3-week placebo phase and after an 8-week phase of captopril treatment (50-100 mg/day). Blood pressure, exchangeable body sodium, blood volume, plasma renin activity, angiotensin II (Ang II), aldosterone, catecholamine levels and the pressor reactivity to infused Ang II or noradrenaline were measured. Compared with placebo, captopril caused a significant decrease in arterial pressure and stimulation of plasma renin activity. Exchangeable sodium, blood volume, plasma Ang II, aldosterone, noradrenaline and adrenaline levels, the pressor and aldosterone responsiveness to infused Ang II and the pressor response to infused noradrenaline (alone or combined with atropine) were not modified. These findings suggest that in hypertensive diabetics angiotensin converting enzyme inhibition causes a marked decrease in blood pressure. The mechanism of action is unrelated to changes in body sodium or noradrenergic-dependent pressor reactivity. In the stable phase of therapy, Ang II-dependent pathways are left unaltered when captopril is administered twice a day.
Assuntos
Captopril/uso terapêutico , Angiopatias Diabéticas/tratamento farmacológico , Hipertensão/tratamento farmacológico , Adulto , Angiotensina II , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Feminino , Humanos , Hipertensão/etiologia , Masculino , Pessoa de Meia-Idade , Norepinefrina , Renina/sangue , Sódio/metabolismo , Fatores de TempoRESUMO
OBJECTIVES: The presence of metastatic lesions is the only acceptable fact to confirm malignant pheochromocytoma. Patients with malignant pheochromocytomas, however, have a very poor survival rate. The aim of our study was to postulate predictive values for malignant pheochromocytomas. METHODS: We evaluated symptoms, diagnostic modalities, treatment, and long-term follow-up of 86 patients with 85 benign and 10 malignant pheochromocytomas. Parameters from the benign were compared with those of the malignant pheochromocytomas. RESULTS: Preoperative 24-hour urinary dopamine was in the normal range for benign pheochromocytomas but increased in malignant pheochromocytomas (P<0.0001). Vanillylmandelic acid was elevated in both benign and malignant pheochromocytomas but higher in malignant than in benign tumors (P = 0.01). No differences could be shown in urinary epinephrine and norepinephrine samplings. Tumor location was divided into 77 adrenal (81%) and 18 extra-adrenal (19%) sites. Malignant pheochromocytomas were located more often at extra-adrenal sites (P = 0.03). There was no increased incidence of malignancy in patients with familial bilateral pheochromocytomas or multiple endocrine neoplasia. Tumors greater than 80 g in weight corresponded to malignancy (P<0.0001). Dopamine tumor concentration was higher in malignant than in benign pheochromocytomas (P = 0.01). Persistent arterial hypertension occurred in 9 (13%) of 72 benign and 6 (60%) of 10 malignant pheochromocytomas (P = 0.001). The 10-year survival rate was 94% for benign pheochromocytomas. All patients with malignant pheochromocytomas died within this period (P = 0.0001). CONCLUSIONS: High preoperative 24-hour urinary dopamine levels, extra-adrenal tumor location, high tumor weight, elevated tumor dopamine concentration, and postoperative persistent arterial hypertension are all factors that increase the likelihood of malignant pheochromocytoma. Patients with these characteristics should have more frequent follow-up evaluations to identify malignancy at earlier states.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Feocromocitoma/diagnóstico , Adolescente , Neoplasias das Glândulas Suprarrenais/terapia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Feocromocitoma/terapia , PrognósticoRESUMO
A patient with pheochromocytoma was found to have typical features of apical left ventricular hypertrophy similar to apical hypertrophic cardiomyopathy of the Japanese type. The electrocardiogram showed giant negative T waves (1.0 mV), and echocardiography as well as angiographic examination revealed left ventricular hypertrophy confined to the apex. Surgical removal of the tumor resulted in striking regression of apical hypertrophy and essential normalization of the electrocardiogram within 1 year of operation. These findings emphasize the possible role of catecholamines in the cause of apical hypertrophic cardiomyopathy and illustrate the potential reversibility of this condition in association with pheochromocytoma. It is suggested that patients with signs of apical left ventricular hypertrophy should undergo thorough screening for a pheochromocytoma.
Assuntos
Neoplasias das Glândulas Suprarrenais/complicações , Hipertrofia Ventricular Esquerda/etiologia , Feocromocitoma/complicações , Neoplasias das Glândulas Suprarrenais/cirurgia , Ecocardiografia , Eletrocardiografia , Feminino , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Pessoa de Meia-Idade , Feocromocitoma/cirurgiaRESUMO
In an open study oral tyramine in variable doses was administered to six healthy volunteers under three different conditions: 1) without moclobemide, 2) under moclobemide steady-state conditions (3 X 200 mg moclobemide daily) one hour after moclobemide intake and 3) under moclobemide steady-state conditions simultaneously with moclobemide. It was shown that the amount of tyramine effecting 30-50 mmHg systolic blood pressure increase was roughly doubled when moclobemide was administered together with tyramine instead of one hour before tyramine intake. The time interval between tyramine ingestion and maximal blood pressure increase did not differ significantly between conditions 2) and 3). The conclusion of this study is that moclobemide should always be taken at the end of a meal, which is anyway the usual time for drug intake.
Assuntos
Benzamidas/efeitos adversos , Hipertensão/induzido quimicamente , Inibidores da Monoaminoxidase/efeitos adversos , Tiramina/efeitos adversos , Administração Oral , Adulto , Benzamidas/administração & dosagem , Esquema de Medicação , Sinergismo Farmacológico , Tolerância a Medicamentos , Alimentos/efeitos adversos , Humanos , Masculino , Moclobemida , Inibidores da Monoaminoxidase/administração & dosagem , Tiramina/administração & dosagemRESUMO
There now exists a set of tightly linked markers to the gene causing multiple endocrine neoplasia type 2A. In this report we discuss the use of these markers for early and accurate prediction of gene carrier status in three different families. Factors that influence the probability of obtaining useful information with DNA markers are available family size, in particular the number of available affected individuals, and the extent of clinical and biochemical screening in the family. At present, DNA analysis has about a 3% risk of misdiagnosis; this risk is even lower if it is used in conjunction with the pentagastrin stimulation test for C-cell hyperplasia. With the combined tests, an individual at age 20 years may be scored as carrier or not with an estimated accuracy of 99%.
Assuntos
DNA de Neoplasias/análise , Ligação Genética , Marcadores Genéticos/análise , Neoplasia Endócrina Múltipla/genética , Adolescente , Adulto , Idoso , Alelos , Feminino , Triagem de Portadores Genéticos/métodos , Testes Genéticos/métodos , Humanos , Masculino , Neoplasia Endócrina Múltipla/diagnóstico , Valor Preditivo dos TestesRESUMO
This study was performed to establish an experimental method for the investigation of interactions between ethanol and drugs under predictable and controlled conditions. The model was tested with flumazenil (Ro 15-1788), a short-acting benzodiazepine antagonist with an elimination half-life of 1 h. Six healthy volunteers (5 males, 1 female) were administered ethanol by intravenous infusion with stepwise changing rates. The infusion rates were adapted to each subject on the basis of individual disposition parameters of ethanol, which were derived from preceding short-term infusions of 120 min duration (1.0 mg/kg in males, 0.8 mg/kg in the female). This two-step procedure led to individual ethanol plasma levels between 1.47 +/- 0.04 and 1.71 +/- 0.03 g/L, which were reached after 2.5 h and thereafter maintained over another 6 h. Within the period of constant ethanol levels, single doses of flumazenil and placebo, respectively, were injected intravenously as a bolus (2 min) in a double-blind fashion according to a randomized two-way crossover design. Three subjects received a dose of 0.10 mg/kg of flumazenil, and the remaining three subjects received a dose of 0.20 mg/kg. Evaluation of the plasma concentration time curves of flumazenil did not reveal evidence of an effect of ethanol on the pharmacokinetics of this drug.
Assuntos
Etanol/farmacologia , Farmacocinética , Adulto , Interações Medicamentosas , Etanol/sangue , Etanol/farmacocinética , Feminino , Flumazenil/farmacocinética , Meia-Vida , Humanos , Masculino , Modelos BiológicosRESUMO
Twenty-eight patients with the clinical diagnosis of pheochromocytoma were studied by adrenal venography and catecholamine determination in selective venous blood sampling. Results of this technique are correlated to pathologic findings. 87% of the existing pheochromocytomas were correctly identified. In cases with corresponding venographic and laboratory results correct preoperative tumor localization was established in 97%. False interpretations are discussed in relation to the phlebographic findings and the assay of the catecholamines.
Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Feocromocitoma/diagnóstico , Adolescente , Neoplasias das Glândulas Suprarrenais/sangue , Neoplasias das Glândulas Suprarrenais/irrigação sanguínea , Adulto , Idoso , Catecolaminas/sangue , Humanos , Métodos , Pessoa de Meia-Idade , Feocromocitoma/sangue , Feocromocitoma/irrigação sanguínea , FlebografiaRESUMO
In 69 patients with uneventful pregnancies, term labor was studied prospectively with respect to length of second stage, number of bearing down efforts, maternal and fetal levels of lactate, epinephrine and norepinephrine. Maternal venous blood concentrations were measured in early labor and at the time of delivery while samples from umbilical artery and vein provided fetal blood. There was a significant rise of lactate and catecholamines in maternal blood during labor and at delivery fetal lactate concentration was lower than the maternal level while for epinephrine and norepinephrine fetal levels were higher. For all three compounds umbilical artery concentrations were higher than umbilical venous levels. While there was no correlation between the biochemical parameters in maternal blood and length of second stage maternal lactate and norepinephrine concentration at the time of delivery significantly correlated with the number of bearing down efforts. Umbilical artery lactate correlated with both, length of second stage and number of bearing down efforts.
Assuntos
Epinefrina/sangue , Sangue Fetal/análise , Trabalho de Parto/sangue , Lactatos/sangue , Norepinefrina/sangue , Feminino , Hipóxia Fetal/diagnóstico , Humanos , Segunda Fase do Trabalho de Parto , Ácido Láctico , Paridade , Gravidez , Fatores de Tempo , Contração Uterina/fisiologiaRESUMO
The response of critical immunological parameters in seven athletes to the sustained physical stress of marathon running was assessed. Variables analysed were the responsiveness of lymphocytes (measured as mitogenic response to concanavalin A), the numbers of lymphocytes, their subsets, and leukocyte numbers. In addition, blood levels of cortisol, epinephrine, and norepinephrine were determined. After the run, lymphocyte responsiveness was severely depressed to 1-70% of the resting values, even though the lymphocyte counts did not change. Leukocyte counts were elevated 2.8-fold. No dramatic changes were found within the lymphocyte subsets, although an increase in pan T-cells and the helper/inducer subset 2 d after the run was significant. In addition, the numbers of B-cells decreased significantly. No change was observed within the suppressor/cytotoxic subset. Cortisol increased 2.1-fold, epinephrine 3.2-fold and norepinephrine 2.7-fold. All these parameters returned to baseline values within 2 d. These data were compared with data obtained during and after spaceflight. We conclude that prolonged physical stress of marathon running induces changes in immunological responsiveness that are strikingly similar to those arising from the stress of spaceflight.
Assuntos
Linfócitos/fisiologia , Voo Espacial , Estresse Fisiológico/imunologia , Epinefrina/sangue , Feminino , Humanos , Hidrocortisona/sangue , Contagem de Leucócitos , Ativação Linfocitária , Masculino , Norepinefrina/sangue , Resistência Física , CorridaRESUMO
The authors have taken the opportunity presented them by having a case of pheochromocytoma observed and diagnosed in the puerperium, of reviewing the various clinical and diagnostic features appropriate to this chromaffin tissue tumour. They also review the cardinal points in the differential diagnosis of any case of arterial hypertension discorvered in connection with pregnancy. A study of the literature shows that failure to recognise pheochromocytomata in pregnant women is accompanied by particularly hight maternal and fetal mortality. This complication of pregnancy, although rare, should be recognised by the obstetrician, who will be in a much better position early to combat and palliate the very grave threat to the mother and her baby.
Assuntos
Feocromocitoma , Complicações na Gravidez , Adolescente , Adulto , Feminino , Morte Fetal , Humanos , Hipertensão/etiologia , Feocromocitoma/diagnóstico , Feocromocitoma/patologia , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/patologiaRESUMO
In 12 healthy volunteers, the pharmacological effects of midazolam were investigated following intravenous (0.15 mg X kg-1 and 12.5 mg in 6 subjects each), intramuscular (12.5 mg in 6 subjects) and oral administration (20 mg in 6 subjects and 10 mg in 4 subjects). The findings were correlated with the plasma concentrations of midazolam and its alpha-hydroxy metabolite. The effects were assessed using objective and subjective methods (reaction time, memory test and subjects' self-assessment with an analog scale covering the degree of sedation). Plasma samples were assayed for midazolam and its alpha-hydroxy metabolite by gas chromatography. The results of the memory test showed that mnemonic retention and recall of a number remained intact for the period preceding intravenous or intramuscular administration. The maximum impairment occurred at 30 min after injection for recall of a number presented at the 15th min. The impairment was no longer detectable 4 h after injection. The plasma concentration time course was similar to that of the reaction time after administration of an identical intravenous or intramuscular dose. The maximum effect was attained within 15 min and 30 min after intravenous and intramuscular administration respectively. Within 2 to 4 h after parenteral administration, the reaction time had returned to normal. At identical plasma concentrations of midazolam, the reaction time was slightly longer in the period immediately following oral administration than after parenteral administration. This result suggested that the alpha-hydroxy metabolite contributed actively to the effect of midazolam. After its intravenous injection, this metabolite's sedative effects attained their maximum with 15 min, having disappeared 4 h later.
Assuntos
Anestésicos , Benzodiazepinas , Adulto , Benzodiazepinas/sangue , Benzodiazepinas/farmacologia , Feminino , Humanos , Injeções Intravenosas , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Midazolam , Tempo de Reação/efeitos dos fármacosRESUMO
Pain represents the most frequent complaint for which patients ask for medical help. Successful treatment of acute and chronic pain syndromes largely depends on the knowledge and the therapy of the underlying disease process and on the rational use of analgesics, such as the nonnarcotic analgesic-antipyretics, the anti-inflammatory agents and the opioid analgesics. In addition, so-called 'adjuvant' analgesics of different chemical structures can be used in special clinical conditions to increase the efficacy of the common analgesics. For optimal therapy, the selection and dosing of a specific agent has to be tailored to the individual needs of the patient. For this purpose it is important to follow some general principles of pain management and to consider the relevant pharmacokinetic and pharmacodynamic properties of the various analgesics. This overview summarizes the most important pharmacological properties of the widely used analgetic drugs, with special emphasis on their risk-benefit ratio in various clinical situations.