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Biomedical subjects

D Hermann

Publications and source records attributed to D Hermann.

At least 37 records · Page 2Linked to original sources
PubMed1999

The pharmacokinetic modelling of GI198745 (dutasteride), a compound with parallel linear and nonlinear elimination.

AIMS: To characterize the pharmacokinetics of the dual 5alpha-reductase inhibitor GI198745 (dutasteride) to allow for more accurate predictions of GI198745 concentrations after different dosing schedules. METHODS: In this randomized, single-blind, parallel group study, 32 healthy male volunteers received single oral doses of GI198745 ranging from 0.01 to 40 mg. Data were analysed by nonlinear mixed effects modelling using NONMEM where both linear and nonlinear pharmacokinetic models were examined. RESULTS: The time course of GI198745 serum concentrations indicated concentration dependent elimination, with the apparent half-life increasing with dose. Data were best described by a two-compartment model with first order absorption and parallel linear and nonlinear elimination pathways. Drug absorption was rapid, and was followed by a short distribution phase. A high volume of distribution (511 l) and a low linear clearance (0.58 l h(-1)) combined to give a half-life of up to 5 (1-7) weeks at high concentrations. As concentrations declined towards Km (0.96 ng ml(-1)), the proportion eliminated by the relatively rapid saturable elimination pathway, with a maximum clearance of 6.2 l h(-1), increased and the half-life reduced to about 3 days. The estimated inter individual variability for the linear clearance was high (CV = 70%). CONCLUSIONS: G1198745 pharmacokinetics are well described by a pharmacokinetic model with parallel linear and nonlinear elimination. Simulations using this model show that at daily doses of 0.1 mg the steady state drug concentrations, and the rate at which these are achieved, are mainly influenced by the nonlinear pathway, while at daily doses above 1 mg they are almost entirely influenced by the linear pathway.

Adult↗
PubMed1999

Hemodynamics and metabolism in stroke-prone spontaneously hypertensive rats before manifestation of brain infarcts.

Genomic screening of hybrids from stroke-prone (SHR-SP) and stroke-resistant spontaneously hypertensive rats (SHR) identified a STR1 locus on the rat chromosome 1, which correlates with the susceptibility to cerebral stroke but not with hypertension. The authors examined whether this genetic abnormality is associated with hemodynamic or metabolic alterations in the brain that can be detected before the manifestation of brain infarction. Starting at 6 weeks of age, SHR-SP were fed with a salt-rich diet to accelerate arterial hypertension. At the age of 12 weeks, animals developed functional symptoms and were age-matched with symptom-negative SHR-SP to differentiate between presymptomatic and postsymptomatic changes. Brains were investigated by multiparametric imaging comprising quantitative double-tracer autoradiography of CBF and cerebral protein synthesis (CPS); bioluminescence imaging of regional ATP, glucose, and lactate content; and umbelliferone fluoroscopic imaging of tissue pH. None of the animals exhibited focal hemodynamic or biochemical abnormalities. In symptom-negative SHR-SP, global CBF was 1.1+/-0.3 mL x g(-1) x min(-1), cortical CPS was 10.1+/-3.1 nmol x g(-1) x min(-1), and cortical ATP, glucose, lactate, and pH levels were in the normal range. In SHR-SP with functional symptoms, ATP, glucose, and lactate levels also were normal, but tissue pH exhibited periventricular alkalosis, CBF was significantly reduced to 0.7+/-0.2 mL x g(-1) x min(-1) (P < 0.001), and cortical CPS was significantly reduced to 6.7+/-2.1 nmol x g(-1) x min(-1) (P < 0.001). The decline in brain perfusion of SHR-SP correlated significantly with both the severity of functional deficits and the decline of protein synthesis. Our observations demonstrate that SHR-SP had already developed functional symptoms before the manifestation of overt brain infarcts and that the symptoms are initiated by a decline in global CBF and cortical CPS. Genetic abnormalities in SHR-SP are associated with a diffuse vascular process that results in global decompensation of blood flow well before the onset of focal brain infarction.

Animals↗
PubMed1999

Effects of granulocyte colony-stimulating factor on night sleep in humans.

Numerous animal studies suggest that cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) mediate increased sleep amount and intensity observed during infection and are, moreover, involved in physiological sleep regulation. In humans the role of cytokines in sleep-wake regulation is largely unknown. In a single-blind, placebo-controlled study, we investigated the effects of granulocyte colony-stimulating factor (G-CSF, 300 microgram sc) on the plasma levels of cytokines, soluble cytokine receptors, and hormones as well as on night sleep. G-CSF did not affect rectal temperature or the plasma levels of cortisol and growth hormone but did induce increases in the plasma levels of IL-1 receptor antagonist and both soluble TNF receptors within 2 h after injection. In parallel, the amount of slow-wave sleep and electroencephalographic delta power were reduced, indicating a lowered sleep intensity. We conclude that G-CSF suppresses sleep intensity via increased circulating amounts of endogenous antagonists of IL-1beta and TNF-alpha activity, suggesting that these cytokines are involved in human sleep regulation.

Adult↗
PubMed1998

A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 alpha-reductase inhibitors GI198745 and finasteride.

OBJECTIVE: To develop a pharmacokinetic-pharmacodynamic model that characterizes the conversion of testosterone to dihydrotestosterone (DHT) by 5 alpha-reductase types 1 and 2 and the irreversible inhibition of 5 alpha-reductase by finasteride, a 5 alpha-reductase type 2 inhibitor and by GI198745 (dutasteride), a potent and specific dual 5 alpha-reductase inhibitor. METHODS: Healthy men (n = 48) received doses of 0.1 to 40 mg GI198745 (n = 4 subjects per dose), 5 mg finasteride (n = 8), or placebo (n = 8) in a parallel-group study. Plasma concentrations of GI198745, finasteride, and DHT were measured frequently up to 8 weeks after dosing. Models were fitted with mixed-effects modeling with the NONMEM program. RESULTS: The pharmacodynamics were well described with a model that accounted for the rates of DHT formation and elimination, 5 alpha-reductase turnover, relative capacity of the 2 5 alpha-reductase isozymes, and the rates of irreversible inhibition of one (finasteride) or both (GI198745) types of 5 alpha-reductase. The model indicated that type 2 5 alpha-reductase contributed approximately 80% of plasma DHT. GI198745 was about 3-fold more potent than finasteride on 5 alpha-reductase type 2. Nearly full blockade of both isozymes was achieved at doses of 10 mg or more GI198745, although the potency of this agent on 5 alpha-reductase type 1 was less than on type 2. CONCLUSIONS: A physiologically based model for the turnover and irreversible inhibition of 5 alpha-reductase and for formation and elimination of DHT described the data well. This model helps explain differences in the rates of onset and offset of effect and offers a way to determine the relative potency of the irreversible 5 alpha-reductase inhibitors.

5-alpha Reductase Inhibitors↗
PubMed1998

A second unrelated bone marrow transplant with an unrelated donor marrow: treatment of a patient with relapsed leukemia.

A second bone marrow transplant might be considered as an option in patients with leukemia relapsing after bone marrow transplantation. We report the successful treatment of a patient with relapsed ALL with a second BMT from the same unrelated donor. We evaluated the usefulness of an unrelated donor as the source of the second BMT in this clinical setting. The conditioning regimen for the first transplantation consisted of BU and CY while fractionated TBI and CY were used for the second BMT. Acute skin GVHD, grade III which developed after second BMT, was successfully treated with the use of a new immunosuppressive drug, mycophenolate mofetil. Hemorrhagic cystitis and a CMV infection developed as complications during the second BMT and were successfully treated. The patient was alive and well after the second BMT with limited chronic skin GVHD up to day +170.

Adult↗
PubMed1997

Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR.

Selective inhibition of type 2 5alpha-reductase has been shown to be efficacious in the treatment of benign prostatic hyperplasia. Pharmacokinetic and pharmacodynamic results are reported of treatment with a potent inhibitor of both 5alpha-reductase isozymes, GG745, in rats, dogs and men. In the rat, GG745 has a similar effect on DHT-driven prostatic growth as finasteride, another dual 5alpha-reductase inhibitor in this species. However, GG745 appears to be more potent in the rat, a result that likely reflects the greater inherent potency and terminal half-life of GG745 (14 hr) compared with that of finasteride (1 hr). These pharmacokinetic differences are also maintained in the dog (65 and 4 hr for GG745 and finasteride, respectively). From these results, the literature, and in vitro studies, we estimated doses of GG745 likely to prove efficacious in reducing DHT levels in man. These estimated values were predictive of single-dose effects of GG745 in man. Results from single-dose evaluations in man indicate that GG745 has a terminal half-life of approximately 240 hr, and single doses of >10 mg decreased DHT levels significantly more than did single 5-mg doses of finasteride. These data support the hypothesis that a molecule (GG745) that effectively inhibits both 5alpha-reductases will lower serum DHT levels significantly more than a molecule that inhibits only a single 5alpha-reductase isozyme (e.g., finasteride, a selective inhibitor of the type 2 enzyme in man).

Animals↗
PubMed1996

Effects of repeated administration of granulocyte colony-stimulating factor (G-CSF) on neutrophil counts, plasma cytokine, and cytokine receptor levels.

Granulocyte colony-stimulating factor (G-CSF) induces the release of mature neutrophils from storage pools and stimulates differentiation of myeloid progenitor cells. Recently, it has been shown that a standard dose of G-CSF induces immunophenotypical and functional changes of neutrophils that persist for 1 week. The authors investigated the effects of 300 micrograms of G-CSF administered subcutaneously twice, 1 week apart, to 10 healthy volunteers, on neutrophil and monocyte counts and on the plasma levels of interleukin 1 receptor antagonist (IL-1ra), tumour necrosis factor-alpha (TNF-alpha), soluble TNF receptor (sTNF-r) p55 and p75. G-CSF on both occasions increased neutrophil and monocyte counts and the plasma levels of all cytokines and cytokine receptors measured. All parameters assessed had returned to baseline prior to the second administration of G-CSF. The increases in neutrophil counts and plasma IL-1ra levels were larger following the second injection, whereas the increase in plasma sTNF-r p75 levels was smaller. G-CSF induced increases in monocyte counts, TNF-alpha and sTNF-R p55 levels did not differ between the first and second injection. Our finding of an increased response of healthy humans to a second G-CSF challenge 1 week following a first one may be due to long-lasting increases in storage pool neutrophils.

Adult↗
PubMed1996

Diurnal variations in the human host response to endotoxin.

To investigate diurnal variations in the host response to endotoxin, Salmonella abortus equi endotoxin (0.8 ng/kg) was given intravenously to healthy men in a placebo-controlled design at 0900 or 1900 h. The time course of rectal temperature and the plasma levels of tumor necrosis factor- alpha (TNF-alpha), interleukin-6 (IL-6), adrenocorticotropic hormone (ACTH), and cortisol were monitored for 11 h following the injections. The time of day did not affect the endotoxin-induced increase in plasma TNF-alpha or IL-6. However, subjects who received endotoxin in the evening, when endogenous glucocorticoid levels were low, showed about twice the increases in rectal temperature and plasma ACTH and cortisol levels as those who received endotoxin in the morning, when endogenous glucocorticoid levels were high. These results demonstrate diurnal variations in the human susceptibility to endotoxin that may be due to a suppression of the biologic effects of TNF-alpha and IL-6 by endogenous glucocorticoids.

Adrenocorticotropic Hormone↗
PubMed1996

Age-dependent suppression of nocturnal growth hormone levels during sleep deprivation.

Although the major daily peak in plasma growth hormone (GH) level normally occurs during the early part of nocturnal sleep, it is known that in about one quarter of young healthy men, peaks in circulating human GH occur before sleep onset. Possible factors associated with these nocturnal peaks were investigated in the absence of sleep, including subjectively defined sleepiness, electroencephalographically defined drowsiness and short lapses into sleep, measures of cortisol and temperature. Healthy men between the ages of 20 and 34 years were studied in a between-subjects design, 16 assigned to a sleep deprivation group, and 16 age matched and assigned to a group permitted to sleep. The average GH peak level in the sleeping subjects was 19.9 micrograms/l (+/- 8.4 SD). In the sleep-deprivation group there was a wide range of nocturnal GH patterns, from no detectable rise to normal nocturnal levels (average peak of 10.5 +/- 10.0 micrograms/l). Within the narrow age range sampled, age, body mass index, temperature and cortisol failed to predict nocturnal GH peak in the sleeping group, but regression analysis found age to be a significant negative predictor of nocturnal GH peak level in sleep-deprived subjects. All sleep-deprived subjects who had peak GH levels over 7 micrograms/l were 24 years of age or less. Subjective sleepiness and electroencephalographically defined drowsiness failed to predict either the peak level of GH during sleep deprivation or the cumulative amount measured across the night. These results suggest that the well-known suppressive effect of sleep deprivation on GH secretion is an age-dependent phenomenon which evolves during early adulthood.

Adult↗
PubMed1993

Preliminary pharmacokinetics and pharmacodynamics of an ultra-short-acting opioid: remifentanil (GI87084B).

Remifentanil is a newly synthesized 4-anilido-piperidine with an ester side chain susceptible to esterase metabolism. We evaluated the safety, analgesic efficacy, and pharmacokinetics of remifentanil in 48 male volunteers. Volunteers were randomized to receive increasing doses of remifentanil, alfentanil, or placebo. Analgesic efficacy was evaluated by increasing tolerance to a spring-loaded rod measured at the tibia and sternum at multiple time points. Respiratory depression was measured by changes in arterial blood gas tensions and peripheral hemoglobin oxygen saturation. Hemodynamics were continuously monitored by means of an intra-arterial catheter. Both remifentanil and alfentanil produced a dose-dependent increase in analgesia and respiratory depression. Remifentanil was 20 to 30 times more potent (milligram to milligram) than alfentanil when assessed by either analgesic efficacy or respiratory measures. The pharmacokinetics of remifentanil were best described by a biexponential decay curve. Remifentanil had a small volume of distribution of 0.39 (SD, +/- 0.25) L/kg (alfentanil, 0.52 +/- 2 L/kg), with a rapid distribution phase of 0.94 (SD, +/- 0.57) min and an extremely short elimination half-life of 9.5 (SD, +/- 4) min compared with an elimination half-life of alfentanil of 58 (SD, +/- 7.6) min. The t1/2 ke0 (half-time for equilibration between plasma and the effect compartment) of remifentanil for analgesia was calculated as 1.3 min. Thus, remifentanil appears to have a pharmacologic profile similar to other potent mu agonists, but with exceptionally short-lasting pharmacokinetics, which is likely to make it a very useful opioid for clinical practice.

Analgesics, Opioid↗
PubMed1993

[Pulsatile tinnitus and arteriovenous fistula. Apropos of a case].

Objective pulsatile tinnitus is an unusual disease. Diagnosis, suspected by the interrogation, can be confirmed by vascular radiography. Treatments are discussed and can use surgical solution or interventional radiology. The authors describe one case of arteriovenous occipito-sinusal fistula revealed by pulsatile tinnitus and treated with success by means of embolisation.

Adult↗
PubMed1990

Surgery for nonpalpable breast lesions.

Nonpalpable lesions detected on mammograms were localized in 475 women between 1976 and 1988 by means of the spot method. A malignant neoplasm was noted in 149 patients (31%), including 69 (33%) of 206 with clusters of microcalcifications, 16 (41%) of 39 with calcifications associated with densities and 64 (28%) of 230 with nonpalpable masses. Infiltrating lesions were present in 89 (60%) of 149 patients. Among women with infiltrating lesions who had axillary dissection, 14 (21%) of 67 had positive nodes. In younger women, microcalcifications were more likely to represent neoplasms, masses frequently represented invasive tumors. Among patients with invasive malignant neoplasms who had calcifications, 39% had positive axillary lymph nodes. Spot localization, rather than monitoring, seems appropriate in young women with microcalcifications suggestive of malignant neoplasms and older patients with nonpalpable masses to achieve earlier and more effective treatment of biologically significant occult neoplasms.

Adult↗
PubMed1989

The effect of caffeine on intraocular pressure in glaucoma patients.

The authors investigated the effect of drinking regular coffee on intraocular pressure (IOP) using a single-masked randomized crossover study comparing coffee and herbal tea in 13 glaucoma patients. Intraocular pressure and blood pressure were monitored before ingestion of coffee or tea and at 30, 60, and 90 minutes after ingestion. The mean (+/- standard error of measurement) change in IOP 30, 60, and 90 minutes after ingestion for the coffee drinkers was 0.96 +/- 0.4, 1.38 +/- 0.53, and 1.04 +/- 0.37 mmHg, respectively. The mean change in IOP for the tea drinkers 30, 60, and 90 minutes after ingestion was 0.85 +/- 0.41, 0.23 +/- 0.36, and -0.42 +/- 0.44 mmHg, respectively. There was a statistically significant difference in the change in IOP at 90 minutes when comparing coffee to tea (P = 0.003) and no significant difference for 30 and 60 minutes. Although there was a statistically significant difference in IOP at 90 minutes between coffee and tea drinkers, the change was not clinically significant.

Beverages↗
PubMed1989

The pediatric acute scrotum.

The pediatric acute scrotum can be a diagnostic dilemma. The history, physical examination, and appropriate tests are important. The correct diagnosis will be arrived at if the systematic approach is remembered (Figure 14). In cases where testicular torsion cannot be ruled out (such as an epididymitis or torsion of the appendix testis where torsion of the testis is mimicked), the patient will need scrotal exploration. It is hoped that with further availability of scanning and expertise by pediatric surgeons the false negative exploration will decrease in number. Remember, occasionally a patient will require scrotal exploration with biopsy of the epididymis to delineate the underlying cause. In most cases of epididymitis, effort should be made to identify the cause by culture of urine, urethral discharge, or appropriate fluid from the epididymis. Urological evaluation will be necessary in the younger boys, particularly those with recurrent episodes, to rule out congenital anomalies. Only by following this systematic approach can clinicians hope to preserve gonadal function and achieve best care of their patients.

Acute Disease↗