Biomedical subjects

Hartmut Hecker

Publications and source records attributed to Hartmut Hecker.

9 recordsLinked to original sources

PubMed2003

An improved model for the binding of lidocaine and structurally related local anaesthetics to fast-inactivated voltage-operated sodium channels, showing evidence of cooperativity.

1. The interaction of lidocaine-like local anaesthetics with voltage-operated sodium channels is traditionally assumed to be characterized by tighter binding of the drugs to depolarized channels. As inactivated and drug-bound channels are both unavailable on depolarization, an indirect approach is required to yield estimates for the dissociation constants from channels in inactivated states. The established model, originally described by Bean et al., describes the difference in affinity between resting and inactivated states in terms of the concentration dependence of the voltage shift in the availability curve. We have tested the hypothesis that this model, which assumes a simple Langmuir relationship, could be improved by introducing a Hill-type exponent, which would take into account potential sources of cooperativity. 2. Steady-state block by lidocaine was studied in heterologously (HEK 293) expressed human skeletal muscle sodium channels and compared with experimental data previously obtained for 2,6-dimethylphenol, 3,5-dimethyl-4-chlorophenol, and 4-chlorophenol. Cells were clamped to membrane potentials from -150 to -5 mV, and a subsequent test pulse was used to assess the number of channels available to open. 3. All compounds shifted the voltage dependence of channel availability in the direction of negative prepulse potentials. Prediction of the concentration dependence of the voltage shift in the availability curve was improved by the modified model, as shown by a marked reduction in the residual sum of squares. 4. For all compounds, the Hill-type exponent was significantly greater than one. These results could be interpreted in the light of the contemporary hypothesis that lidocaine functions as an allosteric gating effector to enhance sodium channel inactivation by strengthening the latch mechanism of inactivation, which is considered to be a particle-binding process allosterically coupled to activation. Alternatively, they could be interpreted by postulating additional binding sites for lidocaine on fast-inactivated sodium channels.

Algorithms↗

PubMed2003

Bradykinesia in minimal hepatic encephalopathy is due to disturbances in movement initiation.

BACKGROUND: One of the predominant symptoms of early stages of hepatic encephalopathy (HE) is bradykinesia. AIMS: To further analyze the pathophysiology of bradykinesia in HE. METHODS: A three-dimensional computer-assisted movement analysis was performed in 36 cirrhotics with grade 0-I HE compared to 18 controls selected with regard to sex and age and 16 patients with Parkinson's disease (PD). Four types of movement were studied: finger tapping, hand tapping, pronation/supination of the forearm and flexion/extension in the hip joint. RESULTS: The patients with PD presented with a decrease of the maximal movement velocity (VMAX) and a prolongation of the time needed to reach VMAX (VTIME). In patients with minimal or grade I HE, the VMAX of all movements was unchanged compared to controls while the VTIME was significantly prolonged. This was caused by a delay before the beginning of each new part of the diadochokinetic movement cycle. CONCLUSIONS: The data suggest an impairment of movement initiation as main cause of bradykinesia in early HE.

Case-Control Studies↗

PubMed2003

Ghrelin in chronic liver disease.

BACKGROUND/AIMS: Ghrelin is a novel endogenous ligand for the growth hormone (GH) secretagogue receptor involved in energy metabolism, glucose homeostasis and food intake. We investigated the role of ghrelin and insulin-like growth factor-1 (IGF-1), the mediator of the GH axis, in patients with chronic liver diseases (CLD). METHODS: Ghrelin and IGF-1 serum levels were determined in 105 CLD patients and 97 healthy controls and correlated with clinical and biochemical parameters. RESULTS: Ghrelin was significantly elevated and IGF-1 reduced in CLD patients compared with healthy controls. IGF-1 serum levels inversely correlated with Child's classification. Ghrelin levels were significantly elevated in Child C cirrhosis patients independent of the aetiology of liver disease. Ghrelin levels did not correlate with liver function. In contrast, there was a correlation of ghrelin with clinical (gastrointestinal bleeding, ascites, encephalopathy) and biochemical (anaemia, inflammatory markers, hypoglycaemia, renal dysfunction) parameters. In a subgroup of patients with CLD and hepatocellular carcinoma (HCC), we observed a strong inverse correlation between alpha-fetoprotein (AFP) and ghrelin levels. CONCLUSIONS: Unlike IGF-1, ghrelin is not correlated with liver function, but increases in Child C cirrhosis and with complications of CLD. The inverse correlation with AFP in HCC patients requires further studies on the potential impact of ghrelin on the pathogenesis of anorexia-cachexia syndrome.

Adolescent↗

PubMed2003

Memory function in early hepatic encephalopathy.

BACKGROUND: Early hepatic encephalopathy (HE) is characterized by deficits in motor performance, visual perception, visuo-constructive abilities and attention. Whether defective memory is a feature of early HE is controversial. AIMS: To analyze memory function in patients with early HE. METHODS: Memory tests were applied to cirrhotic patients with grade 0 HE, minimal HE and grade I HE (n=45) and controls (n=52). The battery included short and long term memory tests requiring free recall or recognition. Minimal HE was diagnosed by assessing the psychometric hepatic encephalopathy score using the PSE-Syndrom-Test and by carrying out a neurological examination. Group differences of the test results were analyzed using analysis of covariance. RESULTS: HE 0 patients achieved test results similar to the controls in all but two tests. Patients with early HE (minimal and grade I HE) scored lower than the controls in all tests applied. A detailed analysis of test performance showed that the patients' deficits were in attention and visual perception, rather than memory. CONCLUSIONS: Patients with early HE score lower than controls in memory tasks predominantly because of deficits in attention and visual perception.

Adolescent↗

PubMed2003

Blockade of voltage-operated neuronal and skeletal muscle sodium channels by S(+)- and R(-)-ketamine.

UNLABELLED: Besides its general anesthetic effect, ketamine has local anesthetic-like actions. We studied the voltage- and use-dependent interaction of S(+)- and R(-)-ketamine with two different isoforms of voltage-operated sodium channels, with a special emphasis on the difference in affinity between resting and inactivated channel states. Rat brain IIa and human skeletal muscle sodium channels were heterologously expressed in human embryonic kidney 293 cells. S(+)- and R(-)-ketamine reversibly suppressed whole-cell sodium inward currents; the 50% inhibitory concentration values at -70 mV holding potential were 240 +/- 60 microM and 333 +/- 93 microM for the neuronal isoform and 59 +/- 10 microM and 181 +/- 49 microM for the skeletal muscle isoform. S(+)-ketamine was significantly more potent than R(-)-ketamine in the skeletal muscle isoform only. Ketamine had a higher affinity to inactivated than to resting channels. However, the estimated difference in affinity between inactivated and resting channels was only 8- to 10-fold, and the time course of drug equilibration between inactivated and resting channels was too fast to cause use-dependent block at 10 Hz up to a concentration of 300 microM. These results suggest that ketamine is less effective than lidocaine-like local anesthetics in stabilizing the inactivated channel state. IMPLICATIONS: Blockade of sodium channels by ketamine shows voltage dependency, an important feature of local anesthetic action. However, ketamine is less effective than lidocaine-like local anesthetics in stabilizing the inactivated state. Because it does not elicit phasic blockade at small concentrations, its ability to reduce the firing frequency of action potentials may be small.

Animals↗

PubMed2002

Pretreatment prognostic factors and treatment results in children with hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB 94.

BACKGROUND: In the past 20 years, a dramatic improvement in the prognosis of patients with hepatoblastoma (HB) has been achieved by combining surgery with chemotherapy in several national and international trials. A worldwide, unsolved problem remains the treatment of patients with advanced or metastatic HB. METHODS: The German Cooperative Pediatric Liver Tumor Study HB 94 was a prospective, multicenter, single-arm study. The study ran from January 1994 to December 1998. The protocol assessed the efficiency of chemotherapy consisting of cisplatin, ifosfamide, and doxorubicin (CDDP/IFO/DOXO) and/or etoposide and carboplatin (VP16/CARBO). The prognostic significance of the surgical strategy, pretreatment factors, and tumor characteristics for disease free survival (DFS) were analyzed. RESULTS: Sixty-nine children with HB were treated in the HB 94 study. The median follow-up of survivors was 58 months (range, 32-93 months). Fifty-three of 69 patients (77%) remained alive, and 16 of 69 patients (23%) died. Long-term DFS was as follows: 26 of 27 patients had Stage I HB, 3 of 3 patients had Stage II HB, 19 of 25 patients had Stage III HB, and 5 of 14 patients had Stage IV. A complete resection of the primary tumor was achieved in 54 of 63 patients (86%). Six children (8%) had no surgical treatment. Twenty-two tumors were resected primarily, and 41 children underwent surgery after initial chemotherapy. Two children underwent liver transplantation. There was no perioperative death. Forty-eight children received primary chemotherapy with CDDP/IFO/DOXO. Forty-one of 48 children achieved partial remission after CDDP/IFO/DOXO. Eighteen children with advanced or recurrent HB underwent VP16/CARBO chemotherapy, with a response achieved by 12 children. The relevant pretreatment prognostic factors were growth pattern of the liver tumor (P = 0.0135), vascular tumor invasion (P = 0.0039), occurrence of distant metastases (P = 0.0001), initial alpha-fetoprotein level (P = 0.0034), and surgical radicality (P < 0.0001). CONCLUSIONS: The current results underline the necessity of preoperative chemotherapy in all children with HB. Complete tumor resection is one of the main prognostic factors.

Child↗

PubMed2002

Thrombopoietin serum levels are elevated in patients with hepatitis B/C infection compared to other causes of chronic liver disease.

BACKGROUND/AIMS: Thrombocytopenia in patients with advanced liver disease may stem from a deficient hepatic thrombopoietin production. METHODS: We determined the relationship between thrombopoietin, thrombocytopenia, aetiology and extent of liver damage by incorporating serum thrombopoietin measurements in the pretransplant evaluation of 111 patients with liver disease. RESULTS: The extent of thrombocytopenia was related to the underlying cause of disease. The platelet count directly correlated with factor V, II, fibrinogen, and PTT, and a negative correlation was found for splenic size and Child's stage. The thrombopoietin concentrations were age-dependent, and no significant difference resulted between the median thrombopoietin level of liver disease patients with age-matched healthy controls. Thrombopoietin concentrations and platelet counts were not correlated. Although noncirrhotic patients had higher platelet counts than those with Child's A-C cirrhosis (p < 0.001, U-test), no such difference was found in thrombopoietin levels. Patients with hepatitis B and/or C had lower platelet counts compared to patients with nonviral diseases (p < 0.001), and their median thrombopoietin concentrations were significantly higher (p < 0.001). CONCLUSION: We conclude that thrombocytopenia in patients with liver disease is unlikely to be explained only based on a deficient hepatic production of thrombopoietin. Patients with chronic viral hepatitis have significantly elevated thrombopoietin levels; the involved pathomechanisms require further study.

Adult↗

PubMed2002

Seasonal variation of endothelin-1, angiotensin II, and plasma catecholamines and their relation to outside temperature.

Circannual rhythmicity in plasma catecholamines is well known, but no chronobiologic data are available on endothelin-1 and angiotensin II. This study was designed to investigate in healthy human subjects whether endothelin-1 and angiotensin II exhibit seasonal variations. Furthermore, we assessed the relation of both variables to plasma catecholamines, to environmental temperature, and to relative humidity in northern Germany, a region of a temperate climate. Plasma concentrations of endothelin-1, angiotensin II, epinephrine, and norepinephrine were prospectively determined in venous blood from 10 healthy subjects at monthly intervals during 13 consecutive months. The single-cosinor method was applied to evaluate the seasonal rhythmicity of these parameters and to assess their temporal relation to both relative humidity and ambient temperature. Whereas relative humidity did not significantly change throughout the year, outdoor temperature was lowest in January and highest in August. Endothelin-1 levels displayed a significant variation, with a sinusoid pattern throughout the year: nadir values occurred in January, peak values in July. Angiotensin II demonstrated a significant correlation with endothelin-1 and paralleled its rhythmicity. In contrast, the two plasma catecholamines exhibited an opposite pattern. We noted a significant inverse correlation between endothelin-1 and norepinephrine. Outside temperature correlated positively with endothelin-1 and angiotensin II levels and correlated negatively with levels of both catecholamines. This is the first study to report a seasonal variation of endothelin-1 and angiotensin II in normal subjects. According to our data, environmental temperature is the climate variable most closely related to the rhythmicity of endothelin-1, angiotensin II, epinephrine, and norepinephrine.

Adult↗

PubMed1996

[Maximum Likelihood classification rule for assessing acute toxicity]

As an alternative to the Acute Toxic Class method a simple procedure for the classification of substances into toxicity classes based on the maximum likelihood principle is proposed. The number of experimental animals needed as well as the reliability of the classification is similar to that of the ATC method. In the case of true LD50 values of 2000 mg/kg body weight and above it even is considerably better.

Journal Article↗