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Biomedical subjects

R Hermann

Publications and source records attributed to R Hermann.

At least 73 records · Page 4Linked to original sources
PubMed1998

Gastric emptying in patients with insulin dependent diabetes mellitus and bioavailability of thioctic acid-enantiomers.

The objective of this study was to determine the impact of prolonged gastric emptying in patients with insulin dependent diabetes mellitus (IDDM) on the bioavailability of the R(+)- and S(-)-thioctic acid (TA) enantiomers. Gastric emptying time (GET) was assessed in 30 healthy volunteers and 22 patients with IDDM using sequential ultrasonography after a standardized solid-liquid test meal. Pharmacokinetics and absolute bioavailability (F) of the TA-enantiomers were studied using a randomized, open two-way crossover design with administrations of oral and intravenous single doses of 200 mg rac-TA. GET in healthy subjects was 134.7+/-21.6 min, the normal range was calculated from 88.3 to 181.1 min. The mean GET in all IDDM patients was significantly prolonged (178.2+/-28.1 min; P<0.001). Only 50% of the patients (n=11) were found to have normal GET (group A), the other half of the population (n=11) were considered to have delayed GET (group B). Mean GET values were 156.9+/-21.5 in group A (P=0.028) and 199.4+/-13.9 min in group B, respectively, suggesting that gastric motility is significantly different from non-diabetic controls even in patients with apparently normal gastric emptying. Times to peak plasma concentrations (t(max)) of both TA-enantiomers were similar in both groups and thus, unrelated to measures of gastric emptying. In contrast, maximum concentrations (C(max)) and area-under-the-curve values (AUC) of both enantiomers were reduced by about 30% in patients with delayed GET. Although these differences resulted in statistical significance for the AUC of both enantiomers (P<0.05), linear regression analysis showed only modest correlation between GET and the extent of TA-enantiomer absorption (r2=0.31 and 0.22 for R(+)-/S(-)-TA, respectively). The study suggests that prolonged gastric emptying is frequently present in IDDM. Delayed gastric emptying, however, does not substantially affect the rate and extent of absorption of both TA-enantiomers.

Administration, Oral↗
PubMed1998

Phase I multicenter study of combined high-dose ifosfamide and doxorubicin in the treatment of advanced sarcomas. Swiss Group for Clinical Research (SAKK).

UNLABELLED: Ifosfamide and doxorubicin are the most active agents in the treatment of sarcomas and are characterized by a marked dose-response relationship. The objective of this study was to determine the maximum tolerated dose (MTD) of both agents in combination under granulocyte-macrophage colony-stimulating factor (GM-CSF) cover. PATIENTS AND METHODS: Thirty-three patients with untreated sarcomas (soft tissue: n = 20; gynecological: n = 11; bone: n = 2) were treated with ifosfamide 12 g/m2 by continuous i.v. infusion over five days and doxorubicin with dose escalation from 50 mg/m2 i.v. bolus divided on two days, then to 60 mg/m2 bolus divided on three days. Ifosfamide was reduced to 10 g/m2 and doxorubicin was further escalated up to 90 mg/m2. GM-CSF (5 micrograms/kg/day subcutaneously) was started 24 hours after chemotherapy and continued for 10 days. RESULTS: The MTD was reached with the combination of ifosfamide at 12 g/m2 and doxorubicin at 60 mg/m2. But with ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 the MTD was not obtained. While severe leukopenia and granulopenia were observed at all-dose levels, severe anemia was more frequently related to the highest dose of ifosfamide. Severe thrombopenia and mucositis were more commonly observed at the highest dose of doxorubicin. Ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 induced WHO grade 4 leukopenia in 58%, grade 3-4 thrombopenia in 42%, and anemia in 31% of cycles. Mucositis was minor in 50% of cycles. The overall response rate among 31 evaluable patients was 55% (95 confidence interval (CI): 36%-73%), with four (13%) complete responders and 13 (42%) partial responders. Response rates based on soft-tissue sarcomas or gynecological sarcomas alone were similar. Ten patients could be treated by elective surgery and/or radiotherapy. The total group of patients reached a median survival of two years, with 25% (SE 8%) survivors after three years. CONCLUSIONS: The dose level of ifosfamide 10 g/m2 and doxorubicin 90 mg/m2 with supportive GM-CSF is manageable in a multicenter setting and should be further tested in regular phase II trials, including patients with gynecological and soft-tissue sarcomas. Transient toxicity with myelosuppression should be accepted in order to obtain a high antitumor activity of this regimen and a potential improvement in survival.

Adolescent↗
PubMed1998

BEACOPP: a new regimen for advanced Hodgkin's disease. German Hodgkin's Lymphoma Study Group.

The BEACOPP chemotherapy regimen for advanced Hodgkin's disease employs a rearranged schedule permitting a shortened three-week cycle. With haematological growth factor support, the dosages of cyclophosphamide, etoposide and adriamycin could be moderately escalated. The 3-armed multicentre HD9 trial (recruitment 1993-1998; 1300 patients randomised) aimed to compare BEACOPP with the standard COPP/ABVD chemotherapy and to detect and measure the gain in efficacy, if any, due to moderate dose escalation of BEACOPP. Eight cycles were given, followed by local irradiation. The most recent interim analysis, with 689 evaluable patients, circa 40% of all expected events and a median observation time of 27 months, showed significant differences in progression rate (P) and in two-year freedom from treatment failure (F) between the treatment arms, with escalated BEACOPP (P = 2%, F = 89%) better than baseline BEACOPP (P = 9%, F = 81%) better than COPP/ABVD (P = 13%, F = 72%). Survival was not significantly different. Acute toxicity was more severe due to dose escalation, but remained manageable. These preliminary results suggest that BEACOPP improves efficacy. Moderate dose escalation is feasible with G-CSF support and appears likely to make a worthwhile improvement in the cure rate. The results must await confirmation (or otherwise) by the final analysis including all randomised patients and sufficiently mature data.

Adolescent↗
PubMed1998

Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist Cetrorelix in healthy female volunteers.

The gonadotrophin-releasing hormone antagonist Cetrorelix is in advanced clinical development for the control of endogenous gonadotrophin secretion during the course of a fertility programme. The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of Cetrorelix following single and multiple s.c. administration of different doses. Thirty-six healthy female volunteers received either 0.25, 0.50 or 1.00 mg Cetrorelix, in a first menstrual cycle as single dose and in a second cycle as multiple dose (daily between cycle days 3 and 16). Frequent blood samples were collected for determination of Cetrorelix, follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and progesterone concentrations. Follicular growth was measured by transvaginal ultrasonography. After single administration of each dose, maximum Cetrorelix concentrations (Cmax) were reached after 1 h, and Cmax and area under curve (AUC) increased linearly with the dose. The median terminal half-life ranged from 5 to 10 h in the three different dose groups. FSH, LH, oestradiol and progesterone concentrations were suppressed, with a nadir at 6-12 h after Cetrorelix administration. During multiple administration, Cmax and AUC also showed dose-linearity. The median terminal half-life of Cetrorelix varied between 20 and 80 h. A dose-dependent suppression of FSH, LH and oestradiol concentrations was observed during treatment. After multiple administration, ovulation was delayed for 5, 10 and 13 days in the 0.25, 0.50 and 1.00 mg dose groups, respectively. In conclusion, Cetrorelix showed linear pharmacokinetics, and effectively delayed the LH surge.

Adolescent↗
PubMed1998

BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin's lymphoma: interim report from a trial of the German Hodgkin's Lymphoma Study Group.

PURPOSE: The HD9 trial aims to evaluate whether moderate dose escalation and/or acceleration of standard polychemotherapy is beneficial for advanced-stage Hodgkin's disease (HD). Two variants of a novel bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) scheme (standard and escalated dose) are compared with cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). PATIENTS AND METHODS: The randomized, three-arm trial recruited patients in stages IIB and IIIA with risk factors and stages IIIB and IV. BEACOPP in baseline dose contains all drug dosages of COPP/ABVD (except vincristine and procarbazine) rearranged in a shorter, 3-week cycle. Escalated BEACOPP uses higher doses of cyclophosphamide, doxorubicin, and etoposide with granulocyte colony-stimulating factor (G-CSF) support. After eight chemotherapy cycles, initial bulky and residual disease is irradiated. The trial is monitored and analyzed by means of a sequential strategy. RESULTS: An interim analysis with 505 assessable patients and a median follow-up of 23 months showed a significant inferiority (according to sequential monitoring strategy) of the COPP/ABVD regimen in progression rate and freedom from treatment failure (FFTF) compared with the pooled results of both BEACOPP variants. The 24-month FFTF rate was 75% for COPP/ABVD and 84% for BEACOPP pooled (P = .034). There was 12% progressive disease with COPP/ABVD and 6% with BEACOPP pooled. Differences in survival were not significant in sequential analysis. The acute toxicity of baseline BEACOPP resembled that of COPP/ABVD; escalated BEACOPP showed increased but manageable hematologic toxicity. CONCLUSION: Combined with local irradiation, BEACOPP in one or both variants shows superior disease control compared with COPP/ABVD, with acceptable acute toxicity. Further follow-up is required to assess the effect of dosage and the effect on survival and late toxicities.

Adolescent↗
PubMed1998

Tolerability and in vivo performance of a novel freon-free metered dose inhaler for a fixed combinational product of reproterol and disodium cromoglycate.

The present study was conducted to describe and compare the in vivo performance (systemic exposure), clinical and laboratory safety of a fixed combinational product of inhaled reproterol (CAS 54063-54-6) plus disodium cromoglycate (DSCG; CAS 15826-37-6) using a novel freon (CFC)-free metered dose inhaler (MDI), which uses 1,1,1,2,3,3,3-heptafluoropropane (HFA-227; CAS 431-89-0) as propellant and polyoxyethylene glyceryl trioleate (Tagat TO; CAS 68958-64-5) as surfactant relative to the conventional freon-driven MDI Allergospasmin in healthy male and female volunteers. Twenty-four young male and female healthy subjects were randomly allocated in gender-balanced fashion to 4 parallel treatment groups with single and repeated dosing of either reproterol + DSCG by HFA- or CFC-MDI (each time N = 8) or placebo by HFA- or CFC-MDI (each time N = 4) using matched placebo devices thus allowing a double-blind (with regard to placebo) approach. Treatments consisted of a single morning dose of 2 actuations followed 4 days later by a 1 week treatment course of 2 actuations four times daily. Subjects were investigated extensively in terms of blood pressure, pulse rate, electrocardiography, spirometry, respiratory rate, body temperature, laboratory safety (haematology, clinical chemistry, urinalysis) and clinical well-being. There were no treatment, compound or device related effects for any of the tolerability and safety end points. The treatments were well tolerated. In particular, there was no irritative cough or any sign of broncho-irritation on application. Adverse events were reported in a total of 9 subjects: 3/8, 4/8, 0/4 and 2/4 subjects treated with reproterol + DSCG by HFA-MDI, reproterol + DSCG by CFC-MDI, placebo by HFA-MDI and placebo by CFC-MDI, respectively. Of these, 6 events in 6 subjects receiving the active treatments were considered probably or definitely related to the test drug administration (i.e. adverse drug reactions): after reproterol + DSCG one subject in each treatment group (HFA-MDI and CFC-MDI) complained of an unpleasant bitter taste immediately after application; one further subject in each group complained of headache. Under treatment with reproterol + DSCG by CFC-MDI one male subject complained of mild transient nausea with onset on day 5. Under treatment with reproterol + DSCG by HFA-MDI one female subject complained of mild dizziness and mildly disturbed (blurred) vision with onset on day 1. All adverse events occurred only transitory and required no treatment. Systemic exposure, evaluated by the plasma concentrations of DSCG at 1 h after application, was slightly higher with the HFA-MDI compared to the CFC-MDI. It is concluded that the safety, tolerability and in vivo performance of the newly developed freon-free MDI is at least as well tolerable as the already marketed freon-driven conventional formulation.

Adolescent↗
PubMed1997

[Gastropathy due to portal hypertension].

After oesophageal and fundus-varices, portal hypertensive gastropathy (PHG) is the second most frequent cause for bleeding in cirrhotic patients. In accounts for 1 to 8% of primary upper gastrointestinal haemorrhage and 30 to 60% of secondary acute or chronic bleeding, mainly after sclerosing therapy of varices. Endoscopy is diagnostic either by showing a typical 'mosaic-pattern' in mild, and a single or confluent 'cherry red spots' in severe forms. Helicobacter pylori or NSAID-induced gastropathy are to be distinguished by biopsies. The therapeutical principles are the same as in therapy of oesophageal varices. Secondary prophylaxis with propranolol especially after sclerosing therapy is recommended, primary prophylaxis not.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor.

The crystal structure of human alpha-thrombin in complex with LY178550, a nonpeptidyl, active site-directed inhibitor, has been solved to 2.07 A resolution by the method of X-ray crystallography. The final model of the complex has a crystallographic R-value of 21.5% (Rfree = 23.1%) with 0.014 A and 2.4 degrees standard deviation from ideal bond lengths and angles, respectively. Well-defined electron density was observed for the inhibitor in the active site. The inhibitor binds to the active site in an L-shaped manner, mimicking the bound conformation of the tripeptide arginal series of thrombin inhibitors (Chirgadze NY et al., 1992, American Crystallographic Association Meeting 20: 116 [Abstr. PB311]). The basic amidine of LY178550 forms a salt bridge with Asp 189 within the specificity pocket, while the 4-benzylpiperidine side chain engages in a number of hydrophobic interactions at the S2 and S3 binding sites. The inhibitor does not interact in any fashion with the active site sequence Ser 214-Gly 216, as occurs with many of the inhibitors studied previously. The indole N-H of the inhibitor forms a hydrogen bond to the gamma-oxygen of the catalytic serine (Ser 195).

Binding Sites↗
PubMed1997

Asexual sporulation in coprinus cinereus: structure and development of oidiophores and oidia in an amut bmut homokaryon

Polak, E., Hermann, R., Kues, U., and Aebi, M. 1997. Asexual sporulation in Coprinus cinereus: Structure and development of oidiophores and oidia in an Amut Bmut homokaryon. 22, 112-126. Coprinus cinereus strain AmutBmut is a homokaryon with mutations in both mating type loci. It produces asexual spores (oidia) in sticky liquid droplets on specialized aerial structures (oidiophores). These oidiophores have uninucleate cells and are organized as those of the monokaryon 5026 from which the strain derived. However, unlike in the monokaryon, oidiophores in strain AmutBmut are induced by light. Young oidiophores are easily detected upon light induction and the process of oidiophore development is readily followed in this strain. Fully grown oidiophores consecutively give rise to short branches (oidial hyphae) that break up into two or occasionally three uninucleate oidia (arthroconidia) until up to 200 oidia are collected at the tip of the oidiophore. Mature spores are enclosed by a mucilage and a double-layered primary cell wall with hair-like structures except for the sides of former cell attachments. In a summary of our microscopic observations on developing oidiophores and nuclear stainings we present a model showing the successive steps of oidiophore and spore development.

Journal Article↗
PubMed1997

Adverse events and discomfort in studies on healthy subjects: the volunteer's perspective. A survey conducted by the German Association for Applied Human Pharmacology.

OBJECTIVE: The various good clinical practice (GCP) guidelines do not define the volunteering subject as an active party. The present survey addresses the volunteer's perception of study-related inconvenience and risk and its impact on their decision to enroll. METHODS: The survey consisted of a questionnaire to be filled out voluntarily and anonymously by healthy subjects who volunteered for enrollment in human pharmacology studies and who had participated in at least one previous study. Twenty-five categorised multiple-choice questions covered previous study experience, motives for volunteering, perception of and compliance with study directives and restrictions, past experience with adverse events, impact of the study environment on perceived well-being and the nature of adverse events likely to discourage them from enrollment. RESULTS: Seven centres contributed by providing at least 30 (range 30-100) evaluable questionnaires. The database consists of a total of 440 healthy subjects (30.5% females, 69.5% males), from 18 to over 60 years of age. Two hundred and seven subjects (47.1%) were company employees and 233 (52.9%) were external volunteers. Eighty nine percent only participated in studies at one particular centre. Some 53.3% indicated financial motives, 27.8% 'contribution to an improvement of pharmacotherapy', 12.7% 'social responsibility', while 6.2% indicated other motives, mainly the opportunity of a free medical check-up. Thirteen subjects (3%) admitted to not answering correctly to the recruitment questions; this limited reliability is suspected to be even larger when the answer might preclude enrollment. From the volunteers' perspective, the environmental study conditions clearly appeared to have a highly relevant impact on their personal well-being. Some 17.1% of the subjects reported to have suffered adverse events occasionally and 2.7% frequently; but 14% admitted not reporting adverse events promptly and about 20% indicated that, with respect to previous adverse events, they first sought advice from other volunteers rather than from the investigator. CONCLUSIONS: Adverse events and inconveniences are inherent to nontherapeutic studies in healthy subjects. From the volunteer's perspective it appears that the incidence of adverse experiences in such studies exceeds the reported frequencies from investigators considerably. This finding suggests that investigators are usually not aware or able to ascertain the true incidence of adverse events. The present survey also confirms that pertinent information on the personal history may be unreliable. Volunteers are reluctant to answer questions regarding, in particular, their smoking habits, caffeine and alcohol consumption. Regarding the matter of informed consent, a noteworthy contradiction between the volunteers' attitude and behaviour became apparent. Although the volunteers admit that even rather minor adverse events ordinarily would discourage them, they still consent to enrollment. In view of this apparent contradiction, there is no alternative to the investigator's personal responsibility to counsel and protect the subject. Surveys such as this one may contribute to the awareness that the explicitness of GCP guidelines merely define the format, but not the content quality of these fundamental ethical values, which remain the unique burden and challenge of the investigator.

Adolescent↗
PubMed1996

The transient receptor potential protein (Trp), a putative store-operated Ca2+ channel essential for phosphoinositide-mediated photoreception, forms a signaling complex with NorpA, InaC and InaD.

The transient receptor potential protein (Trp) is a putative capacitative Ca2+ entry channel present in fly photoreceptors, which use the inositol 1,4,5-trisphosphate (InsP3) signaling pathway for phototransduction. By immunoprecipitation studies, we find that Trp is associated into a multiprotein complex with the norpA-encoded phospholipase C, an eye-specific protein kinase C (InaC) and with the InaD protein (InaD). InaD is a putative substrate of InaC and contains two PDZ repeats, putative protein-protein interaction domains. These proteins are present in the photoreceptor membrane at about equimolar ratios. The Trp homolog analyzed here is isolated together with NorpA, InaC and InaD from blowfly (Calliphora) photoreceptors. Compared to Drosophila Trp, the Calliphora Trp homolog displays 77% amino acid identity. The highest sequence conservation is found in the region that contains the putative transmembrane domains S1-S6 (91% amino acid identity). As investigated by immunogold labeling with specific antibodies directed against Trp and InaD, the Trp signaling complex is located in the microvillar membranes of the photoreceptor cells. The spatial distribution of the signaling complex argues against a direct conformational coupling of Trp to an InsP3 receptor supposed to be present in the membrane of internal photoreceptor Ca2+ stores. It is suggested that the organization of signal transducing proteins into a multiprotein complex provides the structural basis for an efficient and fast activation and regulation of Ca2+ entry through the Trp channel.

Amino Acid Sequence↗
PubMed1996

[Portal hypertension-induced stomach disease].

After esophageal and fundus varices, portal hypertensive gastropathy (PHG) is the second most frequent cause of bleeding in cirrhotic patients. It accounts for 1-8% of primary upper gastrointestinal hemorrhage and 30-60% of secondary acute or chronic bleeding in the first 12 months, mainly after sclerosing therapy of varices. Endoscopy is diagnostic by showing either a typical "mosaic pattern" (mild form) or single or confluent "cherry red spots" (severe form). Helicobacter pylori or NSAID-induced gastropathy are to be distinguished. The therapeutic principles are the same as in drug therapy of esophageal varices. Secondary prophylaxis with propranolol, especially after sclerosing therapy, is recommended, but not primary prophylaxis.

Diagnosis, Differential↗
PubMed1996

Cellular localisation by immunolabelling and transmission electron microscopy of oxaloacetate decarboxylase or its individual subunits synthesised in Escherichia coli.

The genes oadGAB encoding the oxaloacetate decarboxylase gamma, alpha and beta-subunits from Klebsiella pneumoniae were expressed in Escherichia coli. Using different expression vectors, the entire enzyme or its individual subunits were synthesised. The expression was evidenced immunologically in whole cells with polyclonal antibodies raised against the purified oxaloacetate decarboxylase. The expressed alpha-subunit or a combination of alpha and beta-subunits were shown to reside in the cytoplasm, while the entire oxaloacetate decarboxylase or a gammaalpha-complex were located mostly in the cytoplasmic membrane. Interestingly, overexpression of the gammaalpha-complex or the entire oxaloacetate decarboxylase in E. coli led to a significant immunogold labelling in the cytoplasm, indicating that the alpha-subunit was not completely complexed to the membrane-bound gamma or betagamma-subunits.

Carboxy-Lyases↗
PubMed1996

Generation of hydroxytrimethyllysine from trimethyllysine limits the carnitine biosynthesis in premature infants.

epsilon-N-Trimethyl-L-lysine (TML) was given orally for 1 day to two groups of premature infants. There was no change in the output or plasma levels of carnitine at a dose of 100 mumol/day; however, the urinary TML increased 17-fold. In the second group, administration of 1 mmol TML increased the plasma levels and urinary output of carnitine; the output of TML increased 62-fold. During a search of the metabolites of carnitine biosynthesis by 1H NMR analysis of urine, only one new resonance (corresponding to the TML) could be identified in both groups. Fast atom bombardment mass spectrometry (FAB-MS) analysis of urine samples indicated an increase in TML in the treated patients; no changes were found in the relative abundance of any other precursors. These data show that a significant limitation of the conversion of hydroxy-TML to carnitine is not likely; rather, the conversion of TML to hydroxy-TML is regulatory in neonatal carnitine biosynthesis.

Carnitine↗