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Biomedical subjects

H Lindemann

Publications and source records attributed to H Lindemann.

At least 19 recordsLinked to original sources
PubMed2006

[A new breath actuated dry powder inhaler (Auto-Jethaler)].

BACKGROUND: The aim was to examine the handling of the recently developed breath actuated dry powder inhaler Auto-Jethaler (PulmoTec GmbH/Höchstädt, launch by Ratiopharm and CT Berlin). METHOD: 75 patients suffering from asthma, cystic fibrosis or primary ciliary dysfunction (age: 3 to 34 years; 29 female, 46 male) with mild or moderate bronchial obstruction took part in the study. Lung function testing including body plethysmography was performed to measure bronchial obstruction independent of effort. Peak Inspiratory Flow (PIF) was measured using a Fleisch pneumotachograph equipped with or without a Auto-Jethaler. Instead of the commercially available drug tablet a stainless steal ring device of equivalent resistance, easy to disinfect, was used. Actuation of the rotation mechanism which was triggered by inspiration at an inspiratory flow of about 40 L/min was accompanied by a rattling noise. Aims of the study were to examine, whether the subjects were able to handle the new device, and to measure PIF without and via Auto-Jethaler. RESULTS: Handling of the Auto-Jethaler was found to be easy. All patients managed to reach or surpass the critical value of 40 L/min, even those with mild to moderate bronchial obstruction. PIF without Jethaler was 85 to 599 L/min, via Auto-Jethaler 40 to 215 L/min. PIF was significantly age dependent (p<0.001). CONCLUSIONS: These findings suggest that the Auto-Jethaler will be an appropriate device for drug administration in children older than 3 years provided that they understand the inspiratory breathing manoeuvre.

Adolescent↗
PubMed2005

[Quality of life and sexuality after surgery for rectal cancer--a follow-up study].

BACKGROUND: Previous studies have suggested that sexuality following surgery for rectal cancer is better in women than in men and differs with type of surgery in terms of impact on Quality of Life. However, the findings were inconsistent. The aim of the presented study was to address these issues. METHODS: 570 patients that had undergone surgery for rectal cancer in our department from 1992 to 1999 were included. After determination of survival status questionnaires on Quality of Life were sent to 370 patients one to two years post surgery. We analysed data from 215 patients of which 103 were female and 112 male. 248 patients died during the time observed. Statistical analysis was done with descriptive methods, Kaplan-Meier analysis (log rank test), T-test and analysis of variance using SPSS 11.0 for Windows. RESULTS: Significant differences were seen in symptom scales between men and women. Women scored higher for distress through medical treatment and had higher values for insomnia, fatigue and constipation. Both sexes had impaired sexual life but men had significantly higher values and felt more distressed by the impairment of sexuality than women. For patients receiving abdominoperineal resection sexuality was most impaired. Anterior resection with pouch had a detrimental effect on diarrhoea and treatment strain. CONCLUSION: The study showed that sexuality is influenced by gender and type of surgery and impacts Quality of Life after surgery for rectal cancer. Assessing quality of life with generic and specific instruments is helpful to determine differences between surgical procedures, age, gender, and adjuvant therapy where standard parameters such as survival have their limitations.

Age Factors↗
PubMed2003

Effect of immunomodulatory drugs on in vitro production of brain-derived neurotrophic factor.

Multiple sclerosis (MS), a disease of presumably autoimmune aetiology, is characterized by inflammation, demyelination and axonal degeneration in the central nervous system. Current treatment concepts target the inflammatory activity, reducing the number of relapses and inflammatory lesions on magnetic resonance imaging as well as the proinflammatory cytokine production in blood lymphocytes. Recently, the neuroprotective aspect of inflammation has been documented and is thought to be mediated by neurotrophins, like brain-derived neurotrophic factor (BDNF). The question whether the in vitro BDNF production in MS patients and healthy controls is influenced by the immunomodulatory agents interferon beta (IFN-beta) and immunoglobulin G (Ig) is addressed. A significantly increased BDNF production in MS patients was found compared with normal controls (mean +/- SD: 492 +/- 172 pg/mL versus 217 +/- 55 pg/mL, P < 0.001). IFN-beta and low-dose Ig had no effect on BDNF production, whereas high-dose Ig reduced in vitro BDNF production in MS patients significantly (to 409 +/- 125 pg/mL, P = 0.001). These in vitro findings might indicate that Igs in high doses potentially interfere with neuroprotective mechanisms despite their potent anti-inflammatory properties.

Adjuvants, Immunologic↗
PubMed2002

Adjuvant chemotherapy in stage III colon cancer with 5-fluorouracil and levamisole versus 5-fluorouracil and leucovorin.

BACKGROUND: Adjuvant chemotherapy for colon cancer has been established during the past decade. From 1990 until recently treatment with 5- fluorouracil (5-FU) and levamisole (LEV) lasting 12 months was recommended as standard treatment. At the initiation of this study in 1993 improvement of adjuvant therapy was expected by the modulation of 5-FU with folinic acid (FA). Therefore, we decided to perform a prospective randomized multicenter trial to compare standard 5-FU/LEV to 5-FU/FA for either 6 or 12 months. PATIENTS AND METHODS: Patients with stage III colon cancer after curative en bloc resection were randomized in 3 treatment groups: arm A (5-FU/LEV, weekly, 12 months), arm B (5-FU/FA, days 1-5, every 4 weeks, 12 months) and arm C (like B, 6 months). RESULTS: Between March 1993 and November 1997, 180 patients were randomized into the study, 155 were eligible for further evaluation. The interim analysis in November 2000 showed no significant difference for recurrence and disease-free survival in arm B and C, therefore the data from both 5-FU/FA treatment arms (B+C) were combined for comparison with 5-FU/LEV-treatment (A). Most pronounced toxicity in all treatment arms was mild nausea, loss of appetite and leukopenia. A tendency for more diarrhea and stomatitis was observed in arm B+C. After a median follow-up of 36.2 months no significant difference was seen for disease free survival (p = 0.9) and overall survival (p = 1.0). 3-year recurrence rates were 39.6% in arm A and 39.1% in arm B+C, 3-year survival rates amounted to 74.1% in arm A and 74.9% in arm B+C. CONCLUSION: Only a limited number of patients could be recruited in this study. The observed data support the results of other studies, which concluded that 6 months (or 12 months) treatment with 5-FU/FA is equivalent to 12 months treatment with 5-FU/LEV. Therefore the 6 months treatment with 5-FU/FA can be supported as standard for adjuvant therapy of stage III colon cancer.

Adult↗
PubMed2001

Adjuvant radio-chemotherapy in stage II-III rectal cancer with 24-hour infusion of high-dose 5-fluorouracil and folinic acid: evaluation of feasibility.

BACKGROUND: Postoperative radio-chemotherapy has been established as standard treatment for stage II and III rectal cancer patients in the last decade. To improve the efficacy of this therapy, we decided to evaluate continuous 24-hour infusion of 5-fluorouracil (5-FU) with folinic acid (FA) in combination with local radiation versus standard bolus 5-FU/FA with local radiation in a randomized study. Here we report on the first 28 patients to receive the experimental treatment. PATIENTS AND METHODS: Patients with stage II and III rectal cancer received weekly 2-hour infusions of FA 500 mg/m2 followed by continuous 24-hour infusions of 5-FU 2,600 mg/m2 postoperatively via a Port-A-Cath system. The first cycle included 8 consecutive weekly administrations, the 1st-4th in full dose, the 5th-8th with 50% reduced dose while local irradiation (45 or 50.4 Gy) was performed. Thereafter, two further chemotherapy cycles (6 weekly administrations, 100% dose) followed. RESULTS: 28 patients received continuous 5-FU/FA treatment, of whom only 21 were evaluable for tolerability. 19 patients (90.4%) completed the first cycle, only 14 patients entered the second treatment cycle. Especially during the combined radiochemotherapy, increased toxicity was observed with grade III/IV diarrhea (n = 2), nausea (n = 1), leukopenia (n = 1), and cardiac toxicity (n = 1). CONCLUSION: The high rate of premature treatment dropout indicate that the chosen schedule of weekly high-dose 5-FU/FA continuous infusion and combined postoperative radiotherapy should not be recommended for further use in postoperative adjuvant treatment.

Adenocarcinoma↗
PubMed2000

Nitric oxide has no beneficial effects on ion transport defects in cystic fibrosis human nasal epithelium.

Nitric oxide (NO) has been reported to activate Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) and inhibit epithelial Na+ absorption mediated by amiloride-sensitive epithelial Na+ channels (ENaC). These ion transport systems are defective in cystic fibrosis (CF): Cl- secretion by CFTR is impaired and Na+ absorption by ENaC is dramatically increased. By activating CFTR and depressing ENaC, NO is a potentially beneficial therapeutic agent for ion transport defects in human CF respiratory epithelia. To assess the effects of NO on human respiratory epithelial cells, the NO donors sodium nitroprusside (SNP) and spermine NONOate were applied to primary cultured nasal cells, surgically obtained from non-CF and CF patients. Measurements of transepithelial short-circuit current (ISC) showed that NO has no inhibitory potency against amiloride-sensitive nasal ENaC (nENaC) or amiloride-insensitive Na+-absorbing mechanisms in non-CF and CF epithelia. Furthermore, NO had no stimulatory effect on Cl- secretion by CFTR or any other Cl- conductance pathway in either tissue. Although NO elevated the intracellular Ca2+ concentration, we did not detect any activation of Ca2+-dependent Cl- channels. These results demonstrate that NO has no beneficial effect on CF epithelial cells of the upper airways.

Absorption↗
PubMed1999

[Ion transport in nasal and paranasal sinus mucosa in mucoviscidosis and chronic sinusitis].

Cystic fibrosis (CF) is the most commonly inherited disease in Caucasians and is caused by a mutation in the gene encoding a membrane transport protein. This cystic fibrosis transmembrane conductance regulator (CFTR) is thought to be an apical Cl- channel activated by intracellular cAMP. Most recent findings suggest that CFTR is more than a pure Cl- channel and might be involved in the regulation of other transport systems. In the present study we show that CFTR as a Cl- channel plays only a minor role in primary cultured human nasal epithelium derived from non-CF and CF patients. These findings are especially of interest for non-CF human nasal epithelia in which CFTR is correctly inserted. In both tissues Cl- secretion is negligible as compared with Na+ absorption. We confirm and expand our previous observations that Na+ absorption in human nasal epithelium is the dominant ion transport process and that Cl- secretion is detectable in both CF and non-CF tissue. Moreover, we show that cAMP and ATP were not able to stimulate any silent Cl- channels in CF or non-CF human nasal epithelial cells. We further give evidence that in human nasal CF and non-CF epithelium Na+ absorption is mediated by epithelial Na+ channels (ENaC) that are either different from those of other epithelia or which exhibit altered regulation. These differences between Na+ channels of human nasal epithelium and "classical" epithelial Na+ channels include lack of activation by the intracellular second messenger cAMP and the steroid hormone aldosterone. We show further that human nasal Na+ channels are inhibited by Cl- channel blockers and exhibit a different pharmacology towards common Na+ channel blockers.

Chloride Channels↗
PubMed1999

Minor role of Cl- secretion in non-cystic fibrosis and cystic fibrosis human nasal epithelium.

Na+ and Cl- currents were studied in primary cultures of human nasal epithelium derived from non-cystic fibrosis (non-CF) and cystic fibrosis (CF) patients. We found that Na+ absorption dominates transepithelial transport and the Na+ current contains an amiloride-sensitive and amiloride-insensitive component. In non-CF tissue both components contribute about equally to the entire short-circuit current (ISC), whereas in CF tissues the major part of the current is amiloride-sensitive. Na+ removal reduced ISC to values close to zero. Several Cl- channel blockers were used to identify the remaining tiny Na+-independent current. Under unstimulated, physiological conditions in the presence of Cl- on both sides and amiloride on the apical side of the epithelium diphenylamine-2-carboxic acid (DPC), 4,4'-diisothiocyanatostilbene-2, 2'- disulfonic acid (DIDS) and 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB) failed to induce clearcut inhibition of ISC. cAMP as well as ATP did not affect ISC either in CF or in non-CF epithelia. Reduction of apical Cl- increased ISC and depolarized transepithelial potential; however, the observed increase was insensitive to DIDS, DPC and NPPB. From these data we conclude that Cl- conductances in primary cultures of human nasal epithelium derived from CF patients as well as from non-CF patients are present only in low numbers or do not contribute significantly to transepithelial ion transport.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1998

Effects of topically delivered benzamil and amiloride on nasal potential difference in cystic fibrosis.

The raised nasal transepithelial potential difference (PD) in cystic fibrosis (CF) reflects accelerated active transport of Na+, and is inhibited by topical administration of the Na+ channel blocker, amiloride. The aim of this study was to investigate the dose-effect and time course of topically administered Na+ conductance inhibitors to inhibit nasal PD, including benzamil, an analog of amiloride. We measured the magnitude of drug inhibition of Na+ transport [percent inhibition of baseline PD (DeltaPD%)] and duration of inhibition of PD, defined as the time when drug inhibition of PD had recovered by 50% (effective time = ET50). Amiloride [10(-)3 M (n = 16), 3 x 10(-)3 M (n = 9), 6 x 10(-)3 M (n = 7), 10(-)2 M (n = 3)] or benzamil [1.7 x 10(-)3 M (n = 7), and 7 x 10(-)3 M (n = 5)] were administered to the nasal surface via an aerosol generated by a jet nebulizer and a nasal mask. The concentration-dependent magnitude (DeltaPD%) of inhibition was similar for amiloride and benzamil ( approximately 67- 77%), whereas the duration of inhibition (ET50) was about two-and-a-half times longer after benzamil administration as compared with equivalent concentrations of amiloride [1.6 +/- 0. 06 versus 4.5 +/- 0.6 h (ET50 +/- SEM), at 6-7 x 10(-)3 M]. In vitro studies of cultured normal nasal epithelia demonstrated directly that benzamil induced an approximately 2-fold more prolonged inhibition of active Na+ transport than amiloride. These data suggest aerosolized benzamil is a candidate long-duration Na+ channel blocker for CF.

Administration, Intranasal↗
PubMed1998

Sputum rheology changes in cystic fibrosis lung disease following two different types of physiotherapy: flutter vs autogenic drainage.

OBJECTIVE: The aim of the present study was to investigate the efficacy of two frequently used physiotherapies (PTs) for the removal of bronchial secretions in cystic fibrosis (CF) lung disease: autogenic drainage (AD) and the Flutter (Desitin in Germany). AD is believed to improve mucus clearance from peripheral to central airways due to airway caliber changes in combination with a special breathing technique. The Flutter is an easy-to-use physiotherapy device based on oscillations of a steel ball during expiration through a pipe-type device. MATERIALS AND METHODS: To evaluate the acute and chronic physiotherapy effects of these two techniques, 14 CF patients underwent either twice daily AD or Flutter treatment for 4 consecutive weeks in a randomized crossover design. Prior to each therapy interval, for a 1-week wash-out period, no PT was administered, but patients continued regular medication. At the beginning and end of each 4-week interval, pulmonary function was measured before and after an acute 30-min therapy. At the end of the PT session, sputum was collected, weighed, and deep frozen until analyzed. The viscoelasticity of the sputum was evaluated using a magnetic microrheometer. RESULTS: No significant changes were noted for FVC, FEV1, or sputum volume throughout the study. Sputum viscoelasticity (rigidity index), however, was significantly lower (p<0.01) after therapy with the Flutter in comparison with AD, predicting improvements in mucociliary and cough clearability of the secretions. In a companion in vitro experiment, oscillations generated by passing humidified air over CF sputum lining an acrylic tube connected to a Flutter de-ice were found to decrease sputum elasticity, as measured by a filancemeter. These findings suggest that applied oscillations are capable of decreasing mucus viscoelasticity within the airways at frequencies and amplitudes achievable with the Flutter device, and provide direct evidence that PT can reduce the viscoelasticity of sputum.

Adult↗
PubMed1997

Amiloride-sensitive Na+ channels in human nasal epithelium are different from classical epithelial Na+ channels.

We characterized Na+ absorption in confluent monolayers of primary cultured epithelia derived from human nasal cystic fibrosis (CF) and non-CF epithelium in modified Ussing chambers. Amiloride-sensitive Na+ channels in cells obtained from CF as well as from non-CF patients showed properties different from all previously described epithelial Na+ channels (ENaC). DPC, a potent Cl- channel blocker, which has never been described to block ENaC, inhibited a considerable portion of the amiloride-sensitive Na+ absorption. In contrast to classical ENaC, cAMP induced no activation of amiloride-sensitive short-circuit current. Aldosterone failed to induce any functional stimulation of Na+ absorption in vitro when applied to the cell culture medium prior to measurements. Together with the reportedly reversible inhibition by phenamil we propose that Na+ absorption in human nasal epithelia is either regulated differently or is mediated by a yet still unknown member of the ENaC superfamily.

1-Methyl-3-isobutylxanthine↗
PubMed1997

Cystic fibrosis and non-cystic-fibrosis human nasal epithelium show analogous Na+ absorption and reversible block by phenamil.

Transepithelial short-circuit current (ISC), potential (VT) and resistance (RT) of confluent monolayers of human nasal epithelium cultured from patients with and without cystic fibrosis (CF) were measured. In our Ussing chamber experiments with monolayers derived from non-CF and CF patients neither ISC (non-CF: 14.1 +/- 1.0 microA/cm2, n = 77; CF: 16.7 +/- 1.5 microA/cm2, n = 42), nor RT (non-CF: 288 +/- 15 Omega . cm2; CF: 325 +/- 20 Omega . cm2) showed any significant differences, only VT showed moderate but significant different values (non-CF: -3.6 +/- 0.4 mV; CF: -5.6 +/- 0.7 mV, respectively). Total ISC in CF cells was nearly completely inhibited by amiloride (92 +/- 9.6%), while in non-CF tissue amiloride-insensitive conductances mediated a considerable amount of the ISC (36.3 +/- 6.1%), indicating a lower activity of amiloride-sensitive Na+ conductances in non-CF cells. In both tissues the amiloride-sensitive ISC could also be blocked by the amiloride analogues benzamil, phenamil and 5-(N-ethyl-N-isopropyl)2', 4'-amiloride (EIPA) with different affinities. However, amiloride had a significant lower affinity in CF tissue (half-maximal blocker concentration, K1/2 = 586 +/- 59 nM) compared with non-CF tissue (K1/2 = 294 +/- 22 nM). Astonishingly, phenamil, a blocker which irreversibly blocks all epithelial Na+ channels hitherto described, inhibited the Na+ conductances of human nasal epithelium in a completely reversible way, but nevertheless with high affinity (non-CF: K1/2 = 12.5 +/- 1.2 nM; CF: K1/2 = 17.1 +/- 1.1 nM). Even in high doses none of these blockers had any effect on intracellular Ca2+ concentration as measured with Fura-2. From these findings, we conclude that the epithelial Na+ conductances of human CF nasal epithelium show modified regulation or are functionally different from those of other tissues.

Amiloride↗
PubMed1997

Aerosolized amiloride: dose effect on nasal bioelectric properties, pharmacokinetics, and effect on sputum expectoration in patients with cystic fibrosis.

Aerosolized amiloride normalizes the excessive sodium absorption cystic fibrosis (CF) respiratory epithelium. The aims of this study were to assess the dose-effect relationship and the duration for which amiloride inhibits Na+ transport, to determine acute and chronic pharmacokinetics, and to test the effect of acute aerosolized amiloride on the amount of sputum expectorated. The effect of inhaled amiloride was assessed principally by nasal potential difference (PD) measurements. Amiloride serum levels were measured in 23 patients after inhalation of different doses of aerosolized amiloride. Twenty CF patients inhaled amiloride (10(-3)M) or a placebo in a double-blinded, randomized order, and sputum production was quantitated. The results of this study showed that maximal initial PD inhibition was achieved by 6 x 10(-3)M of amiloride. The duration of inhibition of PD (effective time until return to 50% delta PD [ET50] after nasal administration) was dose dependent (10(-3)M, 39 +/- 0.8 minutes; 10(-2)M; 133 +/- 14 minutes). Amiloride serum levels were below 2.5 ng/ml in 20 of 28 patients; levels were above 5 ng/ml only within 4 hours after high dose inhalation (10(-2)M). In the double-blinded, crossover study, more sputum was expectorated after amiloride inhalation as compared with that after a placebo (P < 0.05). In conclusion, the bioelectric effects of amiloride and serum levels after inhalation are dose dependent, and amiloride is effective at inducing sputum expectoration in CF.

Administration, Intranasal↗
PubMed1997

Conventional and modified nasal potential-difference measurement in cystic fibrosis.

Cystic fibrosis (CF) is associated with impaired ion transport across epithelial membranes and an increased transepithelial potential difference (PD) that can be measured in airway epithelium. The aim of this study was to investigate the diagnostic value of nasal PD in CF, and to test a modified approach to the measurement of this PD. The reproducibility and diagnostic sensitivity and specificity of nasal PD measurements were tested with the perfusion technique and with a simplified modification of the technique done with a novel, solid-state exploring electrode. With the perfusion method, basal PD values were different in CF patients (mean +/- SEM: -51.6 +/- 0.9 mV, n = 104) than in normal (-15.5 +/- 0.9 mV, n = 58, p < 0.01) subjects. CF patients with acute rhinitis or other nasal pathology had mean PD values that were intermediate between those of the patients and normal and disease-control groups (-28.3 +/- 1.2 mV, n = 40, p < 0.01, different from normal). The diagnostic sensitivity of the perfusion method for CF was 91.3%, and the specificity was 96.4%. PD measurements with the modified technique correlated highly with the results achieved with the perfusion method (r = 0.94, n +/- 158). The measurement of nasal PD effectively distinguishes CF from control subjects. Care must be taken in the interpretation of measurements made on acutely inflamed epithelium. The modified method was simpler than the conventional perfusion technique, and equally effective.

Adolescent↗