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W Kern

Publications and source records attributed to W Kern.

At least 91 records · Page 5Linked to original sources
PubMed1999

Oxaliplatin pharmacokinetics during a four-hour infusion.

A new platin compound, oxaliplatin, has significant activity in advanced colorectal carcinomas. However, its pharmacokinetics have not been characterized adequately yet. This study extensively analyzes the pharmacokinetics of both ultrafiltrable (free) and protein-bound platin in 13 patients receiving 130 mg/m2 oxaliplatin as a 4-h infusion in combination with 375 mg/m2 5-fluorouracil as a 24-h infusion for advanced colorectal carcinomas. The interpatient variability was very low for all parameters analyzed. The levels of free platin decreased triphasically, with a mean terminal half-life of 27.3+/-10.6 h. The area under the time-concentration curve was 20.17+/-6.97 microg.h/ml and the total and renal clearances amounted to 222+/-65 and 121+/-56 ml/min, respectively. The values for the volume of distribution and for the maximum concentration at the end of infusion were 349+/-132 liters and 1612+/-553 ng/ml, respectively. On the basis of the simulation of the plasma levels and the urinary excretion of platin following the long-term administration of oxaliplatin as a constant-rate and a chronomodulated infusion, additional analyses are warranted to fully characterize the pharmacokinetics of the drug in these settings.

Adult↗
PubMed1999

Leukaemic blasts differ from normal bone marrow mononuclear cells and CD34+ haemopoietic stem cells in their metabolism of cytosine arabinoside.

Different metabolites of cytosine arabinoside (AraC) contribute to its cytotoxicity including incorporation of AraCTP into DNA, the incorporation of AraUMP into RNA, inhibition of polymerase alpha and beta (AraCMP/CTP), an impairment of repair mechanisms (AraCTP), alterations of phospholipid metabolism (AraCDP-choline), a direct membrane interaction (AraC), the alteration of signal transduction pathways (AraCDP-choline, AraCTP) and the induction of apoptosis. Since little is known about the potential differences in AraC metabolism between leukaemic blasts and normal haemopoietic progenitor cells, the formation of all known AraC metabolites was determined in bone marrow samples from patients with acute myeloid leukaemia (AML), healthy volunteers and specimens of cellsorted CD34+ haemopoietic stem cells. Highly significant differences were found for phosphorylated AraC metabolites (AraCMP, -CDP, -CTP, AraUMP) between AML and normal mononuclear bone marrow (ng/107 cells respectively 1.30 v 2.66; 2.65 v 7.50; 33.68 v 99.0; 1.18 v 5.70). The highest differences were found for formation of AraCDP-choline (3.75 v 12.86) which might be relevant for the high efficacy of high-dose AraC regimens. In contrast, no differences were found in the deamination product AraU (2.01 v 2.91). Only minute amounts of phosphorylated AraU derivatives were detected, providing an explanation for the lacking contribution of AraU to cytosine arabinoside cytotoxicity. Results in normal CD34+ haemopoietic stem cells did not differ significantly from normal bone marrow mononuclear cells and therefore justify their use as a surrogate in determining AraC-induced haematotoxicity. These data suggest a metabolic basis for the relative selectivity of AraC cytotoxicity for AML blasts and provide a means to determine the role of different metabolites and their related mechanism of action for overall AraC cytotoxicity.

Acute Disease↗
PubMed1999

[Glucocorticoid-induced diabetes mellitus in gastrointestinal diseases].

Glucocorticoid excess causes insulin resistance i.e. a reduced effectiveness of insulin to suppress hepatic glucose production and to increase glucose uptake in muscle and fat tissue. Persons who cannot compensate for the resulting additional insulin need develop overt diabetes during glucocorticoid therapy. In the field of gastroenterology, glucocorticoids are mainly employed for the therapy of chronic inflammatory bowel diseases, alcoholic and autoimmune hepatitis, and after liver transplantation. The risk of developing steroid diabetes depends among other things on the genetic predisposition, the body composition, the underlying gastrointestinal disease, the age, and the steroid dose. The treatment of glucocorticoid-induced diabetes resembles essentially the treatment of type 2-diabetes. In addition to dietary measures, oral antihypoglycemic drugs and/or insulin are applied. If oral antihypoglycemic drugs are used, specific problems that might result from the gastrointestinal diseases need to be observed. In the short and medium term, the prognosis of glucocorticoid-induced diabetes is good since it is well treatable. If glucocorticoid treatment is continued for a long time, the alterations of glucose metabolism and the resulting hyperinsulinemia may lead to increased cardiovascular risk.

Adolescent↗
PubMed1998

Failure of fluconazole prophylaxis to reduce mortality or the requirement of systemic amphotericin B therapy during treatment for refractory acute myeloid leukemia: results of a prospective randomized phase III study. German AML Cooperative Group.

BACKGROUND: Invasive fungal infections have increasingly become a matter of concern with regard to patients receiving intensive myelosuppressive therapy for hematologic malignancies. Such infections, especially prolonged neutropenia systemic fungal infections, may contribute substantially to infectious complications and early death. Measures for early detection and effective prophylactic strategies using active and nontoxic antifungal agents are therefore urgently needed. METHODS: The current randomized study was initiated to assess the efficacy of oral fluconazole as systemic antifungal prophylaxis for high risk patients with recurrent acute myeloid leukemia undergoing intensive salvage therapy. RESULTS: Of 68 fully evaluable patients, 36 were randomized to fluconazole in addition to standard prophylaxis with oral co-trimoxazol, colistin sulphate, and amphotericin B suspension, and 32 were randomized to standard prophylaxis only. No major differences between the two groups were observed in the number of episodes of fever of unknown origin (61% vs. 50%) or clinically defined infections (56% vs. 50%). Microbiologically defined infections were more frequent in the fluconazole group (50% vs. 31%), mainly due to a higher incidence of bacteremias (42% vs. 22%). There were two cases of proven invasive fungal infections in each group. Systemic amphotericin B was administered more frequently to patients receiving fluconazole prophylaxis (56% vs. 28%). Fluconazole prophylaxis had no impact on the rate of early death or overall survival. CONCLUSIONS: For patients with high risk recurrent acute myeloid leukemia undergoing intensive salvage therapy, antifungal prophylaxis with fluconazole was not superior to standard prophylaxis only.

Acute Disease↗
PubMed1998

Granulocyte colony-stimulating factor shortens duration of critical neutropenia and prolongs disease-free survival after sequential high-dose cytosine arabinoside and mitoxantrone (S-HAM) salvage therapy for refractory and relapsed acute myeloid leukemia. German AML Cooperative Group.

Patients with primary refractory or relapsed acute myeloid leukemia (AML) who undergo intensive salvage chemotherapy carry a high risk of treatment failure due to infectious complications and early relapses. The study presented here assessed the effect of granulocyte colony-stimulating factor (G-CSF) on the duration of post-treatment neutropenia, the incidence of infection-related deaths, and the disease-free and overall survival. Sixty-eight evaluable patients with relapsed and refractory AML received G-CSF 5 microg/kg per day subcutaneously starting 2 days after the completion of salvage treatment with the S-HAM regimen, consisting of high-dose cytosine arabinoside twice daily on days 1, 2, 8, and 9 and mitoxantrone on days 3, 4, 10, and 11. Ninety-one patients who were treated with the identical S-HAM regimen but without G-CSF support during a preceding study served as controls. The application of G-CSF resulted in a significant shortening of critical neutropenia of less than 500 microl (36 vs. 40 days; p = 0.008), which translated into a trend towards a lower early death rate (21% vs. 30%) and an increase of complete remissions (56% vs. 47%, p=0.11). In patients younger than 60 years a significant prolongation of time to treatment failure (159 vs. 93 days, p=0.038) and of duration of disease-free survival (203 vs. 97 days, p=0.003) was observed. These results indicate a beneficial effect of G-CSF on early mortality as well as on long-term outcome when administered after S-HAM salvage therapy for advanced AML.

Acute Disease↗
PubMed1998

Superiority of high-dose over intermediate-dose cytosine arabinoside in the treatment of patients with high-risk acute myeloid leukemia: results of an age-adjusted prospective randomized comparison.

Although cytosine arabinoside (AraC) represents the most effective single agent in the treatment of adults with acute myeloid leukemia (AML) when given at doses exceeding 200 to 500 mg per application, its optimal dosage is still a matter of controversial discussion. While pharmacokinetic investigations suggest that the AraC-activating enzyme deoxycytidine kinase is saturated at drug concentrations achieved by short-term infusion of 0.5 to 1.0 g/m2 AraC and that higher doses are therefore not more effective, recent evidence indicates that additional mechanisms of AraC cytotoxicity may exist which could be enhanced by further dose escalation. In order to test this thesis in the clinical setting, a prospective randomized comparison of high-dose (HD-AraC) vs intermediate-dose (ID-AraC) AraC was carried out in patients with refractory or relapsed AML on the basis of the sequential high-dose AraC and mitoxantrone regimen (S-HAM). AraC was given as a 3-h infusion q 12 h on days 1, 2, 8 and 9. Patients younger than 60 years were randomized to AraC doses of 3.0 g/m2 vs 1.0 g/m2 while older patients received either 1.0 g/m2 or 0.5 g/m2 per single dose. Mitoxantrone was given to all patients on days 3, 4, 10 and 11 at a daily dose of 10 mg/m2. Randomization was stratified for primary refractoriness against induction therapy and length of first remission in relapsed patients. From 186 evaluable patients, 88 (47%) and 10 cases (5%) achieved a complete (CR) or partial (PR) remission, 39 patients (21%) had persisting leukemia (non-response (NR)), and 49 cases (26%) died within 6 weeks after the start of therapy (early death (ED)). In patients younger than 60 years the higher dose level resulted in a significant reduction of NR (12% vs 31%; ordinal chi2 test: P = 0.01) but also a higher rate of ED (32% vs 17%) thus leading to a marginally higher CR rate only (52% vs 45%). Within the subgroup of patients with refractory AML the tendency towards a higher CR rate after HD-AraC was more pronounced (46% vs 26%; P = 0.045). In patients older than 60 years, corresponding though less evident differences were observed with a higher rate of NR in the lower dose group (26% vs 16%) and ED occurring more frequently after higher doses (36% vs 26%). These data indicate that HD-AraC reveals a significantly higher antileukemic efficacy than ID-AraC as expressed by a significant reduction of failure from NR. This advantage, however, does not fully translate into an increase in remission rate due to a higher incidence of ED after HD-AraC predominantly from uncontrolled infections. In order to take full advantage of the higher antileukemic activity of HD-AraC an improvement of supportive care and infection control is warranted.

Acute Disease↗
PubMed1998

Oral cytarabine ocfosfate in acute myeloid leukemia and non-Hodgkin's lymphoma--phase I/II studies and pharmacokinetics.

Cytosine arabinoside (AraC) is rapidly inactivated via systemic deamination with half-lives ranging from 1 h (i.v.) to 4 h (s.c.) -- and cannot be applied orally due to its hydrophilic properties. These limitations might be overcome by YNK01 -- a lipophilic prodrug of AraC -- that is resistant to deoxycytidine deaminase and can be applied orally. In the present study the therapeutic activity, side-effects and pharmacokinetics of YNK01 were evaluated in a phase I/II study including patients with relapsed or refractory acute myeloid leukemia (AML) (n=23) or low-grade non-Hodgkin's lymphoma (NHL) (n=20). YNK01 was given by 14 day cycles with escalating doses starting with a daily dose of 50 mg/m2 (equivalent to 20 mg/m2 AraC on a molar basis). The maximum tolerated dose was reached at the 600 mg/m2 dose level with WHO grade 3-4 diarrhoea as the main toxicity. In the 23 patients with AML two complete remissions, four partial remissions and three patients with stable disease were observed. In the 23 patients with AML two complete remissions, four partial remissions and three patients with NHL two cases reached partial remission and six other patients mainained stable disease. Pharmacokinetic evaluations were performed during 34 treatment cycles in 28 patients. The data suggest that YNK01 was absorbed in the distal part of the small intestine and taken up into hepatocytes. After hepatic psi and subsequent beta-oxydation of YNK01 the released AraC (and its deamination product AraU) appeared in the systemic circulation. Time of maximum concentration (h), half-life (h) and area under the curve (ng x h/ml, at the 1200 mg dose level) were as follows (VC variation coefficient) YNK01: 1.0 (0.58), 10.1 (0.43), 12622 (0.65); AraC: 23.2 (0.57), 22.6 (0.36), 3496 (0.76); AraU: 19.2 (0.58) 22.3 (0.33) 15441 (0.66). Of the total dose of YNK01 15.8% was absorbed and metabolized to AraC and AraU, defining the metabolic bioavailability of this prodrug. A linear relationship was observed between YNK01 dose and YNK01 AUC and AraC AUC over the whole dose range tested. AraC was released from hepatocytes over a prolonged period of time resulting in long lasting plasma levels similar to a continuous i.v. infusion. After administration of YNK01 at a dosage of 100-150 mg/m2 plasma levels of AraC were comparable to those achieved after low-dose AraC treatment (20 mg/m2) while at doses of YNK01 of 450-600 mg/m2 concentrations of standard-dose AraC (100 mg/m2) were obtained. We conclude that YNK01 shows considerable activity against relapsed and refractory AML and NHL and that its pharmacokinetic properties offers advantages in comparison to (standard) i.v. or s.c. AraC in clinical practice.

Acute Disease↗
PubMed1998

Combination of aclarubicin and etoposide for the treatment of advanced acute myeloid leukemia: results of a prospective multicenter phase II trial. German AML Cooperative Group.

In order to develop new strategies for the treatment of relapsed or refractory acute myeloid leukemia, the German AML Cooperative Group performed a prospective multicenter phase II study to evaluate the antileukemic efficacy of aclarubicin 60 mg/m2/day and etoposide 100 mg/m2/day each given for 5 days. Of 37 heavily pretreated evaluable patients (median age 42 years, range 18-81) 15 (40%) achieved a remission after one or two courses of treatment consisting of nine complete (24%) and six partial remissions (16%). Fourteen (38%) cases were non-responders and eight (22%) patients suffered from early deaths. Disease-free survival for patients in remission and overall survival were 3.2 months each. The median duration of critical neutropenia <500/microl was 27 days. The most frequent non-hematologic side-effects were stomatitis (WHO III/IV, 48%), infections (40%), nausea/vomiting (26%) and diarrhea (24%). Cardiac toxicity was mild. This study suggests a substantial antileukemic efficacy and an acceptable toxicity of aclarubicin in combination with etoposide in heavily pretreated patients with advanced acute myeloid leukemia, and warrants further evaluations in a more favorable stage of the disease.

Aclarubicin↗
PubMed1997

High antileukemic activity of sequential high dose cytosine arabinoside and mitoxantrone in patients with refractory acute leukemias. Results of a clinical phase II study.

BACKGROUND: The current study was initiated to assess the efficacy and side effects of a timed sequential application of high dose cytosine arabinoside (AraC) in combination with mitoxantrone (S-HAM) in patients with refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). METHODS: Patients with refractory AML or ALL were eligible for S-HAM salvage therapy, which was comprised of AraC, 1 g/m2 or 3 g/m2 every 12 hours, on Days 1, 2, 8, and 9 and mitoxantrone, 10 mg/m2/day, given on Days 3, 4, 10, and 11. RESULTS: Of 22 fully evaluable patients, 14 patients (64%) achieved a complete remission whereas 5 patients (23%) succumbed to early death and 3 patients (14%) did not respond. Blood counts recovered at a median of 33.5 days after the start of treatment and complete remission was achieved after a median of 38 days. The median duration of complete remission was 4 months (range, 1-14 months) whereas overall survival time lasted for a median of 4.5 months (range, 1-30+ months). Treatment-associated toxicity was comprised predominantly of infection and diarrhea that reached World Health Organization Grades 3 and 4 in 64% and 32% of patients, respectively. Complementary pharmacokinetic evaluations of plasma AraC and AraU levels revealed no impact of initial AraC administration on the pharmacokinetics of subsequent AraC administrations and failed to demonstrate any evidence of self-potentiation. CONCLUSIONS: The clinical data show the S-HAM regimen to be a promising approach for the treatment of patients with advanced acute leukemias. However, further evaluation at earlier stages of treatment is needed.

Acute Disease↗
PubMed1997

Frequency and causes of refractoriness in multiply transfused patients.

The use of leukocyte-depleted blood components has become the standard therapy for multiply transfused patients during the past few years, as a measure to reduce the frequency of alloimmunization and refractoriness. We assessed frequency and causes of refractoriness, defined as a repeated 24-h post-transfusion platelet count below 20,000/microliters, in 145 consecutive patients who received three or more single-donor platelet concentrates during a 1-year period. Flow-cytometric detection of anti-platelet antibodies and a glycoprotein-specific ELISA were applied for the diagnosis of alloimmunization. Forty patients (27.6%) had at least one episode of refractoriness. In 25 of these 40 patients (62.5%), nonimmune factors (fever, sepsis, coagulopathy, splenomegaly) alone were the cause. In 15 refractory patients alloantibodies were detected. In seven patients (17.5%), alloimmunization alone caused an inadequate transfusion response, while in eight refractory patients (20.0%) alloimmunization and fever or sepsis were present. HLA antibodies were detected in 17 patients (11.7%); three patients (2%) had platelet-specific antibodies in addition to HLA antibodies; in two patients panreactive platelet antibodies were detectable. All 17 patients had a history of previous transfusions or pregnancy. We did not observe primary immunization in patients transfused exclusively with filtered (leukodepleted) blood products. Our data suggest that alloimmunization in patients with a negative risk history can be prevented by the exclusive use of leukodepleted blood components.

Antigens, Human Platelet↗
PubMed1997

Cell surface characterization of T lymphocytes and allergen-specific T cell clones: correlation of CD26 expression with T(H1) subsets.

To evaluate the possibility of using surface molecules as markers for human T helper cell subsets, we studied the expression of surface molecules on T cell clones (TCCs) specific for the major birch pollen allergen, Bet v 1. No difference in the expression of the respective receptors for interferon-gamma (IFN-gamma), IL-4, IL-6, or IL-10 could be detected on T(H) subsets, nor did CD25 expression (IL-2R alpha-chain) differ significantly. However, high expression of CD26 antigen (dipeptidyl peptidase IV) correlated with a T(H1)/T(H0)-like phenotype, whereas T(H2)-like clones displayed a lower expression of CD26 antigen. Comparing cytokine production and CD26 expression simultaneously, we found a correlation between the IL-4/IFN-gamma ratio and the density of CD26 per cell. We could show that the amount of IL-4 secretion, and not of IFN-gamma secretion, was responsible for this correlation. To evaluate whether CD26 antigen expression is regulated by stimuli inducing a T(H1)- or T(H2)-like phenotype, peripheral blood mononuclear cells (PBMC) were cultured in the presence of IL-4, IFN-gamma, and IL-12, respectively. Incubation with IL-4 led to T cells with a T(H2)-like cytokine pattern and a significantly lower expression of CD26; IFN-gamma and IL-12 led to a T(H1) shift associated with an increased expression of CD26 on CD4+ T cells. By means of intracellular cytokine detection we analyzed expression of CD26 on CD4+ PBMC stimulated to produce IFN-gamma or IL-4 on a single cell level. All activated, cytokine-producing CD4+ T cells expressed CD26, but the increase in CD26 expression was higher in cells producing IFN-gamma. These data suggest that regulation of CD26 cell surface expression correlates with the production of T(H1)-like cytokines.

Allergens↗
PubMed1997

Evidence for central nervous effects of corticotropin-releasing hormone on gastric acid secretion in humans.

In animals, corticotropin-releasing hormone (CRH) has been shown to decrease gastric acid secretion after intracerebral administration. Evidence exists that in man peptides have a direct access to the brain upon intranasal administration. This study aimed at assessing brain-mediated effects of CRH on gastric pH after intranasal administration in humans. Eleven healthy men were tested on 2 occasions in a double-blind within-subject cross-over comparison during treatment with CRH (versus placebo) administered intranasally at a dose of 20 micrograms every 10 min. Gastric pH values were measured continuously by a gastral pH tube. After 2 h of intranasal treatment, 6 micrograms/kg pentagastrin was injected subcutaneously. The subject's mood was assessed by an adjective list (EWL-N) at the end of each experimental condition. Intranasal CRH increased pH baseline values from (mean +/- SE) 1.70 +/- 0.31 to 2.62 +/- 0.53 (corresponding to 54%), whereas during intranasal treatment with placebo pH values remained unchanged (p < 0.05). After injection of pentagastrin, pH values decreased to 0.73 +/- 0.04 during placebo and to 0.93 +/- 0.14 during CRH treatment (n.s.). During treatment with CRH, subjects felt less tired (p < 0.05) and deactivated (p < 0.05). Plasma cortisol and CRH levels were not affected by intranasal CRH, excluding mediation of the CRH effects via resorption into the bloodstream, and TSH levels were slightly decreased by the end of the treatment. Results confirm the notion of a pathway for CRH from the nose to the brain, initiating, via central nervous mechanisms, inhibition of gastric acid secretion and a change of mood in humans.

Adolescent↗
PubMed1997

Oral idarubicin pharmacokinetics--correlation of trough level with idarubicin area under curve.

Idarubicin is the first anthracycline that can be successfully administered via the oral route and thus may facilitate antineoplastic chemotherapy in an improved quality of life. These perspectives are somewhat hampered by the large variation in bioavailability between individual patients and the obvious requirement to monitor plasma concentration and area-under-the-curve values (AUC) for an appropriate adjustment of idarubicin dose. In this study we describe the pharmacokinetics of idarubicin and its main metabolite idarubicinol in 12 patients after oral application of 20 mg/m2 idarubicin on 3 consecutive days and demonstrate that the 24 h trough levels show a high correlation with AUC and may thus allow a rapid and easy determination of individual drug concentrations and an appropriate dose adjustment. The average terminal half-life was 30.5 h for idarubicin and 66.9 h for idarubicinol. The AUC for idarubicin and its main metabolite idarubicinol revealed a substantial interpatient variation with AUC values ranging from 25.7 to 114 ng x h/ml (average 58.1 ng x h/ml) for idarubicin and from 109.4-445.2 ng x h/ml (average 287.3 ng x h/ml) for idarubicinol. However, the ratio of idarubicin/idarubicinol differed only two folds from 1:3.7 to 1:7.7 with an average of 1:5.1. Both idarubicin and idarubicinol concentrations were highly reproducible, however, upon measurements after repeated applications within individual patients. Moreover, idarubicinol and idarubicin AUCs showed a good correlation with r = 0.78, indicating that the interindividual variation of idarubicin AUC reflects differences in absorption rather than in metabolism. In order to describe the interindividual bioavailability of idarubicin - represented by the respective AUC - measurement of a single data point with a high correlation with the AUC would be ideal. Our study demonstrates that the 24 h trough level shows such an excellent correlation (r = 0.96) with AUC, making it the perfect candidate for fast estimates of the individual bioavailability in a given patient. On this basis, the longitudinal measurement of the 24 h trough level may allow assessment of the impact of interindividual variations in AUC on clinical outcome and toxicity.

Administration, Oral↗
PubMed1996

Response to cytarabine ocfosfate (YNK01) in a patient with chronic lymphocytic leukemia refractory to treatment with chlorambucil/prednisone, fludarabine, and prednimustine/mitoxantrone.

Cytarabine ocfosfate (YNK01) is a novel orally applicable prodrug of cytosine arabinoside. Recent pharmacokinetic studies have revealed a prolonged release of the cytotoxic agent cytosine arabinoside (araC) from hepatocytes into the systemic circulation, resulting in a half-life of approximately 24 h for araC. The specific pharmacokinetic characteristics of cytarabine ocfosfate lead to a prolonged exposure of leukemic cells to this antineoplasstic agent during the 14-day cycle. the oral applicability during outpatient treatment and the sustained antineoplastic activity of araC against slowly proliferating leukemic B-cells suggest that cytarabine ocfosfate might be a useful drug in the treatment of chronic lymphocytic leukemia. Four years after diagnosis of B-CLL, a 50-year-old patient was started on cytarabine ocfosfate. Sequentially, the patient's disease had proved refractory to treatment with chlorambucil/prednisone (31 months), fludarabine (5 months), and prednimustine/mitoxantrone (3 months). These established regimens were discontinued because of increasing lymphocytosis, significant thrombocytopenia, and progressive B-symptoms. Following three cycles of cytarabine ocfosfate B-symptoms resolved, lymphadenopathy disappeared, and thrombocytopenia was significantly reduced. The patient has been free of these symptoms on a dosage of 1500 mg cytarabine ocfosfate/day (cycle of 14 days with intervals of 14-21 days) for 24 months and remains in an ongoing partial remission.

Administration, Oral↗
PubMed1996

A nose-brain pathway for psychotropic peptides: evidence from a brain evoked potential study with cholecystokinin.

The access of substances to the brain is of particular relevance for the etiology and treatment of psychiatric and neurologic diseases. This study provides functional evidence for a direct access of peptides to the human brain after intranasal administration. Effects were compared of intranasal (IN, 10 micrograms) and intravenous (i.v., 0.25 and 2.5 micrograms) administered cholecystokinin-8 (CCK) on the auditory event related potential (AERP) in 20 healthy subjects. Also, plasma concentration of cortisol and ACTH were monitored. The study was designed as a placebo-controlled, double-blind within-subject cross-over comparison. AERPs were recorded while the subject performed on an attention task (oddball task). Plasma CCK concentrations after IN administration of CCK were comparable to those after i.v. administration of 0.25 microgram CCK, but were substantially lower than those after 2.5 micrograms CCK. The P3 complex of the AERP was markedly increased following the IN administration of CCK (p < .01) compared to placebo and to the i.v. administration of 0.25 microgram. This pattern was more obvious in women than men. Increases in plasma ACTH concentrations after CCK reached significance selectively following the IN mode of administration (p < .01).

Administration, Intranasal↗