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Reducing the workload of the beta cell by inhibiting insulin secretion may provide beneficial effects for patients with type 2 diabetes. The aim of this study was to investigate the effect of NN414, a beta cell selective potassium channel opener in patients with type 2 diabetes. 24 patients were treated for seven days (placebo, 1.5, 4.5, and 10 mg/kg). In accordance with the pharmacological profile a significant and selective inhibition of insulin secretion was observed (1 h post dose). There were no statistically significant effects on overall glycaemic control. Based on OGTT derived parameters a borderline significant improvement in beta-cell function (1st and 2nd phase insulin secretion) was observed from Day 1 to Day 7.

Background: Controlled clinical trials have shown efficacy of high-dose ciprofloxacin for hospital-acquired (HAP) or nosocomial pneumonia. But it has yet to be demonstrated whether this good efficacy also holds true for routine intensive-care patients outside of controlled trials., Patients: In a post-marketing surveillance study at 87 intensive-care units in Germany we analyzed 676 cases of nosocomial pneumonia treated with intravenous ciprofloxacin in a daily dosage of at least 400 mg., Results: 538 (80 %) patients were evaluable for efficacy. Cure or improvement was reported in 76 % of the cases. Clinical success rate was higher in previously untreated patients receiving ciprofloxacin as monotherapy (85.3 %) or in combination with other antibiotics (78.4 %) than in those who received ciprofloxacin as monotherapy (73.1 %) or as combination therapy (69.2 %) after an antibiotic pretreatment. In the 66 patients with Pseudomonas aeruginosa as causal pathogen, clinical success rate was 86.4 %. 32 adverse events classified as possibly or probably related to ciprofloxacin occurred in 3.1 % of patients; all of those were reversible., Conclusions: Due to the high success rate, even in cases with failed antimicrobial pretreatment, and the favourable risk-benefit ratio of high-dose ciprofloxacin, ciprofloxacin appears to be an attractive choice in the empiric treatment of hospital-acquired pneumonia.

Gemifloxacin is a novel fluoroquinolone, currently in development for the treatment of respiratory tract infections. This double-blind (with respect to gemifloxacin), randomized, crossover study investigated the possibility of pharmacokinetic interaction between gemifloxacin and theophylline. After a 4-8-day run-in phase to establish the dose of theophylline required to achieve a trough plasma concentration range of 8-15 mg/l, 15 healthy volunteers entered a randomized treatment phase. Volunteers then received oral theophylline, 300-400 mg twice daily, for 22 days. On days 5-11 and 16-22, they also received either placebo or gemifloxacin, 320 mg p.o. once daily, in a crossover fashion. Blood samples were collected up to 12 h after the morning dose of theophylline on days 11 and 22. Theophylline pharmacokinetics were not affected by the co-administration of gemifloxacin. The maximum plasma concentration (C(max)) for theophylline ranged from 8.12 to 17.71 mg/l and from 8. 79 to 16.35 mg/l during concomitant administration with gemifloxacin and placebo, respectively. The corresponding ranges of the area under the plasma concentration-time curve from time zero to the last quantifiable plasma concentration (AUC((0-12))) were 84.6-177.5 mg. h/l and 94.8-165.1 mg.h/l during gemifloxacin and placebo administration, respectively. The point estimates (90% confidence intervals) for dose-normalized AUC((0-12)) and C(max) (theophylline + gemifloxacin):(theophylline + placebo) were 0.99 (0.93, 1.05) and 1.02 (0.93, 1.11), respectively, which were entirely within the equivalence range (0.80, 1.25). The co-administration of gemifloxacin and theophylline was well tolerated, with no clinically significant changes seen in vital signs, 12-lead electrocardiogram readings or laboratory parameters. Adverse events were generally transient, mild to moderate in nature and similar during the gemifloxacin and placebo treatment periods. In conclusion, theophylline and gemifloxacin may be co-administered without any adjustment in theophylline dose., (Copyright 1999 S. Karger AG, Basel.)

Background and Objectives: Omeprazole is an inducer of human cytochrome P450 1A (CYP1A) enzymes, but shows inhibitory effects on CYP2C19 and CYP3A4. In this study, a potential inhibitory effect of omeprazole on caffeine metabolism, a validated CYP1A2 marker, was examined., Methods: A randomized, balanced crossover single-dose study was conducted in 16 healthy volunteers comprising 12 extensive (EM) and 4 poor metabolizers (PM) for CYP2C19. All volunteers received a 40 mg omeprazole dose or placebo 0.5 h prior to caffeine 3 mg/kg body weight. Six EMs were re-tested with 80 mg of omeprazole. In vitro, effects of omeprazole on caffeine N3-demethylation were determined in human liver microsomes., Results: In vivo, non-parametric point estimates (90% confidence intervals) for the ratios of caffeine pharmacokinetics with/without co-administration of the 40 mg omeprazole dose were: AUC 1.08 (1.04 - 1.13), MRT 1.09 (0.99 - 1.19), and plasma ratio of paraxanthine/caffeine 6 h post-dose 0.91 (0.80 - 1.00). Inhibition of caffeine N3-demethylation by omeprazole was slightly more pronounced in PM than in EM of CYP2C19. Estimates for the 80 mg omeprazole dose were: AUC 1.12 (1.05 -1.18), MRT 1.18 (1.07 - 1.30), and paraxanthine/caffeine ratio 0.83 (0.74 -0.94). In vitro, omeprazole was mainly a competitive CYP1A2 inhibitor with K(i) values of around 150 microM., Conclusions: Omeprazole exerts a concentration-dependent inhibition of CYP1A2 activity in man. However, even after single oral doses up to 80 mg, this effect is weak and without clinical relevance.

Gemifloxacin is a novel fluoroquinolone with a broad spectrum of activity. This double-blind, randomized, parallel-group study was designed to demonstrate the lack of effect of steady-state concentrations of gemifloxacin on the pharmacodynamic effects of warfarin. Healthy male subjects received loading doses of warfarin on days 1 and 2. The warfarin dose was freely titrated until day 10, with the aim of achieving a stable international normalized ratio (INR) for prothrombin time within the range 1.3-1.8 by day 14. On days 14-24 the dose of warfarin was fixed. On days 18-24, subjects also received 320 mg of gemifloxacin or matched placebo, once daily. Thirty-five subjects entered into and completed the co-administration phase of the study. The mean (standard deviation) baseline INR (mean of days 16-18) and INR for day 24 for gemifloxacin plus warfarin were 1.52 (0.12) and 1.46 (0.15), respectively. Corresponding values for placebo plus warfarin were 1. 46 (0.11) and 1.42 (0.17). The point estimate (90% confidence interval) for the difference in day 24 INR, adjusted for baseline, between gemifloxacin and placebo was 0.02 (-0.08, 0.12), which translates to an INR (relative to placebo least squares mean of 1.43) of 1.02 (0.95, 1.09). The 90% confidence interval for the difference in INR between the gemifloxacin and placebo groups was completely contained within the 25% equivalence range. There were no changes of clinical significance in vital signs, 12-lead electrocardiogram readings or laboratory parameters for any subject during the co-administration phase of the study, and no adverse experiences relating to coagulation were reported during this period. It is concluded that the pharmacodynamic effects of warfarin are not affected by gemifloxacin, and therefore both drugs can be co-administered without dosage adjustment., (Copyright 1999 S. Karger AG, Basel)

Objectives: Valspodar is a P-glycoprotein modulator currently under development as a multidrug resistance reversal agent in clinical oncology. A multiple-dose drug interaction study was performed to assess the influence of valspodar on digoxin, a substrate for P-glycoprotein., Methods: Twelve healthy volunteers received an oral digoxin loading dose of 1 mg on day 1, followed by 0.125 mg once daily to day 11. On day 7, a single oral 400-mg dose of valspodar was given, followed by a regimen of 200 mg twice daily from days 8 to 11. Serial blood samples and urine collections were obtained on days 6, 7, and 11 for digoxin pharmacokinetics and on days 7 and 11 for valspodar pharmacokinetics. On these days, blood pressure, pulse rate, and electrocardiograms were recorded at multiple time points., Results: Coadministration of single-dose valspodar with steady-state digoxin on day 7 yielded an average 76% increase in digoxin AUC and a 62% decrease in digoxin renal clearance (both P = .0001). After a 5-day coadministration period, digoxin AUC increased by an average 211% and apparent total body clearance was decreased by 67% (day 11) compared with steady-state administration of digoxin alone (day 6). Contributing to the change in total body clearance were decreases in both renal clearance (73%) and apparent nonrenal clearance (58%). Both drugs were well tolerated throughout the study. There was no clinically relevant change in the effect of digoxin on vital signs or electrocardiographic parameters when administered with single- or multiple-dose valspodar compared with administration alone in volunteers with healthy cardiovascular systems., Conclusions: Coadministration of oral valspodar and oral digoxin resulted in a twofold to threefold increase in digoxin systemic exposure. On the basis of these data in healthy volunteers, an initial digoxin dose reduction of 50% would appear to be appropriate when beginning oral valspodar treatment. Throughout the period of coadministration, patients should be carefully monitored for clinical signs of digoxin toxicity in conjunction with digoxin therapeutic drug monitoring. Together, these should serve as the basis for individualized digoxin dose titration.

Objective: Thymosin alpha1, an immunomodulatory endogenous peptide, has been shown to be effective in the treatment of chronic hepatitis B and C. In this study, single- and 5-day multiple-dose pharmacokinetics were characterized in nine Caucasian volunteers after subcutaneous administration of 900 microg/m2 thymosin alpha1., Methods: Using a randomized, 3-way crossover design three available drug formulations were compared: Zadaxin (SciClone), Timosina (Sclavo), and Thymosin alpha1 (Tal-HLR; Hoffmann La Roche). AUC, Cmax, t(max), t(1/2), Cl/f, and the volume of distribution, V(Z)/f, were derived by model-independent methods., Results: Endogenous serum concentrations were below the limit of quantification (0.10 microg/l) of the enzyme-linked immunosorbent assay method in most subjects. Thymosin alpha1 was well absorbed with a mean t(max) between 1-2 hours from all galenic formulations. Cmax concentrations of 30 to 80 microg/l and AUC(0-infinity) from 95 to 267 microg x h/l did not differ between single- and multiple-dose administration of all drugs. This apparent lack of accumulation was supported by the short elimination half-life of less than 3 hours. As indicated by a V(Z)/f in the range of 30-40 l, thymosin alpha1 appears to distribute within the extracellular volume. AUC and Cmax were similar for Zadaxin and T alpha1-HLR, but higher after administration of Timosina., Conclusion: Thymosin alpha1 kinetics from this study are comparable to those previously obtained in Japanese volunteers or cancer patients, but may be influenced by the drug formulation used.

Lansoprazole has been shown to induce cytochrome P450 1A (CYP1A) and CYP3A enzymes in human hepatocytes in vitro. In this study, urinary excretion of 6 beta-hydroxycortisol (6 beta-OHF) and D-glucaric acid (D-GA) were used to investigate the potential enzyme-inducing property of lansoprazole in vivo. Twenty-four healthy female volunteers (aged 19-35 years), who were taking oral contraceptives containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel, were randomized in a cross-over design for the treatment with either 60 mg lansoprazole or placebo once daily during 2 subsequent menstrual cycles. Urinary excretion rates of 6 beta-OHF and D-GA were measured at days 14 and 21 of the menstrual cycles. Median pretreatment urinary excretion of 6 beta-OHF (212 and 218 micrograms/d, n = 24) and D-GA (20.1 and 32.7 mumol/d) did not significantly differ. Upon treatment median excretion of 6 beta-OHF was 255 and 241 micrograms/d (n = 23), and that of D-GA was 25.5 and 33.8 mumol/d, respectively. Thus, the relatively high dose of 60 mg/d lansoprazole failed to statistically significantly alter urinary excretion of 6 beta-OHF and D-GA, indicating that therapeutic doses of lansoprazole might not exhibit a phenobarbital-like induction in vivo.

Caffeine is used to phenotype subjects in vivo for the cytochrome P450 isoforms CYP1A2 and CYP2E1, and for N-acetyltransferase type 2 (NAT2). However, how much of the variation in phenotyping parameters may be attributed to variations in CYP1A2 and CYP2E1 activities has not been determined. Therefore, this study intraindividually compared enzyme activities and/or content in liver samples with pharmacokinetic parameters of caffeine in vivo after administration of a test dose in 25 patients undergoing hepatectomy. Parameters measured in vitro were the high affinity components of caffeine 3-demethylation and phenacetin 0-deethylation, microsomal CYP1A2 and CYP2E1 immunoreactivity, and cytosolic sulfamethazine N-acetylation. Caffeine parameters in vivo included caffeine clearance from plasma and/or saliva, paraxanthine/caffeine ratios in plasma and saliva, plasma theophylline/caffeine ratio, and several metabolite ratios from spot urine sampled 6 h postdose. Correlations between parameters were determined using weighted linear regression analyses. Caffeine clearance and paraxanthine/caffeine ratios correlated most highly to intrinsic clearance of caffeine 3-demethylation and to CYP1A2 immunoreactivity (r= 0.584-0.82), whereas urinary CYP1A2 ratios correlated less strongly with CYP1A2 parameters in vitro. Assignment of acetylator phenotype by urinary NAT2 ratios was concordant with sulfamethazine-N-acetylation in vitro. In contrast to CYP1A2 parameters in vitro, CYP2E1 immunoreactivity was not related to the theophylline/caffeine plasma ratio. CYP1A2 activity, thus, is the major determinant of caffeine clearance and the paraxanthine/caffeine ratios in vivo, of which the saliva ratio 6 h postdose appears as the most advantageous parameter. The results confirm that phenotyping using caffeine provides valid estimates of CYP1A2 and NAT2 activity.

Background/aims: The kinetics of omeprazole and its primary metabolites 5'-hydroxyomeprazole and omeprazole sulfone were studied in healthy volunteers to evaluate omeprazole as a probe drug for the S-mephenytoin hydroxylase (CYP2C19) polymorphism. The plasma metabolic ratio obtained from the concentrations of omeprazole plus omeprazole sulfone over 5'-hydroxyomeprazole was investigated., Methods: The time course of the omeprazole metabolic ratio was studied in 14 extensive metabolizers, one intermediate, and five poor metabolizers of CYP2C19 after a 1-week administration of 40 mg/d omeprazole. The ratio was then determined in 187 randomly selected Caucasian hospital patients and analyzed according to liver disease and co-medication., Results: Between 1 and 4 h after omeprazole intake, the volunteers phenotyped by the urinary S/R-mephenytoin ratio were reliably identified as extensive metabolizers and poor metabolizers by an omeprazole metabolic ratio-antimode of 12. This antimode remained valid in eight extensive metabolizers and one poor metabolizer, who were re-investigated with 60 mg omeprazole b.i.d. for one week. Among 30 patients without concomitant drug intake, only one poor metabolizer (3.3%) was identified by both the S/R-mephenytoin ratio and omeprazole metabolic ratio. However, 30 of 47 patients with liver disease and 20 of 110 co-medicated patients without liver disease had a ratio > 12. This highly exceeded the poor metabolizer frequency of 3-4% in Caucasians., Conclusions: Like other phenotypic tests, the omeprazole metabolic ratio appears to reflect CYP2C19 genotype reliably only in individuals without liver disease or co-medication. The omeprazole metabolic ratio may serve the double purpose of phenotyping for CYP2C19 and to individualize dosing in omeprazole-treated patients.

S-Mephenytoin 4'-hydroxylase (CYP2C19) is a genetically polymorphic cytochrome P450. A modified method for CYP2C19 phenotyping was evaluated in 174 healthy German volunteers and the results were compared with genotyping for the intron4/exon5 G-->A splice site mutation (m1) of CYP2C19, associated with the poor metabolizer (PM) phenotype. A smaller than usual test-dose of 50 mg (R,S)-mephenytoin was used and urine samples were collected from 0 to 5 h and from 5 to 8 h after administration. Trait measurements included the mephenytoin S/R enantiomeric ratio and the hydroxylation index (i.e. the molar ratio of 4'-hydroxy-mephenytoin urinary recovery to the administered S-mephenytoin dose). S- and R-mephenytoin were quantified by isocratic HPLC with a Chiraspher column and 80% n-hexane and 20% dioxane as the mobile phase. All individuals from whom DNA was available (n = 140, including six phenotypically identified PMs) were analysed for the m1 mutation. The population frequency of this CYP2C19 mutation was 0.15. Four individuals were homozygous for m1 having S/R ratios of 0.9 or greater in both intervals of urine collection. Thus, individuals with an S/R ratio > or = 0.9 were classified as PMs and seven of all 174 phenotyped individuals were PMs (4%; 95% confidence limits: 1.6-8.1%). Heterozygous carriers of m1 (n = 34) had a median S/R ratio (5-8 h urine) of 0.06 compared to 0.01 in individuals without this mutation (n = 102; p = 0.0005, Mann-Whitney U-test). No such gene-dose relation was apparent with the hydroxylation index.(ABSTRACT TRUNCATED AT 250 WORDS)

Omeprazole induces hepatic cytochrome P-4501A2. In a previous study this effect was shown to be significant in vivo in 6 poor metabolizers, including 1 intermediate metabolizer, but not in 12 extensive metabolizers of S-mephenytoin after 7 days of treatment with 40 mg/day omeprazole. In this study, the specificity of the inducing potential of omeprazole was investigated in these volunteers. Furthermore, in eight of the extensive metabolizers the dose-dependence of cytochrome P-450 1A2 induction was evaluated. Cytochrome P-450 1A2 activity was monitored by means of the 13C-[N3-methyl]caffeine breath test and by means of plasma caffeine clearance before omeprazole treatment with 120 mg/day, on the seventh day of dosage and after a 7-day washout. Omeprazole plasma concentration was measured. Results were compared with those after 40 mg. gamma-Glutamyltransferase activity in serum, as well as urinary excretion of D-glucaric acid and 6 beta-hydroxycortisol, were measured on the same study days in all study groups (n = 26). In the eight extensive metabolizers the breath test indicated a dose-dependent increase of cytochrome P-450 1A2 activity of 8.5% +/- 15.0% (40 mg, mean +/- SD, NS) and 27.2% +/- 16.5% (120 mg, p = 0.002). Caffeine clearance was increased by 31.6% +/- 20.7% (p < 0.001) with the higher dose. None of the study groups exhibited a significant increase of gamma-glutamyltransferase activity or urinary excretion of D-glucaric acid or 6 beta-hydroxycortisol. This was in contrast to the phenobarbital-type induction observed after treatment with antiepileptic drugs. Induction by omeprazole seems to be restricted to cytochrome P-450 1A enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

Several procedures to monitor CYP1A2 activity in vivo by the use of caffeine as a probe have been proposed. They comprise caffeine clearance, based on both plasma and saliva concentrations, urinary metabolite ratios, the 13C-caffeine breath test, and the paraxanthine/caffeine ratio in plasma. The latter method is fast, simple, economical and restricted to one sampling point. In this study, we retrospectively analysed four clinical trials comprising 78 subjects to validate the use of the paraxanthine/caffeine ratios in plasma and saliva for CYP1A2 activity. The validation was done by correlation of these ratios to the systemic caffeine clearance as a reference method. Additionally, urinary metabolite ratios and the caffeine breath test were included in the analysis. The paraxanthine/caffeine ratios in plasma and saliva preferably 5-7 h after administration of caffeine most closely resembled systemic caffeine clearance with correlation coefficients typically higher than r = 0.85. An equation to estimate systemic caffeine clearance from the paraxanthine/caffeine ratios taken at any time within 3-7 h postdose was developed. Correlations of systemic clearance with urinary metabolite ratios and the caffeine breath test were less reliable both in this investigation and in the literature. In conclusion, the paraxanthine/caffeine ratios in plasma and saliva appear a valid and inexpensive method of assessing CYP1A2 activity in vivo. Apparent distribution of CYP1A2 activity for all healthy subjects appeared bimodal in nonsmokers (n = 29) and smokers (n = 17).

Background: Omeprazole has previously been shown to induce hepatic cytochrome P4501A2 activity, as evidenced by an accelerated N-3-demethylation in the 13C-[N-3-methyl]-caffeine breath test. In this study we investigated whether the inducing potency of omeprazole can be quantified by the determination of urinary caffeine metabolite ratios, which are based on the urinary excretion of N-3-demethylated metabolites. These data were also compared with changes in plasma clearance., Methods: Twelve healthy volunteers were phenotyped as extensive metabolizers of S-mephenytoin and received seven daily doses of 40 mg omeprazole; eight of these were also treated with 120 mg/day. Moreover, six poor metabolizers were treated with 40 mg/day omeprazole. Three different urinary caffeine metabolite ratios were evaluated from urine samples collected between 5 and 8 hours after caffeine intake., Results: The extensive metabolizers had a slight and nonsignificant acceleration between 7.8% and 17.0% after 40 mg omeprazole by the urinary ratios. However, treatment with 120 mg/day led to highly significant increases ranging from 25.0% to 32.1% (p < 0.002) in this group. Poor metabolizers responded with the highest increases of 40.2% to 41.2%. There was a good correlation between these parameters and the caffeine breath test, as well as the plasma caffeine clearance., Conclusion: The study showed an equivalent caffeine N-3-demethylation activity by all evaluation methods. The three urinary caffeine metabolite ratios sampled at the convenient interval of 5 to 8 hours after administration showed the dependence of CYP1A2 induction by omeprazole on the dose and genetic trait of S-mephenytoin hydroxylase.

Omeprazole has been shown to induce cytochrome P450IA1 and P450IA2 activity in vitro. To reflect cytochrome P450IA2 (CYP1A2) activity in vivo, the 13C-[N-3-methyl]-caffeine breath test was conducted in 18 volunteers: 12 extensive metabolizers, one intermediate metabolizer, and five poor metabolizers of S-mephenytoin. Breath tests were performed before treatment with an oral dose of 40 mg omeprazole, on the seventh day of treatment, and after a 7-day washout period. The mean percentage exhalation of the 13C test dose, as determined by 13CO2 in breath during 8 hours, was 23.0% +/- 8.0% (n = 18) before treatment. The largest increases in exhalation rate of 13CO2 were observed in the poor metabolizers and the intermediate metabolizers (range, 12.8% to 62.9%; median, 38.9%); median area under the plasma concentration-time curves (AUC) of omeprazole was four times higher than in the extensive metabolizers. The change after omeprazole treatment in extensive metabolizers ranged from -9.8% to +47.7% (median, 12.3%; n = 12) of pretreatment values. In both groups exhalation rates of 13CO2 returned to near pretreatment values within the 7-day washout period (24.2% +/- 7.8%; n = 17). Changes in the 13C-caffeine breath test correlated well with both the pretreatment value (R = -0.67, p = 0.003; n = 18) and the plasma AUC of omeprazole (R = 0.61, p = 0.007; n = 18). Therapeutic doses of omeprazole seem to induce CYP1A2 activity in poor metabolizers, whereas they exert minor inducing effects in extensive metabolizers of S-mephenytoin.

Ganglioside GM1 multiple-dose pharmacokinetics were investigated in five healthy male volunteers. Doses of 100 mg were administered either intravenously or intramuscularly for 21 days, and the washout was followed-up for a further 21 days. The highly specific binding of the beta-subunit of cholera toxin was used to quantify ganglioside GM1 levels in plasma, urine, and feces. This dose regime increased the ganglioside GM1 steady-state plasma levels two to three orders of magnitude above the endogenous levels of 0.132 mg/L (coefficient of variation, 8.9%). Large and variable amounts of ganglioside GM1 were found in feces before and during treatment without relation to the dosage. No ganglioside GM1 could be detected in urine at any time. Plasma kinetics were linear with a biexponential disposition. Exogenously administered ganglioside GM1 was confined mainly to the blood volume as indicated by a steady-state volume of distribution of 6.98 +/- 3.57 L and appears to be excreted mainly in the form of metabolites. The total clearance was very slow at 1.61 +/- 0.37 ml/min. Absorption after intramuscular administration was slow (time to reach maximum concentration greater than 12 hours) and yielded steady-state concentrations somewhat lower compared with the intravenous infusion.

Dose-effect relations of ?-nerve growth factor (NGF) have been established on the induction of choline acetyltransferase (ChAT) in basal forebrain nuclei, striatum, cortex and hippocampus of newborn rats after single intracerebroventricular (i.c.v.) injections. Doses above 2 ?g were maximally effective in each of the four brain regions. With the same doses and in the same time course acetylcholine (ACh) concentrations were elevated in the same brain regions. ChAT activity was increased up to 220% in the septum, 200% in the striatum, 160% in the cortex and 120% in the hippocampus. The ACh concentration was elevated up to 175% in the septum, 140% in the striatum, 130% in the cortex and 117% in the hippocampus. The incorporation of labelled choline into ACh showed an increase in ACh turnover of about 60% after i.c.v. application of 5 ?g NGF. Unspecific effects of NGF on brain growth have been excluded. NGF may possibly be useful for the treatment of memory and cognitive impairment as in senile dementia of Alzheimer's type.