Population pharmacokinetic modelling of NS2330 (tesofensine) and its major metabolite in patients with Alzheimer's disease.

Aims: To develop a population pharmacokinetic model for NS2330 and its major metabolite M1 based on data from a 14 week proof of concept study in patients with Alzheimer's disease, and to identify covariates that might influence the pharmacokinetic characteristics of the drug and/or its metabolite.

Methods: Plasma data from 320 subjects undergoing multiple oral dosing, and consisting of 1969 NS2330 and 1714 metabolite concentrations were fitted simultaneously using NONMEM.

Results: Plasma concentration-time profiles of NS2330 and M1 were best described by one-compartment models with first-order elimination for both compounds.

Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer's disease.

The amyloid beta-peptides A beta 40 and A beta 42 are highly amyloidogenic constituents of brain beta-amyloid plaques in Alzheimer's disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (A beta PP), including alpha- beta-, and gamma-secretases. Talsaclidine is a functionally selective muscarinic m1 agonist that stimulates non-amyloidogenic alpha-secretase processing in vitro.

Pharmacodynamic profile of the M1 agonist talsaclidine in animals and man.

In functional pharmacological assays, talsaclidine has been described as a functionally preferential M1 agonist with full intrinsic activity, and less pronounced effects at M2- and M3 receptors. In accordance with this, cholinomimetic central activation measured in rabbits by EEG recordings occurred at a 10 fold lower dose than that inducing predominantly M3-mediated side effects. This pharmacological profile is also reflected in the clinical situation: Both in healthy volunteers and in Alzheimer patients--unlike after unspecific receptor stimulation through cholinesterase inhibitors--the mainly M3-mediated gastrointestinal effects (like nausea and vomiting) were not dose-limiting.

Treatment with the selective muscarinic agonist talsaclidine decreases cerebrospinal fluid levels of total amyloid beta-peptide in patients with Alzheimer's disease.

Brain amyloid load in Alzheimer's disease (AD) is, at least in genetic forms, associated with overproduction of amyloid beta-peptides (A beta). Thus, lowering A beta production is a central therapeutic target in AD and may be achieved by modulating such key enzymes of amyloid precursor protein (APP) processing as beta-, gamma-, and alpha-secretase activities. Talsaclidine is a selective muscarinic M1 agonist that stimulates the nonamyloidogenic alpha-secretase pathway in model systems.

[Haemodynamic investigations with the new antihypertensive drug guanfacine (author's transl)].

Guanfacine, a new centrally acting alpha-mimetic antihypertensive drug, was given to two groups of 7 patients each, one with essential and the other with renal hypertension. Both in the acute trial (after short-term intermittent initial blood pressure increase) and in the long-term treatment (4 weeks) lowering of blood pressure occurred, mediated via decrease of peripheral vascular resistance. In addition, support of cardiac function, especially of the afterload and possibly also the preload, was induced.

[A new antihypertensive agent used in a clinical setting].

In a multicenter study with 54 patients with essential and renal hypertension (WHO I to III) the antihypertensive efficacy and safety of guanfacine were evaluated against clonidine in a double blind cross-over design. The treatment period for each drug lasted five weeks. There was a two week's wash-out period with placebo between the application of the respective preparations.

Differences in psychic performance with guanfacine and clonidine in normotensive subjects.

1. Doses of clonidine 0.15 mg or guanfacine 1.

[Synthesis of a fragment of the active center of the streptococcal proteinase (EC 3.4.22.10), IX].

The synthesis of the protected pentapeptide tert-butyloxycarbonly-Gln-Ile-Met-Lys(X)-Gly-p-nitrobenzylester (X = benzyloxycarbonyl, 3-chlor-benzyloxycarbonyl) which is part of the carboxylend of a partial sequence of the active center of the streptococcal proteinase is described. Side reactions are observed if the tert-butyloxycarbonyl-protective group is cleaved by trifluoroacetic acid, not with HC1/dioxane. Obviously the presence of methionine is responsible for the formation of by products.

[Synthesis of a fragment of the active center of the streptococcal proteinase (EC 3.4.22.10), VIII (author's transl)].

The synthesis of the protected tricosapeptide Z-Val-Lys(Z)-Pro-Gly-Glu(OBzl)-Gln-Ser-Phe-Val-Gly-Gln-Ala-Ala-Thr-Gly-His-Cys(MBzl)-Val-Ala-Thr-Ala-Thr-Ala-ONB is described. The tricosapeptide was built up from the decapeptide Z-Val-Lys(Z)-Pro-Gly-Glu(OBzl)-Gln-Ser-Phe-Val-Gly-ONp and the tridecapeptideester Gln-Ala-Ala-Thr-Gly-His-Cys(MBzl)-Val-Ala-Thr-Ala-Thr-Ala-ONB. A further nonadecapeptide with tert-butylmercapto protection of the SH group was also synthetized.

[Synthesis of a fragment of the active center of the streptococcal proteinase (EC 3.4.22.10), VII (author's transl)].

The synthesis of the protected peptides Boc-Ala-Ala-Thr-Gly-ONp, Boc-Ala-Thr-Ala-Thr-Ala-ONB and Boc-Ala-Ala-Thr-Gly-His-Cys(X)-Val-Ala-Thr-Ala-Thr-Ala-ONB [X = p-methoxybenzyl, tert-butylmercapto, tetrahydropyranyl-(2)] is described. These peptides are fragments of an active center sequence of the streptococcal proteinase (EC 3.4.

[Synthesis of a fragment of the active center of the streptococcal proteinase (EC 3.4.22.10), VI (author's transl)].

The synthesis and properties of the protected peptide Boc-His(Boc)-Cys(X)-Val-OH(ONP) [X = tert-butylmercapto, p-methoxybenzyl, tetrahydropyranyl-(2)] are described. This peptide is a fragment of an active center sequence of the streptococcal proteinase (EC 3.4.