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Alaptide

DOI:10.1358/dof.1990.015.05.127620
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Stanislav Rádl at Sanofi
Stanislav Rádl
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DRUGS OF THE FUTURE Vol. 15, No.5, 1990 445
1-carboxylate (III). Debenzylation of (III) by hydro-
genation with Hz over Pd/C in methanol followed by
a cyclization reaction in refluxing toluene yields alap-
tide (1). Scheme 1.
ALAPTIDE
Description
M.p. 308-12°; [a!bO -21.9 (c 0.2: MeOH). White
crystals, sparingly soluble in water (1 mg/ml at 20°).
The substance is stable in the sunlight and can be
stored at room temperature (2).
Cyclo( 1-Amino-1-cyclopentanecarbonyl-L-alanyl)
6' (S)-Methyl-2' , 5'-dioxospiro[cyclopentane-1 ,3'-
piperazine]
8(S)-Methyl-6, 9-diazaspiro[4. 5]decane- 7,1 O-dione
VUFB-15754
c(Acp-Ala)
CPA
[CAS-90058-29-0]
EN=101198
Nootropic
Introduction
Melanocyte-stimulating hormone-release inhibiting
factor (MIF), which is structurally L-prolyl-L-leucyl-
glycinamide (PLG), influences behavior of laboratory
animals under conditions used fo," evaluation of drug
effects on learning and memor,{ processes. MIF has
also been shown to inhibit deveioprnent of dopamine
receptor supersensitivity which i11 expressed as an
increased response to dopam!ne..Jic agonists and
the development of tolerance t:) c:opaminergic an-
tagonists (3). However, there ale some limitations
to the use of MIF in therapy, in particular, for its
peptidase-induced splitting which prevents oral ap-
plication of MIF. In order to overc,ome this disadvan-
tage several cyclic and spiro derivatives of MIF have
been studied. Alaptide can be co,"lsi(iered as a spiro
derivative of MIF which has sim:,.ar, but not iden-
tical, effects as the parent compound. It is now
under development as a nootro;;il; agent with possi-
ble oral administration.
C9H14N2O2; Mol wt: 182.22
C 59.32%; H 7.74%; N 15.38%; 017.56%
Synthesis
The condensation of methyl 1-aminocyclopentane-
1-carboxylate (I) with N-benzyloxycarbonyl-L-alanine
(II) by the mixed anhydride method gives methyl
1-(benzyloxycarbonyl-L -alanyl)aminocyclopentane-
446
perimental wounds after skin abrasion, revealed
faster dermal regeneration. Alaptide was applied as
an ointment in 0.5 and 1% concentrations; the rate
of healing was estimated both macro- and
microscopically. In the 0.5% concentration the drug
was also applied on experimental skin wounds in
rats and on injured cornea in rabbits. In both cases
the healing process was accelerated (2).
Alaptide at doses of 5 or 10 mg/kg s.c. reduced
the number and extent of experimental gastric ulcers
produced by several methods (pylorus ligation,
water restraint, reserpine administration). The
gastric juice quantity, acidity and enzymatic activi-
ty were not substantially affected (8).
Pharmacokinetics
In rats rH)-alaptide is readily absorbed from the
gastrointestinal tract and penetrates the blood-brain
barrier. The maximum concentration in brain is
reached within 1 h and thereafter the level slowly
decreases. Alaptide does not appear to be
metabolized (2).
Toxicity
Owing to the low water solubility of alaptide
(1 mg/ml), lethal doses could be obtained only after
oral administration. In mice doses of 500 mg/kg and
higher had to be administered to obtain first in-
cidence of mortality. In rats lethal doses exceeded
1000 mg/kg. Long-term toxicity studies lasting 28
days were performed in rats and dogs. No toxic con-
sequences of the treatment were found (2). Testing
of genotoxic effects indicated that doses 10 times
higher than the expected daily therapeutic dosage
can be considered safe (2, 9, 10).
Source
Research Institute for Pharmacy and
Biochemistry, Prague (Czechoslovakia).
Pharmacological Actions
Alaptide improved the performance of laboratory
rodents in several types of learning and memory
tests. Given s.c. or orally at a dose of 1 mg/kg the
drug increased avoidance latencies in a step-through
type of passive avoidance in rats. The results in-
dicate that alaptide has a long-term effect on
avoidance response when administered at different
phases of the experimental procedure. In addition,
alaptide administered either before the acquisition
trial or before the retention test attenuated amnesia
induced by electroconvulsive shock in rats (4). Alap-
tide also accelerated the acquisition of aversively
motivated conditioning in a one-way active
avoidance (pole-jumping) test. Rats impaired either
by ligation of one art. carotis communis or by sub-
chronic administration of ethanol performed sig-
nificantly better in the pole-jumping test under the
influence of alaptide ( 1 mg/kg/day, orally) (2).
In another experimental approach, appetite rein-
forced conditioning, the drug did not increase the
rate of acquisition but accelerated the extinction,
which can be interpreted as an ameliorating effect
on learning of the changed situation (5).
Several results indicate that alaptide influences
the central dopamine neuronal system. It exhibited
a weak anticataleptic effect when given repeated-
ly (5 daily doses of 2 and 10 mg/kg p.o.) before the
administration of a neuroleptic drug. Alaptide in-
hibited the development of tolerance and of striatal
dopamine receptors supersensitivity induced by sub-
chronic administration of a long-acting neuroleptic,
isofloxythepin (6). Alaptide did not displace PH]-
spiperone from its binding sites in the striatum.
However, a dose of 10 mg/kg p.o. markedly in-
creased the level of striatal homovanillic acid (HVA)
in the interval of 1-6 h. Rapid tolerance develops to
this effect; a second dose given after 24 h exerted
a much weaker effect and no changes in the HV A
concentration were found after 3 daily doses of the
drug. Alaptide did not induce any change in the con-
centration of serotonin and 5-hydroxyindolylacetic
acid in the rat hypothalamus after doses up to 80
mg/kg p.o. (7).
In tests in vitro no affinity of alaptide was found
to al-noradrenergic, muscarinic, imipramine,
desimipramine and benzodiazepine receptors in rat
brain (2, 7). Alaptide was found to exert beneficial
effects on the growth of the diploid cell structure
of human embryonic lungs. This finding stimulated
experiments evaluating the possible influence of the
drug on epidermal regeneration. Experiments on
domestic pigs, where alaptide was aDDlied on ex-
References
1. Kasafirek, E., Vanzura, J., Krejci, I., Krepelka, J., Dlabac, A.,
Valchar, M. (SPOFA). 2,5-Piperazinedione derivs. CS
231227, GB 2127807.
2. Unpublished data.
3. Mishra, R.K., Chin, S., Chin, P., Mishra, C.P. Pharmacology
of L-prolyl-L-leucyl-glycinamide (PLG}: A review. Meth Find
Exp Clin Pharmacol 1983, 5: 203-33.
4. Krejci, I., Dlabac, A., Vanzura, J., Kosnar, J. Effect of a
spirocyclic cyclodipeptide derivative of MIF on passive
avoidance behaviour and amnesia in rats. Activ Nerv Super
1986,28(4): 241-6.
5. Vanzura, J., Kasafirek, E., Krejci, I., Valchar, M. Spirocyclic
2,5-piperazinediones-oral/y active analogues of MIF. In: Proc
Vlllth Int Symp Med Chem Vol. 2. R. Dahlbom, J.L.G. Nilsson
(Eds.). Swedish Pharm. Press: Stockholm 1985,461-3.
6. VaJchar, M., Krejci, 1.,Kasafirek, E., Schuh, J., Dlabac, A.
DRUGS OF THE FUTURE Vol. 15, No.5, 1990 447
The use of striatal dopaminergic supersensitivity for the
evaluation of drugs with possible antidyskinetic properties.
Pol J Pharmacol Pharm 1985, 37(3).311-5.
7. Krejci, 1., Schuh, J., Pragerova, H. et al. Pharmacological pro-
perties of an orally active analogue of MIF. Activ Nerv Super
1986, 28(4): 318-20.
8. Kasafirek, E., Plaisner, V., Korbova, L. et al. (SPOFA). Phar-
maceutical compsns. for the treatment of gastrointestinal
di~eases. EP 268868.
9. Kosar, K., Vanzura, J. Embryotoxicity of L-prolyl-L-leucyl-
glycinamide, cyclo( l-amino-cyclopentanecarbonyl-alanyl) and
cyclo (glycyl-Ieucyl), new potential neuropeptides in chick
embryos. Pharmazie 1988, 43; 715-6.
10. Vanzura, J., Kosar, K., Kasafirek, E. Inhibition of proliferative
activity by cyclic dipeptides: Spirocyclic derivatives of
l-aminocyclopentanecarboxylic acid. Toxicol Lett 1986, 31;
189-93.
Additional References
Dlohozkov8, N., Krejci, 1., Hlinak, Z., Schuh, J., Valchar, M. Bio-
chemical and behavioral effects of alaptide, a spirocyclic dipep-
tide derived from Pro-Leu-Gly-NH2. Activ Nerv Super 1989,
31(1): 79-80.
Valchar, M., Dlohozkova, N., Krejci, 1., Dlabac, A. Dopaminergic
effects of alaptide IVUFB-15754), a potential nootropic drug. 7th
Noordwijkerhout -Camerino Symp Trends Drug Res (Sept 5-8,
Noordwijkerhout) 1989, Abst P07.
Palus, M., David, 1., Albrecht, V., Filip, V ., Dvorak, I. The effects
of alaptide (a cyclic derivative of MIF) on EEG in healthy
volunteers. Cong Eur CoIl Neuropsychopharmacol (May 23-26,
Gothenburg) 1989, Abst P-37b.
Hlinak, Z., Krejci, 1., Hondlik, J., Yamamoto, A. Behavioral
consequences of sodium nitrite hypoxia in male rats: Ameliora-
tion with alaptide. Meth Find Exp Clin Pharmacol 1990, 12(5):
in press.
*Research Institute for Pharmacy and Biochemistry .Kourimska 17.
13060 Prague. Czechoslovakia.
... However, in the current study, alaptide was chosen mainly for its favorable results in dermatological experiments: a considerable number of tests have shown that alaptide can have a positive influence on epidermal regeneration. In vivo experiments, performed on domestic pigs, rats and mice, proved that alaptide accelerated skin regeneration and the curing of experimental skin injuries [14]. Moreover, very low acute toxicity was observed in rats and mice, i.e. a 1 g/1 kg dose caused only 20% mortality of female rats [12,13]. ...
... Two additives have been investigated in this work. Alaptide-a partially forgotten compound-was chosen mainly due to its positive influence on epidermal regeneration and due to its low acute toxicity [14]. This dipeptide is already used in veterinary practice as a component of a skin healing ointment. ...
... However, the size of the wounds treated with PCL membranes with alaptide or with the alaptide/arginine combination decreased rapidly immediately after the wound was created and almost without eschar formation, as demonstrated in figure 16. This is in accordance with many experimental studies, in which alaptide stimulated epithelialization and epidermal regeneration (for a review, see [11,14]. Alaptide is an analogue of the melanocyte-stimulating hormone release-inhibiting factor (MIF), also referred to as macrophage migration inhibitory factor (MIF), which is known to be a key player in cutaneous biology and wound healing. ...
In vitro and in vivo testing of nanofibrous membranes doped with alaptide and L-arginine for wound treatment
Article
Full-text available
We have prepared a candidate biocompatible construct for skin wound healing based on electrospun polycaprolactone (PCL) nanofibrous membranes. The membrane material was loaded either with L-arginine or with alaptide, or with a mixture of both bioactive components. Alaptide is a spirocyclic synthetic dipeptide, an analogue of melanocyte-stimulating hormone release-inhibiting factor. L-arginine is an amino acid with a basic guanidine side chain. It is a direct precursor of nitric oxide, which plays a pivotal role in skin repair. The presence and the distribution of the additives were proved with HPLC, FTIR and Raman spectroscopy. The influence of L-arginine and alaptide on the morphology of the membrane was characterized using SEM. No statistically significant correlation between fiber diameter and drug concentration was observed. The membranes were then tested in vitro for their cytotoxicity, using primary human dermal fibroblasts, in order to obtain the optimal concentrations of the additives for in vivo tests in a rat model. The membranes with the highest concentration of L-arginine (10 wt. %) proved to be cytotoxic. The membranes with alaptide in concentrations from 0.1 to 2.5 wt.%, and with the other L-arginine concentrations (1 and 5 wt.%) did not show high toxicity. In addition, there was no observed improvement in cell proliferation on the membranes. The in vivo experiments revealed that membranes with 1.5 wt.% of alaptide or with 1.5 wt.% of alaptide in combination with 5 wt.% of L-arginine markedly accelerated the healing of skin incisions, and particularly the healing of skin burns, i.e. wounds of relatively large extent. These results indicate that our newly-developed nanofibrous membranes are promising for treating wounds with large damaged areas, where a supporting material is needed.
... (alaptide, 1), an original Czech compound prepared by Kasafirek et al. in the 1980s [11,12], was investigated as a CPE with very good results [13][14][15][16][17][18]. Unfortunately, alaptide is very poorly soluble [12,19] and therefore selected "non-spirocyclic" derivatives of alaptide were designed, synthesized, and their transdermal enhancement effects as potential CPEs on the permeation of the model drug theophylline through the skin were investigated. ...
Investigation of Permeation of Theophylline through Skin Using Selected Piperazine-2,5-Diones
Article
Full-text available
Transdermal administration of drugs that penetrate, in this case directly into the blood circulation, has many advantages and is promising for many drugs thanks to its easy application and good patient compliance. (S)-8-Methyl-6,9-diazaspiro[4.5]decan-7,10-dione (alaptide), has been studied as a potential chemical permeation enhancer. Based on its structure, four selected piperazine-2,5-diones were synthesized by means of multi-step synthetic pathways. All the compounds were investigated on their ability to enhance the permeation of the model drug theophylline from the hydrophilic medium propylene glycol:water (1:1). In vitro experiments were performed using vertical Franz diffusion cells at constant temperature 34 ± 0.5 °C and using full-thickness pig (Sus scrofa f. domestica) ear skin. Withdrawn samples were analyzed by RP-HPLC for determination of the permeated amount of theophylline. All the compounds were applied in ratio 1:10 (w/w) relative to the amount of theophylline. One hour after application, the permeated amount of theophylline from formulations with alaptide and (3S,6S)-3,6-dimethylpiperazine-2,5-dione, was ca. 15- and 12-fold higher, respectively, than from the formulation without the tested compounds. Despite the enhancement ratio of both enhancers in a steady state was ca. 2.3, the pseudo-enhancement ratio in the time range from 1 to 3 h was 4.4. These enhancement ratios indicate that the compounds are able to enhance the permeation of agents through the skin; however, the short-term application of both compound formulations seems to be more advantageous. In addition, the screening of the cytotoxicity of all the prepared compounds was performed using three cell lines, and the compounds did not show any significant toxic effect.
A novel approach to studying the kinetics of release of Alaptide from Poly-ε-caprolactone nanofibers
Article
A considerable number of experimental studies have been conducted on drug release from nanofibers. However, only a small number of attempts have been made to determine a mechanistic approach to the kinetics of drug release from nanofibers. This paper describes the fabrication of electrospun nanofibers from Poly-ε-caprolactone with different loadings of Alaptide aimed at the examination of a mechanistic model based on the solution of the diffusion equation in cylindrical coordinates. The model took into account the weighting of the distribution of the fiber diameters inside the nanofiber membrane. The results revealed that it was possible to describe the release of all the loadings and the forms of the drug inside the fibers using the diffusion equation. The estimated diffusion coefficients were 3.10±1.07 ×10⁻¹³, 1.18±0.10 ×10⁻¹³ cm²/s and 1.11±0.14×10⁻¹⁴ cm²/s for 0.1, 1 and 2.5 wt.% of Alaptide loadings, respectively. The estimated values of the diffusion coefficients correlated with the concentration in which Alaptide was present in the fibers. It is anticipated that this model extension will help to enhance the versatility of the approach to the quantification of the amount of released drug, since it can be applied to highly-heterogeneous nanofibrous layers with wide diameter distributions.
Alaptide as Transdermal Permeation Modifier
Chapter
  • Jan 2015
Based on the fact that alaptide is able to influence the creation and function of keratinocytes, it was supposed that alaptide could be used as a transdermal permeation modifier. Various APIs (bases, acids, salts, neutral molecules, small molecules, steroid-like molecules) were tested on their transdermal permeation in the mixture with micronized and/or nanonized alaptide as a transdermal permeation modifier. Also the influence of the type of formulation (ointment, cream, gel) on the effect of alaptide on skin was investigated intensively. It was observed that under specific conditions alaptide is able to suppress permeation/absorption of compounds through the skin, which can limit the site of action of potentially hazardous/toxic drugs to skin surface. The skin curative activity of alaptide can be helpful in reduction of possible skin irritant/injurious effects of permeating compounds. In transdermal application alaptide causes an increase or a decrease, in dependence on the used concentration, physical state and supporting medium (pharmaceutical formulation), in permeation/absorption of drugs into the skin and/or through the skin. The concentration of the used drug was increased at the place of administration, and/or the systemic concentration was increased, or it was ensured that drugs acted only on the skin surface/in the skin surface layer and did not penetrate into the deeper skin layers or did not have any systemic effect. Although alaptide was found in the 1980s of the twentieth century, even now it has great potential either as an active pharmaceutical ingredient or a permeation modifier.
RAPID INFORMATIVE SCREENING OF NANO-ALAPTIDE AS POTENTIAL TRANSDERMAL PERMEATION ENHANCER OF ACETYLSALICYLIC ACID AND PARACETAMOL
Article
Full-text available
  • Apr 2014
This investigation deals with the affection of permeation of acetylsalicylic acid and paracetamol applied in the system propylene glycol-water 1:1 through full-thickness pig ear skin by alaptide that was applied in nanonized form as a potential chemical penetration enhancer. Alaptide, (S)-8-methyl-6,9-diazaspiro[4.5]decan-7,10-dione, is the original Czech compound. The application of nanonized alaptide significantly enhanced the permeation of both drugs through the skin. Enhancement ratios in the studied time interval 0.5-2.0 h varied from 1.11 to 17.70 for acetylsalicylic acid and from 6.83 to 19.83 for paracetamol.
In Vitro Permeation of Micronized and Nanonized Alaptide from Semisolid Formulations
Article
Full-text available
This study is focused on in vitro permeation of the original Czech compound, a skin/mucosa tissue regeneration promoter, known under the international nonproprietary name "alaptide," in micronized and nanonized forms. Alaptide showed a great potential for local applications for treatment and/or regeneration of the injured skin. The above mentioned technological modifications influence the permeation of alaptide through artificial or biological membranes, such as PAMPA or skin. The permeation of micronized and nanonized form of alaptide formulated to various semisolid pharmaceutical compositions through full-thickness pig ear skin using a Franz cell has been investigated in detail. In general, it can be concluded that the nanonized alaptide permeated through the skin less than the micronized form; different observations were made for permeation through the PAMPA system, where the micronized form showed lower permeation than the nanonized alaptide.
Product of alaptide synthesis: Determination of the absolute configuration
Article
  • Dec 2010
Alaptide is the active substance of the veterinary dermatological ointment ALAPTID and a potential drug in human medicine. Electronic circular dichroism spectroscopy (ECD), transparent spectral region optical rotation (OR), and ab initio calculations were employed to determine the absolute configuration of alaptide. No X-ray structural data determining the absolute configuration were available. It was not possible to employ vibrational circular dichroism spectroscopy (VCD), because alaptide was not sufficiently soluble in common solvents used in VCD spectroscopy to generate reliable spectra. Both ECD spectra and OR values of alaptide solution were in good agreement with predicted data and determined unambiguously the absolute configuration of alaptide synthesized from (S)-alanine as being (S).
Two-step generation of spirocyclic dipeptides from linear peptide ethyl ester precursors
Article
Linear tri- and tetrapeptide precursors of 2,5-piperazinedione were prepared and their conversion to spirocyclic dipeptidase enzymes, the spirocyclic dipeptides (SpDp) were generated from the precursors by a two-step mechanism consisting in the proteolytic release of the C-terminal dipeptide ethyl ester and its subsequent spontaneous cyclization. After intraperitoneal administration of urokinase and Ac-Leu-Lys-Gly-Acp-OEt, a SpDp precursor targeted to endogenous plasmin, or the administration of the activated Hageman factor fragment and Ac-Leu-Arg-Ala-Acp-OEt, a SpDp precursor, targeted to endogenous kallikrein, the generated corresponding C-terminal dipeptide ethylester intermediates and SpDp, cyclo(Gly-Acp) and cyclo (Ala-Acp), respectively, were detected in the blood serum of C57B1 mice. Suppression of partial amnesia induced by sodium nitrite was observed in rats where it was subcutaneously administered with H-Leu-Ala-Acp-OEt, a peptide precursor of alaptide, the active SpDp, i.e. cyclo(1-amino-1-cyclopentanecarbonyl-L-alanyl).
An Analog of MIF, Alaptide: Effect on Serum Prolactin, Dopamine Receptors and Growth of Rat Adenohypophysis
Article
  • Mar 1994
Alaptide is a drug chemically derived from prolyl-leucyl-glycin amide (PLG) which is effective after oral administration. We studied the effect of long term treatment with alaptide and estradiol-benzoate on serum prolactin, growth reactivity and dopamine DA-2 receptors in the anterior pituitary of male rats. Alaptide reduced adenohypophyseal weight when given alone, but only nonsignificantly reduced growth reactivity of the anterior pituitary (AP) raised by estradiol-benzoate (EB). Alaptide significantly decreased the serum level of prolactin but, on the other hand, significantly increased the binding of 3H-spiperone to dopamine DA-2 receptors in AP membrane preparations, without affecting affinity. The administration of alaptide plus EB together resulted in an additional increase of dopamine DA-2 binding sites. We assume that alaptide has a weak dopaminergic activity on the AP of male rats.
Effect of alaptide, its analogues and oxiracetam on memory for an elevated plus-maze in mice
Article
In the present study, the elevated plus-maze was used to evaluate memory in female mice. In Experiment 1, the mice retested on day 1, 4 or 7 after the initial session escaped from the open arm into the enclosed arm in a significantly shorter time than those retested on day 10 or 14. Thus, a 10-day inter-session interval was chosen for testing drugs which were expected to enhance memory. In Experiment 2, in the retest performed on day 10, both alaptide (cyclo(L-alanyl-1-amino-1- cyclopentanecarbonyl)) and oxiracetam, given immediately after the 1st session, reduced the transfer latency from the open arm into the enclosed arm as compared with that of the controls. In Experiment 3, a similar effect, i.e., the retention of spatial information, was facilitated by post-session injections of 5 out of 21 alaptide analogues. The new compounds represent the 2,5-piperazinedione derivatives which contain 1-amino-1-cyclo-alkanecarboxylic acid (C3 to C7 ring). The cyclopentane- and cyclohexane-ring was substituted by an alkyl group. In the series with the cycloalkane ring, the importance of the structure of alaptide was confirmed again, which underlines the importance of the cyclopentane ring; the active structures had L-alanine instead of glycine as the second amino acid. Isomers of the cyclohexane series which contained methyl or tert-butyl were most active when the substitution was at position 3. Our results demonstrate that the model of long-term memory can be used to discriminate between closely related chemical structures.
Behavioral consequences of sodium nitrite hypoxia in male rats: Amelioration with alaptide treatment
Article
The short-term effects and long-term consequences of sodium nitrite-induced hypoxia on spontaneous behavior of adult male rats were studied. A short-term suppression of locomotor, exploratory and grooming activities in 3-month-old animals after single NaNO2 does (55 mg per kg, s.c.) was followed by the recovery of normal values within 24 h. A marked decrease in locomotor and exploratory activity as well as of investigatory time combined with an increase of time spent in relaxation patterns was found in 6-month-old males at day 7 after double NaNO2 administration. A more rapid habituation during repeated exposure of 3-month-old males into the same experimental box was found beginning on day 10 after three-fold NaNO2 administration. We suggest that the delayed behavioral deficits could be due to the secondary structural changes developing in the central nervous system over several days after the NaNO2 insult. Alaptide, a dipeptide derived from Pro-Leu-Gly-NH2, administered for five days in a preventive-curative way ameliorated the deficits in spontaneous behavior consequent to the NaNO2 effect. At the moment it is not possible to fully understand the mechanism of action which is responsible for the beneficial effect of alaptide.
Pharmacology of L-prolyl-L-leucyl-glycinamide (PLG): A review
Article
Dopaminergic effects of alaptide IVUFB-15754), a potential nootropic drug
  • Jan 1989
  • M Valchar
  • N Dlohozkova
  • Krejci
  • A Dlabac
Valchar, M., Dlohozkova, N., Krejci, 1., Dlabac, A. Dopaminergic effects of alaptide IVUFB-15754), a potential nootropic drug. 7th Noordwijkerhout -Camerino Symp Trends Drug Res (Sept 5-8, Noordwijkerhout) 1989, Abst P07.
Dvorak, I. The effects of alaptide (a cyclic derivative of MIF) on EEG in healthy volunteers
  • M Palus
  • David
  • V Albrecht
  • V Filip
Palus, M., David, 1., Albrecht, V., Filip, V., Dvorak, I. The effects of alaptide (a cyclic derivative of MIF) on EEG in healthy volunteers. Cong Eur CoIl Neuropsychopharmacol (May 23-26,