Psychopharmacology(t 992) 109:30-40
Psychopharmacology © Springer-Verlag 1992
Original investigations Dose-response studies with co-dergocrine mesylate under hypoxia utilizing EEG mapping and psychometry Bernd Saletu, Josef Griinberger, Leopold Linzmayer, and Peter Anderer Department of Psychiatry,School of Medicine, Universityof Vienna, W~ihringerGfirtel 18-20, A-1090 Vienna, Austria Received November 6, 1991 /Final version May 19, 1992
Abstract. In a double-blind, placebo-controlled trial,
Key words: Cerebral hypoxic hypoxidosis - Brain protec-
human brain function and mental performance were studied under two different degrees of hypoxia after administration of two different doses (6 mg and 9 mg) of co-dergocrine mesylate (CDM) utilizing blood gas analysis, EEG mapping and psychometry. Hypoxic hypoxidosis (i.e. impairment of cerebral metabolism due to hypoxia) was experimentally induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (Nz) (found in 6000 m altitude), and of 8.6% 02, 91.4% N2 (found in 7000 m altitude), which was inhaled for 23 rain under normobaric conditions by 18 healthy volunteers. They received randomized after an adaptation session placebo, 6 mg and 9 mg co-dergocrine mesylate (CDM). Evaluation of blood gases, brain mapping and psychometry was carried out at 0, 2, 4, 6, 8 h after oral drug administration. Blood gas analysis demonstrated a drop in P O 2 to 42 and 32 mm Hg 23 min after inhalation of the 9.8% and 8.6% gas mixture, respectively, PCO2 decreased to 32 and 31 mm Hg, pH increased to 7.46 and 7.47 and base excess increased to 0.50 and 0.90 nmol/1, respectively. EEG mapping demonstrated an increase in delta and decrease of alpha power and a slowing of the centroid over almost the whole brain. 6 mg and slightly less so 9 mg CDM attenuated this deterioration of vigilance (i.e. dynamic state of the neuronal network determining adaptive behavior). At the behavioral level, moderate hypoxia induced a deterioration of noopsychic performance, which was mitigated by 6 mg, but not by 9 mg CDM. A deepening of the hypoxia resulted in a loss of these brain protective effects of both doses. Decrement of the thymopsyche increased after both doses in the moderate hypoxic condition, while under marked hypoxia 6 mg CDM attenuated and 9 mg aggravated this deterioration. Time-wise, brain protective effects reached the level of statistical difference between the 2nd and the 6th hour. Somatic complaints like feeling dazed, giddiness and headache were mitigated dose dependently by CDM in the moderate, but not in the marked hypoxic hypoxidosis.
tion - Blood gases - EEG mapping - Psychometry Co-dergocrine mesylate - Gerontopsychopharmacology - Nootropics
Correspondence to: B. Saletu
Despite the fact that it will soon be 50 years since codergocrine mesylate (CDM), consisting of dihydroergocornine mesylate, dihydroergocristine mesylate and dihydroergokryptine mesylate, was produced by the Sandoz chemists, Stoll and Hoffmann, and that in subsequent decades the drug was widely prescribed in age-related mental decline and dementias because of its favourable action on cerebral circulation, brain metabolism, cerebral neurotransmision and synaptic plasticity (Fanchamps 1990; Saletu 1991a), optimal dose is still being discussed. In controlled studies, doses ranged from 1.5 mg/day to as much as 12 rag/day (Gerin 1969; Triboletti and Ferri 1969; Ditch et al. 1971; Banen 1972; Jennings 1972; Rao and Norris 1972; Roubicek et al. 1972; Bazo 1973; McConnachie 1973; Rehman 1973; Thibault 1974; Rosen 1975; Hollister and Yesavage 1984; Thienhaus et al. 1987; Jenike et al. 1990). In our approach to investigating this problem, and to obtain objective and quantitative data on the central protective effects of CDM, we have utilized the hypoxia model, which originated in animal pharmacology, and has been adapted by us for evaluation of nootropics (i.e. drugs improving the noopsyche - the part of our psyche concerned with intellectual and mnestic performance) in human psychopharmacology (Saletu and Grfinberger 1983, 1984; Saletu et al. 1987a, 1989, 1990a, b). In a first CDM study, hypoxic hypoxidosis was induced by a fixed gas combination of 9.8% oxygen and 90.2% nitrogen (found in 6000 m altitude), which was inhaled for 23 min under normobaric conditions by 15 healthy volunteers. The resulting brain dysfunction was significantly mitigated by 5 mg CDM as the drug attenuated the hypoxiainduced deterioration in vigilance (Saletu et al. 1990b). Moreover, psychometric performance deteriorated under
31 h y p o x i a b y 49 % after placebo, while after 5 m g C D M o n l y b y 26%. H o w e v e r , in a s u b s e q u e n t trial, f u r t h e r a u g m e n t a t i o n o f h y p o x i a i n d u c e d by i n h a l a t i o n o f a gas c o m b i n a t i o n of 8.6% 0 2 a n d 91.4% N2 (found in 7000 m altitude) resulted in a loss o f b r a i n p r o t e c t i o n o f C D M in this dosage, even w h e n the d r u g was given over 2 weeks daily. I n o r d e r to investigate the q u e s t i o n o f w h e t h e r o r n o t higher doses o f C D M offer p r o t e c t i o n even a g a i n s t a m a r k e d h y p o x i a (8.6% 0 2 ) the present d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d , cross-over s t u d y was designed. B r a i n f u n c t i o n a n d p s y c h o m e t r i c p e r f o r m a n c e were studied u n d e r b o t h m o d e r a t e (9,8% 0 2 ) a n d m a r k e d (8,6% 0 2 ) h y p o x i a c o n d i t i o n s after a p p l i c a t i o n o f placebo, 6 m g and 9 mg CDM.
Materials and methods Eighteen healthy volunteers (12 males and 6 females) aged between 20 and 34 years (mean 26 years), weighing from 52 to 99 kg (mean 72 kg) and ranging in height from 164 to 191 cm (mean 176 cm) participated in the double-blind, placebo-controlled trial. They were not allowed to take any psychoactive drugs 3 weeks before and/or during the period of study, which was performed in accordance with the rules and regulations for the conduct of clinical trials stated in the Declaration of Helsinki, as revised by the World Medical Assembly at Tokyo and Venice. Informed written consent was obtained. They had all passed a physical, psychiatric, psychological and EEG examination. After an adaptation session without drugs, they received at weekly intervals randomized oral single doses of placebo, 6 mg and 9 mg eo-dergocrine mesylate (Hydergine SRO capsules: Sandoz GesmbH, Vienna, Austria) under moderate (9,8% 02) and marked (8.6% O2) hypoxia conditions. The Hydergine SRO is a modified release capsule showing a good retard profile both under fed and fasted conditions. The maximum plasma concentrations were achieved 5-6 h later and were lower than after administration of the standard tablet. The relative bioavailability of the modified release capsule was 112% with respect to the standard tablet (Souchet 1989).
Induction of normobaric hypoxic hypoxidosis. For the induction of normobaric hypoxic hypoxidosis, the subjects had to breathe through a mouthpiece (with their noses clipped) and via a pressurereduction valve a special preparation of gas containing 9.8 % O z and 91.2% N, (found at 6000 m altitude) as well as 8.6% Oz and 91.4% N2 (found at 7000 m altitude) for a period of 23 rain. The gas combination was fixed and was stored in 40-1 bottles under a pressure of 150 bar. The correct ratio of the gas mixture in each bottle was quantitatively analyzed and certified by Air Liquide. In the normoxic control condition, the subjects inhaled a gas mixture of 21% 02 and 79% N z. Hypoxemia was controlled by drawing arterialized capillary blood samples from the earlobe (after hyperemization of the latter) at 0 and 14 rain before and 2, 4, 6 and 8 h after drug administration. In the first and last session (h 0 and 8), blood samples were also obtained in the last minute (23rd) of the inhalation of the hypoxic gas mixture. The blood samples were immediately analyzed by means of an Instrumentation Laboratory pH Blood-gas Analyzer IL-1306 resulting in the following measurements: pH, PO2, PCD2, base excess (BE, nmol/1), and standard bicarbonate (nmol/1). Moreover, transcutaneous oxygen tension was continuously monitored by means of Sensor Medics Transend System. Although transcutaneously measured oxygen tension is somewhat lower than the one measured in the arterialized capillary blood, the values have been found to be correlated (+0.90; P,e~....
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Fig. 5. Noopsychic deterioration under moderate (9.8% 02) and marked (8.6% 02) hypoxia after acute oral placebo, 6 mg and 9 mg CDM based on discriminant analysis (centroids) of changes in nine noopsychic variables. Time is shown in the abscissa, changes from normoxic baseline are represented in the ordinate and are expressed in Euclid's distances (mm). Under moderate hypoxia (top), a noopsychic deterioration occurs, which is attenuated only by 6 mg CDM in the 2nd hour after drug administration. Under marked hypoxia, (bottom) noopsychic performance deteriorates after all three substances. There are no differences between placebo-induced and CDM-induced changes (n= 18). * P
Psychopharmacology © Springer-Verlag 1992
Original investigations Dose-response studies with co-dergocrine mesylate under hypoxia utilizing EEG mapping and psychometry Bernd Saletu, Josef Griinberger, Leopold Linzmayer, and Peter Anderer Department of Psychiatry,School of Medicine, Universityof Vienna, W~ihringerGfirtel 18-20, A-1090 Vienna, Austria Received November 6, 1991 /Final version May 19, 1992
Abstract. In a double-blind, placebo-controlled trial,
Key words: Cerebral hypoxic hypoxidosis - Brain protec-
human brain function and mental performance were studied under two different degrees of hypoxia after administration of two different doses (6 mg and 9 mg) of co-dergocrine mesylate (CDM) utilizing blood gas analysis, EEG mapping and psychometry. Hypoxic hypoxidosis (i.e. impairment of cerebral metabolism due to hypoxia) was experimentally induced by a fixed gas combination of 9.8% oxygen (O2) and 90.2% nitrogen (Nz) (found in 6000 m altitude), and of 8.6% 02, 91.4% N2 (found in 7000 m altitude), which was inhaled for 23 rain under normobaric conditions by 18 healthy volunteers. They received randomized after an adaptation session placebo, 6 mg and 9 mg co-dergocrine mesylate (CDM). Evaluation of blood gases, brain mapping and psychometry was carried out at 0, 2, 4, 6, 8 h after oral drug administration. Blood gas analysis demonstrated a drop in P O 2 to 42 and 32 mm Hg 23 min after inhalation of the 9.8% and 8.6% gas mixture, respectively, PCO2 decreased to 32 and 31 mm Hg, pH increased to 7.46 and 7.47 and base excess increased to 0.50 and 0.90 nmol/1, respectively. EEG mapping demonstrated an increase in delta and decrease of alpha power and a slowing of the centroid over almost the whole brain. 6 mg and slightly less so 9 mg CDM attenuated this deterioration of vigilance (i.e. dynamic state of the neuronal network determining adaptive behavior). At the behavioral level, moderate hypoxia induced a deterioration of noopsychic performance, which was mitigated by 6 mg, but not by 9 mg CDM. A deepening of the hypoxia resulted in a loss of these brain protective effects of both doses. Decrement of the thymopsyche increased after both doses in the moderate hypoxic condition, while under marked hypoxia 6 mg CDM attenuated and 9 mg aggravated this deterioration. Time-wise, brain protective effects reached the level of statistical difference between the 2nd and the 6th hour. Somatic complaints like feeling dazed, giddiness and headache were mitigated dose dependently by CDM in the moderate, but not in the marked hypoxic hypoxidosis.
tion - Blood gases - EEG mapping - Psychometry Co-dergocrine mesylate - Gerontopsychopharmacology - Nootropics
Correspondence to: B. Saletu
Despite the fact that it will soon be 50 years since codergocrine mesylate (CDM), consisting of dihydroergocornine mesylate, dihydroergocristine mesylate and dihydroergokryptine mesylate, was produced by the Sandoz chemists, Stoll and Hoffmann, and that in subsequent decades the drug was widely prescribed in age-related mental decline and dementias because of its favourable action on cerebral circulation, brain metabolism, cerebral neurotransmision and synaptic plasticity (Fanchamps 1990; Saletu 1991a), optimal dose is still being discussed. In controlled studies, doses ranged from 1.5 mg/day to as much as 12 rag/day (Gerin 1969; Triboletti and Ferri 1969; Ditch et al. 1971; Banen 1972; Jennings 1972; Rao and Norris 1972; Roubicek et al. 1972; Bazo 1973; McConnachie 1973; Rehman 1973; Thibault 1974; Rosen 1975; Hollister and Yesavage 1984; Thienhaus et al. 1987; Jenike et al. 1990). In our approach to investigating this problem, and to obtain objective and quantitative data on the central protective effects of CDM, we have utilized the hypoxia model, which originated in animal pharmacology, and has been adapted by us for evaluation of nootropics (i.e. drugs improving the noopsyche - the part of our psyche concerned with intellectual and mnestic performance) in human psychopharmacology (Saletu and Grfinberger 1983, 1984; Saletu et al. 1987a, 1989, 1990a, b). In a first CDM study, hypoxic hypoxidosis was induced by a fixed gas combination of 9.8% oxygen and 90.2% nitrogen (found in 6000 m altitude), which was inhaled for 23 min under normobaric conditions by 15 healthy volunteers. The resulting brain dysfunction was significantly mitigated by 5 mg CDM as the drug attenuated the hypoxiainduced deterioration in vigilance (Saletu et al. 1990b). Moreover, psychometric performance deteriorated under
31 h y p o x i a b y 49 % after placebo, while after 5 m g C D M o n l y b y 26%. H o w e v e r , in a s u b s e q u e n t trial, f u r t h e r a u g m e n t a t i o n o f h y p o x i a i n d u c e d by i n h a l a t i o n o f a gas c o m b i n a t i o n of 8.6% 0 2 a n d 91.4% N2 (found in 7000 m altitude) resulted in a loss o f b r a i n p r o t e c t i o n o f C D M in this dosage, even w h e n the d r u g was given over 2 weeks daily. I n o r d e r to investigate the q u e s t i o n o f w h e t h e r o r n o t higher doses o f C D M offer p r o t e c t i o n even a g a i n s t a m a r k e d h y p o x i a (8.6% 0 2 ) the present d o u b l e - b l i n d , p l a c e b o - c o n t r o l l e d , cross-over s t u d y was designed. B r a i n f u n c t i o n a n d p s y c h o m e t r i c p e r f o r m a n c e were studied u n d e r b o t h m o d e r a t e (9,8% 0 2 ) a n d m a r k e d (8,6% 0 2 ) h y p o x i a c o n d i t i o n s after a p p l i c a t i o n o f placebo, 6 m g and 9 mg CDM.
Materials and methods Eighteen healthy volunteers (12 males and 6 females) aged between 20 and 34 years (mean 26 years), weighing from 52 to 99 kg (mean 72 kg) and ranging in height from 164 to 191 cm (mean 176 cm) participated in the double-blind, placebo-controlled trial. They were not allowed to take any psychoactive drugs 3 weeks before and/or during the period of study, which was performed in accordance with the rules and regulations for the conduct of clinical trials stated in the Declaration of Helsinki, as revised by the World Medical Assembly at Tokyo and Venice. Informed written consent was obtained. They had all passed a physical, psychiatric, psychological and EEG examination. After an adaptation session without drugs, they received at weekly intervals randomized oral single doses of placebo, 6 mg and 9 mg eo-dergocrine mesylate (Hydergine SRO capsules: Sandoz GesmbH, Vienna, Austria) under moderate (9,8% 02) and marked (8.6% O2) hypoxia conditions. The Hydergine SRO is a modified release capsule showing a good retard profile both under fed and fasted conditions. The maximum plasma concentrations were achieved 5-6 h later and were lower than after administration of the standard tablet. The relative bioavailability of the modified release capsule was 112% with respect to the standard tablet (Souchet 1989).
Induction of normobaric hypoxic hypoxidosis. For the induction of normobaric hypoxic hypoxidosis, the subjects had to breathe through a mouthpiece (with their noses clipped) and via a pressurereduction valve a special preparation of gas containing 9.8 % O z and 91.2% N, (found at 6000 m altitude) as well as 8.6% Oz and 91.4% N2 (found at 7000 m altitude) for a period of 23 rain. The gas combination was fixed and was stored in 40-1 bottles under a pressure of 150 bar. The correct ratio of the gas mixture in each bottle was quantitatively analyzed and certified by Air Liquide. In the normoxic control condition, the subjects inhaled a gas mixture of 21% 02 and 79% N z. Hypoxemia was controlled by drawing arterialized capillary blood samples from the earlobe (after hyperemization of the latter) at 0 and 14 rain before and 2, 4, 6 and 8 h after drug administration. In the first and last session (h 0 and 8), blood samples were also obtained in the last minute (23rd) of the inhalation of the hypoxic gas mixture. The blood samples were immediately analyzed by means of an Instrumentation Laboratory pH Blood-gas Analyzer IL-1306 resulting in the following measurements: pH, PO2, PCD2, base excess (BE, nmol/1), and standard bicarbonate (nmol/1). Moreover, transcutaneous oxygen tension was continuously monitored by means of Sensor Medics Transend System. Although transcutaneously measured oxygen tension is somewhat lower than the one measured in the arterialized capillary blood, the values have been found to be correlated (+0.90; P,e~....
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Fig. 5. Noopsychic deterioration under moderate (9.8% 02) and marked (8.6% 02) hypoxia after acute oral placebo, 6 mg and 9 mg CDM based on discriminant analysis (centroids) of changes in nine noopsychic variables. Time is shown in the abscissa, changes from normoxic baseline are represented in the ordinate and are expressed in Euclid's distances (mm). Under moderate hypoxia (top), a noopsychic deterioration occurs, which is attenuated only by 6 mg CDM in the 2nd hour after drug administration. Under marked hypoxia, (bottom) noopsychic performance deteriorates after all three substances. There are no differences between placebo-induced and CDM-induced changes (n= 18). * P
