Pharmacokinetics of latanoprost in the cynomolgus monkey. 1st communication: single intravenous, oral or topical administration on the eye.

Latanoprost (13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2a- isopropyl ester, CAS 130209-82-4 PhXA41, Xalatan) is a prodrug used for reduction of the intraocular pressure in the treatment of glaucoma. The pahrmacokinetics of this drug was studied in the cynomolgus monkey after intravenous, oral and topical administration of 9 beta-[3H] labelled latanoprost. The plasma profile of radioactivity from HPLC separation of samples obtained after intravenous as well as topical administration on the eyes showed a rapid and complete hydrolysis of the ester. The pharmacologically active acid of latanoprost showed a maximum concentration 5 min post topical administration and an elimination half-life of about 10 min. Tertiary butyldimethylsilyl derivatives were prepared of the radioactive fractions collected from the HPLC column. The derivatives were analysed by gas chromatography-mass spectrometry (GC-MS). After oral administration no latanoprost and very little of its acid was present in plasma, indicating a first-pass metabolism resulting in more polar compounds. Based on the retention times on the HPLC and GC and on a mass spectrum similar to the acid of latanoprost but 28 daltons lower, the main metabolite in urine and faeces was identified as the 1,2-dinor acid of latanoprost. In a similar way a more polar fraction from urine was identified as the 1,2,3,4-tetranor metabolite of the acid of latanoprost. The tissue distribution after i.v. and topical administration was similar with organs of metabolism (liver) and elimination (kidney) containing the highest concentrations. After topical application much of the dose was found in the anterior ocular tissues but not in the posterior parts of the eye. In conclusion, latanoprost is a prodrug which in vivo rapidly is hydrolysed to the corresponding free acid. The acid of latanoprost has a short half-life in plasma and is extensively metabolised mainly through beta-oxidation before it is excreted into the urine and faeces.

Pharmacokinetics of latanoprost in the cynomolgus monkey. 2nd communication: repeated topical administration on the eye.

Latanoprost (13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2a isopropyl ester, CAS 130209-82-4 PhXA41, Xalatan) is an antiglaucoma prodrug which enhances the bioavailability of the drug into the eye compared to the corresponding acid. The pharmacokinetics and metabolism of this drug was studied in the cynomolgus monkey after daily topical administration on the eye of [13,14-(3) H] labelled latanoprost (6 micrograms per eye) during 21 days. Plasma, urine and homogenised faeces samples were purified by separation on a Sep-Pak C18 cartridge before analysis by reversed phase liquid chromatography (RP-HPLC) with one-line radioactivity detection. The maximum plasma concentration of radioactivity obtained within 10 min post dose was as a mean 7.87 +/- 3.18 ng eq./ml on day 1 and 9.31 +/- 4.21 ng eq./ml on day 21. The plasma concentration of radioactivity declined rapidly up to 3 h post-dose both on day 1 and day 21, but a small amount of tritiated water accumulated with time. The majority of the radioactivity was recovered in urine but substantial amounts were also eliminated in the faces. No latanoprost was found in plasma after repeated topical administration on the eye. The plasma profiles from HPLC separation of samples showed a rapid and complete hydrolysis of the ester. The elimination half-life of the acid of latanoprost was estimated to be 13.8 +/- 1.7 min for day 1 and 12.4 +/- 4.8 min for day 21. No induction or inhibition of the metabolism occurred after the repeated administration. By comparison with reference substances the 15-keto acid of latanoprost was found to be present in plasma and the major metabolites in urine and faeces collected during day 2 and day 20 were identified as 1,2-dinor acid of latanoprost, 1,2,3,4-tetranor acid and 1,2,3,4-tetranor lactone of latanoprost. Tritiated water was excreted in the urine and a small amount of the acid of latanoprost was excreted in the faeces. In conclusion, latanoprost was rapidly absorbed and hydrolysed to the corresponding acid after repeated topical administration to the monkey eye. The acid of latanoprost had a short half-life in plasma and it was partly converted to the 15-keto acid of latanoprost. beta-Oxidation of the acid of latanoprost was the major metabolic pathway. No induction or inhibition of the metabolism occurred upon repeated administration and no indications of accumulation of the drug or drug metabolites were observed. The pharmacokinetics of latanoprost was similar after a single and repeated topical administration.

Pharmacokinetics of latanoprost in the cynomolgus monkey. 3rd communication: tissue distribution after topical administration on the eye studied by whole body autoradiography. Glaucoma Research Laboratories.

Latanoprost (13,14-dihydro-15(R)-17-phenyl-18,19,20-trinor-PGF2 alpha-isopropyl ester, CAS 130209-82-4, PhXA41, Xalatan), an antiglaucoma drug, labelled with tritium at carbon 13 and 14 (4.8 micrograms, 20.8 MBq/eye) was administered topically on the eyes of cynomolgus monkeys. After 0.5 h the concentration of radioactivity in the cornea was estimated to be about 0.6 ng eq/mg tissue. The elimination half-life of total radioactivity in the cornea was about 4 h. The corneal epithelium contained a higher concentration of radioactivity than the stroma. Cornea seemed to act as a slow release depot to the anterior part of the eye. In the iris, anterior chamber and ciliary body the maximal concentrations were 217.0 +/- 12.9 pg eq/mg, 99.8 +/- 7.4 pg eq/mg and 54.0 +/- 4.9 pg eq/mg, respectively, 1 h after administration. The elimination half-life of total radioactivity from these tissues was 3-4 h. Trace amounts (0.4-9 pg eq/mg) remained in these tissues 24 h after administration. Initially the radioactivity was present in the conjunctiva, sclera and choroid as well as in the general circulation. Radioactivity passed through the lachrymal ducts and high concentrations were observed in the oesophagus, stomach content, small intestine, bile and urine of a monkey administered latanoprost topical on the eye 0.5 and 1 h before sacrifice. In this animal concentrations of radioactivity were found in the kidney, liver, wall of the small intestine and blood. All other tissues in this animal contained lower concentrations of radioiactivity than the blood. In an animal sacrificed 2 h after administration of tritium labelled latanoprost on one eye and 6 h after administration on the other eye the highest concentrations of radioactivity were found in urine, bile and in the stomach content. Low concentration of radioactivity remained in the kidney and the liver. In a monkey administered latanoprost 12 and 24 h before death low concentrations remained in the colon, bile and urine. The anterior parts of the eyes from the monkey sacrificed 0.5 and 1 h after administration of latanoprost were cut out from the tissue sections for HPLC analysis. The predominating peak present corresponded to acid of latanoprost (PhXA85). In the stomach the radioactivity chromatographed as latanoprost and the acid of latanoprost. In the small intestine and in bile the main radioactive peak corresponded to 1,2-dinor-acid of latanoprost and in addition several more polar metabolites were present. In conclusion, latanoprost penetrated the cornea, was hydrolysed and slowly released into the anterior parts of the eye the site of action. The maximum concentration in the eye was reached after 1 h with an elimination half-life of 3-4 h. In the body the distribution was limited mainly to the gastro-intestinal tract, the kidney, the gall- and urinary bladder.

Age-related melanogenesis in the eye of mice, studied by microautoradiography of 3H-methimazole, a specific marker of melanin synthesis.

Whether melanogenesis occurs in adult eyes is still a matter of controversy. It has been widely held that the pigment epithelial cells are fully melanized at birth, and that the uveal melanocytes cease their melanin production in the very young individual. Therefore there should be no turnover of melanin in the adult eye. A number of studies have, however, demonstrated that the enzyme involved in melanin synthesis, tyrosinase, seems to be active also in the adult eye. The recent observation that a prostaglandin analogue, used in glaucoma therapy, caused increased iridal pigmentation in the treated eye, but not in the untreated eye, of adult monkeys and in humans, indicate that the adult eye at least has the capacity to produce melanin. In the present study 3H-methimazole, a false melanin precursor, was administered to a series of DBA-mice, 3 weeks to one year of age. The eyes were removed 24 hr after a single i.p. injection of 3H-methimazole. Using microautoradiography the incorporation of radioactivity was studied in X-ray film covered sections comprising the entire eye. A very selective accumulation of radioactivity was seen in uveal melanocytes and in the pigment epithelial cells in the iris and the ciliary body. The level in the retinal pigment epithelium was low in the eyes of all ages. No uptake was seen in any non-pigmented ocular tissue. The most pronounced accumulation was seen in the pigment epithelium and melanocytes in the iris of the young mice, but some activity was seen in these cells also in the older mice. The presence of immature melanosomes seen in electron micrographs from iridal pigment cells and melanocytes of one year old mice indicate that new melanosomes are formed in these cells also in adult animals. The results of this study thus strongly indicate that there seems to be an active melanin synthesis in the adult eye of the mouse, most pronounced in iridal melanocytes and in the iridal pigment epithelium.

The pharmacokinetics of a new antiglaucoma drug, latanoprost, in the rabbit.

Latanoprost (13,14-dihydro-17-phenyl-18,19,20-trinor-prostaglandin F2alpha-1-isopropyl ester) is a unique prostaglandin analogue developed for the treatment of glaucoma. To investigate the pharmacokinetics, tritium-labeled latanoprost was administered topically on the eyes of rabbits and intravenously. About 7.7% of the applied dose was found in the cornea at 15 min after the drug administration. The following Cmax and elimination half-life (interval 1-6 hr) values of the total radioactivity in the eye tissues were found: aqueous humor, 0.09 ng eq/ml and 3.0 hr; anterior sclera, 1.49 ng eq/mg and 1.8 hr; cornea, 1.59 ng eq/mg and 1.8 hr; ciliary body, 0.39 ng eq/mg and 2.8 hr; conjunctiva, 1.41 ng eq/mg and 1.4 hr; and iris, 0.39 ng eq/mg and 2.1 hr. Latanoprost was rapidly hydrolyzed, and most of the radioactivity found in the aqueous humor, anterior eye tissues, and plasma corresponded to the pharmacologically active acid of latanoprost. The initial plasma elimination half-life of the acid of latanoprost was 9.2 +/- 3.2 min after iv and 2.3 +/- 1.9 min after topical administration on the eyes. The plasma clearance of the acid of latanoprost was 1.8 +/- 0.3 liters/hr.kg, and the volume of distribution was 0.4 +/- 0.1 liter/kg after iv administration. Based on the retention times on HPLC and GC-MS, the main metabolite in urine and feces was identified as the 1,2,3,4-tetranor metabolite of acid of latanoprost. This acid existed in equilibration with the corresponding delta-lactone. The AUC of radioactivity in the eye tissues was approximately 1000 times higher than in plasma AUC. The recovery of radioactivity was complete.

Development of a radioimmunoassay for latanoprost and its application in a long-term study in monkeys.

13,14-Dihydro-17-phenyl-18,19,20-trinor-PGF2 alpha-isopropyl ester (latanoprost) is a new prostaglandin drug developed for the treatment of glaucoma. In clinical trials a daily dose of 1.5 micrograms is effective in reducing the intraocular pressure. In toxicological studies doses from 2 micrograms/eye to 100 micrograms/eye have been used in various species. This paper reports the development and validation of a radioimmunoassay of latanoprost acid (PhXA85) and its application to toxicokinetic studies performed in monkeys. An antiserum was raised in rabbits by immunization with PhXA85 coupled to BSA at the carboxylic acid by the mixed anhydride method. The antibody titre was found to be about 1:2000 to 1:3000. The cross-reactivity with 13,14-dihydro-15(R,S)-17-phenyl-trinor-PGF2 alpha, 13,14-dihydro-15(S)-17-phenyl-trinor-PGF2 alpha, dinor-PhXA85. 17-phenyl-trinor-PGF2 alpha, latanoprost and PGF2 alpha was 46.4, 4.2, 7.6, 2.2, 0.1 and 0.039%, respectively. The intra-assay precision was between +/-7.7 and 11.7% (CV) at the level of 320 pg/ml and +/-8.3 and 9.7% with 1280 pg/ml in plasma samples from man, monkey, rat and aqueous humour from human and rabbit. Similarly, the intra-assay accuracy varied between 95.9 and 102.5% and 89.0 and 109.0% for the low and high standards, respectively. The inter-assay precision and accuracy were between +/- 6.0 and 13.4% and 91.0 and 92.8% in the monkey plasma samples. The limit of detection was 3 pg/tube or 30 pg/ml. In a long-term study, the acid of latanoprost was rapidly cleared from plasma in monkeys treated with eye drops of latanoprost (2 x 3 micrograms/day) over a period of 1 year.

Corneal permeability to and ocular metabolism of phenyl substituted prostaglandin esters in vitro.

The corneal permeability to and metabolism of four phenyl substituted prostaglandin analogues have been studied in vitro. Porcine corneas were mounted in incubation chambers dividing each chamber into an epithelial and endothelial side compartment. The analogues were added to incubation medium on the epithelial side. The permeability coefficients of 17-phenyl-18,19,20-trinor-PGF2 alpha-1-isopropyl ester (PhDH100A), 15-keto-17-phenyl-18,19,20-trinor-PGF2 alpha-1-isopropyl ester (PhXA12), 13,14-dihydro-15-hydroxy (R, S)-17-phenyl-18,19,20-trinor-PGF2 alpha-1-isopropyl ester (PhXA34) and 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2 alpha-1-isopropyl ester (PhXA41) were determined to be in the range of 5.1-11.0 x 10(-6) cm x s-1. All analogues in the endothelial compartment had been hydrolysed to corresponding acids but any other metabolism of PhDH100A, PhXA34 and PhXA41 after 4 h of incubation was minimal. In contrast, PhXA12 free acid was extensively metabolised to the 13,14-dihydro metabolite. To investigate whether the porcine ocular tissues contain 15-hyroxyprostaglandin dehydrogenase (15-PGDH) activity, prostaglandin F2 alpha (PGF2 alpha) and PhDH100A were used as substrates. PGF2 alpha and the phenyl-substituted analogues were also tested for their capacity as substrate to 15-PGDH in general. The 15-PGDH activity was low in all ocular tissues. The capacity of various ocular tissues or purified 15-PGDH to metabolise PhDH100A was lower than with PGF2 alpha as substrate. PhXA34 and PhXA41 were found not to be metabolised by 15-PGDH. Thus, the phenyl substituted PG esters penetrated the cornea and in the process were hydrolysed to their corresponding acids. No appreciable further metabolism occurred except for PhXA12 which was reduced by delta 13-reductase.

Effects of sulfasalazine and a sulfasalazine analogue on the formation of lipoxygenase and cyclooxygenase products.

A sulfasalazine analogue, 5'-(2,4-dichlorobenzoyl)2'-hydroxyphenylacetic acid (CL 42A), potently inhibited the formation of 5-lipoxygenase products (leukotrienes B4 and C4 and 5-hydroxyeicosatetraenoic acid) by human leukocytes. Half-maximal inhibition of leukotriene production was obtained with 5 and 10 microM CL 42A after stimulation with serum-treated zymosan or ionophore A23187, respectively. CL 42A was equipotent to nordihydroguaiaretic acid and about 50 times more potent than sulfasalazine and benoxaprofen in studies on the inhibition of LTB4 formation in leukocyte suspensions stimulated with serum-treated zymosan. Furthermore, CL 42A had no inhibitory effect on the production of 15-hydroxyeicosatetraenoic acid after incubation of human leukocytes with ionophore A23187 in the presence of exogenous arachidonic acid. Sulfasalazine inhibited the synthesis of 5-lipoxygenase products (5-hydroxyeicosatetraenoic acid and leukotriene B4: IC50 250 microM, leukotriene C4: IC50 100 microM) in a concentration-dependent manner but had no effect on 15-hydroxyeicosatetraenoic acid formation. The metabolites of sulfasalazine, sulfapyridine and 5-aminosalicylic acid, and the isomer, 4-aminosalicylic acid, were all less potent than sulfasalazine as inhibitors of leukotriene formation. Both CL 42A (IC50 20 microM) and sulfasalazine (IC50 500 microM) inhibited the synthesis of thromboxane B2 and hydroxyheptadecatrienoic acid in human platelet suspensions after arachidonic acid stimulation. However, while CL 42A inhibited cyclooxygenase, the inhibitory effect of sulfasalazine was exerted mainly on thromboxane synthase. The platelet formation of 12-hydroxyeicosatetraenoic acid was not inhibited by CL 42A whereas sulfasalazine had a weak inhibitory effect.

The influence of thiamine deficiency and ethanol on rat brain catecholamines.

In rats treated with a thiamine deficient diet for 30 days the brain content of total thiamine decreased by 27-50%. Thiamine deficiency decreased the dopamine (DA) concentration of the striatum indicating a reduced synthesis of DA. In the hypothalamus the levels of the catecholamine metabolites homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenyl glycol (HMPG) were reduced indicating a reduced DA and noradrenaline (NA) turnover. Animals on a diet containing 5% ethanol had increased concentrations of HVA and HMPG in rest brain indicating an increased DA and NA turnover. The concentration of 1-carboxysalsolinol (1-CSAL) and salsolinol (SAL) in the brain stem was increased in animals receiving ethanol. Thus, both thiamine deficiency and ethanol treatment influenced the catecholamine system in a complex region-dependent way. In the brain regions most susceptible to brain damage in thiamine deficiency, i.e., hypothalamus and brain stem, 1-CSAL and SAL increased most following thiamine deficiency combined with ethanol intake.

Ethanol-induced hypothermia and biogenic amine metabolites.

Ethanol is known to cause hypothermia. The rectal temperature of rats receiving ethanol, 4 g/kg i.p., at an ambient temperature of 23 degrees C decreased by 2 degrees C. This body temperature decrease could be prevented by keeping the animals at an ambient temperature of 34 degrees C. Irrespective of the body temperature it was found that the concentration of the major metabolites of dopamine and serotonin in brain tissue was significantly increased. Thus, the change in brain monoamine metabolite levels in rats after administration of ethanol are not due to ethanol-induced hypothermia.

The effect of ethanol on the brain catecholamine systems in female mice, rats, and guinea pigs.

The effect of acute ethanol administration on the concentrations of dopamine (DA), norepinephrine (NE) and their metabolites (3,4-dihydroxyphenylacetic acid [DOPAC], homovanillic acid [HVA], 3,4-dihydroxyphenylglycol [DHPG] and 4-hydroxy-3-methoxyphenylglycol [HMPG]) in brains of female mice, rats, and guinea pigs were investigated. A subhypnotic dose (2 g/kg) or a hypnotic dose (4 g/kg) of ethanol was administered intraperitoneally and the animals were killed 45 min later. In the rat the DA levels were unchanged, while the NE concentrations were decreased after both doses of ethanol. The DA levels did not change in the mouse and guinea pig, while the concentrations of NE showed a minor decrease in the mouse but were unaffected in the guinea pig. After 4 g/kg of ethanol the DOPAC and HVA concentrations were elevated significantly in all three species, and after 2 g/kg the DOPAC levels were increased in the rat and guinea pig brains and the HVA levels in the mouse and guinea pig brains. In the mouse and rat brain the DOPAC + HVA concentrations indicated a dose response relationship: 4 g/kg was significantly more effective than 2 g/kg. The DHPG concentration increased in the rat brain after both 2 and 4 g/kg, while the HMPG concentrations increased significantly only after 2 g/kg. In the mouse and guinea pig the brain DHPG concentrations remained unchanged, while the HMPG concentrations increased after both 2 and 4 g/kg ethanol. These data suggest, that the turnover of both DA and NE was increased 45 min after a subhypnotic as well as after a hypnotic dose of ethanol in all three species studied.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of acute ethanol on the catecholamine system in man as reflected in cerebrospinal fluid and urine. A new condensation product, 1-carboxysalsolinol.

Urine and cerebrospinal fluid (CSF) were collected from 10 healthy male volunteers after ingestion of 120 g ethanol and under similar conditions without ethanol. Dopamine (DA), homovanillic acid (HVA), norepinephrine (NE), 4-hydroxy-3-methoxyphenylglycol (HMPG), 4-hydroxy-3-methoxymandelic acid (HMMA = VMA), 1-carboxysalsolinol (1-CSAL), salsolinol (SAL) and methylated salsolinol (M-SAL) were analyzed with gas chromatography-mass spectrometry. In CSF collected 6 h after ethanol intake the concentration of NE and its metabolite HMPG were significantly elevated (P less than 0.025 and P less than 0.005, respectively) compared to control conditions. The other compounds analyzed did not change significantly. In urine collected during 10 h after ethanol administration the excretion of HMMA was significantly reduced (P less than 0.01) and the HMPG/HMMA ratio was significantly elevated (P less than 0.005) reflecting a change in the peripheral red-ox state during ethanol oxidation. The excretion of DA and its major metabolite HVA did not change. However, the DA-derived condensation products 1-CSAL (from DA and pyruvate) increased (P less than 0.001), while SAL (from DA and acetaldehyde) decreased (P less than 0.005) after ethanol ingestion compared to the control situation. The increased excretion of 1-CSAL indicated that the ethanol metabolism interferes with the glucose metabolism, probably through an acetaldehyde-mediated inhibition of the pyruvate dehydrogenase complex.

Identification and quantification of 1-carboxysalsolinol and salsolinol in biological samples by gas chromatography--mass spectrometry.

1-Carboxysalsolinol was found to be present in rat striatum, human urine and caudate nucleus of post mortem human brain, according to capillary column gas chromatographic retention times and selected ion monitoring of the hexafluoropropionyl ester pentafluoropropyl derivative. Simultaneous quantification of 1-carboxysalsolinol and salsolinol was performed in biological samples using deuterium labelled internal standards. In human urine, the precision of the method was +/- 7.1% (coefficient of variation, n = 25) for 1-carboxysalsolinol at 15 pmol/ml and +/- 8.5% for salsolinol at 10 pmol/ml. According to enzymatic hydrolysis, 68% of 1-carboxysalsolinol was found as conjugates in urine, and the corresponding figure for salsolinol was 92%. In human caudate nucleus, the amounts of 1-carboxysalsolinol were found to be significantly greater in brains from alcoholics, who at autopsy had ethanol present in the blood, whereas alcoholics without blood ethanol levels at autopsy had significantly lower concentrations of salsolinol.

Catecholamines and metabolites in cerebrospinal fluid of teetotallers and sober alcoholics.

Dopamine (DA), homovanillic acid (HVA), salsolinol (SAL), methylated salsolinol (M-SAL), norepinephrine (NE) and 4-hydroxy-3-methoxyphenylglycol (HMPG) were measured in cerebrospinal fluid (CSF) from 8 alcoholics who had abstained from ethanol for 3 months and from 8 teetotallers. No significant differences in the concentrations of any of these catecholamines or their metabolites were found between the two groups. In the alcoholics there was a positive correlation between age and DA (P less than 0.005), NE (P less than 0.025) and SAL (P less than 0.005) and also between DA and SAL (P less than 0.01).

Association with persistent neuroleptic-induced dyskinesia of regional changes in brain GABA synthesis.

The movement disorder tardive dyskinesia is a serious side effect of the long-term treatment of schizophrenia with neuroleptic drugs. Similar symptoms to those of tardive dyskinesia have been observed in Cebus apella monkeys following long-term treatment with neuroleptic drugs, and these monkeys may therefore be a useful animal model of tardive dyskinesia. Motor defects have persisted in these dyskinetic monkeys for periods of 1-6 yr after the cessation of neuroleptic treatment. We report here that in three regions of the brains of dyskinetic monkeys (substantia nigra, medial globus pallidus and subthalamic nucleus) glutamate decarboxylase activities and gamma-aminobutyric acid (GABA) levels are reduced relative to control monkeys that had been treated with neuroleptics but which showed none of the symptoms of tardive dyskinesia. These results suggest that alterations in the GABA neurone system are involved in neuroleptic drug-induced tardive dyskinesia.

Discrete regional distribution of biochemical markers for the dopamine, noradrenaline, serotonin, GABA and acetylcholine systems in the monkey brain (Cebus Apella). Effects of stress.

Brains from Cebus Apella monkeys have been mapped biochemically using a cryo-section technique which enables exact micro-dissectioning of tissue. Two neurotransmitters; noradrenaline (NA) and gamma-amino-butyric acid (GABA) were measured by gas chromatography-masspectrometry technique. In addition biochemical markers reflecting metabolic activity in the dopamine (homovanillic acid, HVA, 3, 4-dihydroxyphenylacetic acid, DOPAC), serotonin (5-hydroxyindoleacetic acid, 5-HIAA), noradrenaline (4-hydroxy-3-methoxy-phenylglycol, HMPG), acetylcholine (choline acetyltransferase, CAT) and GABA (glutamic acid decarboxylase, GAD) transmitter systems were assayed. The distribution of these transmitter markers roughly corresponded to earlier studies in other non-human primates, whereas similar studies on the human brain generally show lower concentrations and enzyme activities. One monkey exposed to severe stress immediately before death deviated from the normal animals with regard to HVA, 5-HIAA, GAD and GABA. For the study of neuroleptic drugs, and notably their neurological side-effects, Cebus Apella monkeys have turned out to be particularly useful. In our laboratory we have employed this species of monkey to develop a model for acute dystonia and tardive dyskinesia (Gunne and Barany 1976, 1979, Barany et al. 1979). As a first step in the topological mapping of brain neuro-chemistry in these animals we here present data from normal monkeys, not treated with neuroleptics. During the ongoing project there was an unplanned "stress experiment" in one monkey, which had a nightly fight with a cage partner and had to be sacrificed the morning after due to severe wounds. The present communication describes a method for obtaining well-defined samples from monkey brains and presents the data on homovanillic acid (HVA), 3.4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline (NA), 4-hydroxy-3-methoxy-phenyl glycol (HMPG), choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD), and gamma-amino-butyric acid (GABA) in discrete regions from 7 drug-naive control monkeys. Also data from the stressed animal are presented.