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Lumbar and ventricular CSF concentration of homovanillic acid (HVA) and 5-hydroxy-indole-acetic acid (5-HIAA) have been determined in 13 patients admitted to hospital for suspected normal pressure hydrocephalus. Low values of HVA in lumbar CSF were found in all patients with reduced CSF absorption and CSF flow inversion. The HVA lumbar concentration remained low after shunt procedure; it increased if obstruction of the shunt occurred. The ventricular CSF concentration of HVA was normal before surgery; it became higher, in two cases, after surgery. No important variations were found in the lumbar and ventricular CSF concentration of 5-HIAA. The possible mechanisms and diagnostic value of these findings are discussed.

The uptake of imipramine- 14 C, desipramine- 14 C, amitriptyline- 14 C and chlorimipramine- 14 C was studied in rat isolated atria incubated in a medium containing concentrations of the drugs ranging from 10 −8 to 10 −5 M: the tissue levels were linearly related to the concentration in the incubation medium, the four lines sharing almost the same equation: accumulation appeared to be a passive unsaturable process for each drug. Desmethyldoxepin, desmethyl-chlorimipramine, nortriptyline were 4–5 times less potent than desipramine in inhibiting l- 3 H-noradrenaline uptake, while the tertiary amines (imipramine, amitriptyline, chlorimipramine and doxepin) were far less potent. Apart from desipramine, which showed some sympathomimetic activity, the main effect of the drugs was a slowing of the spontaneous atrial rate which was more evident for the dimethyl than for the monomethyl compounds. All drugs potentiated l-noradrenaline chronotropic response to varying degrees, but the potentiation of noradrenaline response was not always correlated with the inhibition of its uptake. Thus, inhibition of uptake is not a valid parameter for prediction of noradrenaline potentiation and vice versa. Drug tissue concentrations correlated with l- 3 H-noradrenaline uptake inhibition but not with potentiation of l-noradrenaline chronotropic response.

Diazepam (DZ) placental transfer in pregnant women at term, following single or repeated drug administration by various routes, was evaluated. DZ and its metabolite N-demethyldiazepam (NDZ) were constantly present in umbilical cord plasma at concentrations comparable to the mother's shortly after drug administration. N-methyloxazepam (MOX) was detected in cord plasma only in a limited number of cases following chronic DZ treatment. Postmortem analysis of fetal tissue concentrations showed accumulation of NDZ in heart and lungs. Differences in NDZ concentrations between venous cord (VC) and arterial cord (AC) plasms suggest metabolic degradation of DZ in the fetus. The DZ apparent plasma half-life in the newborn was found to be longer (31 plus or minus 2 hr) than previously observed in infants and children. The low drug clearance appears to be linked to reduced urinary excretion of hydroxylated metabolites, suggesting limited capability to dispose of DZ in the newborn.

I.p. administration of d-amphetamine sulphate and fenfluramine · HCl at various doses induced significant modifications of brain noradrenaline (NA) and MOPEG-SO4 (3-methoxy-4-hydrorxyphenylethyleneglycol) in the rat. Both drugs induced a decrease in brain noradrenaline but the two compounds seem to interact with the central noradrenergic system through a different mechanism. The decreased levels of noradrenaline after 1-fenfluramine administration were paralleled by increased MOPEG-SO4 levels. The d-isomer of fenfluramine was less active than the l-isomer. Amphetamine was considerably more effective than 1-fenfluramine in reducing NA concentration. However, in spite of the long lasting effect on noradrenaline levels the i.p. administration of amphetamine did not lead to an increased MOPEG-SO4 concentrations suggesting a more complex interaction with the noradrenergic system.

Carbamazepine (CBZ) binding by human plasma proteins was studied by means of three different techniques : ultrafiltration, equilibrium dialysis and MSA (Microspheres of Serum Albumin). The validity of the new MSA procedure for determining binding parameters was confirmed. The effects of plasma dilution and of temperature were also investigated. The association constant for albumin was found to be relatively low : 1.35 × 10 3 l/mole with an n value of 1.06 sites/mole. The data suggest that other proteins may be implicated in CBZ binding by human plasma. For concentrations within the therapeutic range (5–30 μg/ml) the unbound fraction of CBZ was 24%.

1. In patients with mild or moderate essential hypertension, oral propranolol, given in incremental doses, produced a moderate but significant lowering of blood pressure which was correlated with the concentration of propranolol in plasma. 2. Propranolol also reduced plasma renin activity (PRA) in the supine posture, on standing and after intravenous frusemide. However, ‘supine’ and ‘frusemide’ PRA values were markedly reduced at a plasma concentration of propranolol that had little effect on blood pressure. 3. On administration of propranolol there was little correlation between blood pressure decrease and PRA suppression, and even less between pretreatment PRA values and hypotensive response. 4. It is concluded that in patients with mild and moderate hypertension and low or normal plasma renin activity, suppression of PRA is not an important determinant of the hypotensive response to propranolol.

A procedure for determining carbamazepine in biological specimens both from animals and humans is described. Carbamazepine was found to enter the brain relatively rapidly and its distribution is uniform through the body. In animals absorption and tissue distribution was found to be influenced to a certain extent by the vehicle employed. A clear correlation between the brain levels and the protection towards maximal electroshock was observed. Preliminary data on humans suggest a relatively slow absorption. An oral dose of 6 mg/kg gives plasma levels comparable to the ones obtained after an administration of 400 mg/kg in rats.

A method to measure butyrophenones as such in GLC was developed and applied for the determination of these drugs in biological materials. Haloperidol and trifluperidol show many properties in common when they are injected. They penetrate very rapidly into brain where they reach levels several times higher than in plasma. The brain concentration able to inhibit completely the effects of amphetamine is for both drugs between 30 and 40 ng/g. Haloperidol and trifluperidol are different in their capacity to accumulate in the adipose tissue in vivo and in vitro. The GLC method to measure butyrophenones has been employed for determining haloperidol in the plasma of psychiatric patients treated with this drug for therapeutical reasons.

Levels of diphenylhydantoin (DPH) and phenobarbital (PB) in plasma and brain of rats after single or combined, acute or chronic treatment have been determined. The results obtained indicate (a) drug plasma levels are not always a reliable index of brain levels because DPH disappearance from plasma is frequently more rapid than from brain; (b) DPH administration enhances the plasma and brain levels of PB; (c) levels of DPH or PB in brain correlate with the protection against a maximal electroshock.

Tryptophan injected intracerebrally in rats increases the level of brain serotonin. This increase occurs also in animals pretreated with reserpine or with a monoamineoxidase inhibitor. Other studies show that tryptophan, tryptamine or 6-hydroxytryptamine are not interfering in the determination of brain serotonin.

1. The uptake of unlabelled and [(14)C]-desipramine was studied in rat isolated atria incubated in a medium containing concentrations of desipramine ranging from 200 pg/ml to 2 mug/ml. The uptake was found to be dose- and time-dependent. Equilibrium was not reached after 2-3 h of incubation unless concentrations of desipramine higher than 1 mug/ml were used.2. The washout curves of atria previously loaded with desipramine showed that the drug is slowly released and that this release is not influenced by its initial tissue concentration.3. The binding appeared to be at non-specific sites and not at sites where noradrenaline is stored since atria taken from rats treated with 6-hydroxydopamine accumulated the drug at the same rate as control atria.4. The inhibition of (-)-noradrenaline uptake and the potentiation of the chronotropic response to (-)-noradrenaline is correlated with the concentration of desipramine in atria for tissue levels of the drug ranging from 0.01 to 1 mug/g. Higher tissue levels show less potentiation of the effect of (-)-noradrenaline or even inhibition of the maximal response to (-)-noradrenaline. These concentrations of desipramine (> 7 mug/g) markedly depressed the atrial rate.5. The results show that despite the accumulation of desipramine by unspecific sites, concentrations of desipramine in the tissue are correlated with the pharmacological response. Furthermore a gradual shift from potentiation to inhibition of noradrenaline response can be obtained with the same bath concentrations of desipramine by increasing the time of incubation.

Summary Benzodiazepines are often used during labor, and they arealso frequently administered to newborns in cases ofseizure. In adults this class of drug requires an extensivemetabolization in order to be eliminated.The physiological elimination of diazepam admi-nistered at the dose of 0.3 mg/kg by intramuscular route(Tab. I), was followed up in three groups of subjects{premature infants, full-term infants and children). Plasma levels of diazepam (DZ) and of its major metaboliteN-demethyldiazepam (NDZ) could be followed up for48 hours after drug administration in 4 premature infantsand 4 children. 24 hour urinary excretion of DZ, NDZ, N-Methyl-oxazepam (MeOX) and Oxazepam (OX) was followed upin 7 premature infants, 8 full term infants and 5 children.Determination of benzodiazepine compounds both inplasma and urine, was performed, after etheral extraction,by GLC-ECD. In the urine samples free and conjugatedcompounds were measured (Tab. HD.The apparent disappearance rate of diazepam plasma wassignificantly reduced

A variation in the rate of disappearance from plasma, at different times of the day, has been observed for exogenous Cortisol in humans after i.v. administration. This appears to correlate with the endogenous cortisol plasma levels. The possibility of a circadian fluctuation of drug metabolizing enzyme activities in man is discussed.

Imipramine and desipramine injected intracerebrally increase the temperature of fully reserpinised rats. Desipramine is more effective than imipramine in this. The effect of imipramine seems to be independent of the formation of desipramine in the brain. That imipramine, injected intraperitoneally, leads to an accumulation of brain desipramine has been confirmed.

A sensitive and specific method for the quantitative determination of imipramine in human biological fluids is described. After extraction with n -hexane, imipramine is detected by gas-liquid chromatography-mass fragmentography. The procedure permits routine analysis on relatively small amounts of plasma (1–2 ml) containing as little as 10 ng/ml of imipramine without any interference from endogenous substrates.

A gas chromatographic method for the determination of propranolol in plasma has been developed. After solvent extraction, a difluorobutyrate derivative is formed, which is measured by an electron capture detector. The quantification is controlled by using an internal standard, pronethalol, which is added to all samples. The electron capture detector response was linear between 5 and 80 ng/ml. No interference from common cardiovascular drugs was found. Concentrations of propranolol in the plasma determined by this method were directly related to the administered dose of the drug.

A simple and sensitive gas-chromatographic method for the determination of methyloxazepam in small samples of blood or plasma is described. After ethereal extraction the methyloxazepam was converted to its O-trimethylsilyl derivative and then processed gas-chromatographically. The procedure allows routine analysis on blood capillary samples (100–200 μl) containing as little as 5 ng/ml of methyloxazepam without any interferences from endogenous substrates

The effect of DMI on the absorption of orally administered phenylutazone was studied in human subjects. A single pretreatment with 50 mg of DMI delayed the time to peak absorption of phenylbutazone in 4 volunteer subjects. Peak phenylbutazone plasma levels in untreated subjects were reached 2–6 hr after oral phenylbutazone administration while peaks were not attained even 10 hr after DMI treatment. A seven-day chronic pretreatment with DMI (25 mg, 3 X day) delayed time to peak absorption of phenylbutazone in 4 chronically depressed females from 2 hr (before DMI) to 4–10 hr when phenylbutazone was administered 30 min after the last dose of DMI. When phenylbutazone was given 14 hr after the last dose of a ten-day chronic treatment with DMI (25 mg, 3 X day) to another group of 4 females, no clear effect on the time to peak absorption was observed although plasma levels of phenylbutazone were lower in all 4 patients. The individual differences in phenylbutazone plasma levels may be due to individual variations in the metabolism of DMI.

I.p. administration of piribedil methansulphonate to male Sprague-Dawley rats resulted in a remarkable increase of brain MOPEG-SO4 which was consistent over time. In parallel experiments brain content of NA was found significantly reduced 30 and 60 min after drug administration. The effect seems to be dose dependent. These data cast some doubts on the relative specificity of action of piribedil as a dopaminergic activator.

A new analytical procedure is described for the determination of fenfluramine and norfenfluramine in biological specimens. Fenfluramine and norfenfluramine are converted to the trichloroacetyl derivatives, separated on a 3% OV 17 — Chromosorb Q glass column and measured by ECD. The rapidity, sensitivity and specificity of the technique fulfil all the requirements for routine clinical use.

Lumbar CSF concentrations of homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5HIAA) have been determined in ten patients suffering from chronic brain post-traumatic syndromes, at various length of time after the brain trauma. Lower concentrations of HVA (mean 21 +/- 14 mug/ml) compared to controls (mean 46 +/- 10 mug/ml) was observed in 7 cases; 5HIAA levels were within normal values. The 5HIAA/HVA ratio (1.59 +/- 0.66) was significantly higher (p less than 0.001) than the one recorded in controls (0.66 +/- 0.10). Monitoring of lumbar HVA and 5HIAA over time, before, during and after L-dopa treatment, revealed interesting correlations between modification of clinical picture and the levels of monoamines acid metabolites. The data indicate a profound alteration of brain monoamines in chronic syndromes following a severe head injury and suggest that measurements of lumbar HVA and 5HIAA in these patients may be of euristic and diagnostic value.

(1975). Metabolism and Pharmacokinetics of Carbamazepine. Drug Metabolism Reviews: Vol. 4, No. 1, pp. 97-113.

Ventricular concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were evaluated in 17 patients suffering from brain tumor and 4 pseudo-tumor patients. Significant differences were observed in those patients in whom the tumor leads to a marked modified CSF dynamic. No relationship were on the contrary observed between VFP and HVA or 5-HIAA levels.

It has become evident in recent years that duration and intensity of the action of a given drug are in many instances closely related to its biological availability and disposition.

Drug plasma levels of N-desmethyldiazepam (10 and 20 mg/day given at night) and amylobarbitone sodium (200 mg/day given at night) were determined in 45 patients after 1 and 7 days of treatment together with estimates of hypnotic and residual effects. No relationships were found between clinical rati ngs of hypnotic effect and drug plasma levels, while significant correlations were observed between some performance taska and drug plasma concentrations of amylobarbitone sodium, and of the higher dose of N-desmethyldiazepam.

Ventricular concentrations of homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5HIAA) were measured in 7 patients a few days after a severe traumatic brain injury. Both acid metabolites were elevated in respect to control patients values, however, the rise was more consistent for 5HIAA (258 +/- 86 ng/ml) with a 5HIAA/HVA ratio of 0.85 +/- 0.35. The data support previous hypothesis on the profound involvement of serotoninergic structures in the early stages of acute traumatic brain syndromes and on the role of 5HT in maintaining edema and vasospasm.

Nomifensine pharmacokinetics were determined in healthy volunteers after the oral administration of 50 mg of the drug. Peak plasma levels of 95-177 ng/ml were attained within 1 to 4 hrs, and the apparent plasma half-lives ranged from 3.3 to 4.9 hrs. Assuming 100% bioavailability the drug has a relatively large apparent volume of distribution. From these findings it appears that the pharmacokinetics profile of nomifensine is considerably different from those of other known antidepressants. Implications for dosages schedules are discussed.

The levels of diazepam and its N-desmethyl metabolites were measured in adipose tissue of rats and mice, at different times after administration of diazepam (5 mg/kg i.v.). In the adpose tissue there was a progressive accumulation of diazepam for up to 30 min after injection and even after 5 hr diazepam was measurable. Diazepam was present in both white (epidydimal) and brown (intrascapular) adipose tissue. In rats N-desmethyl metabolites were present only in traces while in mice they reached high levels. In humans diazepam was detectable in the scapular adipose tissue only 30 and 60 min after intravenous injection of 10 mg of the drug, while at earlier or later times the levels were under 25 ng/g.

Carbamazepine-10,11-epoxide was identified in human urine collected after the oral administration of 400 mg. of carbamazepine. Mass spectrometric characterization confirmed the structure of this metabolic product, which was postulated after comparison with the synthetic epoxide.

IT has been suggested1–4 that monosodium glutamate (MSG) is responsible for the “Chinese restaurant syndrome”—a burning sensation in the back of the neck spreading to the forearms and to the anterior thorax, accompanied by a feeling of infraorbital pressure, tightness and substernal discomfort. But no study of this phenomenon involved a double blind technique, or any other experimental condition which can be used to assess the significance of subjective reactions.

Intracerebral injection of fluoroacetate and fluorocitrate were made in rats by manual and stereotaxic technique. Fluorocitrate was found to be at least 100 times more toxic than fluoroacetate under various experimental conditions. Fluorocitrate was more toxic when injected in the third cerebral ventricle, or in the nucleus reuniens thalami than when injected in the lobus frontalis. Gas chromatographic determination of fluoroacetate shows that this compound is rapidly removed as such from the brain. These results and their implications are discussed in relation to current views of the action of these compounds.