Altered growth hormone release in Huntington''s chorea.

Glucose tolerance tests have been performed on five patients with Huntington's chorea and no difference in response has been observed compared with seven controls. Insulin tolerance tests have been performed on 12 patients with Huntington's chorea and 10 controls. Blood samples were taken at regular intervals for 75 minutes and analysed for blood glucose, insulin, and growth hormone (HGH). There was no difference between the groups in the hypoglycaemia which developed. The patients, however, had an earlier elevation of HGH than the controls. The difference was highly significant (P less than 0.001, P less than 0.02) 30 and 35 minutes after the intravenous injection of insulin. The patients, although awake, ceased to have choreiform movements for at least the last 60 minutes of the insulin tolerance tests. Our observations of HGH release imply that hypothalamic activity is altered in Huntington's chorea. Further observations of HGH release may therefore be of value in its diagnosis.     

Effects of Intracerebroventricular Infusion of Somatostatin‐14 on Peripheral Glucoregulation in Dogs

Somatostatin (SST) is an inhibitory hormone that regulates numerous biological processes and circulates in two bioactive isoforms: SST‐14 and SST‐28. SST‐14 is the predominant form in the hypothalamus and regulates the secretion of growth hormone (GH) (directly) and of thyroid‐stimulating hormone (indirectly). In the periphery, SST is a potent inhibitor of glucagon and insulin secretion. In the present study, we aimed to investigate the effect of i.c.v. administration of SST‐14 on glucose metabolism. Twenty healthy adult dogs randomly received either a bolus i.c.v. infusion of 5, 25 or 50 μg of SST‐14 or an equivalent amount of artificial cerebrospinal fluid through an epicranial apparatus during fasting. The same experiment was repeated during concomitant intraduodenal infusion of glucose solution through a Mann–Bollman fistula. Serum levels of glucose, insulin and glucose‐dependent insulinotrophic peptide (GIP), plasma SST and serum GH levels were assayed. Circulating levels of SST and GH did not change significantly during i.c.v. infusions. Bolus infusion of 50 μg of SST‐14 produced an increase in serum glucose levels at 10 min (94 ± 2.5 mg/dl at baseline versus 101 ± 3 mg/dl, P = 0.04) and significantly suppressed insulin levels, reaching maximal suppression at 60 min after infusion (9 ± 1.3 μIU/ml at baseline versus 4.6 ± 0.5 μIU/ml P = 0.04) in fasting animals. Similar results were obtained during intraduodenal infusion of glucose through a Mann–Bollman fistula. GIP levels did not change significantly during i.c.v. administration of SST‐14. Intracerebroventricular infusion of SST‐14 increases glucose and suppresses insulin levels in the periphery independently of circulating SST levels.     

Distribution of growth hormone and thyroid-stimulating hormone in cerebrospinal fluid and pathological compartments of the central nervous system

Human growth hormone (HGH) radio-immunoassay (RIA) was adapted for an accurate measurement of immunoreactive HGH concentrations in the CSF in different cases of hypothalamic-somatotropin dysfunctions.In control subjects (n = 43) mean HGH levels were 0.35 ± 0.03 ng/ml in CSF and 1.95 ± 0.2 ng/ml in plasma with a $\text{CSF}\text{plasma}$ ratio of 17%. The thyroid-stimulating hormone (TSH) RIA gave in controls mean basal levels of 2.65 ± 0.2 μU/ml in CSF and 5.95 ± 0.3 μU/ml in plasma with a $\text{CSF}\text{plasma}$ ratio of 44%. HGH and TSH concentrations in CSF and plasma show a very good correlation; but the regression curves for both hormones are distinctly different and appear specific for each polypeptide hormone.Hypothalamic-somatotropin hyperreactivity was reported in diabetic retinopathy (DR). CSF and plasma HGH concentrations in a group of diabetic patients with progressing retinopathy (n = 27) were not different from those in normal subjects (respectively 0.35 ± 0.05 in CSF and 2.10 ± 0.25 ng/ml in plasma with a $\text{CSF}\text{plasma}$ ratio of 16%). The HGH regression curve obtained in diabetics is similar to that of controls. These data do not substantiate the hypothesis of an HGH hyperreactivity in diabetic retinopathy.In somatotropin hypersecretion (acromegaly) without adenoma suprasellar extension, higher HGH concentrations recorded in CSF than in plasma cannot be attributed to an anatomical break-down of the CSF blood-brain barrier and suggest an active transport process of pituitary hormones to the CNS.HGH and TSH concentrations were measured in the cystic fluid of CNS tumors. In 1 case of a cystic dysembryoma, the HGH and TSH of CF were considerably increased. In gliomas (n = 8) the HGH and TSH cystic fluid concentrations were more elevated (respectively 0.72 ± 0.2 ng/ml and 3.6 ± 0.7 μU/ml) than in the CSF of controls.     

[Na+] of lateral ventricular cerebrospinal fluid in conscious rabbits before and after osmotic and hypovolemic stimuli

Results from direct electrode measurements of lateral ventricular cerebrospinal fluid (CSF) [Na⁺] before and after the development of water-deprived, hypovolemic, and relative cellular dehydrative thirst indicated that temporal and directional changes in CSF [Na⁺] parallel changes in plasma [Na⁺] in conscious, male rabbits. The CSF [Na⁺] of rabbits increased by 10.8 meq/liter after 48 h of water deprivation, and 7.6 meq/liter after the i.v. injection of 3 ml/kg 2 m NaCl. The CSF [Na⁺] increased immediately after the injection of hypertonic sodium and rapidly returned to control values after water gavage or voluntary water ingestion. The CSF [Na⁺] of rabbits dehydrated by the i.v. injection of 3 ml/kg 2 m sucrose and in hypovolemic rabbits (15 ml/kg 20% polyethylene glycol, s.c.) remained the same as that of controls. No change in plasma or CSF [Na⁺] occurred in rabbits injected with isotonic saline. An elevation in CSF [Na⁺] was not required for the initiation of drinking behavior in the rabbit. The data support an osmoreceptor mechanism for the development of relative cellular dehydrative thirst.     

Ralitoline: a reevaluation of anticonvulsant profile and determination of "active" plasma concentrations in comparison with prototype antiepileptic drugs in mice

Ralitoline (RLT) is a new thiazolidinone derivative with potent anticonvulsant activity in different seizure models. During Phase I studies, RLT was well tolerated in human volunteers and showed linear pharmacokinetics in the dose range tested (up to 150 mg). Since RLT will soon be entering clinical Phase II studies, we were interested in obtaining predictive data for effective plasma concentrations in patients. For this purpose, the anticonvulsant potency of RLT was determined in four seizure models in mice, and plasma levels were measured at time of peak drug effect. The four models were the threshold for maximal (tonic extension) electroshock seizures (MES), the threshold for clonic seizures determined by i.v. infusion of pentylenetetrazol (PTZ), the traditional MES test with supramaximal (50 mA) stimulation, and generalized clonic seizures induced by s.c. administration of PTZ. Furthermore, median minimal "neurotoxic" doses (TD50s) were determined by the rotorod and chimney test for calculation of protective indices. All data obtained for RLT were compared with data obtained with standard antiepileptic drugs: phenobarbital, phenytoin, valproate, and diazepam. The onset of anticonvulsant action after i.p. injection of RLT was very rapid, and the peak drug effect was already obtained after 2 min. In the MES models, RLT was the most potent compound. "Active" plasma levels ranged from approximately 300 ng/ml in the MES threshold test to approximately 1,300 ng/ml in the MES test. RLT was also capable of increasing the PTZ threshold, whereas, possibly because of its short duration of action in mice, it was not very active in the s.c. PTZ seizure test.(ABSTRACT TRUNCATED AT 250 WORDS)     

Determination of the threshold for convulsions by direct cortical stimulation

In this study we investigated whether determination of the convulsion threshold by electrical stimulation of the cortex could be used as a simple test for measuring anticonvulsant drug activity in unrestrained, unanaesthetized rats. Pulse trains delivered to electrodes implanted in the frontoparietal cortex elicited convulsions, similar to those seen in the classical electroshock tests. The threshold could be determined rapidly with pulse trains which increased in strength in a ramp-shaped fashion (bipolar pulses of 2 msec, 50 pulses/sec, increment 1.3 microA/pulse). The threshold was defined as the current needed to elicit forelimb clonus. Upon repeated stimulation the threshold declined from a value of about 600 microA to about 350 microA in 20 sessions. Thereafter, continued testing did not result in considerable changes in threshold. After stabilization, the convulsion threshold could be determined repeatedly with intervals as short as 5 min. Following i.p. injection of 5 mg/kg of diazepam an elevation of the threshold of 30% was observed 0.5 h after injection. After 5 daily injections, evidence for the development of complete tolerance was obtained. After i.v. injection of 8 mg/kg oxazepam, the threshold increase reached a peak level of 75% after 20 min. The changes in threshold followed arterial blood concentration of oxazepam, which was maximally 4.8 micrograms/ml immediately after injection. The threshold returned to baseline in approximately 6 h. The results of the present study show that with our procedure anticonvulsant drug activity can be accurately, rapidly and repeatedly determined in individual animals, both in acute and chronic experiments.     

The Origins of Electroconvulsive Therapy (ECT)

Prior to the 1930s, the prime mode of treatment for psychiatric outpatients was psychoanalysis. Little could be done for inpatients, other than provide sedation and social support. In the 1930s, four major somatotherapies, all interventionist in technique, were developed: insulin coma therapy, Metrazol convulsive therapy, lobotomy (psychosurgery), and electroconvulsive therapy (ECT), the only one of these therapies still in use today. This paper focuses on the development of ECT by Ugo Cerletti and Lucio Bini at the Clinic for Nervous and Mental Disorders in Rome in 1938. The first electroshock treatment with humans is discussed in detail and the export of ECT to North America is described. Fifty years after the first treatment, ECT remains a controversial method of psychiatric treatment.     

Comparative single-dose pharmacokinetics of clonazepam following intravenous,intramuscular and oral administration to healthy volunteers

The objective was to assess the single-dose pharmacokinetics of clonazepam following i.m., p.o. and i.v. administration. In an open-label, three-way crossover study, 12 healthy volunteers were randomized to receive a single dose of 2 mg clonazepam either by the i.m., p.o. or i.v. route. Serial blood samples were collected up to 120 h after drug administration. Plasma concentrations of clonazepam were determined by electron-capture gas-liquid chromatography. The absorption rates of clonazepam after i.m. and p.o. administration of clonazepam were significantly different from each other, as reflected by the respective mean values of maximum plasma concentration (C(max) 11.0 vs. 14.9 ng.ml(-1)) and time to reach maximum concentration (t(max) 3.1 vs. 1.7 h). Secondary plasma peaks of clonazepam were observed in 9 volunteers after i.m. injection (C(max) 9.9 ng.ml(-1); t(max) 10.4 h). A comparison of the area under the plasma concentration-time curves (AUC) shows that the i.m. route is equivalent to the oral route (AUC(0- infinity ) 620 vs. 561 ng.h.ml(-1)). Clonazepam was almost completely absorbed after i.m. and p.o. administration, as shown by the mean absolute bioavailability of 93 and 90%, respectively. No significant differences existed between the elimination half-lives (i.v. 38.0 h; i.m. 43.6 h; p.o. 39.0 h). The average clearance and volume of distribution (V(Z)) were 55 ml.min(-1) and 180 liters, respectively. In conclusion, the observed differences in C(max) and t(max) after i.m. and p.o. administration were consistent with a slower absorption rate of clonazepam after i.m. injection. The systemic exposure to clonazepam was not affected by the route of extravascular administration. Statistical evaluation of these kinetic data showed differences in the absorption rate, so that clonazepam given by the i.m. route is not bioequivalent to the oral route. On the basis of the results of this study, we would recommend the same i.m. and p.o. dose in epileptic patients, but therapeutic response would be expected to be less predictable and to occur later in the case of i.m. administration.     

Results of phase II pharmacokinetic study of levetiracetam for prevention of post-traumatic epilepsy

Levetiracetam (LEV) has antiepileptogenic effects in animals and is a candidate for prevention of epilepsy after traumatic brain injury. Pharmacokinetics of LEV in TBI patients was unknown. We report pharmacokinetics of TBI subjects≥6years with high PTE risk treated with LEV 55mg/kg/day orally, nasogastrically or intravenously for 30days starting ≤8h after injury in a phase II safety and pharmacokinetic study. Forty-one subjects (26 adults and 15 children) were randomized to PK studies on treatment days 3 and 30. Thirty-six out of forty-one randomized subjects underwent PK study on treatment day 3, and 24/41 subjects underwent PK study on day 30. On day 3, mean T(max) was 2.2h, C(max) was 60.2μg/ml and AUC was 403.7μg/h/ml. T(max) was longer in the elderly than in children and non-elderly adults (5.96h vs. 1.5h and 1.8h; p=0.0001). AUC was non-significantly lower in children compared with adults and the elderly (317.4μg/h/ml vs. 461.4μg/h/ml and 450.2μg/h/ml; p=0.08). C(max) trended higher in i.v.- versus tablet- or n.g.-treated subjects (78.4μg/ml vs. 59μg/ml and 48.2μg/ml; p=0.07). AUC of n.g. and i.v. administrations was 79% and 88% of AUC of oral administration. There were no significant PK differences between days 3 and 30. Treatment of TBI patients with high PTE risk with 55mg/kg/day LEV, a dose with antiepileptogenic effect in animals, results in plasma LEV levels comparable to those in animal studies.     

Successful use of alternate waste nitrogen agents and hemodialysis in a patient with hyperammonemic coma after heart-lung transplantation

BACKGROUND: Lethal hyperammonemic coma has been reported in 2 adults after lung transplantation. It was associated with a massive elevation of brain glutamine levels, while plasma glutamine levels were normal or only slightly elevated. In liver tissue, glutamine synthetase activity was markedly reduced, and the histologic findings resembled those of Reye syndrome. The adequacy of therapy commonly used for inherited disorders of the urea cycle has not been adequately evaluated in patients with this form of secondary hyperammonemia. OBJECTIVE: To determine whether hemodialysis, in conjunction with intravenous sodium phenylacetate, sodium benzoate, and arginine hydrochloride therapy, would be efficacious in a patient with hyperammonemic coma after solid-organ transplantation. DESIGN: Case report. SETTING: A children's hospital. PATIENT: A 41-year-old woman with congenital heart disease developed a hyperammonemic coma with brain edema 19 days after undergoing a combined heart and lung transplantation. METHODS: Ammonium was measured in plasma. Amino acids were quantitated in plasma and cerebrospinal fluid by column chromatography. The effectiveness of therapy was assessed by measuring plasma ammonium levels and intracranial pressure and performing sequential neurological examinations. RESULTS: The patient had the anomalous combination of increased cerebrospinal fluid and decreased plasma glutamine levels. To our knowledge, she is the first patient with this complication after solid-organ transplantation to survive after combined therapy with sodium phenylacetate, sodium benzoate, arginine hydrochloride, and hemodialysis. Complications of the acute coma included focal motor seizures, which were controlled with carbamazepine, and difficulty with short-term memory. CONCLUSIONS: The aggressive use of hemodialysis in conjunction with intravenous sodium phenylacetate, sodium benzoate, and arginine hydrochloride therapy may allow survival in patients after solid-organ transplantation. An acute acquired derangement in extra-central nervous system glutamine metabolism may play a role in the production of hyperammonemia in this illness that resembles Reye syndrome, and, as in other hyperammonemic disorders, the duration and degree of elevation of brain glutamine levels may be the important determining factors in responsiveness to therapy.     

Dexamethasone differentially alters naltrexone effects on vasopressin and oxytocin release during tail electroshock

The origin of endogenous opioid peptides that inhibit release of vasopressin (VP) and oxytocin (OT) into the bloodstream after tail electroshock was investigated. We hypothesized that endogenous opioid peptides derived from the anterior pituitary reduced secretion of VP and OT during this stimulus. To test this hypothesis, dexamethasone (DEX) was used to preferentially suppress release of endorphins with ACTH from the anterior pituitary. We evaluated the effects of an opiate receptor antagonist, naltrexone, on the rise in plasma [VP] and [OT] after tail electroshock in male Sprague-Dawley rats given DEX either chronically or acutely before the shock. In the chronic study rats were injected SC daily with saline (3.2 ml/kg) or DEX (0.2 mg/kg) for 17 days. In the short term study, rats were injected IP with saline (5 ml/kg) or DEX (0.5 mg/kg) the day before and again 105 min prior to tail electroshock. Thirty min (chronic study) or 90 min (acute study) after saline or DEX was given on the last day, rats were injected SC with saline (1 ml/kg) or naltrexone (1 mg/kg). Fifteen min later, animals received tail electroshock (41 V, 30 sec) and were decapitated 15 sec after shock was completed. Control animals were treated similarly but not shocked. Amounts of VP and OT in plasma and the neurointermediate lobe were quantified by RIA. [VP] and [OT] were elevated in plasma of all rats given tail electroshock. Greater increases (p less than 0.05) in hormone concentrations were measured in plasma of shocked rats treated with DEX.(ABSTRACT TRUNCATED AT 250 WORDS)     

Successful Treatment by Direct Hemoperfusion of Coma Possibly Resulting From Mitochondria1 Dysfunction in Acute Valproate Intoxication

: Purpose: We evaluated the efficacy of direct hemoperfusion (DHP) for treatment of acute valproate (VPA) intoxication and speculate on the biochemical perturbations that suggest a mechanism of coma induced by VPA overdose. Patient and Methods: The comatose patient was hospitalized ?6 h after ingesting 18 g VPA. DHP, with 200 g activated charcoal, was performed for 6 h. The plasma concentrations of VPA and Glasgow coma scale scores after admission were estimated. Before and after DHP, urine samples were tested in serial fashion for VPA metabolites, organic acids, and acyl carnitine esters of fatty acids. Results: Plasma VPA was efficiently adsorbed on activated charcoal. The patient's plasma concentration of VPA decreased from 471 μml (2,830 μM) to 45 pg/ml (270 μM), at which point the patient became alert. The half-life (t1/2) of VPA was calculated as 4.4 h before DHP and as 1.8 h during DHP. Before DHP, lactate and VPA-glucuronide markedly increased in urine samples, but β-keto-VPA, a major mitochondria1 metabolite, was not detected. Urinary excretion of carnitine esters of medium chain (C₈-C₁₀) dicarboxylic acids was increased. After DHP, lactate and VPA-glucuronide decreased, but a significant amount of β-keto-VPA was demonstrated. Carnitine esters of medium chain dicarboxylic acids were decreased. Conclusions: DHP with activated charcoal was effective treatment for the patient with acute VPA intoxication and coma. The onset of coma may have been related to inhibition of β-oxidation in the mitochondria, which was reversible by elimination of plasma VPA by DHP.     

Long-term effect of electroshock treatment on the entry of calcium into the cerebroventricular fluid in the rat

The rate of appearance (R_a) of calcium (Ca) in the cerebroventricular compartment of urethane-anesthesized rats was determined by two methods: one is measurement of isotope dilution during ventricular-cisternal perfusion with artificial cerebrospinal fluid (CSF) containing ⁴⁵Ca, the other is estimation of the rate of entry of ⁴⁵Ca from plasma after rapid injection of tracer ⁴⁵CaCl₂ intravenously. Electroshock treatment (EST) for 3 successive days resulted in a marked increase in the rate of entry of calcium from blood to CSF. The effect of EST on the permeability of the blood-CSF bamer to Ca could be observed even 24 hr after the generalized seizure induced by electroshock has terminated.     

Growth Hormone Responses to Administration of L-5-Hydroxytryptophan (L-5-HTP) in Manic-Depressive Psychoses

Fourteen hospitalized patients with manic-depressive psychoses received L-5-hydroxy-tryptophan (L-5-HTP), a serotonin precursor, which has been postulated as a potent antidepressive agent. Plasma human growth hormone (HGH) and glucose levels were measured at 30 minute intervals after oral administration of 200mg of L-5-HTP. Plasma cortisol levels prior to L-5-HTP administration were also measured. 1. In five manic-depressive (bipolar) patients, aged 17 to 60, each subject studied in manic state showed an adequate HGH response of more than 5.0ng/ml (maximum levels:17.7±7.1 ng/ml Mean± S.E.M., controls, aged 27 to 41:10.5±1.6 ng/ml), while those in depressive state failed to secrete HGH adequately (maximum levels ranged 1.4-4.8 ng/ml) (p>0.05). 2. Of five determinations from three endogenous depressive (unipolar) patients, aged 30 to 51, three showed adequate responses (maximum levels ranged 2.6–16.5 ng/ml). Nine out of 10 tests from six patients with protracted depressive symptoms prolonged for 2 to 6 years, aged 45 to 65, had deficient responses of HGH (maxi mum levels: 2.1±k0.5 ng/ml Mean±S.E.M., ranged 0.1–5.6 ng/ml) (p>0.01). 3. Deficiency of pituitary HGH secretion appeared to correlate neither with the score of Hamilton's Depression Scale nor with the global judgement on the severity of the illness. Increments in the blood glucose levels after L-5-HTP administration were only mild ones, to which HGH insensitivity may be irrelevant. Morning plasma cortisol levels in depressives, ob served as high as those in manics, also may be unrelated. 4. Treatment with 300 mg of L-5HTP daily for two weeks proved to have no favorable clinical effects on four depressive patients, who were categorized as non-responders of HGH. Because there is evidence suggesting pituitary hormone release related to brain bio-genic amines, the deficient HGH responses to L-5-HTP in depressed patients may be due to a neurochemical defect hypothesized in the manic-depressive psychoses. The HGH responses were most distinctly diminished in the protracted depressive patients, suggesting an endocrine hypofunction which may cause the fixation of the depressive symptoms.     

Differential hemodynamic, metabolic and hormonal effects of morphine and morphine-6-glucuronide

Although the hyperglycemic effect of morphine has been previously described, it is not clear whether this is the result of increased glucose production and/or decreased glucose utilization and if this metabolic effect is lost with glucuronidation. This study assessed the hemodynamic (heart rate; HR and mean arterial blood pressure; MABP), hormonal and whole body glucose metabolic effects of morphine (MOR) and its metabolite morphine 6-glucuronide (MOR-6G) in conscious unrestrained chronically catheterized rats. Whole body glucose kinetics were assessed with a primed constant intravenous infusion of [3-³H]gluccose in rats infused i.c.v. with H₂O (Con; 5 μl/h), MOR (80 μg/h) or MOR-6G (1 μg/h) for a total of 4 h. MOR administration resulted in a significant 20% elevation in HR and no change in MABP. MOR-6G produced a 14% increase in HR and no change in MABP. A significant rise in plasma glucose (+23%), hepatic glucose production (R_a; +27–61%) and whole body glucose utilization (R_d; +31–61%) was also observed within 60 min of MOR administration. I.c.v. MOR-6G resulted in hemodynamic, metabolic and hormonal parameters of H₂O infused rats. I.c.v. MOR resulted in a significant increases in epinephrine (2-fold), norepinephrine (50%), corticosterone (97%) with no alterations in plasma insulin and glucagon. I.c.v. MOR-6G resulted in more marked elevations in norepinephrine (5-fold), epinephrine (7-fold) and similar elevation in corticosterone (99%) and modest elevation of glucagon (40%). These results indicate that (i) MOR-induced hyperglycemia is the result of direct central (CNS) mechanisms that result in increased hepatic glucose production, (ii) MOR-induced stress response is enhanced at least 80-fold with glucuronidation, and (iii) MOR inhibits the pancreatic glucose-stimulated insulin release.     

Abnormal growth hormone release following luteinizing hormone releasing hormone in anorexia nervosa

We studied the luteinizing hormone (LH), follicle stimulating hormone (FSH) and growth hormone (GH) secretion following an i.v. injection of 0.1 mg of luteinizing hormone releasing hormone (LHRH) in patients with anorexia nervosa, who showed the GH secretion after thyrotropin releasing hormone (TRH). Five out of 11 patients had an elevated plasma GH level in a fasting state. The administration of LHRH resulted in a significant increase in the plasma GH concentrations in 3 of the 11 patients. Three other patients also showed an elevation of the plasma GH concentration to 7.0, 18.4 and 29.6 ng/ml, which were 212, 175 and 191% of the preinjection levels, respectively. There is a positive correlation between the basal and peak plasma GH levels after LHRH. These increases, however, were related to neither the plasma gonadotropin responses to LHRH nor the plasma GH responses to TRH. The basal levels of plasma LH were reduced in 8 patients and normal responses to LHRH were observed in only one patient. Although plasma FSH was undetectable in 5 patients, the FSH response to LHRH appeared normal in 9 patients. These results indicate that an elevation of the plasma GH level after LHRH is not confined to patients with a GH secreting pituitary tumor but observed in subjects with anorexia nervosa and further suggest that the GH responsiveness to non-specific hypothalamic releasing hormones may be due to the impaired hypothalamic control in anorexia nervosa.     

7-Chlorokynurenic acid antagonizes the anticonvulsant activity of D-cycloserine in maximal electroshock seizures.

This study evaluated the anticonvulsant activity of D-cycloserine against maximal electroshock seizures in rats. Systematically administered D-cycloserine (i.p.) inhibited maximal electroshock-induced tonic hindlimb extension in a dose-dependent manner with an ED50 of 153 mg/kg. No neurological deficit was detected at any dose of D-cycloserine. In contrast, L-cycloserine had no effect on the maximal electroshock seizures. Administration of the strychnine-insensitive glycine receptor antagonist 7-chlorokynurenic acid (100 nmol, i.c.v.) significantly antagonized the anticonvulsant activity induced by D-cycloserine. Centrally administered D-cycloserine (i.c.v.) induced significant anticonvulsant activity 1-2 h after administration with an approximate ED50 of 5 mumol. 7-Chlorokynurenic acid (100 nmol, i.c.v.) significantly antagonized the anticonvulsant activity of centrally administered D-cycloserine. L-Cycloserine (i.c.v., 2 h) induced no significant anticonvulsant activity. These results provide evidence that the anticonvulsant activity of D-cycloserine in maximal electroshock seizures may be mediated by strychnine-insensitive glycine receptors.     

Insulin coma therapy: Decrease of plasma tryptophan in man

Summary A biochemical study was performed in two patients submitted to insulin coma therapy. The injection of insulin resulted in a decrease of free and total tryptophan as well as tyrosine in plasma, while NEFA were not influenced by this treatment. The ratio of tryptophan to tyrosine was enhanced. The administration of glucose after insulin provoked an increase of free and total tryptophan. The results support the hypothesis that in man insulin may favor the uptake of tryptophan by the brain, and enhance the synthesis of cerebral serotonin.     

Ghrelin prevents levodopa-induced inhibition of gastric emptying and increases circulating levodopa in fasted rats

Background Levodopa (l ‐dopa) is the most commonly used treatment for alleviating symptoms of Parkinson’s disease. However, l ‐dopa delays gastric emptying, which dampens its absorption. We investigated whether ghrelin prevents l ‐dopa action on gastric emptying and enhances circulating l ‐dopa in rats. Methods Gastric emptying of non‐nutrient methylcellulose/phenol red viscous solution was determined in fasted rats treated with orogastric or intraperitoneal (i.p.) l ‐dopa, or intravenous (i.v.) ghrelin 10 min before orogastric l ‐dopa. Plasma l ‐dopa and dopamine levels were determined by high pressure liquid chromatography. Plasma acyl ghrelin levels were assessed by radioimmunoassay. Fos expression in the brain was immunostained after i.v. ghrelin (30 μg kg^?1) 10 min before i.p. l ‐dopa. Key Results Levodopa (5 and 15 mg kg^?1) decreased significantly gastric emptying by 32% and 62%, respectively, when administered orally, and by 91% and 83% when injected i.p. Ghrelin (30 or 100 μg kg^?1, i.v.) completely prevented l ‐dopa’s (15 mg kg^?1, orogastrically) inhibitory action on gastric emptying and enhanced plasma l ‐dopa and dopamine levels compared with vehicle 15 min after orogastric l ‐dopa. Levodopa (5 mg kg^?1) did not modify plasma acyl ghrelin levels at 30 min, 1, and 2 h after i.v. injection. Levodopa (15 mg kg^?1, i.p.) induced Fos in brain autonomic centers, which was not modified by i.v. ghrelin. Conclusions & Inferences Ghrelin counteracts l ‐dopa‐induced delayed gastric emptying but not Fos induction in the brain and enhances circulating l ‐dopa levels. Potential therapeutic benefits of ghrelin agonists in Parkinson’s disease patients treated with l ‐dopa remain to be investigated.     

Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and factor VIII responses

When desmopressin (DDAVP) is given to mild and moderate hemophiliacs intravenously (i.v.) or subcutaneously (s.c.), there is a very large between-patient variability for peak levels of factor VIII coagulant activity (VIII:C). To evaluate whether or not between-patient variability is related to DDAVP levels achieved in plasma, we measured drug levels in 14 hemophilic volunteers (VIII:C 2 to 31 U/dL) who were randomly given 0.3 micrograms/Kg of i.v. or s.c. DDAVP and crossed-over to the other treatment after an interval of 15-30 days. Peak DDAVP levels (Cmax) were higher for i.v. DDAVP (p less than 0.02), times to peak levels (tmax) were shorter for i.v. DDAVP (p less than 0.001). There was no difference between the i.v. and s.c. routes for plasma DDAVP time curve (AUC) and half-life (t 1/2), but there was much larger variability for pharmacokinetic parameters with i.v. than with s.c. DDAVP. Post-DDAVP VIII:C increased 3.4 +/- 1.6 fold (i.v.) and 3.3 +/- 1.3 fold (s.c.) over baseline levels, with no significant correlation between peak VIII:C and DDAVP levels for either route of administration. These findings establish the s.c. route of DDAVP administration to be bioequivalent in effect to the i.v. route, albeit with less variability. At the DDAVP dosage used in this study and currently recommended for therapy, the VIII:C response is neither a function of the rate of absorption of the compound nor of the magnitude of its plasma concentration.