Olanzapine. Pharmacokinetic and pharmacodynamic profile.

Multicentre trials in patients with schizophrenia confirm that olanzapine is a novel antipsychotic agent with broad efficacy, eliciting a response in both the positive and negative symptoms of schizophrenia. Compared with traditional antipsychotic agents, olanzapine causes a lower incidence of extrapyramidal symptoms and minimal perturbation of prolactin levels. Generally, olanzapine is well tolerated. The pharmacokinetics of olanzapine are linear and dose-proportional within the approved dosage range. Its mean half-life in healthy individuals was 33 hours, ranging from 21 to 54 hours. The mean apparent plasma clearance was 26 L/h, ranging from 12 to 47 L/h. Smokers and men have a higher clearance of olanzapine than women and nonsmokers. After administering [14C]olanzapine, approximately 60% of the radioactivity was excreted in urine and 30% in faeces. Olanzapine is predominantly bound to albumin (90%) and alpha 1-acid glycoprotein (77%). Olanzapine is metabolised to its 10- and 4'-N-glucuronides, 4'-N-desmethylolanzapine [cytochrome P450 (CYP) 1A2] and olanzapine N-oxide (flavin mono-oxygenase 3). Metabolism to 2-hydroxymethylolanzapine via CYP2D6 is a minor pathway. The 10-N-glucuronide is the most abundant metabolite, but formation of 4'-N-desmethylolanzapine is correlated with the clearance of olanzapine. Olanzapine does not inhibit CYP isozymes. No clinically significant metabolic interactions were found between olanzapine and diazepam, alcohol (ethanol), imipramine, R/S-warfarin, aminophylline, biperiden, lithium or fluoxetine. Fluvoxamine, an inhibitor of CYP1A2, increases plasma concentrations of olanzapine; inducers of CYP1A2, including tobacco smoke and carbamazepine, decrease olanzapine concentrations. Orthostatic changes were observed when olanzapine and diazepam or alcohol were coadministered. Pharmacodynamic interactions occurred between olanzapine and alcohol, and olanzapine and imipramine, implying that patients should avoid operating hazardous equipment or driving an automobile while experiencing the short term effects of the combinations. Individual factors with the largest impact on olanzapine pharmacokinetics are gender and smoking status. The plasma clearance of olanzapine generally varies over a 4-fold range, but the variability in the clearance and concentration of olanzapine does not appear to be associated with the severity or duration of adverse effects or the degree of efficacy. Thus, dosage adjustments appear unnecessary for these individual factors. However, dosage modification should be considered for patients characterised by a combination of factors associated with decreased oxidative metabolism, for example, debilitated or elderly women who are nonsmokers.

Isolation and manipulation of rostral mesencephalic tegmental progenitor cells from rat.

A technique for isolating mitotic progenitor cells from the embryonic rostral mesencephalon is described. Culture of the progenitor cells in complete media with subsequent staining for neuron specific enolase (NSE) revealed that only 0.6% of the cells were NSE immunoreactive. Co-culturing the progenitor cells with established striatal cultures did not result in conversion of any of the cells to the dopamine neuron phenotype (tyrosine hydroxylase immunoreactive (THir) neurons). In contrast, co-culture of progenitor cells with established mesencephalic cultures produced a statistically significant, and in some cases (three of twelve), dramatic increase in the number of THir cells. The THir cells that were present had more pronounced process extension than those observed in mesencephalic mono-cultures. Culturing progenitor cells in transwell baskets that were continuously exposed to media but physically separated from established mesencephalic cultures growing underneath the baskets led to the conversion of only a few progenitor cells to THir neurons in four of twelve transwell studies suggesting that cell-cell contact between progenitor cells and mesencephalic cells is required for the conversion. This co-culture technique also increased the number of THir neurons in the mesencephalic cultures although the increase was not profound enough to explain the increase observed in traditional co-culture. These data suggest that mitotic progenitor cells can be isolated from fetal rat tissue and successfully converted to the dopamine neuron phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypoxia after prenatal cocaine attenuates striatal dopamine and neurotrophic activity.

We have previously shown that newborn rabbits exposed to cocaine prenatally have an altered cardiorespiratory response to hypoxia. We report the effect of postnatal hypoxia on brain DA and neurotrophic activity in New Zealand White rabbit pups (n = 41) born to cocaine-exposed does (30 mg/kg/day SC from days 7-15 of a 32-day gestation = COCaine) and control does (sterile H2O = VEHicle). Four to 6-day-old pups were exposed to 20 min of room air (0.21 fractional inspired oxygen tension, FIO2). One third of each group was then exposed to 20 min of either 0.15 (moderate hypoxia) or 0.08 (severe hypoxia) FIO2. Immediately following hypoxic challenge the pups were sacrificed. Striatal tissue extracts were subsequently assessed for DA and striatal trophic activity by monitoring the number of neuron specific enolase immunoreactive (NSEir) cells in mesencephalic culture following incubation with striatal extracts. Increasing the severity of hypoxia increased DA content (p < 0.005), but reduced DA activity (p < 0.0001) and trophic activity (p < 0.001). Cocaine exposure reduced striatal DA (p < 0.005) as well as NSEir (p < 0.001) in all conditions relative to vehicle-treated controls. These data suggest that prenatal cocaine exposure enhances the vulnerability of the DA system to the stress of hypoxia, possibly through alterations in neurotrophic activity.

Alterations in striatal neurotrophic activity induced by dopaminergic drugs.

The administration of dopaminergic drugs induces a variety of compensatory responses ostensibly designed to reinstate normal dopamine (DA) tone. We have hypothesized that drug-induced alterations in striatal-derived neurotrophic activity contributes to these compensatory processes. This phenomenon has been studied by examining the growth of mesencephalic cultures incubated with cell-free extracts of striatal tissue taken from patients or rats treated with various drugs. Our results reveal that reducing striatal DA tone by administering the DA antagonist haloperidol, the DA neurotoxin 6-hydroxydopamine, or as occurs naturally in Parkinson's disease, increases striatal trophic activity. Conversely, increasing striatal DA tone by administering the indirect DA agonists amphetamine or levodopa reduces trophic activity in the striatum. Kainic acid lesions of the striatum similarly reduce this trophic activity. The implications of these drug-induced alterations in trophic activity are discussed and reviewed.

Striatal extracts from patients with Parkinson's disease promote dopamine neuron growth in mesencephalic cultures.

The caudate, putamen, and cerebellum from five patients with Parkinson's disease (PD) and five normal, aged controls were studied to determine if cell-free extracts from these tissues influenced dopamine neuron growth in culture. Cultures incubated with extracts of the caudate and putamen, but not the cerebellum, from PD patients contained more tyrosine hydroxylase immunoreactive neurons than aged controls. These data suggest that the parkinsonian striatum compensates for dopamine loss by increasing neurotrophic factor production.

Levodopa reduces the growth promoting effects of striatal extracts on rostral mesencephalic tegmentum cultures.

Rats with unilateral 6-hydroxydopamine lesions (6-OHDA) of the mesencephalon and vehicle controls (SHAM) were chronically treated with carbidopa (CD) or CD plus levodopa (CD/LD) for 18 days. Seventy-two hours following the last treatment, ipsilateral striata, contralateral striata, and cerebellums from each treatment group were homogenized separately and the supernatant extracts were incubated with rostral mesencephalic tegmentum cultures. As indices of growth-promoting activity (GPA), number of viable neurons and their process lengths were measured 40 h later. In all cultures exposed to striatal extracts, the 6-OHDA lesion was associated with greater GPA than the SHAM extracts. CD/LD consumption reduced this GPA in a dose-dependent fashion in both the lesioned and the SHAM animals. These data suggest that denervation of the striatum enhances the production of a striatally derived neurotrophic factor, the production of which is sensitive to levodopa. Chronic levodopa treatment in Parkinson's disease may therefore contribute to disease progression by reducing the compensating effects of this neurotrophic factor on remaining mesencephalic neurons.

The potential use of a dopamine neuron antibody and a striatal-derived neurotrophic factor as diagnostic markers in Parkinson's disease.

The cerebral spinal fluid (CSF) of patients with Parkinson's disease (PD) contains an antibody that immunocytochemically reacts with dopamine (DA) neurons in the substantia nigra (SN). This antibody was found in 78% of the CSF samples taken from patients with clinical PD. In contrast, only 3% of the CSF samples taken from control patients or patients with neurologic symptoms other than PD possessed this antibody. The production of this antibody might contribute to disease progression but does not appear to be the etiologic factor responsible for PD. In other experiments, concentrates of the CSF of patients with PD enhanced growth of mesencephalic cultures relative to control CSF. Both the antibody and the growth-promoting activity found in CSF are associated with degeneration of the SN and might therefore be useful as potential diagnostic markers for PD.

Striatal homogenates from animals chronically treated with haloperidol stimulate dopamine and GABA uptake in cultures of rostral mesencephalic tegmentum.

The effect of pharmacologic denervation of striatal tissue on the production of growth promoting factors was examined in a cell culture system. Relative to saline-treated controls, rats were rendered behaviorally hypersensitive to a subsequent apomorphine challenge by 2 months of chronic treatment with haloperidol. Four days following chronic treatment, the animals were killed and the striata and cerebella were homogenized in Hank's Balanced Salt solution. The supernatants of these crude homogenates were then added to E-13 rostral mesencephalic tegmentum cultures for 6 days. Within 24 h, the haloperidol-treated striatal supernatants induced an overt increase in culture growth relative to all other supernatants. After 6 days, cultures incubated with haloperidol-treated striatal supernatants exhibited a significant increase in dopamine and GABA uptake relative to cultures incubated with all other supernatants. This effect was observed in the presence and absence of glia. The relative degree of this increased uptake was dependent upon the amount of haloperidol-treated striatal supernatant added. Boiling the supernatant removed the growth promoting effect. These results suggest that pharmacologic denervation of striatal tissue leads to a "target-specific" increase in growth promoting activity that may play a role in the pharmacologic and behavioral effects of haloperidol.