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An efficient direct injection/on-line guard cartridge extraction-tandem mass spectrometry (DI/GCE--MS--MS) method has been validated for high-throughput evaluation of cytochrome P450 (CYP) 1A2 inhibition potential using human hepatic microsomes and 96-well microtiter plates. Microsomal incubations were terminated with formic acid, centrifuged, and the resulting supernatants were injected for DI/GCE--MS--MS analysis. Due to the use of an extremely short C(18) guard cartridge, this method offers several advantages such as no sample preparation, excellent on-line extraction, short run time and minimal source contamination and performance deterioration. The DI/GCE--MS--MS method demonstrates acceptable accuracy and precision for the quantification of resorufin, a marker metabolite of ethoxyresorufin mediated by CYP1A2, in microsomal incubations. The inhibition potential of CYP1A2 has been evaluated using its selective inhibitors, alpha-naphthoflavone and furafylline. The IC(50) values (120 nM for alpha-naphthoflavone and 5.1 microM for furafylline) measured by the new method are in agreement with the literature values.

Aims We investigated the pharmacokinetics and safety profile of oral ganciclovir coadministered with trimethoprim in HIV-and CMV-seropositive patients. Methods In an open-label, randomized, 3-way crossover study, 12 adult males received oral ganciclovir 1000 mg every 8h, oral trimethoprim 200 mg once daily, or both drugs concomitantly in a sequence of three 7-day treatment periods. Pharmacokinetic parameters were determined and adverse events recorded for each treatment. Results The presence of trimethoprim significantly decreased CLr (12.9%, P=0.0068) and increased t1/2 (18.1%, P=0.0378) of ganciclovir. However, these changes are unlikely to be clinically meaningful. There were no statistically significant changes in trimethoprim pharmacokinetic parameters in the presence of ganciclovir, with the exception of a 12.7% increase in Cmin. Ganciclovir was well tolerated when administered alone or in combination with trimethoprim. Conclusions There was no clinically significant pharmacokinetic interaction between oral ganciclovir and trimethoprim when coadministered.

The word “synthetic” in the title of this paper has three meanings, each of which highlights a fundamental problem with physiological psychology, and. at the same time, offers a solution. (1) Synthetic means artificial—made by man, not by nature. To separate physiological psychology from medicine, and to build a science of pure function in humans (which is what psychology is), apart from a science of the mechanics of living human tissue (which is what medicine is), synthetic physiological psychology adopts a physically achieved analytic approach to the design, not of people, but of robots that behave like people. This avoids the misuse of reductionism. (2) Analysis by itself is not adequate; every analysis must be validated immediately by synthesis. Some forms of physically achieved analysis and resynthesis, particularly appropriate for synthetic physiological psychology, are contrasted with the hypothetico-deductive method, as a complementary scientific method of arriving at simple facts about complex living systems. (3) Synthetic also means integrative—at present, the various subfields of psychology are not united by principles based on the action of common units of function, derived by a physically achieved analysis. A simple procedure is described that can provide them.

Gait in Parkinson's disease is characterised by slowed velocity; shuffling, small steps; and absent arm swing. Drug therapy intervention is beneficial in improving mobility, though with prolonged use its effects may diminish. The purpose of this study was to examine whether Parkinsonian patients could improve their gait patterns in response to five instructional sets: natural walking; walking while deliberately swinging the arms; walking with large steps; fast walking; and walking while counting aloud. Eight subjects with idiopathic Parkinson's disease and eight age matched control subjects were tested using motion analysis. The findings indicated that parkinsonian patients followed the instructions which immediately altered a series of single walking variables. Simultaneously, automatically activated changes occurred in other gait variables producing more normal gait. The instructional set is a strategy which can aid normalisation of Parkinsonian gait although its benefits may depend on the stage of disease progression and the degree of attention to the instructions.

Localized lesions or local applications of gamma-aminobutyric acid (GABA) in the nucleus reticularis tegmenti pontis (NRTP) of rats cause rapidly accelerating forward locomotion. Such "festination" can coexist with blockade of the dopamine system. We suggest that (i) the akinesia produced by dopamine deficiency results at least in part from release of excessive inhibition of locomotion by a neural system whose final common inhibitory path includes the region of the NRTP and (ii) when it occurs in addition to nigrostriatal damage, destruction in the region of the NRTP might be the cause of a form of festination seen in some patients suffering from Parkinsonism.

Excessive, abnormal locomotion occurs after a high dose (25-50 mg/kg) of atropine sulfate to rats already akinetic due to catecholamine deficiency from intraventricular administration of 6-hydroxydopamine. This abnormal locomotion involves an abnormal gait sequence [right (R) hindleg (H), left (L) foreleg (F), LH, RF] instead of the normal gait sequence (RH, RF, LH, LF). In such animals atropine progressively (i) decreases hindleg step size, (ii) decreases arching of the trunk, and (iii) increases foreleg step size. These factors combine to change the ratio of front/hind body support. If the body stretches too far and the hindleg step is too small, a given hindleg step supports insufficient weight to remove weight from the ipsilateral foreleg; consequently, the opposite foreleg must execute the next step, producing the abnormal gait sequence. Thus, atropine affects gait sequence indirectly; it acts on at least three variables that affect how body weight is distributed and shifted during locomotion. To maintain stability during such locomotion, gait sequence is appropriately altered.

Cortical and hippocampal EEG patterns that persist after atropine sulfate administration are defined as atropine-resistant. In the rat, such patterns are movement-related, cortical low-voltage fast activity (LVFA) and movement-related, hippocampal rhythmic slow activity (RSA or “theta”). A close relationship exists between head movement and activation of atropine-resistant EEG. In the present study, we asked whether manipulation of vestibular sensory input would affect atropine-resistant EEG. To allow experimenter control, 6 vestibular-intact rats were made cataleptic with haloperidol and were then injected with atropine sulfate. Movement of the rats* heads by the experimenter (passive head movement) failed to activate atropine-resistant EEG. These animals were then rotated on a turntable. Such vestibular stimulation, the effectiveness of which was reflected by postrotatory ocular nystagmus, &lso failed to activate atropine-resistant EEG. These and 5 other rats were then subjected to surgical or chemical deafferentation of the labyrinth. They were tested for EEG atropine resistance before and after this surgery. Although atropine-resistant EEG patterns in response to active bodily movements still appeared after vestibular deafferentation, the frequency of hippocampal RSA during active movement was reduced with or without atropine. In contrast, &n atropine-sensitive component in the hippocampal EEG during immobility was not changed by vestibular deafferentation. We conclude that vestibular reafferent feedback is neither necessary nor sufficient for the atropine-resistant EEG, but that such feedback from active movement has a modulatory effect on hippocampal RSA.

After lateral hypothalamic damage in rats, somnolence, akinesia, and sensory neglect combine to produce complete aphagia. Only simple automatisms (such as grooming, chewing, licking) are present, but intense stimuli can activate more complex actions (walking, orientation, swimming). In the anorexic stage, tactile stimuli dominate in steering locomotion and "spontaneous" locomotion depends on activation from the empty stomach.

In cataleptic clinging, produced either by catecholamine-blocking drugs or lateral hypothalamic damage in adult cats, rats, or monkeys, bandaging the face and neck causes the head to fall backwards.Early in development, a similar reaction can be seen in normal undrugged infants.

Hypothalamic sites which control feeding exert a corresponding control over lateral hypothalamic self-stimulation. This was demonstrated in rats bearing four, intrahypothalamic electrode-cannulas for electrical stimulation or chemical injection. Self-stimulation of the lateral hypothalamus was inhibited by ventromedial excitation or by excessive feeding. Both self-stimulation and feeding were accelerated (disinhibited) by ventromedial ablation or anesthetization. Thus food acts via the ventromedial hypothalamus to inhibit not only feeding, but also lateral hypothalamic self-stimulation.

When some infant mammals are placed outside their nest, a sequence of exploratory behavior occurs, displaying a regular buildup and spread of activity. This "warm-up" involves repetition of movement along specific dimensions and an orderly transition from one dimension to the next, with cephalocaudal recruitment of body and limb segments. A similar principle of organization applies to neurological recovery from lateral hypothalamic akinesia.

In otherwise profoundly akinetic rats that had been severely depleted of brain catecholamines, anticholinergic drugs caused excessive walking. The effect did not appear until 10 days after surgery and then increased with time, suggesting that a phenomenon analogous to denervation supersensitivity may be involved. If the animals walked into corners, they were unable to turn around or back out. Their gait (extremely short steps) was reminiscent of that of patients with Parkinson9s disease. The results are consistent with a mutually antagonistic interaction between cholinergic and dopaminergic brain systems and emphasize certain complexities in this interaction.

Spreading cortical depression reinstates aphagia and adipsia in rats recovered from lateral hypothalamic lesions. We suggest that cortical activity facilitates and maintains recovery by enhancing the activity of depressed, but intact, tissue adjacent to the lesions.

Unilateral lateral hypothalamlic lesions in rats produce deficits in orientation to contralateral visucal, olfactory, whisker-toluch, and somatosetnsory stimuli. This syndrome of sensory neglect appears to be involved in some of the deficits in feedinig and attack which follow bilateral lateral hypothalamic lesions.

Stereotyped behavior is a term used widely to describe behavior induced by psychostimulant drugs. However, a historical examination of what is meant by this term shows that different researchers use it to label different behavioral manifestations of the drug-induced syndrome. Moreover, the drug-induced syndrome has not been described adequately. We suggest that to do so requires a morphogenetic approach that will reveal the structure of the behavior as it unfolds during the course of the drug’s action. This can be accomplished by decomposing the observed motor activity into independent kinematic variables. Using this approach, we have identified three kinematic variables (snout contact, progression, and turning) whose coupling explains much of the structure of behavior under apomorphine. Moreover, these variables can help us to understand the topography of drug-induced behavior in different environments and enhance the use of behavior to measure drug action.