Exercise hemodynamics and catecholamine metabolism after catechol-O-methyltransferase inhibition with nitecapone.

The effect of catechol-O-methyltransferase inhibition with nitecapone (OR-462) on the hemodynamic responses to exercise and catecholamine metabolism was studied in 10 healthy male volunteers (aged 19 to 26 years). Nitecapone, a new specific and selective catechol-O-methyltransferase inhibitor, was given at increasing single oral doses up to 100 mg. Nitecapone did not influence resting or exercise heart rate, blood pressure, systolic time intervals, or plasma catecholamine levels. It altered the metabolic profile of catecholamines as shown by (1) an increase of 140% in the plasma concentration of the monoamine oxidase-dependent metabolite 3,4-dihydroxyphenylethyleneglycol (p less than 0.001), (2) a decrease of 27% in the plasma concentration of its methylation product 3-methoxy-4-hydroxyphenylethyleneglycol (p less than 0.05), and (3) a 25% reduction in the urinary excretion of the methylated metabolites 3-methoxy-4-hydroxymandelic acid and homovanillic acid (p less than 0.05). Nitecapone was well tolerated and seemed to be hemodynamically safe in humans.

Effect of entacapone, a COMT inhibitor, on clinical disability and levodopa metabolism in parkinsonian patients.

We studied the effect of entacapone, a selective catechol-O-methyltransferase inhibitor, on the bioavailability and clinical effect of levodopa in Parkinson's disease (PD). On day 1 (control day), nine patients received their own levodopa (plus benserazide) medication only; for the next 7 days they received 200 mg of entacapone with each dose of levodopa (tid or qid). We evaluated disability in the morning (8 AM) before drug administration and then at 1-hour intervals until 6 PM on days 1, 2, and 8, using a modified motor part of the Unified Parkinson's Disease Rating Scale. Repeated blood samples were taken before and during the 4 hours after the morning drugs for pharmacokinetic evaluation of entacapone and of levodopa and its metabolites. Added to the levodopa treatment, entacapone decreased clinical disability by about 16% (p < 0.05) from day 1 to day 8. The area under the curve (AUC) of levodopa increased by 38% (p < 0.01) after administration of a single dose of entacapone and by 40% (p < 0.05) after 7 days of multiple dosing with entacapone. Entacapone did not change the Tmax and Cmax values of levodopa. After 7 days of treatment with entacapone, the AUC of 3-O-methyldopa had decreased by 44% (p < 0.01) and of homovanillic acid by 26% (p < 0.05) as compared with treatment with levodopa alone. Four patients became slightly more dyskinetic during entacapone treatment than before it. The combination of entacapone and levodopa was well tolerated, judged by the lack of significant changes in hemodynamic and safety variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of haloperidol on selective attention: a combined whole-head MEG and high-resolution EEG study.

We used 122-channel magnetoencephalography (MEG) and 64-channel electroencephalogrphy (EEG) simultaneously to study the effects of dopaminergic transmission on human selective attention in a randomized, double-blind placebo-controlled cross-over design. A single dose of dopamine D2 receptor antagonist haloperidol (2 mg) or placebo was given orally to 12 right-handed healthy volunteers 3 hours before measurement. In a dichotic selective attention task, subjects were presented with two trains of standard (700 Hz to the left ear, 1,100 Hz to the right ear) and deviant (770 and 1,210 Hz, respectively) tones. Subjects were instructed to count the tones presented to one ear; whereas, the tones presented to the other ear were to be ignored. Haloperidol significantly attenuated processing negativity (PN), an event-related potential (ERP) component elicited by selectively attended standard tones at 300-500 ms after stimulus presentation. These results, indicating impaired selective attention by a blockade of dopamine D2 receptors, were further accompanied with increased mismatch negativity (MMN), elicited by involuntary detection of task-irrelevant deviants. Taken together, haloperidol seemed to induce functional changes in neural networks accounting for both selective and involuntary attention, suggesting modulation of these functions by dopamine D2 receptors.

Synthesis of some novel potent and selective catechol O-methyltransferase inhibitors.

A series of disubstituted catechol derivatives was synthesized and tested as potential COMT inhibitors. The most active compounds were more than 1000 times more potent (IC50 = 3-6 nM) in vitro than the known COMT inhibitor, 3',4'-dihydroxy-2-methylpropiophenone (U 0521, IC50 = 6000 nM). The new compounds were also highly selective COMT inhibitors with no activity against other essential enzymes involved in the synthesis and metabolism of catecholamines.

Effect of mecamylamine on the fate of dopamine in striatal and mesolimbic areas of rat brain; interaction with morphine and haloperidol.

1 The effects of the nicotinic cholinoceptor blocking drug, mecamylamine (alone or in combination with morphine or haloperidol) were investigated on the striatal homovanillic acid (HVA) concentration and on the alpha-methyl-p-tyrosine (AMPT)-induced depletion of striatal or mesolimbic dopamine content in the brain of rats. 2 Mecamylamine (2 mg/kg) alone did not alter the striatal HVA concentration, but it reduced the probenecid-induced accumulation of HVA. Mecamylamine pretreatment reduced the morphine- and haloperidol-induced elevation of striatal HVA concentrations. Hexamethonium did not alter the striatal HVA concentration when given alone or in probenecid- or morphine-treated rats, whereas pempidine (8 mg/kg) clearly reduced the probenecid-induced accumulation of HVA in the striatum. 3 Mecamylamine (2 and 8 mg/kg) slowed the rate of AMPT-induced depletion of dopamine from the striatum and mesolimbic area both in the brain of control rats treated with morphine or haloperidol. 4 Mecamylamine slightly prolonged the cataleptic effect of morphine. 5 The results indicate that mecamylamine inhibits the release of dopamine both from the striatal and mesolimbic dopaminergic neurones.

Comparison of two new inhibitors of catechol O-methylation on striatal dopamine metabolism: a microdialysis study in rats.

1. Effects of two new inhibitors of catechol O-methylation (CGP 28014 and entacapone; 30 mg kg-1, i.p.) were compared by means of brain microdialysis in rats treated with L-3,4-dihydroxyphenylalanine (L-dopa)/carbidopa (50/50 mg kg-1, i.p., respectively) or saline. 2. In saline-treated rats, CGP 28014 maximally (max) increased striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) effluxes by 41% and 49%, respectively, whereas homovanillic acid (HVA) levels were decreased by 71%. 3. In the presence of L-dopa/carbidopa, a peripherally active inhibitor of catechol O-methyltransferase (COMT) entacapone had a short-lasting increasing effect on L-dopa efflux. Compared to the effects of L-dopa/carbidopa alone 3-O-methyldopa (3-OMD) levels were effectively reduced (max 79%) by entacapone, but not by CGP 28014. 4. Entacapone, in contrast to CGP 28014, increased striatal dopamine efflux (max 492% of that after L-dopa/carbidopa alone). Also DOPAC levels were increased by entacapone (255% at 180 min), but not significantly by CGP 28014 (159% at 180 min). 5. Both compounds initially decreased HVA efflux. The effect of CGP 18014 was longer-lasting. By the end of the measurement, entacapone even increased HVA levels (max 259%). 6. Our results demonstrate that entacapone is a peripheral COMT inhibitor and support the view that CGP 18014 is mainly a centrally acting inhibitor of O-methylation.

Clinical pharmacology, therapeutic use and potential of COMT inhibitors in Parkinson's disease.

When peripheral decarboxylation is blocked by carbidopa or benserazide, the main metabolic pathway of levodopa is O-methylation by catechol-O-methyltransferase (COMT). Entacapone and tolcapone are new potent, selective and reversible nitrocatechol-type COMT inhibitors. Animal studies have demonstrated that entacapone mainly has a peripheral effect whereas tolcapone also inhibits O-methylation in the brain. In human volunteers, both entacapone and tolcapone dose-dependently inhibit the COMT activity in erythrocytes, improve the bioavailability and decrease the elimination of levodopa, and inhibit the formation of 3-O-methyldopa (3-OMD). Entacapone is administered with every scheduled dose of levodopa whereas tolcapone is administered 3 times daily. The different administration regimens for these agents are based on their different pharmacokinetic and pharmacodynamic profiles. Both entacapone and tolcapone enhance and extend the therapeutic effect of levodopa in patients with advanced and fluctuating Parkinson's disease. They prolong the duration of levodopa effect. Clinical studies show that they increase the daily ON time by an average 1 to 3 hours, improve the activities of daily living and allow daily levodopa dosage to be decreased. Correspondingly, they significantly reduce the daily OFF time. No comparative studies between entacapone and tolcapone have been performed. Tolcapone also appears to have a beneficial effect in patients with nonfluctuating Parkinson's disease. The main adverse effects of the COMT inhibitors are related to their dopaminergic and gastrointestinal effects. Enhancement of dopaminergic activity may cause an initial worsening of levodopa-induced adverse effects, such as dyskinesia, nausea, vomiting, orthostatic hypotension, sleep disorders and hallucinations. Levodopa dose adjustment is recommended to avoid these events. Tolcapone is associated with diarrhoea in about 16 to 18% of patients and entacapone in less than 10% of patients. Diarrhoea has led to discontinuation in 5 to 6% of patients treated with tolcapone and in 2.5% of those treated with entacapone. Urine discoloration to dark yellow or orange is related to the colour of COMT inhibitors and their metabolites. Elevated liver transaminase levels are reported in 1 to 3% of patients treated with tolcapone but very rarely, if at all, in patients treated with entacapone. The descriptions of acute, fatal fulminant hepatitis and potentially fatal neurological reactions, such as neuroleptic malignant syndrome and rhabdomyolysis, in association with tolcapone led to the suspension of its marketing authorisation in the European Community and Canada. In many other countries, the use of tolcapone is restricted to patients who are not responding satisfactorily to other therapies. Regular monitoring of liver enzymes is required if tolcapone is used. No such adverse reactions have so far been described for entacapone and no laboratory monitoring has been proposed. COMT inhibitors added to levodopa therapy are beneficial, particularly in patients with fluctuating disease. They may be combined with other antiparkinsonian drugs, such as dopamine agonists, selegiline and anticholinergics without adverse interactions. They provide a new treatment possibility in patients with Parkinson's disease who have problems with their present levodopa therapy.

Effect of muscarinic cholinergic drugs on morphine-induced catalepsy, antinociception and changes in brain dopamine metabolism.

The effects of drugs acting on muscarinic cholinergic receptors on the catalepsy, antinociception and changes in rectal temperature and in brain dopamine metabolism induced by morphine were studied in Wistar rats. Scopolamine (0.3 - 30 mg/kg) was about three times as potent as atropine (1 - 30 mg/kg) in potentiating the cataleptic effect of morphine. Methylscopolamine and methylatropine did not alter the cataleptic effect of morphine. Pilocarpine (100 mg/kg) and arecoline (10 mg/kg) slightly but significantly and RS86 (20 - 40 mg/kg) clearly antagonized the morphine-catalepsy. RS86 antagonized the atropine-induced potentiation of morphine catalepsy. The antinociceptive effect of pilocarpine was additive and that of RS86 less than additive with morphine. The antimuscarinic compounds did not alter the antinociceptive effect of morphine. Antimuscarinic compounds enhanced the hypothermic effect of morphine, but none of the compounds studied altered the hyperthermic effect of morphine. The antimuscarinic drugs reduced the concentration of striatal homovanillic acid (HVA) in about same proportion in control and morphine-treated rats. Both the muscarinic compounds and morphine increased the concentration of striatal HVA, but when combined their effects were not significantly different from those of morphine alone. Scopolamine antagonized and pilocarpine accelerated the morphine-induced increase in the rate of depletion of cerebral dopamine content. The present results show that the effects of muscarinic aand antimuscarinic cholinergic drugs on the cataleptic effect of morphine were opposite to their effects on the catalepsy induced by neuroleptic compounds.

Circling behavior induced by intranigral injections of GABA and muscimol in rats.

Circling behavior induced by unilateral intranigral injections of GABA or muscimol was studied in rats. Both GABA (10--400 micrograms) and muscimol (1--100 ng) evoked the same kind of contralateral circling behavior dose-dependently when injected into the substantia nigra. Muscinol was much more potent that GABA and its effect lasted longer. Neither GABA nor muscimol induced any ipsilateral circling. Pretreatment with bicuculline (3 mg/kg IP) significantly attenuated the intensity of circling behavior induced by intranigral injections of GABA or muscimol. Pretreatment with haloperidol (0.5 and 1.0 mg/kg SC) also significantly antagonized the circling behavior induced by GABA and muscimol. Pretreatment with atropine (10 mg/kg IP) significantly increased the intensity of circling behavior induced by intranigral injections of muscimol and tended to increase the intensity of circling behavior induced by intranigral injections of GABA. Pretreatment with struchnine (0.25 mg/gk IP) did not modify circling behavior induced by GABA, but did to some extent increase that induced by muscimol. These results indicate that the contralateral circling behavior induced by intranigral injections of GAB and muscimol seems to be dependent both on the activation of the dopaminergic nigrostriatal system and on the nondopaminergic nigral output system.

Neurofilament profile in olfactory mucosa of patients with a clinical diagnosis of Alzheimer's disease.

In an attempt to find a reliable peripheral marker of Alzheimer's disease (AD), pieces of olfactory mucosa were removed by biopsy from 11 patients with probable AD and from eight control patients. The samples were analysed immunocytochemically using monoclonal and polyclonal antibodies. The olfactory and peripheral neurons of the olfactory mucosa in both AD and control patients typically exhibited immunoreactivity to neurofilament (NF) triplet proteins, including both phosphorylated and non-phosphorylated epitopes, as well as to synaptophysin, but lacked reactivity to other intermediate filament proteins, microtubule-associated protein 2 and tau. Our results do not support the recent findings suggesting the lack of NF proteins in olfactory neurons or the preferential phosphorylated status of NF proteins in olfactory neurons solely in AD.

Scopolamine reduces the P35m and P60m deflections of the human somatosensory evoked magnetic fields.

Acetylcholine (ACh) is a potent neuromodulator in the brain with multiple, complex effects on neuronal function, most of which are mediated by muscarinic receptors. Generally, the most significant effect is excitation of pyramidal neurones and facilitation of responses to afferent stimulation. Much of the information on the ACh effects comes from studies utilizing in vitro or anesthetized in vivo preparations, while fewer data are available from awake animals or humans. We studied human somatosensory evoked magnetic fields (SEFs), which reflect summated postsynaptic currents in pyramidal neurones in area 3b, and in the opercular somatosensory cortex, when cholinergic transmission was modulated either by a central (scopolamine, 0.3 mg, i.v.) or peripheral (glycopyrrolate, 0.2 mg, i.v.) muscarinic antagonist. A randomized, double-blind, cross-over design was employed. SEFs were elicited by right median nerve stimulation at the wrist with constant-current pulses above motor threshold. The first excitatory cortical response from area 3b (N20m) was not affected by the central muscarinic blockade, while later P35m and P60m deflections were significantly reduced. The responses from the opercular somatosensory cortex showed some tendency toward reduction, but no significant alterations. The results show that somatosensory cortical processing can be modulated by muscarinic transmission at a relatively early stage. Relative membrane hyperpolarization of pyramidal neurons due to scopolamine (caused by blocking an ACh-induced tonic depolarization) is discussed as a possible mechanism underlying the observed effects.

Effects of COMT inhibitors on striatal dopamine metabolism: a microdialysis study.

In vivo microdialysis was used to examine the effect of two new catechol-O-methyltransferase (COMT) inhibitors, Ro 40-7592 and OR-611, on extracellular levels of dopamine, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) in rat striatum. The interactions of the COMT inhibitors with nomifensine, clorgyline and deprenyl were also studied. Ro 40-7592 (3-30 mg/kg, i.p.) decreased dose-dependently the efflux of HVA, increased that of DOPAC, and tended to increase that of dopamine. Higher doses of OR-611 (30-100 mg/kg, i.p.) also decreased the dialysate level of HVA, increased that of DOPAC, and tended to increase that of dopamine. Ro 40-7592 was about ten-fold as potent as OR-611. Neither of the COMT inhibitors changed dialysate levels of 5-HIAA. An OR-611 dose of 10 mg/kg i.p. had no significant effect, in contrast to Ro 40-7592, on any of the parameters studied; this dose was thus used to differentiate between the effects of central and peripheral COMT inhibition. Both nomifensine (15 mg/kg, i.p.) and clorgyline (4 mg/kg, i.p.) alone elevated extracellular dopamine levels, and lowered those of DOPAC and HVA, though there were quantitative and temporal differences between the drugs. L-Deprenyl (1 mg/kg, i.p.) alone had no significant effect on any of the compounds measured. Ro 40-7592 (10 mg/kg, i.p.) potentiated the effect of nomifensine on dopamine efflux, and it tended to increase clorgyline-induced dopamine efflux.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of methiothepin on changes in brain serotonin release induced by repeated administration of high doses of anorectic serotoninergic drugs.

We previously observed, using in vivo microdialysis, that the potassium-evoked release of frontocortical serotonin (5-HT) is suppressed after rats receive high doses (30 mg/kg, i.p., daily for 3 days) of fluoxetine, a selective blocker of 5-HT reuptake. We now describe similar impairments in 5-HT release after repeated administration of two other 5-HT uptake blockers, zimelidine and sertraline (both at 20 mg/kg, i.p. for 3 days) as well as after dexfenfluramine (7.5 mg/kg, i.p. daily for 3 days), a drug which both releases 5-HT and blocks its reuptake. Doses of these indirect serotonin agonists were about 4-6 times the drug's ED50 in producing anorexia, a serotonin-related behavior. In addition, methiothepin (20 microM), a non-selective receptor antagonist, locally perfused through the dialysis probe 24 h after the last drug injection, enhanced K(+)-evoked release of 5-HT at serotoninergic nerve terminals markedly in control rats and slightly in rats treated with high doses of dexfenfluramine or fluoxetine. On the other hand, pretreatment with methiothepin (10 mg/kg, i.p.) one hour before each of the daily doses of fluoxetine or dexfenfluramine given for 3 days, totally prevented the decrease in basal and K(+)-evoked release of 5-HT. Finally, when methiothepin was injected systemically the day before the first of 3 daily injections of dexfenfluramine, it partially attenuated the long-term depletion of brain 5-HT and 5-HIAA levels induced by repeated administration of high doses of dexfenfluramine. These data suggest that drugs which bring about the prolonged blockade of 5-HT reuptake - such as dexfenfluramine and fluoxetine - can, by causing prolonged increases in intrasynaptic 5-HT levels as measured by in vivo microdialysis, produce receptor-mediated long-term changes in the processes controlling serotonin levels and dynamics.

Possible involvement of nigrostriatal dopamine system in the inhibition of thyrotropin secretion in the rat.

The dopaminergic inhibition of cold-stimulated thyrotropin (TSH) secretion was studied in male rats. Serum TSH levels were decreased by apomorphine (1 mg/kg i.p.) but not by dopamine (DA, 0.2--5 mg/kg s.c.). This effect of apomorphine was abolished by haloperidol (1 mg/kg i.p.), metoclopramide and sulpiride (10 mg/kg i.p.) but not by domperidone (0.1--5 mg/kg i.p.). Domperidone does not cross the blood-brain barrier while the other DA receptor antagonists do so. High doses of domperidone itself inhibited the cold-induced TSH secretion whereas the other DA antagonists did not. DA (1--10 micrograms/rat) into the medial basal hypothalamus (MBH) had no effect but 10--50 micrograms/rat into the 3rd ventricle inhibited the cold-stimulated TSH secretion. 6-Hydroxydopamine infusion after desipramine pretreatment (25 mg/kg i.p.) did not affect TSH secretion when given into the MBH (2 micrograms/rat), the 3rd ventricle (100 micrograms/rat) or unilaterally into the substantia nigra (SN, 6 micrograms/nucleus), but bilateral nigral infusions abolished the TSH cold response. The inhibitory effect of apomorphine (0.1 and 0.5 mg/kg i.p.) was amplified only in the rats whose SN was unilaterally destroyed. These results show that tuberoinfundibular DA neurons do not affect TSH secretion. Instead, the inhibition is mediated through the hypothalamic projections of the nigrostriatal DA system.

Inhibition of catechol-O-methyltransferase activity by two novel disubstituted catechols in the rat.

Catechol-O-methyltransferase (COMT) has an important role in the extraneuronal inactivation of catecholamine neurotransmitters and drugs with a catechol structure. Two novel COMT inhibitors, OR-462 and OR-486, were highly effective (IC50 = 18 and 12 nM, respectively) and selective in inhibiting COMT activity in vitro. Tyrosine hydroxylase was not inhibited until micromolar concentrations of these compounds were used: the IC50 values for OR-462 and OR-486 were 10 and 14 microM, respectively. The IC50 values for dopamine-beta-hydroxylase, dopa-decarboxylase and monoamine oxidase forms A and B were greater than 50 microM. In studies ex vivo oral OR-462 inhibited mainly the COMT activity in the duodenum while OR-486 inhibited COMT activity in the liver and red blood cells as well. Oral OR-462 did not penetrate into the brain in doses up to 30 mg/kg while the same dose of OR-486 had some effect on striatal COMT activity. When tested in combination with levodopa-carbidopa, orally administered OR-462 and OR-486 were more effective in reducing the formation of 3-O-methyldopa from levodopa than was the levodopa-carbidopa treatment alone. These results indicate that OR-462 and OR-486 are effective and long-lasting inhibitors of COMT activity.

Scopolamine enhances middle-latency auditory evoked magnetic fields.

To study the influence of central cholinergic muscarinic transmission on human cortical middle-latency auditory evoked magnetic fields (MAEF), centrally acting antagonist scopolamine hydrobromide (0.3 mg, i.v.), and peripheral muscarinic receptor antagonist glycopyrrolate (0.2 mg, i.v.), were administered to 13 healthy subjects in a double-blind randomized cross-over design. MAEF, measured with whole-head magnetoencephalography (MEG), were elicited with clicks applied at 10-Hz rate to the left ear. The amplitudes of N(b)m and P(a)m responses were augmented by scopolamine (P < 0.01 and P < 0.08). These effects were about equally strong for responses from ipsi- and contralateral auditory cortices. Thus, the present MEG findings revealed specific modulation of cortical generators of middle-latency auditory evoked responses by muscarinic transmission. These findings might be associated with auditory processing deficits observed in dementias with cholinergic disturbances.

Scopolamine augments transient auditory 40-hz magnetic response in humans.

The influence of neocortical muscarinic transmission on auditory-evoked 40-Hz magnetic response was studied in 13 healthy subjects in a double-blind randomized cross-over design. Either a centrally (scopolamine hydrobromide, 0.3 mg, i.v.) or a peripherally (glycopyrrolate, 0.2 mg, i.v.) acting antagonist of muscarinic transmission was administered during two sessions of magnetoencephalographic recording of 40-Hz response elicited by monaural tones. Scopolamine significantly (P < 0.01) augmented the 40-Hz magnetic response over the hemispheres ipsi- and contralateral to the ear stimulated. This finding suggests muscarinic modulation of the auditory evoked transient 40-Hz response.

Suppression of transient 40-Hz auditory response by haloperidol suggests modulation of human selective attention by dopamine D2 receptors.

Cognitive processes including selective attention may depend on synchronous activity of neurons at the gamma-band (around 40Hz). To determine the effect of neuroleptic challenge on transient auditory evoked 40-Hz response, simultaneous measurement of 122-channel magnetoencephalogram (MEG) and 64-channel electroencephalogram (EEG) was used. Either 2mg of dopamine D(2)-receptor antagonist haloperidol or a placebo was administered orally to 11healthy subjects in a double-blind randomized crossover design in two separate sessions. The subjects attended to tones presented to one ear and ignored those presented to the other ear. Haloperidol significantly suppressed the transient 40-Hz electric response to the attended stimuli, while no significant effect was observed in the electric responses to the unattended tones or in the magnetic responses. The present result suggests that dopamine D(2) receptors modulate selective attention.

Diagnosis and clinical characteristics of ocular Lyme borreliosis.

PURPOSE: To establish a diagnosis, in a group of patients we studied the characteristics of ocular Lyme borreliosis. METHODS: During a two-year period, 236 patients with prolonged external ocular inflammation, uveitis, retinitis, optic neuritis, or unexplained neuro-ophthalmic symptoms were examined for Lyme borreliosis. Antibodies to Borrelia burgdorferi were measured by indirect ELISA and western blot. Cerebrospinal fluid was also analyzed by polymerase chain reaction. RESULTS: Ocular Lyme borreliosis was diagnosed in ten patients on the basis of medical history, clinical findings, and serologic test results. Results of ELISA disclosed that five patients were seropositive, two patients showed borderline reactivity, and three patients were seronegative. Four of the five patients with borderline or negative results by ELISA had a positive result by western blot analysis. In one seropositive patient, polymerase chain reaction verified a gene of B. burgdorferi endoflagellin from the vitreous and cerebrospinal fluid specimen. In five of the six patients with known onset of the Borrelia infection, the ocular disorder appeared as a late manifestation. Abnormalities of the posterior segment of the eye, such as vitreitis, retinal vasculitis, neuroretinitis, choroiditis, and optic neuropathy were seen in six patients. Bilateral paralytic mydriasis, interstitial keratitis, episcleritis, and anterior uveitis were seen in one patient each. CONCLUSIONS: Late-phase ocular Lyme borreliosis is probably underdiagnosed because of weak seropositivity or seronegativity in ELISA assays. Ocular borrelial manifestations show characteristics resembling those seen in syphilis.

Effects of two diketopiperazines, cyclo (His-Pro) and cyclo (Asp-Phe), on striatal dopamine: a microdialysis study.

The effects of two diketopiperazines, Cyclo (His-Pro) (CHP) and Cyclo (Asp-Phe) (CAP), on striatal extracellular levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were examined using in vivo microdialysis in anaesthetized rats. Treatment with neither CHP (0.1-10 mg/kg IP and 0.3 mg/kg i.v.) nor CAP (0.1-10 mg/kg IP and 10 mg/kg PO) significantly changed the efflux of DA, DOPAC, HVA, or 5-HIAA when compared to the effects of treatment with saline. Our results suggest that systemic administration of CHP or CAP alone does not modify striatal dopaminergic neurotransmission. The previous findings of enhanced DA release by systemic administration of thyrotropin releasing hormone (TRH) are probably not explained by formation of CHP from TRH.