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Organophosphorus (OP) compounds that inhibit acetylcholinesterase are a common cause of poisoning worldwide, resulting in several hundred thousand deaths each year. The pathways activated during OP compound poisoning via overstimulation of muscarinic acetylcholine receptors (mAChRs) play a decisive role in toxidrome. The antidotal therapy includes atropine, which is a nonspecific blocker of all mAChR subtypes. Atropine is efficient for mitigating depression in respiratory control centers but does not benefit patients with OP-induced skeletal muscle weakness. By using an ex vivo model of OP-induced muscle weakness, we studied the effects of the M1/M4 mAChR antagonist pirenzepine and the M2/M4 mAChR antagonist methoctramine on the force of mouse diaphragm muscle contraction. It was shown that weakness caused by the application of paraoxon can be significantly prevented by methoctramine (1 µM). However, neither pirenzepine (0.1 µM) nor atropine (1 µM) was able to prevent muscle weakness. Moreover, the application of pirenzepine significantly reduced the positive effect of methoctramine. Thus, balanced modulation of neuromuscular synaptic transmission via M1 and M2 mAChRs contributes to paraoxon-induced muscle weakness. It was shown that methoctramine (10 µmol/kg, i.p.) and atropine (50 µmol/kg, i.p.) were equieffective toward increasing the survival of mice poisoned with a 2xLD 50 dose of paraoxon., (© 2022. The Author(s).)

Introduction: Myopia is a worldwide epidemic. Plethora of treatments are offered to decrease myopia progression. In this study, we compared between different geographical areas worldwide the practice patterns used by paediatric ophthalmologists to decrease the progression of myopia., Methods: Global responses to a questionnaire were analysed (n=794) for demographic variations. Pharmacological, optical and behavioural categories were defined as effective or ineffective based on the current scientific peer reviewed literature., Results: Treatment rates varied significantly between geographical regions (mean 57%, range 39%-89%, p<0.001). Nearly all participants who treat myopia used at least one form of effective treatment, regardless of location (98%, p=0.16). Among those prescribing pharmacological treatments, European physicians offered the lowest rate of effective treatment compared with other regions (85% vs mean 97%). Rates of effective optical treatment varied significantly between locations (p<0.001), from 16% (Central-South America) to 56% (Far East). Most treating respondents advocated behavioural modifications (92%), between 87% (North America) and 100% (Central Asia). Nearly all respondents used combinations of treatment modalities (95%)-mostly pharmacological, optical and behavioural combination. However, combination rates varied significantly between regions (p<0.001)., Discussion: The utility of treatment to decrease myopia progression differs significantly across the world both in type, combination and efficacy., Conclusion: Paediatric ophthalmologists involvement and proficiency in myopia progression treatment varies around the world. This may entail promoting continuous medical education and other incentives to increase the number and proficiency of paediatric ophthalmologist to have a more effective impact to control the myopia epidemic in children., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose of the study: Kaempferol (KM) is a flavonoid found in plant-derived foods and medicinal plants. Recently, it is well established that KM plays a protective role to develop Alzheimer's disease. The current study aimed at evaluating the effect of intracerebroventricular micro-injection of KM on memory retention of passive avoidance learning (MRPAM) and identifying the potentially related cholinergic mechanisms (ChMs) in rats. Materials and methods: In the current study, male Wistar rats randomly divided into control, vehicle and KM (10, 20 and 40 μg/rat) groups. Moreover, MRPAM was evaluated by shuttle box test. The role of ChM was studied using non-selective and selective acetylcholine antagonists (scopolamine [SCN], 4-DAMP and methoctramine [MN], respectively) as well as pirenzepine (PZ) in combination with KM. Results: The employment of KM (40 μg/rat) improved the SCN-induced memory impairment in MRPAM. Co-treatment with KM (40 μg/rat) plus 4-DAMP significantly increased the step-through latency (STL, P  < 0.05; 167 ± 28 s) and decreased the total dark chamber (TDC, P  < 0.05; 121 ± 31 s) compared with those of the 4-DAMP group (STL: 75 ± 13 s; TDC: 178 ± 46 s). Co-treatment with KM (40 μg/rat) plus PZ attenuated STL, and also increased TDC ( P  < 0.01; 220 ± 28 s) compared with those of the PZ group. Co-treatment with KM (10 and 20 μg/rat) and MN increased STL ( P  < 0.05), and deceased TDC compared with those of the MN group ( P  < 0.01). Conclusions: Totally, the results of the present study showed that cholinergic system may be involved in improving effect of KM on SCN-induced memory impairment.

Sialorrhea is often treated with anticholinergic agents, but they can have undesirable side effects such as drowsiness, sedation, and constipation. Effective medication that acts selectively on the salivary glands is needed. We report the case of a patient with sialorrhea who was successfully treated by the combined use of pirenzepine and solifenacin (M1 and M3 muscarinic receptor antagonists, respectively). The patient was a 51-year-old man with mean unstimulated and stimulated salivary flow rates per 10 min of 6.1 mL and 41.7 mL, respectively (both were measured three times). 99m TcO 4- salivary gland scintigraphy revealed characteristic spontaneous saliva secretion without stimulation. He was treated with Scopolia extract, escitalopram, solifenacin succinate, and the combined administration of solifenacin succinate and pirenzepine. A statistically significant decrease was observed from the pre-medication unstimulated and stimulated salivary flow rates only following the combined administration of solifenacin and pirenzepine. The major muscarinic receptor subtype expressed in the salivary glands is M3; however, M1 is also present. A study using knockout mice demonstrated that the presence of either M1 or M3 receptors was sufficient for salivation. Thus, the combined use of selective M1 and M3 antagonists could provide a good treatment option for sialorrhea.

Introduction: Myopia (short-sightedness) exhibits high prevalence in East Asia. Methods to mitigate myopia progression are important in preventing the vision-threatening complications associated with high myopia. In this review, we examine the regional epidemiology of myopia and provide updated evidence regarding interventions to slow myopia progression in children., Methods: We performed a literature search using PubMed from the date of inception through 25 June 2018. Studies involving myopia epidemiology and control of myopia progression were selected; only studies published in English were reviewed. Preference was given to prospective studies, as well as those conducted in Hong Kong or East Asia., Results: Atropine eye drops and pirenzepine eye gel are highly effective for controlling myopia progression in children. Orthokeratology, peripheral defocus contact lenses, bifocal or progressive addition spectacles, and increased involvement in outdoor activities are also effective for controlling myopia progression; however, myopia undercorrection and single vision contact lenses are ineffective., Conclusion: Although various methods are effective for controlling myopia progression in children, no curative remedy exists for myopia. Health care professionals should be aware of the available methods, as well as their risks and benefits. Treatment should be individualised and based on the preferences of the patient's family, after full discussion of the risks and benefits of each modality.

The mitogen-activated protein kinase (MAPK), especially its extracellular signal-regulated kinase (ERK) subfamily, is a group of kinases enriched in the mammalian brain. While ERK is central to cell signaling and neural activities, the regulation of ERK by transmitters is poorly understood. In this study, the role of acetylcholine in the regulation of ERK was investigated in adult rat striatum in vivo. We focused on muscarinic M1 and M4 receptors, two principal muscarinic acetylcholine (mACh) receptor subtypes in the striatum. A systemic injection of the M1-preferring antagonist telenzepine did not alter ERK phosphorylation in the two subdivisions of the striatum, the caudate putamen and nucleus accumbens. Similarly, telenzepine did not affect ERK phosphorylation in the medial prefrontal cortex (mPFC), hippocampus, and cerebellum. Moreover, telenzepine had no effect on the ERK phosphorylation induced by dopamine stimulation with the psychostimulant amphetamine. In contrast to telenzepine, the M4-preferring antagonist tropicamide consistently increased ERK phosphorylation in the striatum and mPFC. This increase was rapid and transient. Tropicamide and amphetamine when coadministered at subthreshold doses induced a significant increase in ERK phosphorylation. These results demonstrate that mACh receptors exert a subtype-specific modulation of ERK in striatal and mPFC neurons. While the M1 receptor antagonist has no effect on ERK phosphorylation, M4 receptors inhibit constitutive and dopamine-stimulated ERK phosphorylation in these dopamine-innervated brain regions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aims: We have isolated a new muscarinic protein (MT-Mlα) from the venom of the Brazilian coral snake Micrurus lemniscatus., Main Methods: This small protein, which had a molecular mass of 7,048Da, shared high sequence homology with three-finger proteins that act on cholinergic receptors. The first 12 amino acid residues of the N-terminal sequence were determined to be: Leu-Ile-Cys-Phe-Ile-Cys-Phe-Ser-Pro-Thr-Ala-His., Key Findings: The MT-Mlα was able to displace the [(3)H]QNB binding in the hippocampus of rats. The binding curve in competition experiments with MT-Mlα was indicative of two types of [(3)H]QNB-binding site with pK(i) values of 9.08±0.67 and 6.17±0.19, n=4, suggesting that various muscarinic acetylcholine receptor (mAChR) subtypes may be the target proteins of MT-Mlα. The MT-Mlα and the M(1) antagonist pirenzepine caused a dose-dependent block on total [(3)H]inositol phosphate accumulation induced by carbachol. The IC(50) values for MT-Mlα and pirenzepine were, respectively, 33.1 and 2.26 nM. Taken together, these studies indicate that the MT-Mlα has antagonist effect on mAChRs in rat hippocampus., Significance: The results of the present study show, for the first time, that mAChRs function is drastically affected by MT-Mlα since it not only has affinity for mAChRs but also has the ability to inhibit mAChRs., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aims: Morphine slows the respiratory cycle due to a predominant prolongation of inspiration (apneusis) by postponing the spontaneous termination of inspiration (inspiratory off-switching). The present study investigates whether the morphine-induced apneusis results from impairment of cholinergic mechanisms in the central respiratory network., Main Methods: The efferent discharge was recorded from the phrenic nerve in artificially ventilated and anesthetized rats with vagotomy. All drugs were injected intravenously., Key Findings: The phrenic nerve displayed an augmenting discharge during inspiration and arrest of discharge during expiration in normal condition. Administration of morphine (0.3-10.0mg/kg) dose-dependently provoked apneusis characterized by a long-lasting, plateau inspiratory discharge of the phrenic nerve. It shortened the expiratory duration. Subsequent administration of physostigmine (0.1mg/kg) restored the morphine-induced apneusis to eupnea with a partial recovery of the augmenting inspiratory discharge. This modification of physostigmine was blocked by a non-specific muscarinic antagonist scopolamine (3.0mg/kg), leading to re-prolongation of inspiration. A similar antagonism was affected by an antagonist of M3 cholinergic receptors, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 1.0 and 10.0mg/kg) but not by an antagonist of M1 cholinergic receptors, pirenzepine (1.0 and 10.0mg/kg)., Significance: These results demonstrate that the activation of endogenous M3 cholinergic mechanisms counteracts the morphine-induced apneusis., (Copyright © 2011 Elsevier Inc. All rights reserved.)

It has been previously shown that cross-tolerance to the discriminative stimulus properties of clozapine can be demonstrated with the drug discrimination paradigm. This study examined the ability of N-desmethylclozapine and N-desmethylolanzapine (metabolites of the atypical antipsychotic drugs clozapine and olanzapine, respectively) to induce cross-tolerance to the discriminative stimulus effects of clozapine. After C57BL/6 mice were trained to reliably discriminate 2.5 mg/kg clozapine from vehicle, a clozapine generalization curve was generated. Next, training was suspended and the mice received a maintenance dosing regimen in which they were injected twice daily with 10 mg/kg N-desmethylclozapine for 10 days. Then a second clozapine generalization curve was generated. This was followed by a 10-day washout period during which the mice did not receive drug injections or discrimination training. Finally, a third clozapine generalization curve was generated. These same procedures were followed for N-desmethylolanzapine (10 mg/kg twice daily during maintenance dosing). Both N-desmethylclozapine and N-desmethylolanzapine produced significant rightward shifts in the clozapine generalization curve indicating cross-tolerance between N-desmethylclozapine and clozapine and between N-desmethylolanzapine and clozapine. After a washout period with no training or drug administration this cross-tolerance effect was lost for both metabolites. This cross-tolerance drug discrimination procedure demonstrated in-vivo similarities between these two metabolites and clozapine and suggests that common underlying pharmacological mechanisms were responsible for the cross-tolerance that was observed. These findings also demonstrated that this procedure may be useful for identifying drugs with therapeutic efficacy similar to the atypical antipsychotic clozapine under repeated dosing conditions.

Purpose: The selective muscarinic antagonist pirenzepine inhibits experimentally induced myopia in avian and mammalian species, including nonhuman primates and adolescent humans. Transient positive lens defocus has a potent inhibitory effect on negative-lens-induced myopia in avian and mammalian models. The purpose of the present study was to determine the influence of daily treatment with pirenzepine on ocular growth and refractive error in chicks wearing positive lenses., Methods: The chicks were allocated to one of eight groups (n = 6 each group) on the basis of whether they wore +10 or -10 D lenses monocularly and whether they received daily intravitreal injections of pirenzepine (700 μg) or vehicle (phosphate-buffered saline) in the lens-defocused eye. In vivo refractive and biometric data were collected, and glycosaminoglycan synthesis in the sclera was assessed., Results: Pirenzepine did not alter the level of positive-lens-induced hyperopia in chicks wearing +10 D lenses compared with that in the vehicle control group (+8.1 ± 0.6 D vs. +8.9 ± 2.4 D, mean ± SEM; P = 0.76). In contrast, pirenzepine caused significant inhibition of negative-lens-induced myopia compared with that in the vehicle group (-1.1 ± 1.5 D vs. -8.8 ± 1.1 D; P = 0.001). Glycosaminoglycan synthesis in the posterior sclera was significantly increased in the negative-lens-treated groups and showed small decreases in the positive-lens-treated groups., Conclusions: The influence of pirenzepine on ocular growth in chicks differed by sign of lens defocus, with pirenzepine blocking negative-lens effects on ocular growth, but not positive-lens effects. The most likely reason that hyperopia was not enhanced by pirenzepine treatment was that the rapid compensatory eye growth associated with positive lenses eliminated the imposed myopic defocus, and the clear retinal image prevented any additional hyperopia from developing.

At the rat motor nerve terminals, activation of muscarinic M(1) receptors negatively modulates the activity of inhibitory muscarinic M(2) receptors. The present work was designed to investigate if the negative crosstalk between muscarinic M(1) and M(2) autoreceptors involved endogenous adenosine tonically activating A(1) receptors on phrenic motor nerve terminals. The experiments were performed on rat phrenic nerve-hemidiaphragm preparations loaded with [(3)H]-choline (2.5 microCi/ml). Selective activation of muscarinic M(1) and adenosine A(1) receptors with 4-(N-[3-clorophenyl]-carbamoyloxy)-2-butyryltrimethylammonium (McN-A-343, 3 microM) and R-N(6)-phenylisopropyladenosine (R-PIA, 100 nM), respectively, significantly attenuated inhibition of evoked [(3)H]-ACh release induced by muscarinic M(2) receptor activation with oxotremorine (10 microM). Attenuation of the inhibitory effect of oxotremorine (10 microM) by R-PIA (100 nM) was detected even in the presence of pirenzepine (1 nM) blocking M(1) autoreceptors, suggesting that suppression of M(2)-inhibiton by A(1) receptor activation is independent on muscarinic M(1) receptor activity. Conversely, the negative crosstalk between M(1) and M(2) autoreceptors seems to involve endogenous adenosine tonically activating A(1) receptors. This was suggested, since attenuation of the inhibitory effect of oxotremorine (10 microM) by McN-A-343 (3 microM) was suppressed by the A(1) receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (2.5 nM), and by reducing extracellular adenosine with adenosine deaminase (0.5 U/mL) or with the adenosine transport blocker, S-(p-nitrobenzyl)-6-thioinosine (NBTI, 10 microM). The results suggest that the negative crosstalk between muscarinic M(1) and M(2) autoreceptors involves endogenous adenosine outflow via NBTI-sensitive (es) nucleoside transport system channelling to the activation of presynaptic inhibitory A(1) receptors at the rat motor endplate.

Trace conditioning is considered a model of higher cognitive involvement in simple associative tasks. Studies of trace conditioning have shown that cortical areas and the hippocampal formation are required to associate events that occur at different times. However, the mechanisms that bridge the trace interval during the acquisition of trace conditioning remain unknown. In four experiments with fear conditioning in rats, we explored the involvement of the entorhinal cortex (EC) in the acquisition of fear under a trace-30 s protocol. We first determined that pretraining neurotoxic lesions of the EC selectively impaired trace-, but not delay-conditioned fear as evaluated by freezing behavior. A local cholinergic deafferentation of the EC using 192-IgG-saporin did not replicate this deficit, presumably because cholinergic interneurons were spared by the toxin. However, pretraining local blockade of EC muscarinic receptors with the M1 antagonist pirenzepine yielded a specific and dose-dependent deficit in trace-conditioned responses. The same microinjections performed after conditioning were without effect on trace fear responses. These effects of blocking M1 receptors are consistent with the notion that conditioned stimulus (CS)-elicited, acetylcholine-dependent persistent activities in the EC are needed to maintain a representation of a tone CS across the trace interval during the acquisition of trace conditioning. This function of the EC is consistent with recent views of this region as a short-term stimulus buffer.

Objective: To observe the inhibitive effect of pirenzepine on form deprivation myopia in guinea pigs and to explore the mechanism of Smad3 signaling pathway and connective tissue growth factor (CTGF) in the inhibition of myopia by pirenzepine., Methods: Forty 1-week-old guinea pigs of either sex were randomly divided into 4 groups: a control group (Group I), a form deprivation group (Group II), a pirenzepine ophthalmic solution group (Group III), and a sodium chloride ophthalmic solution group (Group IV). Translucent blinders were used in the right eyes of Group II, III and IV. The left eyes were not given any treatment as the normal control group. Covered eyes of Group III and IV were given 3% pirenzepine ophthalmic solution and 0.1% azone ophthalmic solution respectively twice every day. Six weeks later, refraction and axial length were measured at the end of the experiment, and immunohistochemistry and Western blot were used to analyze the expression levels of Smad3 and CTGF in the sclera of all 4 groups., Results: There was no significant difference between Group III and I in relative refraction and changes of axial length (P>0.05). The difference of Group II and IV compared with Group I was statistically significant (P<0.05). The number of Smad3 and CTGF positive cells in the sclera between Group III and I was not significantly different (P>0.05), while the difference in Group II, IV and I was significant (P<0.05). Western blot showed that the expression levels of Smad3 and CTGF in Group II and IV were much lower than those in Group I (P<0.05), but not evident in Group III and I (P>0.05)., Conclusion: Pirenzepine ophthalmic solution can inhibit the development of form deprivation myopia. Pirenzepine may affect Smad3 signaling pathway in the sclera by inhibiting the development of form deprivation myopia.

Separate groups of food-deprived rats were given 2h access to food after receiving bilateral nucleus accumbens infusions of the muscarinic antagonist scopolamine methyl bromide (at 0, 1.0, and 10.0 microg/side), the M2-preferring agonist oxotremorine sesquifumarate (Oxo-S; at 0, 1.0, or 10.0 microg/side) or the M2 antagonist AFDX-116 (at 0, 0.2, or 1.0 microg/side). Injections of scopolamine or Oxo-S, but not AFDX-116, reduced food consumption across the 2h. These experiments confirm a critical role for Acb acetylcholine in promoting food ingestion, and suggest that decreased acetylcholine tone at post-synaptic muscarinic receptors disrupts normal consummatory behavior.

Purpose: To evaluate if the safety and efficacy of the relatively selective M1-antagonist, pirenzepine, in slowing the progression of myopia in children is sustained over a 2-year period., Methods: This was a multicenter, parallel-group, placebo-controlled, double-masked, randomized clinical trial. Enrolled were children aged 8 to 12 years, with entry spherical equivalent refractive error of -0.75 to -4.00 D and astigmatism

Methoxy poly(ethylene glycol)-poly(D, L-lactide) block copolymer was tested as an ocular permeation enhancer for pirenzepine hydrochloride. The block copolymers with the methoxy poly(ethylene glycol) to poly(D, L-lactide) weight ratio of 80/20, 50/50, 40/60 were synthesized by a ring-opening polymerization procedure. In vitro transcorneal experiments demonstrated that the block copolymer 80/20 significantly enhanced the transcorneal permeation of pirenzepine at the mass ratio of 1/1.4 (pirenzepine hydrochloride/copolymer). Interaction between pirenzepine and copolymer was identified by infrared spectroscopy analysis and dialysis experiments. Ocular pharmacokinetics of pirenzepine/copolymer preparation by in vivo instillation experiments confirmed that block copolymer could enhance the ocular penetration of pirenzepine. Ocular chronic toxicity experiments of block copolymer and pirenzepine/copolymer preparation were studied on rabbits, and no significant toxicity in both groups was observed within 9 months. It could conclude that pirenzepine/copolymer preparation is effective and safe in ocular delivery of pirenzepine.

Objective: To study the corneal permeability of three different pirenzepine eye-drop solutions and provide reference for further clinical use., Methods: Sixty-three New Zealand white rabbits were divided into three groups. Each group of rabbits received 2% pirenzepine (pirenzepine group), 2% pirenzepine with 0.1% hyaluronic acid (hyaluronic acid group), or 2% pirenzepine with 0.1% azone (azone group). One drop eye-drops was applied to conjunctive sac every 5 min for six times. Aqueous samples were obtained from each group at 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 24.0 h after the last drop, respectively. Concentration of pirenzepine in these samples was determined by the HPLC (high pressure liquid chromatography). Stimulation symptom of rabbit eyes was also observed., Results: The concentrations of pirenzepine in aqueous humor were (0.40 +/- 0.06) microg/ml at 0.5 h, (0.53 +/- 0.03) microg/ml at 1.0 h, (1.52 +/- 0.33) microg/ml at 2.0 h and (0.15 +/- 0.02) microg/ml at 4.0 h in pirenzepine group. Aqueous humor concentration of pirenzepine in both 2% pirenzepine with 0.1% azone and 2% pirenzepine with 0.1% hyaluronic acid were significantly higher than that of single pirenzepine application, and their bioavailability in the groups with combinations of pirenzepine with 0.1% azone or 0.1% hyaluronic acid were 23.0 times and 3.4 times higher than that of single pirenzepine usage. No obvious irritate symptom was found in rabbit of all three groups after eye-drop applying., Conclusions: The combination application of pirenzepine with azone or hyaluronic acid has higher corneal permeability compared with pirenzepine alone. This result indicates that azone and hyaluronic acid could be used in pirenzepine eye-drop solution to increase corneal permeability.

Background: It has been shown that mortality risk in patients after myocardial infarction could be estimated by heart rate turbulence (HRT), a short-term change in heart rate after ventricular premature beat (VPB), presumably caused by baroreceptor mechanism. We sought to determine whether pharmacological blockade with atropine, or augmentation of vagal tone with pirenzepine given in small doses would influence HRT., Methods: In 30 patients with normal echocardiogram, and without signs or symptoms of coronary artery disease, after electrophysiologic examination or radiofrequency ablation for supraventricular arrhythmias was completed, turbulence onset (TO) and turbulence slope (TS) in basal state, after 1.3 mg IV pirenzepine and finally, after atropine in dose of 0.04 mg/kg of body weight were compared., Results: As assessed by Friedman ANOVA test both pirenzepine and atropine caused a significant change in both TO (P < 0.01) and TS (P < 0.01). The mean basal TO of -3.6 +/- 2.9%, changed after pirenzepine to -5.99 +/- 5.6% (P < 0.01), and after atropine it changed to -3.3 +/- 18.1% (P < 0.01). The mean basal TS of 18.6 +/- 10.1 ms/R-R interval increased after pirenzepine to 26.8 +/- 19.9 ms/R-R interval (P < 0.05), and decreased after atropine to 1.2 +/- 0.8 ms/R-R interval (P < 0.01). Mean cycle length increased after pirenzepine from 706.8 +/- 106.8 to 830 +/- 151.9 ms (P < 0.01), and decreased after atropine to 454.2 +/- 58.1 ms (P < 0.01)., Conclusion: A conclusion could be drawn that vagomymetic manipulation with intravenous pirenzepine increases HRT; vagal blockade with atropine decreases HRT. This finding suggests that a normal vagal innervation of heart is a prerequisite for the phenomenon of HRT.

Objective: To observe the effect of M1-selective muscarinic antagonist, pirenzepine, on form deprivation myopia and investigate the expression of MMP-2 and its inhibitor TIMP-2 in the fibrous sclera in order to better understand the mechanism by which pirenzepine inhibits myopia., Methods: 40 chicks after birth one day were divided into 4 groups randomly: I. Control group; II. Form deprivation group; III. Vehicle application group; IV. Pirenzepine injected group. Form deprivation myopia was established in right eyes of group II, III, IV by placement of a translucent occluder. The deprived eyes of group III and IV received daily subconjunctival administration of vehicle PBS and pirenzepine respectively. Optical measures such as refraction, axial length, equatorial diameter were made at the end of the experiment. Total RNA and protein were extracted from the posterior fibrous sclera chicks. The expression of MMP-2 and TIMP-2 mRNA and protein were investigated with RT-PCR and Western blot analysis respectively., Results: Refraction status, axial length, equatorial diameter of the eyes in pirenzepine injected group were significantly lower when compared with form deprivation group (P < 0.01), but the parameters were higher when compared with normal control group therefore relatively myopic changes were detected. There were no significant difference between drug control and pirenzepine injected group when optical measures and the expression of MMP-2, TIMP-2 were concerned (P > 0.05). The expressions (mRNA and protein) of both MMP-2 and TIMP-2 were significantly different in form deprivation group when compared with normal control group (MMP-2 mRNA increased by 143.51%, P < 0.01; protein increased by 114.60%, P < 0.01; TIMP-2 mRNA decreased by 55.05%, P < 0.01; protein decreased by 53.73%, P < 0.01). In pirenzepine injected group the relative expression of MMP-2 mRNA and protein were decreased obviously by 41.95% (P < 0.01) and by 36.16% (P < 0.01), while TIMP-2 mRNA and protein expression was increased significantly by 72.46% (P < 0.01) and by 53.05% (P < 0.01) respectively compared with the form deprived group., Conclusion: Subconjunctivally administration of the M1 selective muscarinic antagonist, pirenzepine, partly prevents or restrains form deprivation induced myopia. It may exert its inhibitory effect by modulating the expression of MMP-2 and TIMP-2 in fibrous sclera.

A discrimination conditioned active avoidance reflex (CAAR) model in a T maze was used in 18 rats to study the effects of bilateral microinjections of the selective muscarinic M1 receptor blocker pirenzepine into the neostriatum on the acquisition of the CAAR and behavior in an open field test. There was sharp degradation of learning of the CAAR and a significant improvement in motor activity both in the open field test and in the maze itself in rats given bilateral microinjections (pirenzepine, 0.004 mg) into the neostriatum as compared with intact controls. This suggests that changes in motor behavior (a sharp increase in locomotor activity) may be among the reasons for difficulty in learning the CAAR in rats after pirenzepine microinjections. Another reason for difficulty in learning the CAAR in these animals may be impairment of the perception of the conditioned signals (a flashing light) and poor differentiation. This is particularly indicated by the delay in the start chamber (double that seen in intact animals) on presentation of conditioned signals despite the high level of motor activity. These results and published data provide evidence for the complex nature of changes induced by blockade of muscarinic M1 receptors in the neostriatum.

Purpose: The aim of this paper is to present and discuss modern concepts on the treatment of myopia., Material and Methods: Recent literature dealing with management of myopia has been reviewed., Results: The history of experimental studies on myopia is presented. Anatomical and biochemical changes taking place in the eyeball during experimental induction of myopia are described. Additionally, the following substances inhibiting the progress of experimental myopia are discussed: atropine, oxyphenonium, pirenzepine, chlorpyrifos, apomorphine, reserpine, 6-hydroxy dopamine, dextromethorphan, MK-801, APV, bicuculline, SR95531, CACA, TPMPA, dextrorphanol, levorphanol, D- and L-naloxane, L-NAME, formoguanamine, beta-xyloside, central and peripheral antagonists of VIP, and basic fibroblast growth factor. As the pathogenesis of experimental myopia is similar to progressive myopia, the above-mentioned substances can be treated as potential remedies inhibiting the process of myopia in man. Since 1991, apomorphine and pirenzepine continue to stir hope among researchers because it has been shown that apomorphine in the form of subconjunctival or intravitreal injections or topical preparation inhibits the progression of experimental myopia in primates and chickens. Apart from that it has been observed that pirenzepine administered subconjunctivally or intravitreally inhibits the progression of myopia in tree shrews and chickens. These observations led Siatkowski et al. and Tan et al. to undertake clinical studies in humans. Administration for one year of 2% pirenzepine ophthalmic gel in children resulted in reduction of myopia by 44-51 % as compared with a control group. This result of Siatkowski et al. and Tan et al. represents a breakthrough in the treatment of myopia and clearly indicates that we will be able in the near future to slow down or even block the progression of this refractive anomaly.

Objective: To evaluate the safety and efficacy of the relatively selective M(1)-antagonist, pirenzepine ophthalmic gel (gel), in slowing the progression of myopia in school-aged children., Design: Parallel-group, placebo-controlled, randomized, double-masked study., Participants: Three hundred fifty-three healthy children, 6 to 12 years old, with a spherical equivalent (SE) of -0.75 to -4.00 diopters (D) and astigmatism of

The study shows that, in spite of high criteria of performing inctrumental reflex, the ability to repeat the reflex performance, the increase in tonic component of the response, a dostinct diagonal pattern of posture readjustment, and the local (not diffuse) projection of the mass centre position upon tensoplatforms of anterior paws were only observed after a prolonged training that led to automation of the skill. The instrumental response automation effect could be obtained at once following a bilateral microinjection of carbacholine into the neostriatum. The same albeit a weaker effect could be obtained with bilateral microinjections of D2 Dopamine receptor blocking agent Raclopride into the neostriatum. Bilateral injections of Pyrenzepine yield an opposite result: an increase in the physical component of the response < a disorder in the diagonal pattern of posture readjustment, and a diffuse nature of projection of the mass centre position of anterior paws on tensoplatforms. Indirect efferent output of the neostriatum seems to play an important role in motor instrumental reflex as well as in the process of automation of the motor skill.

The present studies determined whether blockade of M(1)-like muscarinic or nicotinic cholinergic receptors in the dorsomedial striatum affects acquisition or reversal learning of a response discrimination. Testing occurred in a modified cross-maze across two consecutive sessions. In the acquisition phase, a rat learned to turn to the left or to the right. In the reversal learning phase, a rat learned to turn in the opposite direction as required during acquisition. Experiment 1 investigated the effects of the M(1)-like muscarinic receptor antagonist, pirenzepine infused into the dorsomedial striatum on acquisition and reversal learning. Experiment 2 examined the effects of the nicotinic cholinergic antagonist, mecamylamine injected into the dorsomedial striatum on acquisition and reversal learning. Bilateral injections of pirenzepine at 10 microg, but not 1 microg, selectively impaired reversal learning. Analysis of the errors indicated that pirenzepine treatment did not impair the initial shift, but increased reversions back to the original response choice following the initial shift. Bilateral injections of mecamylamine, 6 or 18 microg, did not affect acquisition or reversal learning. The results suggest that activation of M(1) muscarinic cholinergic receptors, but not nicotinic cholinergic receptors, in the dorsomedial striatum is important for facilitating the flexible shifting of response patterns.

Objective: Psychotic symptoms are seen in numerous psychiatric illnesses afflicting the elderly. This article reviews the efficacy of the pharmacologic management of psychotic symptoms in primary psychotic disorders, affective disorders, and neurodegenerative disorders., Method: A comprehensive literature review., Results: Evidence to support the use of pharmacologic interventions to manage psychotic symptoms in elderly patients afflicted with primary psychotic disorders and affective disorders is limited by the absence of randomized, placebo-controlled trials (RCTs). The use of low-dose clozapine is supported by RCTs in Parkinson's disease. The efficacy of risperidone and olanzapine for the treatment of psychotic symptoms has been demonstrated by large RCTs in Alzheimer's disease., Conclusion: There is evidence of the efficacy of antipsychotic medications to manage psychotic symptoms in elderly patients. However, the absence of published evidence from RCTs in primary psychotic and affective disorders, and the limited evidence in the neurodegenerative illnesses, is notable.

Background: The olanzapine/fluoxetine combination has demonstrated effectiveness in treatment-resistant depression (TRD). Although this combination is being used by prescribers, this is the first study to examine long-term use. Long-term efficacy and safety were therefore investigated in a group of patients with major depressive disorder (MDD) with and without TRD., Method: 560 patients who met DSM-IV diagnostic criteria for MDD were enrolled in this 76-week, open-label study (Feb. 2000-July 2002). The Montgomery-Asberg Depression Rating Scale (MADRS) total score was the primary efficacy measure. Safety was assessed via adverse events, vital signs, laboratory analytes, electrocardiography, and extrapyramidal symptom measures., Results: MADRS mean total scores decreased 7 points from baseline (31.6 [N = 552]) at 1/2 week of treatment, 11 points at 1 week of treatment, and 18 points at 8 weeks of treatment. This effect was maintained to endpoint with a mean decrease of 22 points at 76 weeks. Response and remission rates for the total sample were high (62% and 56%, respectively), and the relapse rate was low (15%). Response, remission, and relapse rates for TRD patients (N = 145) were 53%, 44%, and 25%, respectively. The most frequently reported adverse events were somnolence, weight gain, dry mouth, increased appetite, and headache. At endpoint, there were no clinically meaningful changes in vital signs, laboratory analytes, or electrocardiography. There were no significant increases on any measure of extrapyramidal symptoms., Conclusions: The olanzapine/fluoxetine combination showed rapid, robust, and sustained improvement in depressive symptoms in patients with MDD, including patients with TRD. The long-term safety profile of the combination was similar to that of its component monotherapies.

Background: Despite the longer duration of the depressive phase in bipolar disorder and the frequent clinical use of antidepressants combined with antipsychotics or mood stabilizers, relatively few controlled studies have examined treatment strategies for bipolar depression., Objective: To examine the use of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression., Design: Double-blind, 8-week, randomized controlled trial., Setting: Eighty-four sites (inpatient and outpatient) in 13 countries. Patients A total of 833 randomized adults with bipolar I depression with a Montgomery-Asberg Depression Rating Scale (MADRS) score of at least 20. Intervention Patients were randomly assigned to receive placebo (n = 377); olanzapine, 5 to 20 mg/d (n = 370); or olanzapine-fluoxetine combination, 6 and 25, 6 and 50, or 12 and 50 mg/d (n = 86)., Main Outcome Measure: Changes in MADRS total scores using mixed-effects model repeated-measures analyses., Results: During all 8 study weeks, the olanzapine and olanzapine-fluoxetine groups showed statistically significant improvement in depressive symptoms vs the placebo group (P<.001 for all). The olanzapine-fluoxetine group also showed statistically greater improvement than the olanzapine group at weeks 4 through 8. At week 8, MADRS total scores were lower than at baseline by 11.9, 15.0, and 18.5 points in the placebo, olanzapine, and olanzapine-fluoxetine groups, respectively. Remission criteria were met by 24.5% (87/355) of the placebo group, 32.8% (115/351) of the olanzapine group, and 48.8% (40/82) of the olanzapine-fluoxetine group. Treatment-emergent mania (Young Mania Rating Scale score <15 at baseline and > or =15 subsequently) did not differ among groups (placebo, 6.7% [23/345]; olanzapine, 5.7% [19/335]; and olanzapine-fluoxetine, 6.4% [5/78]). Adverse events for olanzapine-fluoxetine therapy were similar to those for olanzapine therapy but also included higher rates of nausea and diarrhea., Conclusions: Olanzapine is more effective than placebo, and combined olanzapine-fluoxetine is more effective than olanzapine and placebo in the treatment of bipolar I depression without increased risk of developing manic symptoms.

Background: This study evaluates whether high-dose olanzapine is associated with elevation of serum prolactin levels., Method: Twenty-four patients taking daily doses of olanzapine of 20, 25, 30, and 40 mg for DSM-IV schizophrenia or schizoaffective disorder had serum prolactin levels measured. The patients were all from one author's (J.L.K.'s) clinical practice. The mean duration of olanzapine therapy was 15.3 months at a dose of at least 20 mg/day. Data were gathered in 2000 and 2001., Results: There was no significant correlation between olanzapine dose and prolactin level (Pearson product moment correlation coefficient = 0.09). No significant differences were found between mean prolactin values in each dose group., Conclusion: There was no significant elevation of prolactin with higher doses of olanzapine. Thus, preliminary evidence suggests that using higher doses of olanzapine is generally safe with regard to prolactin levels.

Objective: To evaluate hepatic enzyme elevations during treatment with olanzapine, divalproex, and their combination., Method: Fifty-two children, aged 4 to 18 years, with hepatic enzyme levels measured during treatment with olanzapine (n = 17), divalproex (n = 23), or their combination (n = 12), were identified in the computerized records at a pediatric medical center. Clinical characteristics as well as serial alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels were collected., Results: Mean and peak hepatic enzyme levels were significantly higher for the combined treatment group compared to the olanzapine or divalproex groups. All 12 patients who received combined treatment had at least one peak enzyme elevation during the treatment. For 42% of these patients, at least one enzyme level remained elevated during the time for which values were available (mean 8 +/- 6 months). For those treated with divalproex either alone or in combination, the findings were not explained by variations in divalproex plasma levels. Two patients receiving combined treatment had the combination treatment discontinued because of medical complications (pancreatitis in one and steatohepatitis in the other)., Conclusions: Combined treatment with olanzapine and divalproex was associated with more elevations of hepatic enzymes than treatment with either agent alone. The long-term significance of this is unknown but warrants study.

Background: The effectiveness of olanzapine in treating challenging behaviors in the intellectually disabled and its ability to substitute for conventional antipsychotic drugs were evaluated., Method: A total of 20 institutionalized adults with a mean age of 42.7 years (range, 18-55 years) with intellectual disability and aggression, self-injurious behavior, destructive/disruptive behavior, or combinations of these behaviors were studied. These individuals were receiving multiple psychotropic medications at baseline and were given additional treatment with the atypical antipsychotic agent olanzapine. The mean dose of olanzapine was 9.1 mg/day (range, 2.5-22.5 mg/day). Effectiveness was determined by retrospective review of the summaries of quarterly neuropsychiatric behavioral reviews and retrospective review of longitudinal behavioral graphs of target symptoms. Data were collected from 1995 to 2000., Results: A significant decrease in global challenging behaviors and specific target behaviors (i.e., aggression, self-injurious behaviors, destructive/disruptive behaviors) occurred (p <.05). A numerical decrease in the dosage of concurrent conventional antipsychotic medications occurred over the course of the first 6 months of olanzapine therapy, and a statistically significant (p <.005) decrease from the start of olanzapine therapy occurred in those subjects who received olanzapine for longer than 6 months (mean = 20.3 months). A significant increase in weight occurred in the subject group during the first 6 months of olanzapine treatment (p <.006), and sedation and constipation were the other common side effects noted., Conclusions: Olanzapine was found to be effective in the treatment of challenging behaviors in the intellectually disabled and in part could be substituted for administration of conventional antipsychotic drugs.

Objective: This study assessed the current state of antipsychotic prescription practices regarding race among veterans receiving care through the Department of Veterans Affairs., Method: The authors examined pharmacy records over a 12-month period for all veterans with schizophrenia and antipsychotic prescriptions in fiscal year 1999. They used logistic regression analysis to assess the effect of race on the use of various atypical antipsychotic agents. Analytic models controlled for age, sex, comorbid substance use, bipolar disorder, and other psychosis., Results: The sample of 69,787 veterans with schizophrenia was 61.3% white, 30.1% African American, and 8.5% Hispanic. Among them, 39% had prescriptions for conventional antipsychotics, 37% for atypical antipsychotics, and 23% for both atypical and conventional antipsychotics. Use of any atypical agent during the year was less likely for Hispanic veterans (55%) than for two other groups (both 61%). When examining specific medications in a multivariate model, the authors found that African American and Hispanic veterans were much less likely to receive clozapine than were white veterans., Conclusions: Overall use of atypical antipsychotics was slightly less common for African American and Hispanic veterans with schizophrenia than for white patients. However, use of clozapine, the first choice for refractory illness and possibly uniquely effective for patients with comorbid substance abuse, did vary greatly by race. This may reflect concern over serious side effects, such as loss of white blood cells and fluctuations of serum glucose levels, or patient preference.

The use of typical antipsychotics is limited in children with schizophrenia, owing to the high rate of response failure and early appearance of extrapyramidal syndromes as well as tardive and withdrawal dyskinesia. The aim of the present study was to examine the effectiveness of the atypical antipsychotic olanzapine in the treatment of childhood-onset schizophrenia. The study sample included nine children hospitalized for schizophrenia who had proven refractory to treatment with at least two antipsychotic drugs. Olanzapine was administered after a 2-week washout period in gradually increasing doses to a maximum of 5 mg/day on day 5 and 10 mg/day in week 3; six patients received up to 20 mg/day as of week 5. The duration of the study was 12 weeks. Patient psychiatric status was measured with three scales at onset of therapy and thereafter once weekly. Patients also underwent regular blood, laboratory, and liver function tests, and we also monitored their blood pressure and weight and performed electrocardiography and electroencephalography. A reduction in all psychopathology scores was obtained at 12 weeks from baseline. All extrapyramidal symptoms of previous medications resolved, and there were no new incidents. Side effects were mild. There were no adverse changes in blood chemistry, hematological tests, or electrocardiography parameters, but the treatment was associated with a significant weight gain (6.10 +/- 3.25 kg). At 1-year follow-up, the improvement in psychiatric symptoms was sustained in eight children. We conclude that olanzapine may have potential as a first-line drug in the treatment of drug-resistant childhood-onset schizophrenia. Large-scale, double-blind, placebo-controlled comparative studies are needed to clarify the role of the various atypical antipsychotics in both treatment-resistant and treatment-naïve populations with psychotic symptoms/disorders.

Rationale: The cognitive impairments evident in many schizophrenics are related to the severity of their negative symptoms and ability to function in society. Drugs that alleviate cognitive impairments, in addition to other psychotic symptoms, may have an important influence on treatment outcome and the course of the illness., Objectives: A delayed non-match to sample task conducted in an eight-arm radial maze was used to determine the influence of four atypical antipsychotics (olanzapine, ziprasidone, risperidone, and clozapine), as well as a typical neuroleptic (haloperidol) on consolidation processes in healthy rats., Method: Well-trained rats were required to recall after a 7-h delay where they had received food pellets during an information phase (first four arm choices) in order to obtain the remaining food pellets during a retention phase (second four arm choices)., Results: The total number of errors that occurred during the retention session increased with increasing delay periods from 0 to 7 h. When administered orally immediately after the information phase, olanzapine (3 and 5 mg/kg) and risperidone (0.1 mg/kg) significantly reduced the number of errors made during the retention phase. Under the same conditions, clozapine, ziprasidone and haloperidol failed to affect the total number of retention phase errors., Conclusion: Some atypical antipsychotics, such as olanzapine and risperidone, improve consolidation processes and may alleviate the cognitive impairments associated with schizophrenia.

Serial verbal learning task (explicit long-term memory) and verbal fluency (generation of a response) are tests that are usually severely impaired in schizophrenia. Despite the growing literature supporting the clinical efficacy of olanzapine, psychiatrists still question its cognitive consequences. This study assessed the efficacy of olanzapine on neurocognitive functioning. Patients (N = 134) meeting diagnostic criteria for schizophrenia, schizophreniform, or schizoaffective disorders began an 8-week, open-label olanzapine treatment at a dose of 5 mg/d, which was increased to 10 mg/d after 1 week. Daily dosage was subsequently adjusted between 5 and 20 mg/d based on individual clinical status. All previous antipsychotics were tapered and discontinued during the first 2 weeks of the study. Neuropsychologic assessments were carried out at baseline and at 4 and 8 weeks. Explicit long-term memory was assessed with the Rey Auditory-Verbal Learning Test: the average immediate recall score significantly improved (P < 0.001), as did the delayed recall score (P < 0.001). The average total score on category fluency improved from 34.6 words at baseline to 37.6 words at end point (P < 0.0001). Time on both Trail A and B making tasks significantly decreased (P < 0.0001). Lack of a control arm makes it impossible to exclude a practice effect as an explanation for the enhanced cognitive performance, although the Word List Recall test represents one of the better resources to avoid a practice effect. After switching to olanzapine, there was a statistically significant improvement of cognitive function in the 3 main domains tested and no significant worsening of any memory or executive function measure.

Background: Patients experiencing an acute decompensation of schizophrenia or bipolar disorder often present in an agitated state. Agitation presents a barrier to therapy, interrupting the typical physician-patient alliance and creating a disruptive, even hazardous, environment. Rapid assessment and effective treatment are necessary to manage agitation and, potentially, to shorten the time to recovery., Methods: One hundred forty-eight acutely agitated patients received either: rapid initial dose escalation (RIDE) in which up to 40 mg of oral olanzapine was allowed on days 1 and 2, up to 30 mg on days 3 and 4, and 5 to 20 mg thereafter; or usual clinical practice (UCP) in which patients received 10 mg/d olanzapine plus up to 4 mg lorazepam on days 1 and 2, up to 2 mg on days 3 and 4, and olanzapine 5 to 20 mg/d thereafter. The Positive and Negative Syndrome Scale-Excited Component (PANSS-EC: poor impulse control, tension, hostility, uncooperativeness, and excitement) measured at 24 hours was the primary measure. Secondary assessments of agitation and safety were also performed., Results: Agitation improved significantly from baseline for both treatment groups; however, improvement with the RIDE strategy was superior to UCP. The RIDE group improvement was superior on the primary efficacy measure (PANSS-Excited) at 24 hours; it was superior on all agitation measures at the end of double-blind treatment. Both treatments were well tolerated, with no clinically significant differences in safety measures. Treatment was not limited by oversedation and attention improved from baseline in both groups., Conclusions: This study demonstrates the value of olanzapine in the treatment of acutely agitated patients. A new approach to olanzapine dosing that expands the initial dose range up to 40 mg/d may offer superior efficacy in rapidly and effectively controlling the symptoms of agitation.

Aim: To compare the pharmacokinetic profiles and dose proportionality of olanzapine in Chinese and Caucasian subjects., Methods: Randomized, three-period study with 12 Chinese and 12 Caucasian, healthy, male subjects administered 2.5, 5 and 10 mg olanzapine. Noncompartmental pharmacokinetic parameters were derived., Results: No statistically significant racial differences in the weight-normalized pharmacokinetic parameters were observed except for Vz/Fnorm, which was 17% lower at the 5- and 10-mg dose in the Chinese group (95% confidence interval 8.49, 10.1 and 8.05, 9.73, respectively), compared with the Caucasian group (9.53, 12.8 and 9.39, 12.0, respectively). Olanzapine's pharmacokinetics were linear and dose proportional in both racial groups., Conclusion: The pharmacokinetics of olanzapine are similar in both Chinese and Caucasian racial groups.

Background: Previous studies have examined the safety and tolerability of oral-loaded divalproex sodium in the treatment of acute mania, but not the early efficacy of this dosing strategy. The purpose of this study was to evaluate the early efficacy of oral-loaded divalproex., Method: In this pooled analysis, 348 subjects from 3 randomized, double-blind, parallel-group, active- or placebo-controlled studies were used to compare the efficacy, safety, and tolerability of oral-loaded divalproex with standard-titration divalproex, lithium, olanzapine, or placebo. Subjects were inpatients diagnosed with acute mania associated with bipolar I disorder (DSM-III-R or -IV and SADS-Change Version). Patients were administered oral-loaded divalproex (20 or 30 mg/kg/day on days 1 and 2 followed by 20 mg/kg/day, and increased at physician's discretion), standard-titration divalproex initiated at 250 mg t.i.d. and titrated to 40-150 microg/mL, lithium (300 mg t.i.d. initial dose) titrated to 0.4 to 1.5 mEq/L, olanzapine (10 mg q.d. initial dose) up to 20 mg/day, or placebo., Results: The results demonstrate an early efficacy advantage for oral-loaded divalproex compared to standard-titration divalproex at days 5, 7/8, and 10. Efficacy was improved over lithium on day 7/8. There were no efficacy differences between divalproex loading and olanzapine. Divalproex loading showed greater efficacy than placebo at all time points. Divalproex loading was as well tolerated or better tolerated than the other active treatments as measured by adverse events and changes in laboratory parameters., Conclusion: These results suggest the oral loading of divalproex leads to a more rapid antimanic effect when compared with standard-titration divalproex, lithium, or placebo and is better tolerated than olanzapine and as well tolerated as lithium or standard-titration divalproex.

Aim: The primary objective of the study was to evaluate the severity of extrapyramidal symptoms during treatment with olanzapine (10-20 mg) versus perphenazine (8-40 mg) using the Simpson Angus Scale (SAS). The secondary objective was to assess the safety profile and clinical efficacy of the investigated drugs., Material and Method: A total of 95 patients with schizophrenia who met the criteria for DSM-IV were randomized to a double-blind, 18 week prospective comparative trail conducted in Poland. The tolerance of treatment was assessed with the use of scales: BAS, SAS and UKU. The efficacy of treatment was evaluated with BPRS, PANSS and CGOI scales., Results: For olanzapine patients, the severity of extrapyramidal symptoms improved after 3 first weeks of treatment, and significantly decreased from the baseline to endpoint. Perphenazine patients showed an increase of extrapyramidal symptoms. The difference of the SAS scores change was statistically significant between olanzapine and perphenazine groups. Akathisia symptoms decreased significantly in the olanzapine group during the treatment period, whereas symptoms of akathisia increased in the perphenazine group. Statistically significant differences of mean change of BAS total score from baseline to endpoint were noted between treatment groups Treatment--emergent adverse events occurred more frequently in patients receiving perphenazine (46%), than in patients receiving olanzapine (17%). The proportion of patients complying with improvement criteria for CGI scale score was statistically greater in the olanzapine group (72.7%) than in the perphenazine group (47.9%). Results of this study showed that the tolerance profile in patients taking olanzapine is superior to perphenazine., Conclusions: Olanzapine was better tolerated than perphenazine. After olanzapine treatment more subjects fulfilled the criterion of improvement and schizophrenic symptoms were less severe than in patients treated with perphenazine.

Objective: To assess the adverse events associated with the appropriate use of oral risperidone and oral olanzapine in long-term care patients with behavioral and psychotic disturbances associated with dementia., Design: Observational analysis., Setting: Analysis was performed at five consulting pharmacist sites across the United States. Participants were recruited at 89 skilled nursing facilities by consultant pharmacists who provided services at each site., Patients: A total of 730 men and women with dementia who had been residents of a skilled nursing facility for at least 90 days were included in the study. Alzheimer's disease was the primary diagnosis in 47% of patients., Intervention: Patients were treated with risperidone < or =2 mg/day or olanzapine < or =10 mg/day for at least 90 days., Measurements: Targets for antipsychotic use included nonaggressive symptoms of psychosis and verbally and physically aggressive behaviors. The effects of risperidone and olanzapine were determined from progress notes, psychotropic monitoring forms, and physicians' order forms after 91 days of treatment. Adverse events of particular significance in the elderly population, including agitation/anxiety, laxative use, dry eyes, and falls, were collected from audited medical records. The evaluation period extended from 3 months before to 3 months after initiation of treatment with risperidone or olanzapine., Results: There were 474 patients in the risperidone group and 256 patients in the olanzapine group. Mean dosages of risperidone at Days 1 and 91 (0.7 +/- 0.3 mg/day and 1.0 +/- 0.5 mg/day, respectively) and olanzapine (3.3 +/- 1.4 mg/day and 4.7 +/- 2.1 mg/day, respectively) were at least 50% lower than the maximum dosages recommended by the Center for Medicare and Medicaid Services for elderly patients with psychosis or behavioral symptoms of dementia. The need for eye lubrication was minimal in both groups and did not differ significantly between them. Anxiolytic use decreased in the risperidone group and remained constant in the olanzapine group, with no significant difference between groups. In the olanzapine and risperidone groups, the number of patients with orders for laxatives increased 10.2% and 1.8%, respectively (P = 0.003), the mean number of days of laxative administration increased 19.1% and 4.3%, respectively (P < 0.001), and the mean number of doses of laxative administered increased 14.2% and 4.1%, respectively (P = 0.001). Among patients qualifying for analysis, falls were recorded for 17.9% of patients receiving olanzapine and 6.9% receiving risperidone (P = 0.001)., Conclusion: Among long-term care residents with dementia who received low doses of risperidone or olanzapine, the incidence of adverse events was low. When considering adverse events of particular concern in the elderly, specifically falls and laxative use, risperidone may be preferred over olanzapine in this population.

Orally disintegrating olanzapine is a recently marketed form of olanzapine that dissolves rapidly on contact with saliva. We describe six demented patients resistant to treatment with common oral antipsychotic medications who were successfully treated with the formulation. The importance of these case reports is to make physicians aware that orally disintegrating olanzapine may be useful for the management of psychobehavioral disturbances in demented patients who resist or have difficulty taking standard oral medications.

The fact that chronic administration of typical and atypical antipsychotic drugs is required for optimal therapeutic response suggests that drug-induced adaptive neurochemical changes contribute to their mechanism of action. In the present study, the effects of chronic and acute haloperidol and olanzapine were compared on ketamine-induced activation of select brain regions, as reflected by altered regional 14C-2-deoxyglucose (2-DG) uptake. Rats were injected once daily with haloperidol (1 mg/kg) or olanzapine (10 mg/kg) for 21 days, and 20 to 24 h after the final injection was challenged with saline or ketamine (25 mg/kg). The washout period was used to test the effects of chronic drug treatment without the influence of acute drug administration. In vehicle-treated rats, ketamine increased 2-DG uptake in select brain regions, including medial prefrontal cortex, nucleus accumbens, caudate putamen, stratum lacunosum-moleculare of hippocampus, and basolateral nucleus of the amygdala. This selective activation was attenuated by prior chronic treatment with both haloperidol and olanzapine. After acute treatment, olanzapine, but not haloperidol, blocked the ketamine-induced activation of 2-DG uptake. These data suggest that both haloperidol and olanzapine can induce adaptive responses that counteract effects of ketamine. However, the differences observed in the acute effects of the two drugs in the ketamine challenge model suggest that different mechanisms could be responsible for their common chronic action of attenuating ketamine-induced brain metabolic activation.

The objective of this study was to determine if the orally disintegrating tablet formulation of olanzapine, Zyprexa Zydis, would facilitate antipsychotic medication compliance in acutely ill, non-compliant patients. Eighty-five acutely ill patients with schizophrenia or schizoaffective disorder who met medication non-compliance criteria received open-label olanzapine orally disintegrating tablets (1020 mgd) for up to 6 wk. Improvement in medication compliance was assessed using various rating scales to measure changes in psychopathology, medication-taking and compliance attitudes, and nursing care burden. Safety variables were also measured. Significant improvement from baseline was demonstrated in the Positive and Negative Syndrome Scale total score at Week 1 and subsequently (p0.001). Significant improvement from baseline was also seen in various scales measuring medication compliance, attitude, and nursing care burden (p0.05). Olanzapine orally disintegrating tablets were well-tolerated. Olanzapine orally disintegrating tablets may benefit acutely ill, non-compliant schizophrenic patients by facilitating acceptance of active antipsychotic drug therapy.

The term bipolar disorder is no longer limited to the classical manic-depressive condition, but now subsumes a wide spectrum of illnesses. As a consequence of this expansion of the classification systems, the therapeutic utility of lithium and other mood stabilizing agents has to be defined anew. The majority treatment recommendations differentiate, symptom-related, between euphoric mania, mixed conditions, mania with psychotic symptoms and rapid cycling manic episodes. Current acute treatment includes, in addition to lithium, in particular carbamazepine and valproate, but also newer antiepileptic drugs such as lamotrigine or atypical neuroleptic agents such as olanzapine and risperidone. Due to the high suicidal risk, patients with bipolar depression often need to be given an antidepressant as well. It must, however, be remembered that in patients with rapid cycling, antidepressants may re-trigger mania.