[Arthroscopic Subtalar Distraction Arthrodesis in Post-Traumatic Indications]. / Artroskopická subtalární distrakcní artrodéza v poúrazových indikacích.

PURPOSE OF THE STUDY: This manuscript aims to present the method of arthroscopic assisted subtalar arthrodesis and to evaluate the benefi ts of this surgery on our study population. MATERIAL AND METHODS: In the period from 9/2007 to 1/2020, a total of 33 subtalar arthrodesis were performed in 31 patients aged 19-66 years (mean 48 years, median 50 years). The indication for arthrodesis was subtalar arthritis causing pain and gait disorders, or hindfoot deformities (most commonly after a calcaneus bone fracture). The arthroscopic assisted subtalar arthrodesis was performed with autologous tricortical bone block graft harvesting from the pelvis, supplemented by autologous cancellous bone graft. Stabilization was achieved by cannulated screws inserted in neutral ankle position. Patients in our retrospective study were followed up for a mean of 48 months (range, 24-130 months). The patients were evaluated preoperatively and at 2 years after surgery. The hindfoot angles and height (TCA - talocalcaneal angle, CIA - calcaneal inclination angle, TCH - talocalcaneal height) were evaluated on radiographs, bone union was assessed on radiographs and CT scans. The clinical assessment was performed using the ankle-hindfoot scale (AHS) of AOFAS (AOFAS score). RESULTS: The preoperative AOFAS score was 35-68 points (mean 52, median 54), the postoperative AOFAS score at 2 years after arthrodesis was 58-94 points (mean 82, median 82). Both the mean and median values of AOFAS score showed a signifi - cant progress from the poor result to the good and excellent result. After 2 years the TCA value decreased in 18 patients (56%) by no more than 3°. The CIA decrease observed in 21 patients (64%) was by 1° on average. The TCH decrease of 1-5 mm after 2 years since the surgery was seen in 16 patients. In 2 patients incomplete healing of arthrodesis was observed, manifested as a clinically asymptomatic non-union. No deep infection was reported. DISCUSSION: In agreement with the current literature, the arthroscopic subtalar arthrodesis has been confi rmed to be a safe method for the management of consequences of hindfoot fractures, with minimum complications and leading to accelerated bone fusion. Differences can be found in the approach, position, use of cancellous bone graft and surgical techniques. In recent years, prone position, posterior approaches, use of cancellous bone graft, distraction and fi xation with 2-3 screws divergently inserted into the bone prevail. The degree of healing of the bone fusion is generally an important factor. In our study population, non-healing was recorded in 2 patients, namely in the form of a clinically silent non-union. Neurological or early complications and/or osteosynthesis material failure occurred in up to a maximum of 10% of cases. The conclusive results of minimally invasive arthrodesis based on the AOFAS score have been confi rmed by us as well as by most authors. CONCLUSSIONS: Our study confi rmed that the arthroscopic assisted subtalar arthrodesis is a successful, reliable and safe minimally invasive method, with minimum complications, leading to stable arthrodesis. KEY WORDS: subtalar arthrodesis, subtalar arthroscopy.

Blastic plasmacytoid dendritic cell neoplasm: First retrospective study in the Czech Republic.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with aggressive behavior and poor prognosis. We present the first retrospective analysis mapping its incidence and therapeutic outcomes in patients diagnosed and treated from 2000 to 2017 in the Czech Republic. The cohort comprised 14 patients (10 males, 4 females) with a median age at diagnosis of 39 years (range, 5-68 years). Initially, skin involvement was noted in 10 (71%) patients and bone marrow infiltration was present in 9 (64%). The first complete remission was achieved in 6/14 (43%) patients after acute lymphoblastic leukemia/lymphoma induction therapy and in 3/14 (21%) patients after acute myeloid leukemia regimen. Nine patients underwent allogeneic hematopoietic cell transplantation, with two patients achieving the first complete remission only after allogeneic transplantation. Patients undergoing allogeneic hematopoietic cell transplantation had longer overall survival than those treated without transplantation (the median survival over the period 16.4 vs. 8.1 months). Relapse of the disease was a significant predictor of mortality (p=0.05). Over the study period, patients' survival ranged from 3.3 to 44.2 months, with a median overall survival of 13 months. Our results revealed an effectivity of allogeneic hematopoietic cell transplantation on complete remission achievement in refractory/relapsed disease. The study aimed to present the actual data from the Czech Republic and thus contribute to a global understanding of BPDCN.

[Management of care of HIV-positive pregnant women in the period 1996-2014]. / Management péce o HIV pozitivní tehotné v období let 1996-2014.

OBJECTIVE: The evaluation of multidisplinary care about HIV positive pregnant women in the Czech Republic. DESIGN: Review. SETTINGS: Gynekologicko-porodnická klinika 1. LF UK a Nemocnice na Bulovce, Praha. METHODS: The vertical transmission of HIV infection from mother to fetus occurs most often during birth, still 1-2% of HIV-positive pregnant women will transfer the virus transplacenta. Due to careful screening for HIV during pregnancy, counselling, combination antiretroviral (cART) therapy, childbirth planning and its performance by C-section there appears a significant decrease of the virus transmission to the fetus, its occurrence is around 2%. If the HIV infection is detected in the context of screening for sexually transmitted infections (STIs), we begin with combined antiretroviral therapy (cART) depending on the level of viremia and CD4 as soon as possible. All HIV-positive pregnancies are tested for possible coinfection with hepatitis C. Since the first application of the antiretroviral treatment, the therapy is applies throughout the duration of the pregnancy. The labours of the HIV- positive women in the Czech Republic are scheduled. The primary choice is a caesarean section during the 38th week of pregnancy. CONCLUSION: From 1996-2014 the HIV positive status at 18 months of child age was confirmed in 4 cases in the Czech Republic. Three children were born to mothers whose HIV status was unknown at the time of the birth. Thanks to strict adherence to the interdisciplinary care, HIV positive woman have a chance to deliver a HIV-negative newborn and the risk of the transmission of the virus is significantly low.

[Tumour-stroma interactions in urothelial cancer]. / Tumor-Stroma-Interaktionen im Harnblasenkarzinom.

BACKGROUND: The histopathological structure of malignant tumours involves two essential compartments - the tumour parenchyma with the actual transformed cells, and the supportive tumour stroma. The latter consists of specialized mesenchymal cells, such as fibroblasts, macrophages, lymphocytes and vascular cells, as well as of their secreted products, including components of the extracellular matrix, matrix modifying enzymes and numerous regulatory growth factors and cytokines. In consequence, the tumour stroma has the ability to influence virtually all aspects of tumour development and progression, including therapeutic response. AIM: In this article we review the current knowledge of tumor stroma interactions in urothelial carcinoma and present various experimental systems that are currently in use to unravel the biological basis of these heterotypic cell interactions. RESULTS: For urothelial carcinoma, an extensive tumour stroma is quite typical and markers of activated fibroblasts correlate significantly with clinical parameters of advanced disease. Another clinically important variable is provided by the stromal expression of syndecan-1. CONCLUSION: Integration of markers of activated stroma into clinical risk evaluation could aid to better stratification of urothelial bladder carcinoma patients. Elucidation of biological mechanisms underlying tumour-stroma interactions could provide new therapeutical targets.

[Bilateral L3 spondylolysis. A case report and an overview of spondylolytic defect repair techniques]. / Spondylolýza L3. Kazuistika a prehled pouzívaných technik fúze spondylolytického defektu.

The direct fusion methods for repair of spondylolytic defects of the lumbar spine have recently been replaced by transpedicular screw fixation of the affected segment, in combination with PLIF, TLIF or ALIF procedures. However, in clearly indicated cases, such as a younger patient with no intervertebral disc degeneration and only minimal or no displacement of the vertebra, the direct repair techniques have a great advantage over transpedicular fixation because they preserve segmental motion The paper reports on a patient with spondylolysis at L3 who underwent surgery combining the Tokuhashi and Matsuzaki and the Gillet and Petit techniques, which involved a system of transpedicular screws, rods and sublaminar hooks supplemented with a cross-connector to support the base of the spinous process. After surgery, the patient reported pain relief and return to normal activities and CT examination showed bony union of both spondylolytic defects.

[Hyperextension trauma in patients with cervical spondylosis]. / Hyperextenzní poranení krcní pátere pri spondylóze.

PURPOSE OF THE STUDY To evaluate retrospectively a group of patients with hyperextension injury to the cervical spine who were treated at the Department of Spinal Surgery of the University Hospital in Motol, Prague, between 2003 and 2006. MATERIAL The group comprised 22 patients, 17 men (77 %) and five women (23 %) in the age range of 35 to 81 years, with an average of 59.5 years. All patients had, in association with the injury, neurological deficit of varying degree. METHODS All patients underwent X-ray and magnetic resonance imaging examination and received methylprednisolone according to the National Acute Spinal Cord Injury Study (NASCIS) 2 trial. Eleven patients had urgent surgery within 24 hours of injury; eight patients were operated on within an interval of 3 days to 2 months because of the seriousness of their state and multiple morbidity; and three patients were treated conservatively. Neurological deficit in terms of upper- and lower-limb mobility was evaluated by the American Spinal Injury Association (ASIA) motor score. The values obtained for the urgently operated patients and for those operated on after a time interval were compared by Wilcoxons two-sample test. The other aspects evaluated included trauma aetiology, level of spinal cord injury, manner of treatment, and intra-operative and post-operative complications. RESULTS The most frequent cause of injury was a low-height fall (13 patients; 59 %); car accidents ranked second (9 patients; 41 %). In five patients (22.7 %) ebriety was found. Eighteen patients had no skeletal injury (81.8 %). Four patients (18.2 %). Four patients (18.2 %) suffered fractures of articular or spinous processes, but the anterior column skeleton was intact in all. The segment most frequently affected by myopathy was C3-C4, then C4-C5 and C5-C6. Decompression was carried out to the extent of myopathy; and in the adjacent segments only if significant stenosis was present. In both subgroups of surgically treated patients (urgent and delayed management), comparisons of the ASIA scores at the time of injury and at one-year follow-up showed no significat improvement in post-operative mobility, as evaluated by Wilcoxons two-sample test at a level of significance a = 5 %. No intra-operative or post-operative complications, except for early death, were recorded. In all patients the wound healed by first intention and no loosening of instrumentation was foud on follow-ups at the out-patient departments. DISCUSSION Although the greatest narrowing of the spinal canal due to spondylosis occurs at the C5-C6 segment, the C4-C5 segment sustained most injuries. Although some relevant papers report no significant difference in improved neurological deficit between patients treated surgically and those undergoing conservative therapy, we prefer surgical management, in most of the cases from the anterior approach, which allows us to remove dorsal osteophytes and perform careful decompression to prevent damage to nerve structures and to preserve those which are still intact. There was no significant difference in the outcome between urgent and delayed trauma management, which is unusual amongst other injuries associated with neurological lesions and this indicates that the timing of surgery must be strictly individual and should be carried out at a time when operative benefit outweighs operative burden. The surgical treatment used should, in the first place, lead to early recuperation and rehabilitation. CONCLUSIONS Hyperextension injuries of the cervical spine are usually associated with serious neurological deficit. A correct algorithm of examination will result in good treatment outcomes. However, these injuries require a therapy that is long-lasting and difficult, with a need for cooperation of anaesthesiologists, spinal surgeons, physical therapists and, last but not least, psychologists. Key words: cervical spine, hyperextension injury, spondylosis, myelopathy.

Efficacy and safety of sibutramine for weight loss in obese patients with hypertension well controlled by beta-adrenergic blocking agents: a placebo-controlled, double-blind, randomised trial.

Sibutramine is a serotonin-noradrenaline reuptake inhibitor that is effective for long-term weight reduction and maintenance in obese patients when used as an adjunct to dietary and behavioural measures. Because the inhibition of noradrenaline reuptake may be expected to increase systolic and diastolic blood pressure (SBP and DBP) and pulse rate (PR), a 12-week multi-centre, placebo-controlled, double-blind study was designed to evaluate the efficacy and tolerability of sibutramine for weight loss in obese patients whose hypertension was well controlled (DBP < or = 95 mm Hg) by beta-adrenergic blocking agents (beta-blockers), with or without concomitant thiazide diuretics. Of the 61 patients randomised to sibutramine 20 mg once daily or placebo, 55 patients (90%) completed the study. After 12 weeks, sibutramine-treated patients lost significantly more weight than placebo-treated patients: mean weight reductions were 4.2 kg (4.5%) in the sibutramine group vs 0.3 kg (0.4%) in the placebo group (P<0.001). Greater weight reduction on sibutramine was accompanied by trends for greater mean reductions in serum triglycerides and very low density lipoprotein cholesterol. Sibutramine was well tolerated, and most adverse events were mild or moderate in severity. No sibutramine patient discontinued treatment because of an adverse event. Mean supine and standing DBP and SBP were not statistically significantly different between the sibutramine group and the placebo group at any post-baseline visit during the 12-week trial. At week 12, mean increases from baseline supine SBP and DBP, respectively, were 1.6 and 1.7 mm Hg for the sibutramine group vs increases of 0.4 and 1.3 mm Hg for the placebo group. At week 12, mean increases from baseline standing SBP and DBP, respectively, were 1.5 and 1.8 mm Hg for the sibutramine group vs an increase of 0.3 and a decrease of 0.8 mm Hg for the placebo group (P > 0.05 for treatment comparison). A statistically significant mean increase of 5.6 bpm (+/-8.25, s.d.) in supine PR from a baseline of 62 bpm was reported in sibutramine-treated patients at week 12, whereas placebo-treated patients had a mean supine PR decrease of 2.2 bpm (+/-6.43) (P < 0.001). In summary, sibutramine was well tolerated and effective in weight reduction. The addition of sibutramine did not result in an increase in BP in obese patients whose hypertension was well controlled by a beta-blocker. However, based on the potential for changes in BP and PR, obese patients being treated with sibutramine should be monitored periodically for changes in BP and PR and managed appropriately.

Pharmacokinetic-pharmacodynamic modeling of rivastigmine, a cholinesterase inhibitor, in patients with Alzheimer's disease.

Rivastigmine is a cholinersterase inhibitor approved recently for the treatment of Alzheimer's disease (AD). The objective of this study is to characterize the pharmacokinetics-pharmacodynamics of rivastigmine in patients with AD. Eighteen AD patients received doses ranging from 1 to 6 mg bid for about 11 weeks. Rivastigmine and its active (major) metabolite (ZNS 114-666, also called NAP 226-90), plasma, and cerebrospinal fluid (CSF) concentrations were determined together with the AChE activity and computerized neuropsychological test battery (CNTB) scores. Nonlinear mixed-effects modeling of pharmacokinetic and pharmacodynamic data was conducted using NONMEM. Rivastigmine and its metabolite exhibited dose-disproportional pharmacokinetics. The apparent clearance and volume of distribution (plasma) of rivastigmine were estimated to be 120 L/h and 236 L, respectively. The relative bioavailability at the 6 mg dose was about 140%. The metabolite had a clearance of about 100 L/h and a volume of distribution of 256 L. The kinetics of the parent and metabolite in CSF showed an equilibration half-life of about 0.2 and 0.5 hours, respectively. The metabolite levels in CSF correlated very well with the acetylcholinesterase inhibition, with a ZNS 114-666 concentration of about 5.4 microg/L required for half-maximal inhibition of acetylcholinesterase activity. No statistically significant correlation of the CNTB scores with enzyme inhibition, parent or metabolite concentration (plasma/CSF), or rivastigmine dose could be established. The PK-PD model presented in this study can provide valuable information to optimize the drug development of rivastigmine and other related compounds and also in rationalizing dosing recommendations.

The status of ongoing trials for mild cognitive impairment.

Mild cognitive impairment (MCI) is a term used to describe memory decline or other specific cognitive impairment in individuals who do not have dementia or significant impairment of other cognitive functions beyond that expected for their age or education. It has been suggested that as much as 38% of the elderly population would meet criteria for MCI and although the associated memory deficits are mild, the fact that up to 15% of MCI patients, particularly those with a particular type of memory impairment, convert to Alzheimer's disease (AD) annually has prompted serious attention. Despite the high conversion rate, MCI cannot be used synonymously with early or mild AD, as patients with AD are impaired not only in memory performance but in other cognitive domains as well; they meet diagnostic criteria for dementia. However, since there is a high conversion rate from MCI to AD, it is likely many with MCI have the underlying neuropathology of AD, though they do not yet meet clinical diagnostic criteria. Therefore, treatment strategies developed for AD, specifically acetylcholinesterase inhibitors and Cox-2 inhibitors, have been among the first employed to treat MCI. It is hoped that by impeding the progression of MCI in this manner, fewer patients will convert to AD. This article will give a brief overview of the condition of mild cognitive impairment and an account of trial methodology and current treatment strategies being employed for MCI.

Review of the next generation of Alzheimer's disease therapeutics: challenges for drug development.

1. AD is believed to stem from dysfunctional cholinergic signaling in the regions of the brain associated with memory and cognition. 2. The occurrence of AD in afflicted individuals correlates with an increase in the accumulation of A beta-rich senile plaques and neurofibrillary tangles in the brain. 3. Currently, the only FDA-approved AD therapies are a group of acetylcholinesterase inhibitors which slow the turnover of the neurotransmitter acetylcholine in the synapse. 4. Many other compounds which target other aspects of the disease, such as reducing neuronal damage and limiting oxidation, are in clinical trials. These include monoamine oxidase (MAO-B) inhibitors, NSAIDs, antioxidants and estrogen, among others. 5. Recent research discoveries have more completely defined the molecular nature of AD, and are generating new approaches for treatment. One idea is to limit the ability of the protein tau to become phosphorylated in hopes that this will limit the formation of neurofibrillary tangles in the brain. 6. A separate approach that is being pursued is to prevent formation and accumulation of A beta plaques. This may be accomplished by either regulating gamma-secretase activity, or using anti-beta-amyloid antibodies to reduce the size of existing plaques. 7. Employing improved procedural and technological approaches during clinical trials, such as bridging studies, dynabridge studies and PET analysis, promises to streamline the drug development process. 8. The use of biomarkers and MRI analysis may be an effective means by which to identify the disease early. Consequently, early intervention treatment therapies may be an effective way of delaying onset of the disease. 9. Long term AD studies, particularly those focusing on the MCI population, are likely to provide statistically valid results using a smaller study population.

Systemic administration of the immunophilin ligand GPI 1046 in MPTP-treated monkeys.

Systemic administration of immunophilin ligands provides trophic influences to dopaminergic neurons in rodent models of Parkinson's disease (PD) resulting in the initiation of clinical trials in patients with Parkinson's disease. We believe that prior to clinical trials, novel therapeutic strategies should show safety and efficacy in nonhuman models of PD. The present study assessed whether oral administration of the immunophilin 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrollidinecarboxylate (GPI 1046) could prevent the structural and functional consequences of n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in nonhuman primates. Twenty-five rhesus monkeys received daily oral administration of vehicle (n = 5) or one of four doses of GPI 1046 (0.3 mg/kg, n = 5; 1.0 mg/kg, n = 5; 3.0 mg/kg, n = 5; 10.0 mg/kg, n = 5). Two weeks after starting the drug treatment, all monkeys received a unilateral intracarotid injection of MPTP-HCl (3 mg). Daily drug administration continue for 6 weeks postlesion after which time the monkeys were sacrificed. Monkeys were assessed for performance on a hand reach task, general activity, and clinical dysfunction based on a clinical rating scale. All groups of monkeys displayed similar deficits on each behavioral measure as well as similar losses of tyrosine hydroxylase (TH)-immunoreactive (ir) nigral neurons, TH-mRNA, and TH-ir striatal optical density indicating that in general treatment failed to have neuroprotective effects.

Pharmacokinetics and tolerability of buspirone during oral administration to children and adolescents with anxiety disorder and normal healthy adults.

A 21-day, open-label, multisite, dose escalation study comprising three demographic groups (children, adolescents, and adults) was performed to determine the pharmacokinetics and tolerability of orally administered buspirone. Thirteen children and 12 adolescents with anxiety disorder and 14 normal healthy adults were escalated from 5 to 30 mg buspirone bid over the 3-week study. Pharmacokinetic analysis revealed that buspirone was rapidly absorbed in all study groups, reaching peak levels at about 1 hour after administration. Peak plasma buspirone concentrations (Cmax) were highest in children and lowest in adults at all three dose levels (7.5, 15, 30 mg bid). However, 1-pyrimidinylpiperazine (1-PP), the primary metabolite of buspirone, exhibited a different plasma concentration-time profile; Cmax was significantly higher in children than in either adolescents or adults at all concentrations. In addition, TAUC0-T for 1-PP was significantly higher in the children cohort relative to adolescents and adults. Buspirone was generally safe and well tolerated at doses up to 30 mg bid in adolescents and adults and most of the children. The most frequently reported adverse events in children and adolescents were lightheadedness (68%), headache (48%), and dyspepsia (20%); 2 children withdrewfrom the study at the higher doses (15 mg and 30 mg bid) due to adverse effects. In adults, the most common adverse effect was somnolence (21.4%); lightheadedness, nausea, vomiting, and diarrhea were also reported, although these were mild in intensity.

Ongoing trials in Alzheimer's disease.

Researchers have sought to understand the underlying pathophysiology of Alzheimer's disease (AD) ever since Dr A Alzheimer first described the condition in 1907. Unfortunately however, until recently, they have done so with limited success. This lack of clarity has deterred advancements in therapeutic drug research beyond all but the purely symptomatic treatment relief currently available. However, through spatio-temporal analysis of the two types of cerebral lesions that characterise the disorder (senile plaques and neurofibrillary tangles) and the compilation of genetic data concerning familial AD, there now exists the foundation for a more comprehensive understanding of the disease. Although symptomatic cholinergic strategies have beneficial effects, their benefits are modest and current research has turned to the development of other promising strategies, including oestrogen replacement, anti-inflammatory agents, free radical scavengers, anti-oxidants and monoamine oxidase-B (MAO-B) inhibitors. Many of these strategies may have some merit, however further analysis and structured research are necessary before a definitive decision can be made about their efficacy and possible role in AD therapy. Strategies that are directed at halting the underlying biochemical changes in AD are nearing clinical testing and offer the promise for meaningful therapeutic outcomes.

Review of the acetylcholinesterase inhibitor galanthamine.

Galanthamine (or galantamine, Reminyl) is a tertiary alkaloid acetylcholinesterase inhibitor (AChEI) which has been approved in several countries for the symptomatic treatment of senile dementia of the Alzheimer's type. Derived from bulbs of the common snowdrop and several Amaryllidaceae plants, (-)-galanthamine (GAL) has long been used in anaesthetics to reverse neuromuscular paralysis induced by turbocurarine-like muscle relaxants and more recently, has been shown to attenuate drug- and lesion-induced cognitive deficits in animal models of learning and memory. GAL directly inhibits acetylcholinesterase activity, while demonstrating much weaker activity on butyrylcholinesterase (BuChE). GAL also stimulates pre- and postsynaptic nicotinic receptors, although the clinical significance of this finding is yet unclear. Numerous variants and analogues of GAL have also been developed, with varying potency in inhibiting AChE activity. GAL is readily absorbed after oral administration, with a t(max) of 52 min and a plasma elimination t(1/2) of 5.7 h. The efficacy of GAL administered to Alzheimer's disease (AD) patients has been well demonstrated by large-scale clinical trials. Typical of AChEIs, the most common adverse events associated with GAL are nausea and vomiting. In conclusion, evidence to date suggests galanthamine to be similar to other AChEIs in improving cognitive function in AD patients.

Mild cognitive impairment: emerging therapeutics.

OBJECTIVE: To present a general overview of the etiology, definition, and prevalence of mild cognitive impairment (MCI), as well as outline possible treatment strategies. DATA SOURCES: A MEDLINE search was conducted for relevant references generated from 1990 to 2000 concerning MCI, mild to moderate Alzheimer disease (AD), and therapeutic strategies. Several books were also used in the compilation of data for this review, as well as the authors' experience in designing and conducting MCI trials. DATA EXTRACTION: All of the references listed were assessed, and all relevant information was included in this review. DATA SYNTHESIS: Forgetful individuals most likely to develop AD have a condition known as MCI previous to their development of dementia. This condition is hallmarked by memory impairment that is abnormal for the individual's age and educational level. While not all individuals with MCI develop AD, it is apparent that the condition can serve as a potential marker for early onset of AD. CONCLUSIONS: As many clinicians can attest, occasional forgetfulness is a common aspect of the aging process. Eventually, however, a large portion of forgetful individuals, especially those with MCI, will be diagnosed with AD or some other form of dementia. Indeed, many researchers have suggested that MCI should be regarded as incipient AD and that these individuals would benefit from drug therapy. Thus, MCI screening may be beneficial in terms of both early AD intervention and perhaps even AD prevention.

Delayed onset of progressive dystonia following subacute 3-nitropropionic acid treatment in Cebus apella monkeys.

Delayed abnormal movements can be observed in patients with acute neurologic insult after a prolonged period of apparent neurologic stability. To reproduce such a secondary neurologic manifestation in primates, the present experiment investigated whether systemic administration of subacute 3-nitropropionic acid (3NP), a mitochondrial toxin, could induce abnormal movements that were delayed and progressive over time. Four Cebus apella monkeys received systemic 3NP injections until acute neurologic signs manifested. The monkeys were regularly video-recorded and rated for abnormal movements for up to 15 weeks after the cessation of 3NP treatment. Five to 6 weeks after the 3NP treatment, monkeys displayed a significant increase in dyskinesias compared with pretreatment conditions. Over time the chorea attenuated, whereas the dystonic movements increased in intensity and severity which was characterized by a delayed decrease of peak tangential velocity. The intensity of abnormal movements and extent of affected body regions observed in each monkey were consistent with the size of basal ganglia hypersignal as documented by T2 sequence on magnetic resonance imaging. Thus, more severe motor impairments were associated with large magnetic resonance image abnormalities. This novel primate model may be particularly useful for studying the structural changes underlying delayed and progressive manifestations of abnormal movements with the ultimate goal of facilitating the evaluation of novel therapeutic strategies.

Gender differences in depression and antidepressant pharmacokinetics and adverse events.

OBJECTIVE: To review data generated by studies examining gender differences in the prevalence of depression, as well as in antidepressant pharmacokinetics, pharmacodynamics, and adverse events. DATA SOURCES: Published articles and abstracts were identified through MEDLINE (January 1966-April 1999) using the following search terms: antidepressant, response, gender, pharmacokinetic, pharmacodynamic, female, side effect, and adverse events. All articles that assessed gender differences in antidepressant response, pharmacokinetics, and adverse events, as well as articles that evaluated postulated mechanisms for these differences, were reviewed. Additional articles were identified from bibliographies of retrieved articles. STUDY SELECTION AND DATA EXTRACTION: All relevant abstracts, studies, and review articles were evaluated. DATA SYNTHESIS: Gender differences in the prevalence of depression have been reported and may result from the interaction of several factors. Women have been shown to have a higher incidence of depression, which may be due to artifact, social, or biologic reasons. Studies suggest that the pharmacokinetic disposition of popular antidepressants varies between men and women, and women taking antidepressants may exhibit a different adverse event profile. Only one study specifically evaluated gender differences in antidepressant treatment response. CONCLUSIONS: Further research elucidating gender differences in response to antidepressant treatment and on depression prevalence is needed. Some studies report that the pharmacokinetics of antidepressants may vary between men and women. Therefore, clinicians should be aware that potential differences in antidepressant pharmacokinetics may exist, and a dosage adjustment may be necessary for women to ensure a favorable drug response, compliance, and decreased incidence of adverse events.

RBC cholinesterase inhibition: a useful surrogate marker for cholinesterase inhibitor activity in Alzheimer disease therapy?

Red blood cell (RBC) acetylcholinesterase (AChE) inhibition has been used as a peripheral surrogate marker for the activity of centrally acting AChE inhibitors (AChEIs) in the treatment of Alzheimer disease. As a valid peripheral surrogate marker, RBC AChE inhibition should reflect the central pharmacodynamic activity of the compound and should demonstrate a relation with cognitive or global improvement in patients with Alzheimer disease. As a useful clinical tool, RBC AChE inhibition should also provide an advantage in dose optimization. However, the application of surrogate markers in research and clinical use is controversial (Prentice, 1989; Gotzsche, 1996; Colburn, 1997; De Gruttola et al., 1997). For instance, surrogate markers that have been identified or applied inappropriately can lead to erroneous conclusions, slowing the drug development process (Colburn, 1997). Also, the validation of surrogate markers for the pharmacodynamic activity of central nervous system drugs is not always possible because samples of brain tissue cannot be analyzed in humans. Finally, although validation of peripheral markers for central nervous system drugs has been approached via analysis of cerebrospinal fluid (Cutler et al., 1998a), few markers have been subjected to such rigorous evaluation in clinical studies. The extent to which measures of peripheral AChE inhibition accurately model central drug activity and therapeutic effectiveness of AChEIs, both as individual agents and as a drug class, is the focus of this review. AChEIs comprise a group of structurally diverse compounds with a wide range of relative specificities for the various molecular species of cholinesterase found in plasma, RBCs, and the brain. Studies of RBC AChE inhibition after administration of AChEIs in animals are of limited utility because of the differential sensitivity of AChEIs for human versus animal forms of AChE, the poor correlation between effective doses in animals and humans, and the lack of standardized measurements of effectiveness. Although clinical studies of donepezil, metrifonate, and eptastigmine have suggested the potential use of RBC AChE inhibition as a predictor of clinical response, the degree of inhibition yielding maximum cognitive improvements was highly variable from compound to compound (30-80%). Further, investigators did not prove a relation between central and peripheral pharmacodynamics or demonstrate an advantage over dose in the ability of RBC AChE inhibition to predict clinical response. A study of rivastigmine in patients with Alzheimer disease revealed that cerebrospinal fluid AChE inhibition correlated well with cognitive performance, whereas peripheral inhibition did not. Therefore, RBC cholinesterase inhibition is not a reliable surrogate marker for the activity of AChEIs as a class of drugs, and its usefulness as a dose optimization tool for individual agents has yet to be demonstrated clearly.

Recent developments in the drug treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder with an impact on public health which continues to increase with the increasing longevity of the population. The disease is characterised clinically by a progressive loss of cognitive and behavioural function. These deficits are thought to result from decreased cholinergic transmission; therefore, restoring cholinergic function has been the main focus in the development of drugs for AD. Several pharmacological approaches to enhancing cholinergic function have been developed for symptomatic or palliative therapy of AD. Although these strategies have resulted in modest cognitive and behavioural improvements in patients with AD, they do not address the underlying progression of the disease. New strategies will be required to slow, stop or reverse the effects of neurodegeneration in AD. A number of potential therapies are currently under investigation, including estrogen replacement, anti-inflammatory agents, free radical scavengers and antioxidants, and monoamine oxidase-B (MAO-B) inhibitors. The evidence for a protective effect of estrogens or nonsteroidal anti-inflammatory drugs (NSAIDs) is controversial, and largely based on retrospective studies. More controlled prospective studies are needed to definitively demonstrate the benefits of long term estrogen or NSAID use in the prevention of AD. Free radical scavengers/antioxidants such as idebenone, and selective prevention MAO-B inhibitors such as lazabemide are well tolerated, but require additional studies in order to demonstrate preventative effects. In addition, other approaches, such as anti-amyloid treatments that affect beta-amylase secretion, aggregation and toxicity, appear promising; treatments that hinder neurofibrillary tangle construction and nerve growth factor (NGF) induction are in the very early stages of development.