Evidence that small molecule enhancement of ß-hexosaminidase activity corrects the behavioral phenotype in Dutch APP(E693Q) mice through reduction of ganglioside-bound Aß.

Certain mutant Alzheimer's amyloid-ß (Aß) peptides (that is, Dutch mutant APP(E693Q)) form complexes with gangliosides (GAß). These mutant Aß peptides may also undergo accelerated aggregation and accumulation upon exposure to GM2 and GM3. We hypothesized that increasing ß-hexosaminidase (ß-hex) activity would lead to a reduction in GM2 levels, which in turn, would cause a reduction in Aß aggregation and accumulation. The small molecule OT1001 is a ß-hex-targeted pharmacological chaperone with good bioavailability, blood-brain barrier penetration, high selectivity for ß-hex and low cytotoxicity. Dutch APP(E693Q) transgenic mice accumulate oligomeric Aß as they age, as well as Aß oligomer-dose-dependent anxiety and impaired novel object recognition (NOR). Treatment of Dutch APP(E693Q) mice with OT1001 caused a dose-dependent increase in brain ß-hex levels up to threefold over those observed at baseline. OT1001 treatment was associated with reduced anxiety, improved learning behavior in the NOR task and dramatically reduced GAß accumulation in the subiculum and perirhinal cortex, both of which are brain regions required for normal NOR. Pharmacological chaperones that increase ß-hex activity may be useful in reducing accumulation of certain mutant species of Aß and in preventing the associated behavioral pathology.

Proneurogenic Group II mGluR antagonist improves learning and reduces anxiety in Alzheimer Aß oligomer mouse.

Proneurogenic compounds have recently shown promise in some mouse models of Alzheimer's pathology. Antagonists at Group II metabotropic glutamate receptors (Group II mGluR: mGlu2, mGlu3) are reported to stimulate neurogenesis. Agonists at those receptors trigger γ-secretase-inhibitor-sensitive biogenesis of Aß42 peptides from isolated synaptic terminals, which is selectively suppressed by antagonist pretreatment. We have assessed the therapeutic potential of chronic pharmacological inhibition of Group II mGluR in Dutch APP (Alzheimer's amyloid precursor protein E693Q) transgenic mice that accumulate Dutch amyloid-ß (Aß) oligomers but never develop Aß plaques. BCI-838 is a clinically well-tolerated, orally bioavailable, investigational prodrug that delivers to the brain BCI-632, the active Group II mGluR antagonist metabolite. Dutch Aß-oligomer-forming APP transgenic mice (APP E693Q) were dosed with BCI-838 for 3 months. Chronic treatment with BCI-838 was associated with reversal of transgene-related amnestic behavior, reduction in anxiety, reduction in levels of brain Aß monomers and oligomers, and stimulation of hippocampal neurogenesis. Group II mGluR inhibition may offer a unique package of relevant properties as an Alzheimer's disease therapeutic or prophylactic by providing both attenuation of neuropathology and stimulation of repair.

Latrepirdine: molecular mechanisms underlying potential therapeutic roles in Alzheimer's and other neurodegenerative diseases.

Latrepirdine (Dimebon(TM)) was originally marketed as a non-selective antihistamine in Russia. It was repurposed as an effective treatment for patients suffering from Alzheimer's disease (AD) and Huntington's disease (HD) following preliminary reports showing its neuroprotective functions and ability to enhance cognition in AD and HD models. However, latrepirdine failed to show efficacy in phase III trials in AD and HD patients following encouraging phase II trials. The failure of latrepirdine in the clinical trials has highlighted the importance of understanding the precise mechanism underlying its cognitive benefits in neurodegenerative diseases before clinical evaluation. Latrepirdine has shown to affect a number of cellular functions including multireceptor activity, mitochondrial function, calcium influx and intracellular catabolic pathways; however, it is unclear how these properties contribute to its clinical benefits. Here, we review the studies investigating latrepirdine in cellular and animal models to provide a complete evaluation of its mechanisms of action in the central nervous system. In addition, we review recent studies that demonstrate neuroprotective functions for latrepirdine-related class of molecules including the ß-carbolines and aminopropyl carbazoles in AD, Parkinson's disease and amyotrophic lateral sclerosis models. Assessment of their neuroprotective effects and underlying biological functions presents obvious value for developing structural analogues of latrepirdine for dementia treatment.

Latrepirdine stimulates autophagy and reduces accumulation of α-synuclein in cells and in mouse brain.

Latrepirdine (Dimebon; dimebolin) is a neuroactive compound that was associated with enhanced cognition, neuroprotection and neurogenesis in laboratory animals, and has entered phase II clinical trials for both Alzheimer's disease and Huntington's disease (HD). Based on recent indications that latrepirdine protects cells against cytotoxicity associated with expression of aggregatable neurodegeneration-related proteins, including Aß42 and γ-synuclein, we sought to determine whether latrepirdine offers protection to Saccharomyces cerevisiae. We utilized separate and parallel expression in yeast of several neurodegeneration-related proteins, including α-synuclein (α-syn), the amyotrophic lateral sclerosis-associated genes TDP43 and FUS, and the HD-associated protein huntingtin with a 103 copy-polyglutamine expansion (HTT gene; htt-103Q). Latrepirdine effects on α-syn clearance and toxicity were also measured following treatment of SH-SY5Y cells or chronic treatment of wild-type mice. Latrepirdine only protected yeast against the cytotoxicity associated with α-syn, and this appeared to occur via induction of autophagy. We further report that latrepirdine stimulated the degradation of α-syn in differentiated SH-SY5Y neurons, and in mouse brain following chronic administration, in parallel with elevation of the levels of markers of autophagic activity. Ongoing experiments will determine the utility of latrepirdine to abrogate α-syn accumulation in transgenic mouse models of α-syn neuropathology. We propose that latrepirdine may represent a novel scaffold for discovery of robust pro-autophagic/anti-neurodegeneration compounds, which might yield clinical benefit for synucleinopathies including Parkinson's disease, Lewy body dementia, rapid eye movement (REM) sleep disorder and/or multiple system atrophy, following optimization of its pro-autophagic and pro-neurogenic activities.

Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model.

Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aß42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.

The medication information line for the elderly: an 8-year cumulative analysis.

OBJECTIVE: To present an 8-year (1985-1992) cumulative analysis of the 12,743 calls received by the Medication Information Line for the Elderly (MILE), a consumer-oriented drug information service. DESIGN: Data on all calls received by MILE were documented using a standard format. Certain calls were selected by the pharmacist for follow-up based on the nature and predicted severity of the inquiry. SETTING: MILE is located within the Faculty of Pharmacy of the University of Manitoba and staffed by experienced, practicing pharmacists. Calls were received from the elderly and their care providers. Calls were initially taken on a local Winnipeg line, although in 1987 a toll-free number was made available to rural Manitoba residents. RESULTS: The majority of the calls received by MILE were from women aged 65 years or older who accessed MILE on their own initiative. Ninety-one percent of the calls were rated as not serious. Only 6% of calls were from outside Winnipeg. Although 94% of the older consumers reported having a regular pharmacist, they commonly never thought of using their pharmacist for inquiries. The drugs cited most often by consumers, nurses, physicians, and dentists were the nonsteroidal antiinflammatory agents, cardiac drugs, diuretics, antihypertensives, benzodiazepines, and antidepressants. The type of inquiries most frequently involved adverse drug reactions, drug interactions, and therapeutic use. The drugs cited and inquiries made by pharmacist callers were more diverse than those of consumers and other healthcare professionals. CONCLUSIONS: Many older drug consumers have medication information needs that are not being met. Since a large proportion of the callers appeared to be self-motivated women, MILE may not be accessing all older consumers in need of information. This analysis also suggests that many older consumers are not aware that the pharmacist is available and capable of providing drug information.

Generic competition in Canada.

This study was designed to assess the potential impact of generic drug competition on prescription prices in Ontario, Canada, and the costs and benefits of the passage of Bill C-22 by the Canadian federal government. Bill C-22, passed in 1987, extended the period during which a patented drug is exempt from compulsory licensing by a generic drug manufacturer, and created the Patented Medicine Prices Review Board (PMPRB). The purpose of the PMPRB is to 'ensure that the prices of patented medicines charged by patentees are not excessive' and to 'report annually on the ratios of research-and-development expenditures to sales for individual patentees and for the patented pharmaceutical industry as a whole'. Lexchin analysed prices in the 1991 Drug Benefit Formulary of Ontario for interchangeable products which were manufactured by more than one company. He also noted the best available price for the highest and lowest priced versions, and the number of manufacturers of that product. Products were then grouped according to the number of manufacturers, and the price of the least expensive version of each product was expressed as a percentage of that of the most expensive version (i.e. the proportional cost). For products marketed by 2 to 6 companies, the data were further subdivided into 4 categories representing 0%, non-maximal, maximal and 100% generic competition.(ABSTRACT TRUNCATED AT 250 WORDS)

Epalrestat. A review of its pharmacology, and therapeutic potential in late-onset complications of diabetes mellitus.

Epalrestat is a carboxylic acid derivative which inhibits aldose reductase, an enzyme of the sorbitol (polyol) pathway. Under hyperglycaemic conditions epalrestat reduces intracellular sorbitol accumulation, which has been implicated in the pathogenesis of late-onset complications of diabetes mellitus. Epalrestat 150 mg/day for 12 weeks improved motor and sensory nerve conduction velocity, and vibration threshold compared with baseline and placebo in patients with diabetic neuropathy. Subjective symptoms including pain, numbness, hyperaesthesia, coldness in the extremities, muscular weakness, dizziness, and orthostatic fainting were also improved. Similar benefits were seen in a comparison with historical controls. Epalrestat 300 mg/day for 1 or 3 years was also significantly superior to placebo or no treatment in improving electroretinogram parameters and photo stress recovery time in patients with diabetic retinopathy. Improvements were also documented by funduscopy and fluorescein angiography. Epalrestat appeared most effective in patients with less severe diabetes mellitus and more recent development of late-onset complications. Epalrestat is apparently well tolerated with predominantly minor adverse events reported in clinical trials. Liver enzyme elevations were most commonly reported but generally resolved spontaneously on dose reduction or discontinuation. The effects of age and renal impairment on the efficacy and tolerability of epalrestat require clarification, and data on its use in other late-onset complications of diabetes such as nephropathy are also lacking. Comparisons with other aldose reductase inhibitors are also required to fully determine the role of epalrestat. The suggested ability of epalrestat to prevent the onset of diabetic complications should also be investigated. Thus, available data suggest epalrestat produces some improvement in the late-onset neuropathy and retinopathy associated with diabetes mellitus, although additional trials are required to determine whether ongoing therapy is necessary to maintain the improvements achieved and to confirm tolerability in the long term. Nevertheless, preliminary results suggest that epalrestat may be a useful drug in an area where there is a need for effective therapy.

Tiapride. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in geriatric agitation.

Tiapride is a substituted benzamide derivative with selective dopamine D2-receptor antagonist properties which appears to have preferential affinity for extrastriatal dopamine receptors. Animal and clinical studies show that tiapride has anxiolytic properties but the mechanism of action is uncertain. Results from limited studies indicate that the clinical efficacy of tiapride in the treatment of agitation, aggressiveness, anxiety and sleep disorders in the elderly appears superior to that of placebo, chlorpromazine, lorazepam and meprobamate. Tiapride also exerts a beneficial effect on vigilance and alertness in elderly patients and causes less sedation than chlorpromazine. Tiapride is well tolerated at the dosages recommended for elderly patients. Further well designed comparative studies with newer drugs are needed to determine the relative place of tiapride in the treatment of geriatric agitation, and such studies should also address the quality-of-life benefits for the patient. Additional clinical experience to determine the efficacy of tiapride in elderly patients with more than one disease condition, receiving concomitant medications, and/or with renal impairment is also required. However, despite these current limitations, tiapride may have potentially important applications in this difficult area of clinical medicine.

Collection and management of fecal wastes for space missions.

An improved type of human waste collection subsystem has been developed for Space Station Freedom which is designed to meet the challenges of zero gravity collection and system performance. Fecal collection is followed by passive storage for relatively short duration missions. The benefits of utilizing components in solid wastes as part of a partial or completely closed Environmental Control and Life Support System (ECLSS) become more apparent as the duration of the mission increases. The purpose of this review is to summarize the development issues associated with the current waste management subsystem for Space Station Freedom. Also reviewed are current ideas associated with the evolutionary development of this waste management subsystem for longer duration missions.

The Medication Information Line for the Elderly. A consumer/health care professional-oriented drug information service.

The experiences of a drug information telephone service aimed at older adults, their care providers, and health care professionals are presented. The Medication Information Line for the Elderly received 1,561 telephone calls over the 12 months since its opening. The majority of callers (73%) were female and 723 (46%) of the 1,561 calls came from people in the 65 to 79 age group. Nearly one-third of all enquiries were about suspected drug-related adverse drug reactions. The drugs most commonly causing concern (as classified by the American Hospital Formulary Service) were nonsteroidal anti-inflammatory drugs, cardiac drugs, and benzodiazepines; a list comparable to the most frequently prescribed drugs in older adults. The pharmacist was able to respond to 853 (27%) of the 3,172 enquiries without reference material. The most frequently used sources of information were the USP Drug information, Volumes I & II, and the Compendium of Pharmaceuticals and Specialties. Follow-up calls on certain consumer enquiries indicated that 89% of the recommendations were adhered to, suggesting a beneficial influence of this type of drug information service on medication use.

Methandrostenolone: metabolism in the rabbit.

Methandrostenolone and the fully reduced metabolites 17 alpha-methyl-5 alpha-androstane-3 beta, 17 beta-diol and 17 alpha-methyl-5 beta-androstane-3 alpha, 17 beta-diol, the partially reduced and hydroxylated metabolites 16 alpha, 17 beta-dihydroxy-17 alpha-methyl-5 beta-androst-1-en-3-one and 16 beta, 17 beta-dihydroxy-17 alpha-methyl-5 beta-androst-1-en-3-one, the monohydroxylated metabolites 6 beta, 17 beta-dihydroxy-17 alpha-methyl-1,4-androstadien-3-one and 16 beta, 17 beta-dihydroxy-17 alpha-methyl-1,4-androstadien-3-one, and the dihydroxylated metabolite 6 beta, 16 beta, 17 beta-trihydroxy-17 beta-trihydroxy-17 alpha-methyl-1,4-androstadien-3-one have been isolated and identified in the urine of rabbits orally dosed with methandrostenolone. C-16 Hydroxylated and dihydroxylated metabolites have not been previously reported from methandrostenolone. No evidence for epimerization at the C-17 position was observed in the rabbit.

The metabolism and excretion of styrene oxide-glutathione conjugates in the rat and by isolated perfused liver, lung and kidney preparations.

The metabolism and excretion of styrene oxide-glutathione conjugates were studied in the intact rat and by isolated perfusion techniques in rat lung, liver and kidney. The intact animals converted the styrene oxide-glutathione conjugates almost entirely to styrene oxide-n-acetylcysteine derivatives mercapturic acids), with much smaller amounts of cysteine, cysteinylglycine and (unchanged) glutathione conjugates. Only small amounts of biliary excretion (approximately 5%) and less than 1% of fecal excretion of radioactivity were found. The isolated perfused kidney retains the capacity to transform virtually all of the glutathione conjugates at the dose level studied (25-30 mumol/kidney) and the principal component in urine from the isolated kidney was the cysteine conjugate. Isolated perfused lung experiments demonstrated that this organ has a minor role in styrene oxide-thioether conjugate. Isolated perfused lung experiments demonstrated that this organ has a minor role in styrene oxide-thioether conjugate metabolism. The isolated perfused liver experiments showed that phenobarbital pretreatment has little effect on biliary excretion but barbital pretreatment has little effect on biliary excretion but that it causes profound qualitative and quantitative effects on metabolism of styrene oxide-glutathione conjugates in the perfusion medium. The high level of styrene oxide-cysteine conjugates in the perfusion medium of an isolated perfused liver, especially after phenobarbital treatment, is consistent with the theory that gamma-glutamyltransferase activity is extracellular. The high-pressure liquid chromatography system of analysis described offers the ability to simultaneously separate and quantitate the major thioether conjugates of styrene oxide and other electrophilic epoxides.

Anabolic steroids. Part 2: the disposition of ethylestrenol in the rat.

1. The absorption, distribution, metabolism and excretion of [3H]ethylestrenol were studied in the rat. 2. Approximately one third of an intragastric dose was absorbed; 17% of the dose was excreted in urine and 83% in faeces within 10 days. 3. The dose is distributed throughout the rat, and kidney and liver were found to contain respectively 2.5-3 and 5-7 times the average specific activity of all other tissues. 4. Unchanged ethylestrenol was the only component detected in urine. Ethylestrenol was also found in faeces, along with two different dihydroxylated dihydro derivatives and one trihydroxylated dihydro derivative.

Anabolic steroids. Part 3: metabolism of ethylestrenol in rat liver preparations in vitro.

1. Ethylestrenol incubated with a post-mitochondrial supernatant fraction of rat liver plus co-factors gives norethandrolone as the major metabolite. 2. A second (minor) metabolite was tentatively identified as 17 alpha-ethyl-5 epsilon-estrane-3 epsilon,17 beta-diol. 3. A pathway is suggested for the metabolism of ethylestrenol in the rat.