Latrepirdine scientific update |
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Drug Dev Ind Pharm. 2010 Jun 14. [Epub ahead of print]
Vaka SR, Murthy SN, O'Haver JH, Repka MA.
Department of Pharmaceutics, School of Pharmacy, University of Mississippi, University, MS, USA.
A platform for predicting and enhancing model drug delivery across the human nail plate.
Purpose: The objective of the present study was to assess the effect of pretreatment using chemical etchants on the delivery of terbinafine hydrochloride (TH) and 5-fluorouracil (5-FU) into and across the human nail plate. Methods: The TranScreen-N method was used to screen five potential etchants. Based on these results, the dorsal surface of nails was pretreated with chemical etchants, 1% or 10% (w/w) phosphoric acid (PA) or 10% (w/w) lactic acid (LA) gels, for a period of 60 seconds. The nail pretreated with a plain gel formulation (no PA or LA incorporated) was used as the control. Results: Despite the differences in physicochemical properties between TH (log P = 3.3) and 5-FU (log P = -0.83), the in vitro permeation as well as drug load of these drugs in the nail plate was enhanced because of pretreatment with the PA gels, whereas LA pretreatment failed to enhance the drug load and permeation. Optical microscopic and atomic force microscopy studies revealed that the PA enhanced the trans-ungual drug delivery by decreasing the keratin density of the dorsal layer of the nail plate and by microstructural alterations. Conclusions: This study demonstrated that pretreatment of the nail plate with PA (1% or 10%, w/w) for a short duration could be a potential method of improving the efficiency of topical monotherapy treatment for nail diseases.
Acta Derm Venereol. 2010 May;90(3):239-45.
Alsterholm M, Karami N, Faergemann J.
Department of Dermatology and Venereology, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.
Antimicrobial activity of topical skin pharmaceuticals - an in vitro study.
The aim of this study was to investigate the antimicrobial activity of currently available topical skin pharmaceuticals against Candida albicans, Escherichia coli, Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus pyogenes. The agar dilution assay was used to determine the minimal inhibitory concentration for cream formulations and their active substances. Corticosteroid formulations with the antiseptics clioquinol or halquinol were active against all microbes. The hydrogen peroxide formulation was primarily active against staphylococci. Clotrimazole, miconazole and econazole showed an effect against staphylococci in addition to their effect on C. albicans. In contrast, terbinafine had no antibacterial effect. Fusidic acid was active against staphylococci, with slightly weaker activity against S. pyogenes and no activity against C. albicans or E. coli. In summary, some topical skin pharmaceuticals have broad antimicrobial activity in vitro, clioquinol and halquinol being the most diverse. In limited superficial skin infection topical treatment can be an alternative to systemic antibiotics and should be considered. With the global threat of multi-resistant bacteria there is a need for new, topical, non-resistance-promoting, antimicrobial preparations for the treatment of skin infections.
J Dermatol. 2010 Apr;37(4):367-73.
Arakaki O, Asato Y, Yagi N, Taira K, Yamamoto Y, Nonaka K, Hosokawa A, Kayo S, Hagiwara K, Uezato H.
Division of Dermatology, Department of Organ-oriented Medicine, School of Medicine, University of the Ryukyus, Uehara, Nishihara, Okinawa, Japan. hihuka@jim.u-ryukyu.ac.jp
Phaeohyphomycosis caused by Exophiala jeanselmei in a patient with polymyalgia rheumatica.
An 87-year-old man, a gardener in Okinawa, first noticed a tumor on the dorsum of his right hand in November 2005. He had been taking prednisolone for the treatment of polymyalgia rheumatica since 2000. A nearby dermatologist incised the tumor for pus drainage in February 2006. In April of the same year, the dome-like tumor reappeared. The same treatment was repeated. Because the culture of the pus revealed fungi at that time, terbinafine hydrochloride and minocycline were administrated under the diagnosis of a deep fungal infection. After a short remission, the tumor recurred in November of the same year and in May and August of 2007 regardless of the repeated incision and pus drainage. He was referred to our hospital on 27 September 2007. His first physical examination at our outpatient office showed a skin-colored, well-demarcated, multilocular, cystic subcutaneous tumor on the dorsum of his right hand. Histopathological examination revealed a pseudocyst with fibrous walls of connective tissue. Continuous, bead-like hyphae, positive with periodic acid-Schiff stain and Grocott stain, were found within the pseudocyst. Morphological and molecular biological examinations of the separately cultured specimens identified the causative agent as Exophiala jeanselmei. The entire cyst was removed under local anesthesia, and an artificial dermis made of silicon membrane was applied to the wound. Skin graft was performed in November after confirming no recurrence of the fungal infection. Terbinafine hydrochloride 125 mg/day has continued. No recurrence has been observed up to now.
G Ital Dermatol Venereol. 2010 Jun;145(3):415-23.
Gianni C.
Department of Dermatology, S. Raffaele Scientific Institute, Milan, Italy.
Update on antifungal therapy with Terbinafine.
Terbinafine, a syntethic antifungal of allylamine class, has fungicidal activity against dermatophytes, moulds and certain dimorphic fungi and fungistatic activity against Candida albicans. Following oral administration the terbinafine is absorbed rapidly (>70%) and reaches within 2 hours the peak plasma concentration. The drug is highly lipophilic and keratophilic and is highly bound to plasma protein (>90%) with a bioavailability of 70% to 80%. The drug is rapidly delivered and it is present in the stratum corneum, sebum, nails and hair for months after stopping the medication. The drug has been proven to be the choice treatment in the therapy of onychomycosis as it is very effective, well tolerated and has a relatively low potential for drug interactions. The pharmacologic and pharmacokinetic properties of terbinafine give strong support to the possibility that the pulse therapy may be equally effective in onychomycoses, possibly reducing medication costs and drug exposure. Several therapeutic patterns have been proposed: weekly intermittent terbinafine (500 mg/d for 1 week each month for 4 months), or single-dose terbinafine (1000 mg per month for 4 months). Use of topical terbinafine 1% may be practical where the tinea involvement is not extensive or chronic. Recently, the terbinafine is available in a novel topical solution (film-forming solution - FFS) effective in the treatment of tinea pedis (athlete's foot).
J Eur Acad Dermatol Venereol. 2009 Dec 17. [Epub ahead of print]
Sigurgeirsson B, Olafsson J, Steinsson J, Kerrouche N, Sidou F.
Dermatology Center, Kopavogur, Iceland.
Efficacy of amorolfine nail lacquer for the prophylaxis of onychomycosis over 3 years.
Abstract Background Standard treatment for onychomycosis often results in less than half of subjects achieving disease-free nails. Onychomycosis is even more challenging to treat as relapses and re-infections are common. Objective To determine if a prophylactic effect exists when a treatment with amorolfine nail lacquer (ANL), with half the frequency of the standard regimen, is instituted following successful treatment of dermatophytic toenail onychomycosis with matrix involvement. Methods Efficacy and safety of a group treated with ANL (once every 2 weeks) were compared with that of an untreated group in a 36-month (3 years), single-centre, randomized, open-label, comparison study. Subjects to be included in the study were required to be cured of confirmed onychomycosis with matrix involvement after an initial treatment with either ANL + oral terbinafine or oral terbinafine alone in a previous study. Prophylaxis of onychomycosis was assessed by global recurrence rate, confirmed onychomycosis, clinical recurrence and mycological recurrence. Results A total of 52 subjects were enrolled (26 in each group) in the study. Throughout the study, recurrences occurred more quickly in the untreated group compared with that in the ANL group. Statistically significant differences were observed at month 12 (ANL, 8.3%; untreated, 31.8%; P = 0.047). At endpoint, 70.8% of the subjects treated with ANL remained cured compared to 50% in the untreated group (P = 0.153). Recurrence was delayed by nearly 200 days for the ANL group compared with that of the untreated group. Amorolfine was safe and well tolerated during the study, with no treatment-related adverse events. Conclusion These results suggest that amorolfine nail lacquer may be effective and is safe for use as a prophylactic treatment for the recurrence of onychomycosis.
Nippon Ishinkin Gakkai Zasshi. 2009;50(4):253-7.
Kobayashi K, Sawada M, Ninomiya J, Ishizaki S, Harada T, Tanaka M.
Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
[Usefulness of pathological diagnosis for two cases of candidal onychomycosis] [Article in Japanese]
We report two cases of candidal onychomycosis with severe nail deformities. Case 1: The patient was an 81-year-old man who complained of onycholysis and nail deformity of the right forefinger nail which had occurred over a period of a year. He had no obvious previous illness. Case 2: The patient was an 81-year-old woman who complained of nail deformity with periungual erythema which had occurred over a period of several months. She had been treated with oral corticosteroid for bronchial asthma and with Ca blocker for hypertension for a long period. The initial KOH-prepared direct microscopy in each case failed to detect any spores or pseudohyphae. Therefore, an incisional biopsy was performed in both cases. Histopathological findings demonstrated numerous fungal elements with similar appearance of dermatophytes in the middle to lower level of the horny cell layer by PAS and Grocott staining in each case. Candida albicans was isolated and identified by cultivation on ATG agar. In case 1, oral itraconazole (100 mg/day) was administered for 14 weeks, which was effective clinically and mycologically. In case 2, however, a coadministered drug (Ca blocker), oral terbinafine (125 mg/day) was not effective mycologically. Therefore, after having changed the antihypertensive agent, oral itraconazole (100 mg/day) was administered for 16 weeks, which was effective clinically and mycologically.
Nippon Ishinkin Gakkai Zasshi. 2009;50(4):207-12.
Katoh T.
Division of Dermatology, Saiseikai Kawaguchi General Hospital.
[Guidelines for diagnosis and treatment of mucocutaneous candidiasis] [Article in Japanese]
This document summarizes current knowledge about diagnosis and treatment of candidiasis affecting the skin and oral mucosa. Several clinical forms of mucocutaneous candidiasis are distinguished depending on a patient's age and infected site, e.g. Candida intertrigo, erythema mycoticum infantile, erosio interdigitalis blastomycetica, candidal paronychia and onychia, Candida onychomycosis, and oral candidiasis. The diagnosis of candidiasis is confirmed by observation of mycelial forms on microscopic examination. Since Candida yeasts (especially C. albicans) are normal inhabitants of the skin and oral mucosa, it must always be noted that positive culture does not always indicate the presence of candidal infection. The pathogenicity of Candida species is relatively low, and some special conditions are required for tissue invasion by the fungus. Predisposing factors, such as disturbances of the cutaneous and mucosal microenvironment and systemic or local immunosuppression, should be checked in patients with recurrent infection. Therapy for cutaneous candidiasis is dominated by topical antifungal agents. Azole antifungal cream (e.g., bifonazole, ketoconazole, neticonazole hydrochloride, lanoconazole and luliconazole) is most effective. Terbinafine hydrochloride and amorolfine hydrochloride are also useful. Cutaneous candidiasis usually requires a shorter duration of topical treatment (1-2 weeks) than superficial dermatophyte infections. For candidal paronychia and onychomycosis, oral therapy with itraconazole is recommended. The daily dose of itraconazole should be taken for several months, while its pulse therapy for candidiasis is not approved in Japan. Itraconazole oral solution is commonly used for oral candidiasis, and miconazole gel is also effective.
Nippon Ishinkin Gakkai Zasshi. 2009;50(4):199-205.
Ogawa Y, Hiruma M.
Department of Dermatology, Juntendo University.
[Dermatophytosis: a summary of dermatomycosis as a proposal for future revision of the guidelines] [Article in Japanese]
In preparing guidelines for dermatomycosis (tinea, trichophytia, dermatophytosis), we have primarily summarized the disease types and treatments as described in 4 textbooks used in Japan and abroad. We present our classification draft based on these following descriptions. In Japan, any dermatophytosis other than favus or tinea imbricata is considered to be tinea, while outside Japan, favus and tinea imbricata are also classified as tinea. Tinea capitis is classified together with trichophytia superficialis capillitii and kerion celsi, in a group that tends to include asymptomatic carriers. Most textbooks generally classify trichophytia profunda of the glabrous skin and granuloma trichophyticum as subtypes of tinea corporis. Tinea faciei can easily be misdiagnosed, but in many cases can be distinguished from tinea corporis by its specific clinical picture. Tinea unguium is regarded as one type of onychomycosis. We present a summary of dermatomycosis treatment as a proposal for future revision of the guidelines. One of the problems in the treatment of tinea capitis is that the safety of itraconazole (ITZ) and terbinafine hydrochloride (TBF) in children has not been established. Severity criteria for concomitant use of oral medications in the treatment of tinea pedis remains to should be established. Although many clinical studies concerning tinea unguium have been published, 3 of the 4 textbooks we consulted clearly stated that most of those studies were conducted by pharmaceutical companies. Further studies on the etiology and disease severity of tinea unguium are needed.
Vet Dermatol. 2008 Dec;19(6):405-10.
Nuttall TJ, German AJ, Holden SL, Hopkinson C, McEwan NA.
The University of Liverpool Small Animal Teaching Hospital, Leahurst Campus, Chester High Road, Neston, Cheshire CH64 7TE, UK.
Successful resolution of dermatophyte mycetoma following terbinafine treatment in two cats.
Microsporum canis sensitive to itraconazole and terbinafine was isolated from two cats presented with generalized dermatophytosis and dermatophyte mycetoma. Itraconazole therapy was withdrawn through lack of efficacy in one cat (a Persian) and unacceptable adverse effects in the other (a Maine Coon). Both cats achieved clinical and mycological cure after 12-14 weeks therapy with 26-31 mg kg(-1) terbinafine every 24 h per os (PO). Clinical signs in the Maine Coon resolved completely after 7 weeks treatment. Four weeks of therapy with additional weekly washes with a 2% chlorhexidine/2% miconazole shampoo following clipping produced a 98% reduction in the Persian cat's mycetoma, which was then surgically excised. Recurrent generalized dermatophytosis in the Persian cat has been managed with pulse therapy with 26 mg kg(-1) terbinafine every 24 h PO for 1 week in every month. No underlying conditions predisposing to dermatophytosis were found in either cat despite extensive investigation. Terbinafine administration was associated with mild to moderate lethargy in the Persian cat, but no other adverse effects or changes in blood parameters were seen. To the best of the authors' knowledge this is the first report of a dermatophyte mycetoma in a Maine Coon and of successful resolution of this condition in cats following terbinafine therapy.
Plast Reconstr Surg. 2008 Dec;122(6):186e-194e.
Rampazzo A, Salgado CJ, Gharb BB, Mardini S, Spanio di Spilimbergo S, Chen HC.
Department of Plastic Surgery, E-Da Hospital, I-Shou University, Kaohsiung County, Taiwan, Republic of China.
Donor-site morbidity after free ileocolon flap transfer for esophageal and voice reconstruction.
BACKGROUND: Radical excision of advanced hypopharyngeal and laryngeal tumors usually compromises both swallowing and speech. Among the available reconstruction methods, the free ileocolon flap allows rehabilitation of both functions in one stage. The donor-site morbidity of this flap has not been addressed in head and neck cancer patients. METHODS: A retrospective study was conducted in 34 patients between April of 2003 and December of 2007 to investigate donor-site morbidity in patients undergoing reconstruction with free ileocolon flaps. Complications such as diarrhea, upper gastrointestinal tract distress, bowel leak, abscess, or hernia formation were evaluated. Significant association of diarrhea and upper gastrointestinal distress, previous abdominal operations, systemic diseases, primary versus secondary reconstruction, flap length, and postoperative chemotherapy were subsequently evaluated. Differences were considered significant for values of p
J Med Microbiol. 2008 Dec;57(Pt 12):1581-4.
Chang BP, Sun PL, Huang FY, Tsai TC, Lin CC, Lee MD, Chen YC, Sheu JC, Tsai JD.
Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan.
Paecilomyces lilacinus peritonitis complicating peritoneal dialysis cured by oral voriconazole and terbinafine combination therapy.
Fungal peritonitis (FP) is a serious complication in patients on continuous ambulatory peritoneal dialysis (CAPD). We report a case of CAPD-related FP caused by Paecilomyces lilacinus in a 15-year-old uraemic boy. The infection was successfully treated by combination therapy consisting of oral voriconazole and terbinafine, which has not been previously reported in the treatment of FP.
Infection. 2008 Dec;36(6):594-6. Epub 2008 Nov 8.
Fischer N, Ruef Ch, Ebnöther C, Bächli EB.
Dept. of Medicine, Medical Clinic, University Hospital, Zurich, Zurich, Switzerland.
Rhinofacial Conidiobolus coronatus infection presenting with nasal enlargement.
Rhinofacial Conidiobolus coronatus infection is a rare form of zygomycosis in humans living in the northern hemispheres. Most human cases are observed in the periequatorial areas of Africa, Asia, or South America. Only limited information regarding optimal treatment is available. We report a case of rhinofacial C. coronatus infection in an emigrated Sudanese patient. The infection was successfully treated with terbinafin and itraconazole for 12 months. Diagnosis was confirmed by microbiological culture from a tissue biopsy. Antimicrobial susceptibility testing of this organism was not predictive of optimal therapy.
Acta Dermatovenerol Alp Panonica Adriat. 2007 Dec;16(4):170-3.
Khaled A, Chtourou O, Zeglaoui F, Fazaa B, Jones M, Kamoun MR.
Department of Dermatology, Charles Nicolle Hospital, Tunis, Tunisia. aida.khaled@rns.tn
Tinea faciei: a report on four cases.
Four cases of tinea faciei that were observed at the Department of Dermatology of Charles Nicolle Hospital in Tunis are reported. All patients were females, ages 54 (patient 1), 38 (patient 2), 30 (patient 3), and 50 (patient 4). The lesions lasted 1 year, 2 months, 4 months, and 1 month, respectively. Tinea faciei was initially suspected in three patients, whereas for the second patient eczema was initially suspected. She was first treated topically with corticosteroids leading to exacerbation. Through mycological examination, Trichophyton rubrum was isolated in three patients, but was negative in patient 2. Three patients recovered completely after one month of griseofulvin associated with topical terbinafine. Patient 3 was topically treated because she was pregnant. Erythematous lesions of the face must be checked for fungi.
Am J Med Sci. 2007 Dec;334(6):497-8.
Joubert M, Reznik Y, Verdon R.
Department of Endocrinology, University Hospital of Caen, Caen Cedex, France. joubert-m@chu-caen.fr
"Rescue" bilateral adrenalectomy in paraneoplastic Cushing's syndrome with invasive Aspergillus fumigatus infection.
We report the case of a patient with life-threatening Aspergillosis during paraneoplastic Cushing's syndrome. Anticortisolic drug ketoconazole was unable to lower severe hypercortisolism and despite antifungal treatment available at this time (liposomal amphotericine B and terbinafine), Aspergillus fumigatus infection was uncontrolled and extensive. "Rescue" bilateral adrenalectomy was performed to control hypercortisolism, leading to rapid fungal infection cure. We emphasize surgical management of hypercortisolism to achieve rapid blunting of cortisol production in a such life-threatening situation.
Am J Clin Dermatol. 2007;8(6):357-64.
Korting HC, Kiencke P, Nelles S, Rychlik R.
Klinik und Poliklinik für Dermatologie und Allergologie, Ludwig-Maximilians-Universität München, Munich, Germany.
Comparable efficacy and safety of various topical formulations of terbinafine in tinea pedis irrespective of the treatment regimen: results of a meta-analysis.
BACKGROUND: Terbinafine has been widely used with major success as a topical antifungal therapy for tinea pedis (athlete's foot). Its efficacy and safety have been validated in several clinical trials, which have demonstrated clinical efficacy for the drug after only 1 week of treatment when applied once daily, a reflection of the high fungicidal potency of the drug and its ability to form a depot in the upper skin layer. To improve patients' compliance further, a terbinafine-containing film-forming solution has been developed for single-dose therapy of athlete's foot. This novel formulation delivers terbinafine in high amounts and for a prolonged period of time into the skin, making one-shot treatment feasible. Over the past years there have been a variety of trials evaluating use of topical terbinafine addressing different pharmaceutical formulations, treatment durations, and application frequencies, but a detailed meta-analysis of these trials has not been conducted to date. OBJECTIVE: The present study is the first meta-analytic evaluation of the available data on the efficacy (clinical and mycologic cure rates) and safety (adverse events) of all topical forms of terbinafine for the treatment of tinea pedis. METHODS: An international, systematic literature search of 12 electronic databases (including MEDLINE, EMBASE, and Cochrane databases) using a pre-specified search strategy was conducted in March 2006. This meta-analysis included only randomized controlled trials in which terbinafine had been used for topical treatment of tinea pedis in comparison with placebo or an active control. Studies of all available topical formulations of terbinafine, frequencies of application, and durations of treatment were included. RESULTS: Of 100 identified articles published between 1990 and 2006, 19 met the criteria for analysis. These 19 studies involved 2899 patients with clinical and mycologic diagnoses of tinea pedis (nine placebo-controlled trials and ten active-controlled trials). Efficacy analysis demonstrated that the mycologic cure rate was significantly superior with terbinafine compared with placebo (relative risk [RR] 3.17; p < 0.001). No significant differences in efficacy were found amongst different formulations of terbinafine, treatment durations, or frequencies of application. Comparable results were obtained with respect to clinical cure rate for terbinafine compared with placebo (RR 2.75; p < 0.001). Comparison of the efficacy of terbinafine versus active control indicated a nonsignificant difference in favor of terbinafine with regard to mycologic cure rate (RR 1.03; p = 0.423) and clinical cure rate (RR 1.09; p = 0.11). The median duration of treatment was also shorter with terbinafine (1 week) compared with active controls (2 weeks). Analysis of the placebo-controlled studies showed that there was no significant difference in the risk of adverse events with terbinafine compared with placebo (RR 1.34; p = 0.34). Likewise, no significant differences in adverse events were found between terbinafine and active controls (RR 1.08; p = 0.72). CONCLUSION: Terbinafine is very well tolerated in any topical pharmaceutical formulation and also has high efficacy as a cure for tinea pedis, irrespective of type of pharmaceutical formulation, treatment duration, and frequency of application, including the recently established one-shot regimen. In addition, terbinafine has an apparently unique advantage over other antifungal agents with respect to the required duration of treatment for tinea pedis.
Indian J Dermatol Venereol Leprol. 2007 Nov-Dec;73(6):393-6.
Jaiswal A, Sharma RP, Garg AP.
Department of Dermatology and Venereology, L. L. R. M. Medical College, Meerut, Uttar Pradesh, India.
An open randomized comparative study to test the efficacy and safety of oral terbinafine pulse as a monotherapy and in combination with topical ciclopirox olamine 8% or topical amorolfine hydrochloride 5% in the treatment of onychomycosis.
BACKGROUND: Onychomycosis is a fungal infection of nails caused by dermatophytes, yeasts and molds. AIMS: To study the efficacy and safety of oral terbinafine pulse as a monotherapy and in combination with topical ciclopirox olamine 8% or topical amorolfine hydrochloride 5% in onychomycosis. METHODS: A clinical comparative study was undertaken on 96 Patients of onychomycosis during the period between August 2005 to July 2006. Forty-eight patients were randomly assigned in group A to receive oral terbinafine 250 mg, one tablet twice daily for seven days every month (pulse therapy); 24 patients in group B to receive oral terbinafine pulse therapy plus topical ciclopirox olamine 8% to be applied once daily at night on all affected nails; and 24 patients in group C to receive oral terbinafine pulse therapy plus topical amorolfine hydrochloride 5% to be applied once weekly at night on all the affected nails. The treatment was continued for four months. The patients were evaluated at four weekly intervals till sixteen weeks and then at 24 and 36 weeks. RESULTS: We observed clinical cure in 71.73, 82.60 and 73.91% patients in groups A, B and C, respectively; Mycological cure rates against dematophytes were 88.9, 88.9 and 85.7 in groups A, B and C, respectively. The yeast mycological cure rates were 66.7, 100 and 50 in groups A, B and C, respectively. In the case of nondermatophytes, the overall response was poor: one out of two cases (50%) responded in group A, while one case each in group B and group C did not respond at all. CONCLUSION: Terbinafine pulse therapy is effective and safe alternative in treatment of onychomycosis due to dermatophytes; and combination therapy with topical ciclopirox or amorolfine do not show any significant difference in efficacy in comparison to monotherapy with oral terbinafine.
Rev Inst Med Trop Sao Paulo. 2007 Sep-Oct;49(5):293-5.
Nweze EI, Ogbonna CC, Okafor JI.
Department of Microbiology, University of Nigeria, Nsukka, Nigeria. newezemeka@yahoo.com
In vitro susceptibility testing of dermatophytes isolated from pediatric cases in Nigeria against five antifungals.
The antifungal activities of itraconazole, ketoconazole, fluconazole, terbinafine and griseofulvin were tested by broth microdilution methods against 71 isolates of dermatophytes isolated from Nigerian children. Most drugs were very active against all the dermatophytes and the MIC 90 ranged from 0.03 to 8.0 microg/mL. This appears to be the first documented data on the antifungal susceptibility testing of isolates of dermatophytes from Nigerian children.
CNS Neurosci Ther. 2010 Jun 11. [Epub ahead of print]
Sachdeva D, Burns A.
Moor Side Unit, Trafford General Hospital, Urmston, Manchester, UK.
Dimebolin in Dementia.
The treatment options for Alzheimer's type dementia are limited to the use of acetyl-cholinesterase inhibitors, along with memantine in some cases, and offer variable success in the treatment of cognitive impairment and to improve or stabilize activities of daily living, behavioral abnormalities, and impairment of global function. This review examines dimebolin, a nonselective antihistamine drug that has been used in Russia in the past for its antihistamine effect and has now generated considerable interest in the treatment of Alzheimer's type dementia, following results in the initial trials (Doody et al., 2008) and is currently under further evaluation. This article considers various theories proposed to explain its effect in the treatment of dementia. The results from further trials will help to clarify the future of dimebolin as a potential treatment for chronic neurodegenerative disorders that include dementia that affects 25 million people worldwide.
J Pharmacol Exp Ther. 2010 Jun;333(3):748-57. Epub 2010 Mar 1.
Giorgetti M, Gibbons JA, Bernales S, Alfaro IE, Drieu La Rochelle C, Cremers T, Altar CA, Wronski R, Hutter-Paier B, Protter AA.
Medivation, Inc., San Francisco, California 94105, USA.
Cognition-enhancing properties of Dimebon in a rat novel object recognition task are unlikely to be associated with acetylcholinesterase inhibition or N-methyl-D-aspartate receptor antagonism.
Dimebon (dimebolin) treatment enhances cognition in patients with Alzheimer's disease (AD) or Huntington's disease. Although Dimebon was originally thought to improve cognition and memory through inhibition of acetylcholinesterase (AChE) and the N-methyl-d-aspartate (NMDA) receptor, the low in vitro affinity for these targets suggests that these mechanisms may not contribute to its clinical effects. To test this hypothesis, we assessed whether Dimebon enhances cognition in rats and if such an action is related to either mechanism or additional candidate mechanisms. Acute oral administration of Dimebon to rats (0.05, 0.5, and 5 mg/kg) enhanced cognition in a novel object recognition task and produced Dimebon brain concentrations of 1.7 +/- 0.43, 14 +/- 5.1, and 172 +/- 94 nM, respectively. At these concentrations, Dimebon did not alter the activity of recombinant human or rat brain AChE. Unlike the AChE inhibitors donepezil and galantamine, Dimebon did not change acetylcholine levels in the hippocampus or prefrontal cortex of freely moving rats. Dimebon displays affinity for the NMDA receptor (K(i) = 105 +/- 18 microM) that is considerably higher than brain concentrations associated with cognition enhancement in the novel object recognition task and 200-fold weaker than that of memantine (K(i) = 0.54 +/- 0.05 microM). Dimebon did not block NMDA-induced calcium influx in primary neuronal cells (IC(50) > 50 microM), consistent with a lack of significant effect on this pathway. The cognition-enhancing effects of Dimebon are unlikely to be mediated by AChE inhibition or NMDA receptor antagonism, and its mechanism of action appears to be distinct from currently approved medications for AD.
Curr Opin Investig Drugs. 2010 Jan;11(1):80-91.
Sabbagh MN, Shill HA.
Banner Sun Health Research Institute, The Cleo Roberts Center for Clinical Research, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. marwan.sabbagh@bannerhealth.com
Latrepirdine, a potential novel treatment for Alzheimer's disease and Huntington's chorea.
Latrepirdine (Dimebon) is a small-molecule compound under development by Medivation Inc and Pfizer Inc for the treatment of Alzheimer's disease and Huntington's chorea. Originally developed and marketed as an antihistamine in Russia, latrepirdine has since demonstrated potential for the treatment of neurodegenerative diseases. Early research suggested that the mechanism of action was centered on AChE inhibition and NMDA antagonism. More recent research questions these early findings, and other mechanisms of action have been proposed and investigated. In phase II clinical trials, latrepirdine demonstrated clinically relevant improvements in patients with Alzheimer's disease and Huntington's chorea. At the time of publication, phase III clinical trials had been initiated. Given the robustness of the phase II clinical data, latrepirdine has a high likelihood of success in phase III trials and in subsequently being granted regulatory approval.
Arch Neurol. 2010 Feb;67(2):154-60.
Kieburtz K, McDermott MP, Voss TS, Corey-Bloom J, Deuel LM, Dorsey ER, Factor S, Geschwind MD, Hodgeman K, Kayson E, Noonberg S, Pourfar M, Rabinowitz K, Ravina B, Sanchez-Ramos J, Seely L, Walker F, Feigin A; Huntington Disease Study Group DIMOND In
Department of Neurology, University of Virginia, Charlottesville, VA 22908, USA.
A randomized, placebo-controlled trial of latrepirdine in Huntington disease.
OBJECTIVES: To evaluate the safety and tolerability of latrepirdine in Huntington disease (HD) and explore its effects on cognition, behavior, and motor symptoms. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Multicenter outpatient trial. PARTICIPANTS: Ninety-one participants with mild to moderate HD enrolled at 17 US and UK centers from July 18, 2007, through July 16, 2008. INTERVENTION: Latrepirdine, 20 mg 3 times daily (n = 46), or matching placebo (n = 45) for a 90-day treatment period. MAIN OUTCOME MEASURES: The primary outcome variable was tolerability, defined as the ability to complete the study at the assigned drug dosage. Secondary outcome variables included score changes from baseline to day 90 on the Unified Huntington's Disease Rating Scale (UHDRS), the Mini-Mental State Examination (MMSE), and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). RESULTS: Latrepirdine was well tolerated (87% of the patients given latrepirdine completed the study vs 82% in the placebo group), and adverse event rates were comparable in the 2 groups (70% in the latrepirdine group and 80% in the placebo group). Treatment with latrepirdine resulted in improved mean MMSE scores compared with stable performance in the placebo group (treatment effect, 0.97 points; 95% confidence interval, 0.10-1.85; P = .03). No significant treatment effects were seen on the UHDRS or the ADAS-cog. CONCLUSIONS: Short-term administration of latrepirdine is well tolerated in patients with HD and may have a beneficial effect on cognition. Further investigation of latrepirdine is warranted in this population with HD.
Mol Neurodegener. 2009 Dec 17;4:51.
Steele JW, Kim SH, Cirrito JR, Verges DK, Restivo JL, Westaway D, Fraser P, Hyslop PS, Sano M, Bezprozvanny I, Ehrlich ME, Holtzman DM, Gandy S.
Departments of Neurology, Psychiatry and Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY, 10029, USA.
Acute dosing of latrepirdine (Dimebon), a possible Alzheimer therapeutic, elevates extracellular amyloid-beta levels in vitro and in vivo.
BACKGROUND: Recent reports suggest that latrepirdine (Dimebon, dimebolin), a retired Russian antihistamine, improves cognitive function in aged rodents and in patients with mild to moderate Alzheimer's disease (AD). However, the mechanism(s) underlying this benefit remain elusive. AD is characterized by extracellular accumulation of the amyloid-beta (Abeta) peptide in the brain, and Abeta-lowering drugs are currently among the most popular anti-amyloid agents under development for the treatment of AD. In the current study, we assessed the effect of acute dosing of latrepirdine on levels of extracellular Abeta using in vitro and in vivo experimental systems. RESULTS: We evaluated extracellular levels of Abeta in three experimental systems, under basal conditions and after treatment with latrepirdine. Mouse N2a neuroblastoma cells overexpressing Swedish APP were incubated for 6 hr in the presence of either vehicle or vehicle + latrepirdine (500pM-5 muM). Synaptoneurosomes were isolated from TgCRND8 mutant APP-overexpressing transgenic mice and incubated for 0 to 10 min in the absence or presence of latrepirdine (1 muM or 10 muM). Drug-naïve Tg2576 Swedish mutant APP overexpressing transgenic mice received a single intraperitoneal injection of either vehicle or vehicle + latrepirdine (3.5 mg/kg). Picomolar to nanomolar concentrations of acutely administered latrepirdine increased the extracellular concentration of Abeta in the conditioned media from Swedish mutant APP-overexpressing N2a cells by up to 64% (p = 0.01), while a clinically relevant acute dose of latrepirdine administered i.p. led to an increase in the interstitial fluid of freely moving APP transgenic mice by up to 40% (p = 0.01). Reconstitution of membrane protein trafficking and processing is frequently inefficient, and, consistent with this interpretation, latrepirdine treatment of isolated TgCRND8 synaptoneurosomes involved higher concentrations of drug (1-10 muM) and led to more modest increases in extracellular Abeta(x-42 )levels (+10%; p = 0.001); of note, however, was the observation that extracellular Abeta(x-40 )levels did not change. CONCLUSIONS: Here, we report the surprising association of acute latrepirdine dosing with elevated levels of extracellular Abeta as measured in three independent neuron-related or neuron-derived systems, including the hippocampus of freely moving Tg2576 mice. Given the reported association of chronic latrepirdine treatment with improvement in cognitive function, the effects of chronic latrepirdine treatment on extracellular Abeta levels must now be determined.
Arch Pharm (Weinheim). 2009 Dec;342(12):740-7.
Ivachtchenko AV, Frolov EB, Mitkin OD, Kysil VM, Khvat AV, Tkachenko SE.
Department of Organic Chemistry, Chemical Diversity Research Institute, Khimki, Moscow Reg, Russia. av@chemdiv.com
Synthesis and biological evaluation of novel 5,8-disubstituted-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indoles as 5-HT(6) and H(1) receptors antagonists.
Synthesis, biological evaluation, and structure-activity relationships (SAR) for a series of novel gamma-carboline analogues of Dimebon are described. Among the studied compounds, tetrahydro-gamma-carboline 5b (2,8-dimethyl-5-[cis-2-pyridin-3-ylvinyl]-2,3,4,5-tetrahydro-carboline) has been identified as the most potent small molecule antagonist, in particular against histamine H(1) and serotonin 5-HT(6) receptors (IC(50) < 0.45 microM and IC(50) = 0.73 microM, respectively). A thorough comparative SAR study performed for the tested compounds has revealed significant correlations between the nature of side substituents and the related antagonistic activity.
J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Nov 1;877(29):3563-71. Epub 2009 Sep 1.
Nirogi R, Kandikere V, Mudigonda K, Komarneni P, Boggavarapu R.
Biopharmaceutical Research, Suven Life Sciences Ltd, Serene Chambers, Road -5, Avenue -7, Banjara Hills, Hyderabad 500034, India. ramakrishna_nirogi@yahoo.co.in
Liquid chromatography-tandem mass spectrometry method for the quantification of dimebon in rat plasma and brain tissue.
A sensitive high-performance liquid chromatography-positive ion electrospray tandem mass spectrometry method was developed and validated for the quantification of dimebon in rat plasma and brain tissue. Following liquid-liquid extraction, the analyte was separated using a gradient mobile phase on a reversed phase column and analyzed by MS/MS in the multiple reaction monitoring mode using the respective [M+H](+) ions, m/z 320-277 for dimebon and m/z 407-100 for the internal standard. The assay exhibited a linear dynamic range of 0.25-250 ng/mL for dimebon in rat plasma and brain tissue. Acceptable precision (<11%) and accuracy (100+/-7%) were obtained for concentrations over the standard curve range. A run time of 2.5 min for each sample made it possible to analyze more than 250 samples per day. The method was successfully applied to quantify dimebon concentrations in a rodent pharmacokinetic study. Moreover, it can be believed that the assay method in rat plasma would facilitate the ease of adaptability of dimebon quantification in human plasma for clinical trials.
Lancet. 2008 Jul 19;372(9634):207-15.
Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, Seely L, Hung D; dimebon investigators.
Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, TX, USA.
Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study.
BACKGROUND: Although treatments for Alzheimer's disease sometimes improve cognition, functional ability, or behaviour compared with baseline levels, such improvements are inconsistent across studies and measures, and effects diminish over time. More effective treatments are needed. We assessed the safety, tolerability, and efficacy of dimebon in the treatment of patients with mild-to-moderate Alzheimer's disease. METHODS: We enrolled 183 patients with mild-to-moderate Alzheimer's disease (mini-mental state examination [MMSE] scores 10-24) at 11 sites in Russia. Patients were randomly assigned by a computer-generated randomisation scheme to receive oral dimebon, 20 mg three times a day (60 mg/day [n=89]), or matched placebo (n=94). Other antidementia drugs were not allowed. The primary outcome measure assessed cognition, the difference in mean change from baseline to week 26, or last completed observation on the cognitive subscale of the Alzheimer's disease assessment scale (ADAS-cog). All patients and study personnel were blinded throughout the study. We compared dimebon with placebo with an intention-to-treat analysis, with last observation carried forward (ITT-LOCF) imputation. Analyses were repeated on the fully evaluable population, defined as all patients in the intention-to-treat population who had an ADAS-cog at week 26 and at least 80% compliance. 134 patients (68 in dimebon group, 66 in placebo group) enrolled in the 6-month blinded extension phase of the study. This trial is registered with Clinicaltrials.gov, number NCT00377715. FINDINGS: 155 (85%) patients completed the trial (78 [88%] in dimebon group, 77 [82%] in placebo group). Treatment with dimebon resulted in significant benefits in ADAS-cog compared with placebo (ITT-LOCF) at week 26 (mean drug-placebo difference -4.0 [95% CI -5.73 to -2.28]; p<0.0001). Results of the ITT-LOCF and the evaluable population analyses were much the same for all measures. Patients given dimebon were significantly improved over baseline for ADAS-cog (mean difference -1.9 [-2.92 to -0.85]; p=0.0005). Dimebon was well tolerated: dry mouth and depressed mood or depression were the most common adverse events associated with dimebon (12 [14%] patients for each symptom by week 26). The percentage of patients who had adverse events in the two groups did not differ. INTERPRETATION: Dimebon was safe, well tolerated, and significantly improved the clinical course of patients with mild-to-moderate Alzheimer's disease.
Mol Neurodegener. 2009 Dec 17;4:51.
Steele JW, Kim SH, Cirrito JR, Verges DK, Restivo JL, Westaway D, Fraser P, Hyslop PS, Sano M, Bezprozvanny I, Ehrlich ME, Holtzman DM, Gandy S.
Departments of Neurology, Psychiatry and Alzheimer's Disease Research Center, Mount Sinai School of Medicine, New York, NY, 10029, USA.
Acute dosing of latrepirdine (Dimebon), a possible Alzheimer therapeutic, elevates extracellular amyloid-beta levels in vitro and in vivo.
BACKGROUND: Recent reports suggest that latrepirdine (Dimebon, dimebolin), a retired Russian antihistamine, improves cognitive function in aged rodents and in patients with mild to moderate Alzheimer's disease (AD). However, the mechanism(s) underlying this benefit remain elusive. AD is characterized by extracellular accumulation of the amyloid-beta (Abeta) peptide in the brain, and Abeta-lowering drugs are currently among the most popular anti-amyloid agents under development for the treatment of AD. In the current study, we assessed the effect of acute dosing of latrepirdine on levels of extracellular Abeta using in vitro and in vivo experimental systems. RESULTS: We evaluated extracellular levels of Abeta in three experimental systems, under basal conditions and after treatment with latrepirdine. Mouse N2a neuroblastoma cells overexpressing Swedish APP were incubated for 6 hr in the presence of either vehicle or vehicle + latrepirdine (500pM-5 muM). Synaptoneurosomes were isolated from TgCRND8 mutant APP-overexpressing transgenic mice and incubated for 0 to 10 min in the absence or presence of latrepirdine (1 muM or 10 muM). Drug-naïve Tg2576 Swedish mutant APP overexpressing transgenic mice received a single intraperitoneal injection of either vehicle or vehicle + latrepirdine (3.5 mg/kg). Picomolar to nanomolar concentrations of acutely administered latrepirdine increased the extracellular concentration of Abeta in the conditioned media from Swedish mutant APP-overexpressing N2a cells by up to 64% (p = 0.01), while a clinically relevant acute dose of latrepirdine administered i.p. led to an increase in the interstitial fluid of freely moving APP transgenic mice by up to 40% (p = 0.01). Reconstitution of membrane protein trafficking and processing is frequently inefficient, and, consistent with this interpretation, latrepirdine treatment of isolated TgCRND8 synaptoneurosomes involved higher concentrations of drug (1-10 muM) and led to more modest increases in extracellular Abeta(x-42 )levels (+10%; p = 0.001); of note, however, was the observation that extracellular Abeta(x-40 )levels did not change. CONCLUSIONS: Here, we report the surprising association of acute latrepirdine dosing with elevated levels of extracellular Abeta as measured in three independent neuron-related or neuron-derived systems, including the hippocampus of freely moving Tg2576 mice. Given the reported association of chronic latrepirdine treatment with improvement in cognitive function, the effects of chronic latrepirdine treatment on extracellular Abeta levels must now be determined.
Curr Opin Investig Drugs. 2010 Jan;11(1):80-91.
Sabbagh MN, Shill HA.
Banner Sun Health Research Institute, The Cleo Roberts Center for Clinical Research, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. marwan.sabbagh@bannerhealth.com
Latrepirdine, a potential novel treatment for Alzheimer's disease and Huntington's chorea.
Latrepirdine (Dimebon) is a small-molecule compound under development by Medivation Inc and Pfizer Inc for the treatment of Alzheimer's disease and Huntington's chorea. Originally developed and marketed as an antihistamine in Russia, latrepirdine has since demonstrated potential for the treatment of neurodegenerative diseases. Early research suggested that the mechanism of action was centered on AChE inhibition and NMDA antagonism. More recent research questions these early findings, and other mechanisms of action have been proposed and investigated. In phase II clinical trials, latrepirdine demonstrated clinically relevant improvements in patients with Alzheimer's disease and Huntington's chorea. At the time of publication, phase III clinical trials had been initiated. Given the robustness of the phase II clinical data, latrepirdine has a high likelihood of success in phase III trials and in subsequently being granted regulatory approval.
Arch Neurol. 2010 Feb;67(2):154-60.
Kieburtz K, McDermott MP, Voss TS, Corey-Bloom J, Deuel LM, Dorsey ER, Factor S, Geschwind MD, Hodgeman K, Kayson E, Noonberg S, Pourfar M, Rabinowitz K, Ravina B, Sanchez-Ramos J, Seely L, Walker F, Feigin A; and The Dimebon in Subjects With Hunting
University of Virginia, Department of Neurology, PO Box 900394, Charlottesville, VA 22908. tv4e@virginia.edu
A randomized, placebo-controlled trial of latrepirdine in huntington disease.
OBJECTIVES: To evaluate the safety and tolerability of latrepirdine in Huntington disease (HD) and explore its effects on cognition, behavior, and motor symptoms. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Multicenter outpatient trial. PARTICIPANTS: Ninety-one participants with mild to moderate HD enrolled at 17 US and UK centers from July 18, 2007, through July 16, 2008. Intervention Latrepirdine, 20 mg 3 times daily (n = 46), or matching placebo (n = 45) for a 90-day treatment period. MAIN OUTCOME MEASURES: The primary outcome variable was tolerability, defined as the ability to complete the study at the assigned drug dosage. Secondary outcome variables included score changes from baseline to day 90 on the Unified Huntington's Disease Rating Scale (UHDRS), the Mini-Mental State Examination (MMSE), and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog). RESULTS: Latrepirdine was well tolerated (87% of the patients given latrepirdine completed the study vs 82% in the placebo group), and adverse event rates were comparable in the 2 groups (70% in the latrepirdine group and 80% in the placebo group). Treatment with latrepirdine resulted in improved mean MMSE scores compared with stable performance in the placebo group (treatment effect, 0.97 points; 95% confidence interval, 0.10-1.85; P = .03). No significant treatment effects were seen on the UHDRS or the ADAS-cog. CONCLUSIONS: Short-term administration of latrepirdine is well tolerated in patients with HD and may have a beneficial effect on cognition. Further investigation of latrepirdine is warranted in this population with HD. Trial Registration clinicaltrials.gov Identifier: NCT00497159.
Indian J Psychiatry. 2009 Jan;51(1):12-25
Andrade C, Radhakrishnan R.
Department of Psychopharmacology, National Institute of Mental Health and Neurosciences, Bangalore - 560 029, India.
The prevention and treatment of cognitive decline and dementia: An overview of recent research on experimental treatments.
The prevention and treatment of cognitive impairment in the elderly has assumed increasing importance in an aging population. This article presents a qualitative review of recent research on experimental interventions for the prevention and treatment of mild cognitive impairment and Alzheimer's disease in elderly subjects. Interventions addressed range from lifestyle measures to pharmacological treatments. Epidemiological studies suggest that dietary measures, physical exercise, and mental activity may reduce the risk of cognitive impairment and Alzheimer's disease in elderly subjects. Statins may protect against incident dementia, and lithium may convey similar benefits to bipolar patients. Ginkgo appears ineffective as a primary preventive measure. Donepezil (Latrepirdine in USA) but not Vitamin E may benefit persons with mild cognitive impairment. Experimental treatments potentially useful for Alzheimer's disease include dimebon, PBT2 and etanercept; the safety and efficacy of the Alzheimer's vaccine remains to be proven, and growth hormone secretagogue and tarenflurbil are likely ineffective. Herbal treatments merit study in elderly subjects with cognitive syndromes.
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Drug category:Anti-Alzheimer's, Anti-Dementia Agents
 Latrepirdine scientific update
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