Fabrication and in vitro characterization of polymeric nanoparticles for Parkinson's therapy: a novel approach

The objective of the research was to formulate and evaluate selegiline hydrochloride loaded chitosan nanoparticles for the Parkinson's therapy in order to improve its therapeutic effect and reducing dosing frequency. Taguchi method of design of experiments (L9 orthogonal array) was used to get optimized formulation. The selegiline hydrochloride loaded chitosan nanoparticles (SHPs) were prepared by ionic gelation of chitosan with tripolyphosphate anions (TPP) and tween 80 as surfactant. The SHPs had a mean size of (303.39 ± 2.01) nm, a zeta potential of +32.50mV, and entrapment efficiency of SHPs was 86.200 ± 1.38%. The in vitro drug release of SHPs was evaluated in phosphate buffer saline (pH 5.5) using goat nasal mucosa and found to be 82.529% ± 1.308 up to 28 h. Release kinetics studies showed that the release of drug from nanoparticles was anomalous (non-fickian) diffusion indicating the drug release is controlled by more than one process i.e. superposition of both phenomenon, the diffusion controlled as well as swelling controlled release. SHPs showed good stability results as found during stability studies at different temperatures as mentioned in ICH guidelines. The results revealed that selegiline hydrochloride loaded chitosan nanoparticles are most suitable mode of delivery of drug for promising therapeutic action.

O objetivo da pesquisa foi formular e avaliar nanopartículas de quitosana contendo cloridrato de selegilina para terapia do Parkinson, a fim de melhorar o seu efeito terapêutico e reduzir a frequência de dosagem. Método de Taguchi, de planejamento experimental, (L9 matriz ortogonal) foi usado para obter a formulação otimizada. As nanopartículas de quitosana contendo cloridrato de selegilina (PCHs) foram preparadas por gelificação iônica de quitosana com ânions tripolifosfato (TPP) e Tween 80 como tensoativo. As PCHs apresentaram tamanho médio de (303.39 ± 2,01) nm, potencial zeta de +32.50 mV e eficiência de encapsulação de 86.200±1,38%. A liberação do fármaco in vitro foi avaliada em solução salina de tampão fosfato (pH 5,5), usando a mucosa nasal de cabra e o resultado encontrado foi de 82.529% ± 1.308, acima de 28 h. Estudos de cinética de liberação mostraram que a liberação do fármaco das nanopartículas foi por difusão anômala (não fickiana), indicando que é controlada por mais de um processo, ou seja, a superposição dos fenômenos de difusão controlada e intumescimento. As PCHs mostraram resultados de boa estabilidade, encontrada durante os estudos de estabilidade em temperaturas diferentes, como mencionado em diretrizes do ICH. Os resultados revelaram que o sistema de nanopartículas de quitosana contendo cloridrato de selegilina é o mais adequado sistema de liberação de fármacos de ação terapêutica promissora.

Selegiline increases heme oxygenase-1 expression and the cytotoxicity produced by dopamine treatment of neuroblastoma SK-N-SH cells

Increased dopamine catabolism may be associated with oxidative stress and neuronal cell death in Parkinson's disease. The present study was carried out to examine the effect of dopamine on the expression of heme oxygenase-1 and -2 (HO-1 and HO-2) in human neuroblastomas (SK-N-SH cell line) and the effects of selegiline and antioxidants on this expression. Cells were kept with close control of pH and were incubated with varying concentrations of dopamine (0.1-100 æM) for 24 h. HO-1 and HO-2 cDNA probes were prepared by reverse transcription-polymerase chain reaction amplification. The mRNA expression of HO-1 and HO-2 was measured by Northern blot analysis. The levels of HO-1 mRNA increased after dopamine treatment, in a dose-dependent manner, in all cell lines studied, whereas levels of the two HO-2 transcripts did not. The HO-1 and HO-2 protein expression was analyzed by Western blotting. HO-1 protein was undetectable in untreated SK-N-SH cells and increased after treatment with dopamine. In contrast, the HO-2 protein (36 kDa) was detected in untreated cells and the levels did not change as a result of treatment. alpha-Tocopherol (10-100 æM) and ascorbic acid (100 æM) did not attenuate the effects of dopamine. Selegiline (10 æM) produced significant increase (P < 0.01) in the induction of HO-1 by dopamine (more than six times the control values). The increased expression of HO-1 following dopamine treatment indicates that dopamine produces oxidative stress in this cell line.

Fármacos antiparkinsonianos / Anti-Parkinson drugs

La enfermedad de Parkinson requiere la administración de diversos fármacos. En el siguiente artículo se describen las diferentes drogas utilizadas, -agentes dopaminérgicos, anticolinérgicos y neuroprotectores- sus modos de acción, efectos adversos y precauciones y advertencias

Terapia neuroprotectora de la Enfermedad de Parkinson / Neuroprotective therapy in Parkinson's Disease

With the current limitations on treating Parkinsonãs disease, neuroprotection should be looked at as a possible way of slowing the varying processes involved in the onset of the disease. A review was made of the work of NINDS experts, who evaluated 59 drugs resulting from their Medline and Pub Med search. Twelve drugs, those considered the most promising, were included in the final analysis. We look at such substances as caffeine, coenzyme q10, estrogens, minocycline, nicotine, rasagiline-selegiline, and ropinirole-pramipexole. These agents acted dissimilarly, but favorably, on some of the diseaseãs processes or on its underlying pathogenesis, although the mechanisms involved and the duration of the beneficial effects were not clear. The challenge is to overcome the difficulties that make the results of the few current studies uncertain, using new methods, such as transgenic models, to maintain hope for effective future treatments.

Escolha do tratamento da narcolepsia / The treatment of narcolepsy

O tratamento da narcolepsia visa seus dois sintomas principais, a sonolência excessiva diurna e a cataplexia. A primeira é usualmente controlada com anfetmina, metilfenidato e pemoline. Mais recentemente, inibidores da MAO, e principalmente os inibidores seletivos de MAO-A e B têm mostrado resultados promissores, com a selegilina. Modafinil, um estimulante alfa-1-adrenérgico tem também evidenciado bons resultados. A cataplexia, por sua vez, é geralmente tratada com antidepressivos tricíclicos. Dentre as novas drogas, sem efeito colateral antropínico, temos o hidrocloreto de viloxazina, um bloqueador de recaptaçäo da noradrenalina

Tratamento neuroprotetor da doença de Parkinson / Neuroprotector treatment of Parkinson's disease

A doença de Parkinson foi descrita em 1817 e desde então os conhecimentos sobre sua patologia e formas de tratamento foram crescendo. A levodopaterapia constituiu um avanço significativo no tratamento sintomático desta doença. Os estudos sobre os possíveis mecanismos etiopatogênicos da doença de Parkinson (DP) formaram a base para proposição de um novo tipo de abordagem terapêutica: um tratamento possivelmente curativo ou neuroprotetor. Neste trabalho é feita uma revisão do uso do deprenil e tocoferol (Vit E) nas fases iniciais da DP. Os resultados mostraram que o tocoferol não apresentou efeito terapêutico e que o efeito do deprenil ainda não foi definido se neuroprotetor, sintomático ou ambos

Potenciales evocados somatosensoriales y respuesta sintomática a medicamentos dopaminérgicos en enfermedad de Parkinson / Somatosensory evoked potentials and sintomatic response to dopaminergic drugs in Parkinson's disease

Short latency somatosensory evoked potentials were measured in 10 patients with Parkinson's disease before and after tha administration of Apomorphine 5 mg sc. Eight of these subjects were reassessed after one month of treatment with Levo-dopa. These potentials were measured in other nine subjects before and after one month of treatment with Selegiline 10 mg od. There was a significant increase of frontal potential N30 in nine of 10 subjects that received apomorphine, in seven of 8 patients treated with Levodopa and 7 of 9 patients treated with Selegiline. No changes in N20 parietal potential were observed. During apomorphine test, changes in N30 potential preceded clinical improvement in 6 patients and occurred simultaneously in 3 patients. No changes with apomorphine in N30 potential were observed in 2 healthy males. There was no relationship between electrophysiological changes and duration of disease or motor fluctuations. It is concluded that short latency somatosensory evoked potentials are an objective means of measuring dopaminergic response in patients with Parkinson's disease

Rationale for (-) deprenyl (Selegiline) therapy in Parkinson's disease and Alzeheimer's disease / Razöes da terapêutica com (-) deprenil (Selegilina) na doença de Parkinson e na doença de Alzeheimer

(-) Deprenil (Selegiline, Jumex, Eldepryl, Movergan), a close structural relative to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. It is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme significantly increases with age. (-) Deprenyl, the first slective inhibitor of MAO-B described in literature, has become the universally used research tool for selectively blocking B-type MAO. It is the only selectively inhibitor in clinical use. (-) Deprenyl interferes with the uptake of catecholamines and indirectly acting sympathomimetics beacuse it is handled by the catecholaminergic neuron in a way similar to the physiological substances transported through the axonal and organ and vesicular membrane. The unique behavior or (-)deprenyl is that, in striking contrast to PEA and its relatives, it does not displace the transmitter from storage, ie, it is not a releaser. The net result is that (-)de inhibits the releasing effect of tyramine, and, at present, is the only safe MAO inhibitor than can be administered without dietary precautions. Maintenance on (-)deprenyl selectively enhances superoxide dismutase (SOD) and catalase activity in the striatum. This effect is unrelated to its effect on MAO-B and the inhibitory effects of thhe drug on neurotransmitter uptake. Maintenance on (-)deprenyl facilitates the activity of the catecholaminergic system in the brain, and this effect, too, is unrelated to either its effects on MAO or on neurotransmitter uptake. (-)Deprenyl protects the nigrostriatal dopaminergic neurons against selective neurotoxins (6-hydroxy-dopamine, MPTP,DSP-4). Maintenance on (-)deprenyl prevents the characteristic age-related morphological changes in the neuromelanin granules of the neurocytes in the substantia nigra. All in all, (-)deprenyl increases the activity of the nigrostriatal dopaminergic system and slows its age-related decline. Maitenance of male rats on (-)deprenyl delays the loss of the capacity to ejaculate, slows the decline of learning and memory, and significanthy lengthens the lifespan as compared with saline-treated rats. Parkinson's disease patients on levodopa plus (-)deprenyl (1o mg daily) live significanthy longer than those on levodopa alone. (-)Deprenyl is the first drug that retards the progress of Parkinson's disease patients maintained on (-)deprenyl need levodopa significanthy later than their placebo-treated peers. Maintenance on (-)deprenyl improves significantly the performance of patients with Alzheimer's disease. It is concluded that Parkinson's disease patients need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication. We propose that the healthy be maintained on 10-15 mg (-)deprenyl weekly starting at 45 in order to combat the age-related decline of the nigrostriatal dopaminergic neurons. Prophylactic (-)deprenyl medication seems to offer a reasonable prospect of improving the quality of life in the later decades, delaying the time of natural death and decreasing the susceptibility of age-related neurological diseases, like Parkinson's disease and Alzheimer's disease

Parkinsonismo: aspéctos clínicos, biológicos e terapêuticos / Parkinsonism: clinical, biological and therapeutical aspects

O parkinsonismo idiopático (doença de Parkinson) e secundário, ou seja, que apresenta etiologia conhecida (pós-encefalítico, por toxinas, por drogas ou por algumas doenças degenerativas) såo processos neurodegenerativos que afetam progressivamente as funçÆes motoras normais do indivíduo. Neste trabalho, os aspéctos clínicos, etiológicos, fisiopatológicos e principalmente a descriçåo do arsenal farmacológico e as medidas utilizadas no combate ou retardo medicamentoso do parkinsonismo såo abordados e discutidos