RESUMEN
Apomorphine, used to treat OFF episodes in patients with Parkinson's disease (PD), is typically administered via subcutaneous injections. Administration of an oromucosal solution could offer a non-invasive and user-friendly alternative. This two-part clinical study evaluated the safety, tolerability, pharmacokinetics (PK), and dose proportionality of a novel apomorphine hydrochloride oromucosal solution, as well as its relative bioavailability to subcutaneous apomorphine injection and apomorphine sublingual film. In part A of the study, 12 patients with PD received 2 mg oromucosal apomorphine (4% weight/volume) and 2 mg subcutaneous apomorphine in a randomized order, followed by 4 and 8 mg oromucosal apomorphine. In part B of the study, 13 patients with PD received 7 mg oromucosal apomorphine (7% weight/volume) and 30 mg sublingual apomorphine in a randomized order, followed by 14 mg oromucosal apomorphine. Washout between dose administrations in both study parts was at least 2 days. Safety, tolerability, and PK were assessed pre- and post-dose. Both study parts showed that oromucosal apomorphine was generally well-tolerated. Observed side effects were typical for apomorphine administration and included asymptomatic orthostatic hypotension, yawning, fatigue, and somnolence. Oromucosal apomorphine exposure increased with dose, although less than dose proportional. The mean (SD) maximum exposure reached with 14 mg oromucosal apomorphine was 753.0 (298.6) ng*min/mL (area under the plasma concentration-time curve from zero to infinity) and 8.0 (3.3) ng/mL (maximum plasma concentration). This was comparable to exposure reached after 2 mg subcutaneous apomorphine and approximately half of the exposure observed with 30 mg sublingual apomorphine. In summary, clinically relevant plasma concentrations could be reached in PD patients without tolerability issues.
Asunto(s)
Apomorfina , Enfermedad de Parkinson , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Administración Oral , Administración Sublingual , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/efectos adversos , Apomorfina/administración & dosificación , Apomorfina/farmacocinética , Apomorfina/efectos adversos , Disponibilidad Biológica , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Inyecciones Subcutáneas , Enfermedad de Parkinson/tratamiento farmacológico , Adulto , Anciano de 80 o más AñosRESUMEN
AIM: To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam. METHODS: In this four-way crossover, double-blind, double-dummy, randomized, placebo-controlled study, 16 subjects received 2.5 mg Nazolam, 5.0 mg Nazolam, 2.5 mg intravenous midazolam or placebo on different occasions. Pharmacokinetics of midazolam and α-hydroxy-midazolam were characterized and related to outcome variables for sedation (saccadic peak velocity, the Bond and Lader visual analogue scale for sedation, the simple reaction time task and the observer's assessment of alertness/sedation). Nasal tolerance was evaluated through subject reporting, and ear, nose and throat examination. RESULTS: Nazolam bioavailability was 75%. Maximal plasma concentrations of 31 ng ml-1 (CV, 42.3%) were reached after 11 min (2.5 mg Nazolam), and of 66 ng ml-1 (coefficient of variability, 31.5%) after 14 min (5.0 mg Nazolam). Nazolam displayed a significant effect on OAA/S scores. Sedation onset (based on SPV change) occurred 1 ± 0.7 min after administration of 2.5 mg intravenous midazolam, 7 ± 4.4 min after 2.5 mg Nazolam, and 4 ± 1.8 min after 5 mg Nazolam. Sedation duration was 118 ± 95.6 min for 2.5 mg intravenous midazolam, 76 ± 80.4 min for 2.5 mg Nazolam, and 145 ± 104.9 min for 5.0 mg Nazolam. Nazolam did not lead to nasal mucosa damage. CONCLUSIONS: This study demonstrates the nasal tolerance, safety and efficacy of Nazolam. When considering the preparation time needed for obtaining venous access, conscious sedation can be achieved in the same time span as needed for intravenous midazolam. Nazolam may offer important advantages in conscious sedation.
Asunto(s)
Sedación Consciente/métodos , Hipnóticos y Sedantes/administración & dosificación , Midazolam/administración & dosificación , Administración Intranasal , Administración Intravenosa , Adulto , Disponibilidad Biológica , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Hipnóticos y Sedantes/farmacocinética , Hipnóticos y Sedantes/farmacología , Masculino , Midazolam/análogos & derivados , Midazolam/farmacocinética , Midazolam/farmacología , Persona de Mediana Edad , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/metabolismo , Tiempo de Reacción/efectos de los fármacos , Adulto JovenRESUMEN
The connection between the nasal cavity and the CNS by the olfactory neurones has been investigated extensively during the last decades with regard to its feasibility to serve as a direct drug transport route to the CSF and brain. This drug transport route has gained much interest as it may circumvent the blood-brain barrier (BBB), which prevents some drugs from entering the brain. Approximately 100 published papers mainly reporting animal experiments were reviewed to evaluate whether the experimental design used and the results generated provided adequate pharmacokinetic information to assess whether the investigated drug was transported directly from the olfactory area to the CNS. In the analysis the large anatomical differences between the olfactory areas of animals and humans and the experimental conditions used were evaluated. The aim of this paper was to establish the actual evidence for the feasibility of this direct transport route in humans. Twelve papers presented a sound experimental design to study direct nose to CNS transport of drugs based on the authors' criteria. Of these, only two studies in rats were able to provide results that can be seen as an indication for direct transport from the nose to the CNS. No pharmacokinetic evidence could be found to support a claim that nasal administration of drugs in humans will result in an enhanced delivery to their target sites in the brain compared with intravenous administration of the same drug under similar dosage conditions.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Mucosa Nasal/metabolismo , Preparaciones Farmacéuticas/administración & dosificación , Preparaciones Farmacéuticas/metabolismo , Administración Intranasal , Animales , Transporte Biológico , Encéfalo/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Humanos , Nariz/anatomía & histología , Farmacocinética , RatasRESUMEN
With the growing number of patients suffering from central nervous system (CNS) diseases a suitable approach for drug targeting to the brain becomes more and more important. In the present study, the contribution of the nose-CSF pathway to the uptake of the model drug fluorescein isothiocyanate-labelled dextran with a molecular weight of 3.0 kDa (FD3) into the CSF was determined in rats. FD3 was administered intranasally (489 microg/rat) and by intravenous infusion (24.4 microg/ml; 119 microg/rat) in the same set of animals (n=6). Blood samples were taken from the tail vein and CSF was sampled by cisternal puncture using a stereotaxic frame. The contribution of the olfactory pathway to the uptake of FD3 into the CSF was determined by comparing the AUCCSF/AUCplasma ratios after intranasal and after intravenous application of FD3 mimicking the blood levels after intranasal delivery. No significant difference was observed between the AUCCSF/AUCplasma ratios of FD3 after intranasal administration (1.33+/-0.40%) and intravenous infusion (1.03+/-0.56%). This indicates that in rats about 1% of the amount of FD3 in plasma reaches the CSF both after nasal and intravenous administration and that no direct transport of FD3 from the nose-CSF could be found.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Dextranos/líquido cefalorraquídeo , Fluoresceína-5-Isotiocianato/análogos & derivados , Administración Intranasal , Animales , Área Bajo la Curva , Dextranos/administración & dosificación , Dextranos/sangre , Fluoresceína-5-Isotiocianato/administración & dosificación , Infusiones Intravenosas , Masculino , Modelos Animales , Ratas , Ratas WistarRESUMEN
PURPOSE: To investigate the possibility of direct transport of melatonin from the nasal cavity into the cerebrospinal fluid (CSF) after nasal administration in rats and to compare the animal results with a human study. METHODS: Rats (n = 8) were given melatonin both intranasally in one nostril (40 microg/rat) and intravenously by bolus injection (40 microg/rat) into the jugular vein using a Vascular Access Port. Just before and after drug administration, blood and CSF samples were taken and analyzed by HPLC. RESULTS: Melatonin is quickly absorbed in plasma (T(max) = 2.5 min) and shows a delayed uptake into CSF (T(max) = 15 min) after nasal administration. The melatonin concentration-time profiles in plasma and CSF are comparable to those after intravenous delivery. The AUC(CSF)/AUC(plasma) ratio after nasal delivery (32.7 +/- 6.3%) does not differ from the one after intravenous injection (46.0 +/- 10.4%), which indicates that melatonin enters the CSF via the blood circulation across the blood-brain barrier. This demonstrates that there is no additional transport via the nose-CSF pathway. These results resemble the outcome of a human study. CONCLUSIONS: The current results in rats show that there is no additional uptake of melatonin in the CSF after nasal delivery compared to intravenous administration. This is in accordance with the results found in humans, indicating that animal experiments could be predictive for the human situation when studying nose-CSF transport.
Asunto(s)
Melatonina/administración & dosificación , Melatonina/líquido cefalorraquídeo , Administración Intranasal , Algoritmos , Animales , Área Bajo la Curva , Química Farmacéutica , Humanos , Inyecciones Intravenosas , Ratas , Ratas Wistar , Especificidad de la EspecieRESUMEN
The uptake of estradiol and progesterone into the cerebrospinal fluid (CSF) after intranasal and intravenous administration in rats was investigated. Each animal received estradiol intranasally (40 microg/rat) and by intravenous infusion (10 microg/rat) into the jugular vein using a vascular access port. Hereafter, the same set of rats was treated with progesterone intranasally (200 microg/rat) and by intravenous infusion (104 microg/rat). Following nasal delivery, both steroid hormones reach Cmax values in plasma and CSF at 15 min after administration. Intravenous infusion of estradiol and progesterone shows comparable plasma and CSF concentration-time profiles compared to the nasal route. For both hormones the AUCCSF/AUCplasma ratios (mean +/- SD) after intranasal delivery (estradiol 2.3 +/- 1.1%; progesterone 1.9 +/- 0.7%) do not differ significantly from the ratios shown after intravenous infusion (estradiol 2.0 +/- 0.6%; progesterone 2.2 +/- 0.8%). These results indicate that after nasal delivery estradiol and progesterone are rapidly absorbed into the systemic circulation, from where the non-protein bound hormones probably enter the CSF by crossing the blood-brain barrier. No extra direct nose-CSF transport could be demonstrated.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Estradiol/administración & dosificación , Estradiol/líquido cefalorraquídeo , Progesterona/administración & dosificación , Progesterona/líquido cefalorraquídeo , Administración Intranasal , Animales , Infusiones Intravenosas , Masculino , Ratas , Ratas WistarRESUMEN
The possibility of direct transport of hydroxocobalamin from the nasal cavity into the cerebrospinal fluid (CSF) after nasal administration in rats was investigated and the results were compared with a human study. Hydroxocobalamin was given to rats (n=8) both intranasally (214 microg/rat) and intravenously (49.5 microg/rat) into the jugular vein using a Vascular Access Port (VAP). Prior to and after drug administration, blood and CSF samples were taken and analysed by radioimmunoassay. The AUCCSF/AUCplasma ratio after nasal delivery does not differ from the ratio after intravenous infusion, indicating that hydroxocobalamin enters the CSF via the blood circulation across the blood-brain barrier (BBB). This same transport route is confirmed by the cumulative AUC-time profiles in CSF and plasma, demonstrating a 30 min delay between plasma absorption and CSF uptake of hydroxocobalamin in rats and in a comparative human study. The present results in rats show that there is no additional uptake of hydroxocobalamin in the CSF after nasal delivery compared to intravenous administration, which is in accordance with the results found in humans. This indicates a predictive value of the used rat model for the human situation when studying the nose to CSF transport of drugs.
Asunto(s)
Hidroxocobalamina/administración & dosificación , Hidroxocobalamina/líquido cefalorraquídeo , Administración Intranasal , Animales , Área Bajo la Curva , Catéteres de Permanencia , Química Farmacéutica , Humanos , Inyecciones Intravenosas , Masculino , Radioinmunoensayo , Ratas , Ratas WistarRESUMEN
It has been suggested that intranasal (IN) drug delivery could be used to administer drugs directly to the brain, bypassing the blood-brain barrier. Conclusive evidence of this proposed route of drug transport has not been observed by IN-IV comparison. In eight neurosurgery patients with a CSF drain, the uptake in CSF and plasma after IN and IV drug administration was compared. No evidence of direct access of the drugs from the nose to the CSF was found.
Asunto(s)
Administración Intranasal , Encéfalo/metabolismo , Hidroxocobalamina/administración & dosificación , Melatonina/administración & dosificación , Adulto , Barrera Hematoencefálica , Femenino , Humanos , Hidroxocobalamina/sangre , Hidroxocobalamina/líquido cefalorraquídeo , Hidroxocobalamina/farmacocinética , Inyecciones Intravenosas , Masculino , Melatonina/sangre , Melatonina/líquido cefalorraquídeo , Melatonina/farmacocinética , Persona de Mediana EdadRESUMEN
Drug transport from the nasal cavity to the brain has gained much interest in the last decade. In the present study, a model was developed to determine the uptake of drugs into the cerebrospinal fluid (CSF) after nasal delivery in rats. CSF samples were taken using a cisternal puncture method. In this method, a needle is advanced through the skin and muscles overlying the atlanto-occipital membrane into the cisterna magna, while the rat is fixed in a stereotaxic frame. This method appears to be superior over cannulation of the atlanto-occipital membrane for CSF sampling. The major advantages of the puncture method is the ability of serial and simultaneous CSF and blood sampling for over 2 h in the same rat. To obtain maximal drug absorption from the nasal cavity and uptake into CSF, different positions of the rat's head (upright-90 degrees, supine-90 degrees, supine-45 degrees and supine-70 degrees angles) were tested in nasal delivery studies using hydrocortisone (HC) as a model drug. Putting the rat in the supine-90 degrees angle position increased the absorption of HC into plasma and CSF 2-fold compared to the upright-90 degrees angle position. The supine-70 degrees angle position did not change the HC plasma and CSF levels compared to the supine-90 degrees angle position. However, the supine-70 degrees angle position showed the fastest CSF sampling rate, enabling more accurate CSF sampling and therefore preferred for further studies. In conclusion, the cisternal puncture method using the supine-70 degrees and 90 degrees angle position is a suitable method to study drug transport from the nasal cavity into the CSF, with the ability of multiple CSF sampling.