Artemisone and Artemiside Are Potent Panreactive Antimalarial Agents That Also Synergize Redox Imbalance in Plasmodium falciparum Transmissible Gametocyte Stages.

The emergence of resistance toward artemisinin combination therapies (ACTs) by the malaria parasite Plasmodium falciparum has the potential to severely compromise malaria control. Therefore, the development of new artemisinins in combination with new drugs that impart activities toward both intraerythrocytic proliferative asexual and transmissible gametocyte stages, in particular, those of resistant parasites, is urgently required. We define artemisinins as oxidant drugs through their ability to oxidize reduced flavin cofactors of flavin disulfide reductases critical for maintaining redox homeostasis in the malaria parasite. Here we compare the activities of 10-amino artemisinin derivatives toward the asexual and gametocyte stages of P. falciparum parasites. Of these, artemisone and artemiside inhibited asexual and gametocyte stages, particularly stage V gametocytes, in the low-nanomolar range. Further, treatment of both early and late gametocyte stages with artemisone or artemiside combined with the pro-oxidant redox partner methylene blue displayed notable synergism. These data suggest that modulation of redox homeostasis is likely an important druggable process, particularly in gametocytes, and this finding thereby enhances the prospect of using combinations of oxidant and redox drugs for malaria control.

Topical Delivery of Withania somnifera Crude Extracts in Niosomes and Solid Lipid Nanoparticles.

BACKGROUND: Withania somnifera is a medicinal plant native to India and is known to have anticancer properties. It has been investigated for its anti-melanoma properties, and since melanoma presents on the skin, it is prudent to probe the use of W. somnifera in topical formulations. To enhance topical drug delivery and to allow for controlled release, the use of niosomes and solid lipid nanoparticles (SLNs) as delivery vesicles were explored. OBJECTIVE: The objective of this study is to determine the stability and topical delivery of W. somnifera crude extracts encapsulated in niosomes and SLNs. MATERIALS AND METHODS: Water, ethanol, and 50% ethanol crude extracts of W. somnifera were prepared using 24 h soxhlet extraction which were each encapsulated in niosomes and SLNs. Franz cell diffusion studies were conducted with the encapsulated extracts to determine the release and skin penetration of the phytomolecules, withaferin A, and withanolide A. RESULTS: The niosome and SLN formulations had average sizes ranging from 165.9 ± 9.4 to 304.6 ± 52.4 nm with the 50% ethanol extract formulations having the largest size. A small particle size seemed to have correlated with a low encapsulation efficiency (EE) of withaferin A, but a high EE of withanolide A. There was a significant difference (P < 0.05) between the amount of withaferin A and withanolide A that were released from each of the formulations, but only the SLN formulations managed to deliver withaferin A to the stratum corneum-epidermis and epidermis-dermis layers of the skin. CONCLUSION: SLNs and niosomes were able to encapsulate crude extracts of W. somnifera and release the marker compounds, withaferin A, and withanolide A, for delivery to certain layers in the skin. SUMMARY: Withania somnifera crude extracts were prepared using ethanol, water, and 50% ethanol as solvents. These three extracts were then incorporated into niosomes and solid lipid nanoparticles (SLNs) for use in skin diffusion studies, thus resulting in six formulations (ethanol niosome, water niosome, 50% ethanol niosome, ethanol SLN, water SLN, and 50% ethanol SLN). The diffusion of two marker compounds (withaferin A and withanolide A) from the formulations into the skin was then determined. Abbreviations used: API: Active pharmaceutical ingredient, ANOVA: Analysis of variance, ED: Epidermis-dermis, HPLC: High-performance liquid chromatography, HLB: Hydrophilic-lipophilic balance, NMR: Nuclear magnetic resonance spectroscopy, PDI: Polydispersity index, SLN: Solid lipid nanoparticle, SD: Standard deviation, SCE: Stratum corneum-epidermis, TEM: Transmission electron microscopy.

In vitro skin permeation of sinigrin from its phytosome complex.

OBJECTIVES: Sinigrin is a major glucosinolate present in plants of the Brassicaceae family. Recently, sinigrin and its phytosome formulations have been investigated for its wound-healing actions, by our research group. The aim of this study was to demonstrate sinigrin drug release from its phytosome complex and also to determine whether the phytosome complex enhances the delivery of sinigrin into the skin when compared to free sinigrin. METHODS: In vitro Franz cell diffusion studies were performed on human abdominal skin. The morphology of the phytosome complex was examined by transmission electron microscopy. The in vitro drug release was determined using dialysis sacks. KEY FINDINGS: The in vitro drug release indicated a controlled and sustained release of sinigrin from the phytosome complex. Tape stripping results showed that the sinigrin-phytosome complex (0.5155 µg/ml) statistically significantly enhanced the delivery of sinigrin into the stratum corneum-epidermis when compared to the free sinigrin (0.0730 µg/ml). CONCLUSIONS: These results suggested the possibility of utilizing sinigrin-phytosome complex, to optimally deliver sinigrin to the skin which can be further used for various skin-related diseases including wound healing.

Physical stability and clinical efficacy of Crocodylus niloticus oil lotion

ABSTRACT The stability and the anti-ageing, skin hydrating and anti-erythema effects of a commercialized Crocodylus niloticus Laurenti, 1768, Crocodylidae, oil lotion was determined. The lotion was stored at controlled conditions over six months during which several stability tests were performed. For the clinical efficacy studies lotion was applied on volar forearm skin (female volunteers) and compared to a liquid paraffin-containing reference product. Skin hydrating and anti-ageing effects were determined with a Corneometer®, Cutometer® and Visioscan®, following single (3 h) and multiple applications (12 weeks). The Vapometer® and Mexameter® were utilized to determine this lotion's anti-erythema effects on sodium lauryl sulfate irritated skin. The lotion demonstrated good stability over 6 months. The reference product increased skin hydration and decreased skin wrinkles to a larger extent than the C. niloticus lotion after a single application, whereas the C. niloticus lotion decreased skin scaliness better than the reference product. During the long-term study, the reference product overall increased skin hydration more than the C. niloticus lotion, whereas C. niloticus lotion increased skin elasticity to a larger extent than the reference product. C. niloticus lotion increased skin wrinkles and decreased skin scaliness over 12 weeks. Compared to non-treated, irritated skin, C. niloticus lotion demonstrated some potential anti-inflammatory characteristics.

In vitro skin permeation of artemisone and its nano-vesicular formulations.

The artemisinin derivative artemisone has antitumor activity. In particular when encapsulated in solid lipid nanoparticles (SLNs) and niosomes, it is active against human melanoma A-375 cells, although such formulations have a negligible effect on human keratinocyte cells. The aim here was to determine whether these formulations could enhance the topical delivery and skin permeation of artemisone as a prelude to evaluating use of artemisone and related compounds for melanoma treatment. In vitro skin permeation studies were conducted to determine the concentration of artemisone delivered into the stratum corneum-epidermis and epidermis-dermis. Artemisone-SLNs delivered artemisone into the stratum corneum-epidermis at significantly higher concentration (62.632 µg/mL) than the artemisone-niosomes (12.792 µg/mL). Neither of the controls delivered artemisone into the stratum corneum-epidermis. In the epidermis-dermis, artemisone (13.404 µg/mL) was only detected after application of the SLN formulation. Overall, the excellent topical delivery of artemisone with the SLN formulation coupled with the intrinsic activity of formulated artemisone confirms potential for use in treatment of melanoma.

In vitro wound healing and cytotoxic effects of sinigrin-phytosome complex.

Sinigrin is a class of glucosinolates found naturally in plants of the Brassicaceae family. Lately, studies have shown that sinigrin possesses anticancer, antibacterial and anti-inflammatory activities. Since its efficacy has not been explored on wound healing, we examined the effect of sinigrin on HaCaT cells. We also aimed at formulating sinigrin into phytosome to form a sinigrin-phytosome complex and study the wound healing and cytotoxic activities on A-375 and HaCaT cells. Sinigrin was efficiently formulated into the phytosome with an average particle size of 153 ± 39 nm, zeta potential of 10.09 ± 0.98 mV and complex efficiency of 69.5 ± 5%. The formation of the sinigrin-phytosome complex was confirmed by DSC and FTIR analysis. The sinigrin-phytosome complex significantly exhibited wound healing effects when compared to sinigrin alone. After 42 h, the phytosome complex completely healed the wound, whereas sinigrin alone showed only 71% wound closure. The sinigrin-phytosome complex displayed minimal toxicity towards HaCaT cells and at higher concentrations, it showed potent activity towards A-375. The results indicated that sinigrin-phytosome complex augmented the therapeutic potential of sinigrin towards the wound healing activity and this approach should be explored further for cancerous wound treatment.

Topical delivery of acyclovir and ketoconazole.

CONTEXT: Viral and fungal cutaneous manifestations are regularly encountered in immunocompromised human immunodeficiency virus/acquired immunodeficiency syndrome individuals and can be treated by drugs such as acyclovir and ketoconazole, respectively. OBJECTIVE: The aim of this study was to determine whether the novel Pheroid delivery system improved the transdermal delivery and/or dermal delivery of acyclovir and ketoconazole when incorporated into semi-solid formulations. MATERIALS AND METHODS: Semi-solid products (creams and emulgels) containing these drug compounds were formulated, either with or without (control) the Pheroid delivery system. The stability of the formulated semi-solid products was examined over a period of six months and included the assay of the actives, pH, viscosity, mass loss and particle size observation. Vertical Franz cell diffusion studies and tape stripping methods were used to determine the in vitro, stratum corneum (SC)-epidermis and epidermis-dermis delivery of these formulations. RESULTS AND DISCUSSION: Stability tests showed that none of the formulations were completely stable. Acyclovir showed a biphasic character during the in vitro skin diffusion studies for all the tested formulations. The Pheroid™ cream enhanced the transdermal, SC-epidermis and epidermis-dermis delivery of acyclovir the most. The average amount of ketoconazole diffused over 12 h showed improved delivery of ketoconazole, with the Pheroid™ emulgel exhibiting the best transdermal and epidermis-dermis delivery. CONCLUSION: The Pheroid formulae increased transdermal penetration as well as delivery to the dermal and epidermal skin layers. The Pheroid emulgel and the Pheroid cream increased the topical delivery of ketoconazole and acyclovir, respectively.

Stability, clinical efficacy, and antioxidant properties of Honeybush extracts in semi-solid formulations.

BACKGROUND: Honeybush extracts (Cyclopia spp.) can be incorporated into skin care products to treat conditions such as skin dryness and can function as an anti-oxidant. OBJECTIVE: To formulate Honeybush formulations and test it for antioxidant activity, skin penetration, and skin hydrating effects. MATERIALS AND METHODS: Semi-solid formulations containing either Cyclopia maculata (2%) or Cyclopia genistoides (2%) underwent accelerated stability studies. Membrane release studies, Franz cell skin diffusion and tape stripping studies were performed. Antioxidant potential was determined with the 2-thiobarbituric acid-assay and clinical efficacy studies were performed to determine the formulations' effect on skin hydration, scaliness, and smoothness after 2 weeks of treatment on the volar forearm. RESULTS: The formulations were unstable over 3 months. Membrane release, skin diffusion studies, and tape stripping showed that both formulations had inconclusive results due to extremely low concentrations mangiferin and hesperidin present in the Franz cell receptor compartments, stratum corneum-epidermis, and epidermis-dermis layers of the skin. Honeybush extracts showed antioxidant activity with concentrations above 0.6250 mg/ml when compared to the toxin; whereas mangiferin and hesperidin did not show any antioxidant activity on their own. The semisolid formulations showed the potential to emit their own antioxidant activity. Both formulations improved skin smoothness, although they did not improve skin hydration compared to the placebos. C. maculata reduced the skin scaliness to a larger extent than the placebos and C. genistoides. CONCLUSION: Honeybush formulations did not penetrate the skin but did, however, show antioxidant activity and the potential to be used to improve skin scaliness and smoothness.

Optimised transdermal delivery of pravastatin.

Wiechers' programme "Formulating for Efficacy" initiated a new strategy to optimise the oil phase of topical formulations in order to achieve optimal transdermal drug delivery. This new approach uses the "Delivery Gap Theory" on any active pharmaceutical ingredients (APIs) to test if it could enhance transdermal drug delivery. The aim of the study was to formulate six different semi-solid formulations (three creams and three emulgels) with 2% pravastatin as the API in order to investigate the "Delivery Gap Principle", by determining which formulation would deliver pravastatin best to the target-site (system circulation). The three cream- and three emulgel formulations had different polarities, i.e. a formulation with polarity equal to that of the stratum corneum (optimised), a non-polar (lipophilic)- and a polar (hydrophilic)-formulation. Franz cell diffusion studies were executed over 12h and the optimised emulgel (2.578µg/cm(2)) had the highest median amount per area obtained. Tape stripping followed the diffusion studies and in the stratum corneum-epidermis, the hydrophilic emulgel (1.448µg/ml) contained the highest median pravastatin concentration and the epidermis-dermis the optimised emulgel (0.849µg/ml) depicted the highest pravastatin concentration. During this study, it was observed that when both emulgel and cream formulations were compared; the emulgels enhanced the delivery of pravastatin more than the creams.

In vitro anti-cancer effects of artemisone nano-vesicular formulations on melanoma cells.

Artemisone is a 10-amino-artemisinin derivative that is markedly superior in vitro and in vivo to current artemisinins against malaria and also possesses antitumor activity. In seeking to capitalise on the last property, we have examined the encapsulation of artemisone in nano-vesicular niosomes and solid lipid nanoparticles, and have evaluated efficacies of the free and encapsulated artemisone against human melanoma A-375 cells and effects on human keratinocytes (HaCaT). Artemisone is successfully encapsulated into the nano-vesicles with encapsulation efficiencies of 67±6% and 79±5%, and with average particle sizes being 211±10nm and 295±18nm respectively. The formulations displayed highly selective cytotoxicity towards the melanoma cells with negligible toxicity towards the normal skin cells. The artemisone-loaded nano-vesicles almost completely inhibited the melanoma cells compared to the free drug. The results overall suggest a potentially more useful therapeutic strategy that needs to be evaluated for the treatment of melanoma and other cancers. FROM THE CLINICAL EDITOR: Apart from being an effective anti-malarial drug, a surprising action of artemisone also has antitumor activity. Nonetheless, its low water solubility and bioavailability has limited its clinical use. In this article, the authors enacapsulated artemisone in nano- vesicles and solid lipid nano-particles (SLNs). In-vitro studies confirmed the selective cytotoxicity towards melanoma cells. Further in-vivo and pre-clinical studies are awaited.

Skin permeation enhancement effects of the gel and whole-leaf materials of Aloe vera, Aloe marlothii and Aloe ferox.

OBJECTIVES: The aim of this study was to investigate the in-vitro permeation enhancement effects of the gel and whole-leaf materials of Aloe vera, Aloe marlothii and Aloe ferox using ketoprofen as a marker compound. METHODS: The permeation studies were conducted across excised female abdominal skin in Franz diffusion cells, and the delivery of ketoprofen into the stratum corneum-epidermis and epidermis-dermis layers of the skin was investigated using a tape-stripping technique. KEY FINDINGS: A. vera gel showed the highest permeation-enhancing effect on ketoprofen (enhancement ratio or ER = 2.551) when compared with the control group, followed by A. marlothii gel (ER = 1.590) and A. ferox whole-leaf material (ER = 1.520). Non-linear curve fitting calculations indicated that the drug permeation-enhancing effect of A. vera gel can be attributed to an increased partitioning of the drug into the skin, while A. ferox whole leaf modified the diffusion characteristics of the skin for ketoprofen. The tape stripping results indicated that A. marlothii whole leaf delivered the highest concentration of the ketoprofen into the different skin layers. CONCLUSIONS: Of the selected aloe species investigated, A. vera gel material showed the highest potential as transdermal drug penetration enhancer across human skin.

N-Acetyl cysteine reverses social isolation rearing induced changes in cortico-striatal monoamines in rats.

Schizophrenia is causally associated with early-life environmental stress, implicating oxidative stress in its pathophysiology. N-acetyl cysteine (NAC), a glutathione precursor and antioxidant, is emerging as a useful agent in the adjunctive treatment of schizophrenia and other psychiatric illnesses. However, its actions on brain monoamine metabolism are unknown. Social isolation rearing (SIR) in rats presents with face, predictive and construct validity for schizophrenia. This study evaluated the dose-dependent effects of NAC (50, 150 and 250 mg/kg/day × 14 days) on SIR- vs. socially reared induced changes in cortico-striatal levels of dopamine (DA), serotonin (5-HT) noradrenaline (NA) and their associated metabolites. SIR induced significant deficits in frontal cortical DA and its metabolites, 3,4-dihydroxyphenylacetic acid (Dopac) and homovanillic acid (HVA), reduced 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), and reduced levels of the NA metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG). In addition, significant elevations in frontal cortical NA and striatal DA, Dopac, HVA, 5-HT, 5-HIAA, NA and MHPG were also observed in SIR rats. NAC at 150 and 250 mg/kg reversed all cortico-striatal DA, Dopac, HVA, 5-HT, 5-HIAA and striatal NA alterations in SIR animals, with 250 mg/kg of NAC also reversing alterations in cortico-striatal MHPG. In conclusion, SIR profoundly alters cortico-striatal DA, 5-HT and NA pathways that parallel observations in schizophrenia, while these changes are dose-dependently reversed or abrogated by sub-chronic NAC treatment. A modulatory action on cortico-striatal monoamines may explain NACs' therapeutic use in schizophrenia and possibly other psychiatric disorders, where redox dysfunction or oxidative stress is a causal factor.

Social isolation rearing induces mitochondrial, immunological, neurochemical and behavioural deficits in rats, and is reversed by clozapine or N-acetyl cysteine.

Apart from altered dopamine (DA) function, schizophrenia displays mitochondrial and immune-inflammatory abnormalities, evidenced by oxidative stress, altered kynurenine metabolism and cytokine release. N-acetyl cysteine (NAC), an antioxidant and glutamate modulator, is effective in the adjunctive treatment of schizophrenia. Social isolation rearing (SIR) in rats is a valid neurodevelopmental animal model of schizophrenia. This study evaluated whether SIR-induced behavioural deficits may be explained by altered plasma pro- and anti-inflammatory cytokines, kynurenine metabolism, and cortico-striatal DA and mitochondrial function (via adenosine triphosphate (ATP) release), and if clozapine or NAC (alone and in combination) reverses these changes. SIR induced pronounced deficits in social interactive behaviours, object recognition memory, and prepulse inhibition (PPI), while simultaneously increasing striatal but reducing frontal cortical accumulation of ATP as well as DA. SIR increased pro- vs. anti-inflammatory cytokine balance and altered kynurenine metabolism with a decrease in neuroprotective ratio. Clozapine (5mg/kg/day×14days) as well as clozapine+NAC (5mg/kg/day and 150mg/kg/day×14days) reversed these changes, with NAC (150mg/kg/day) alone significantly but partially effective in some parameters. Clozapine+NAC was more effective than clozapine alone in reversing SIR-induced PPI, mitochondrial, immune and DA changes. In conclusion, SIR induces mitochondrial and immune-inflammatory changes that underlie cortico-striatal DA perturbations and subsequent behavioural deficits, and responds to treatment with clozapine or NAC, with an additive effect following combination treatment. The data provides insight into the mechanisms that might underlie the utility of NAC as an adjunctive treatment in schizophrenia.

Development and validation of a single analytical method for the determination of tryptophan, and its kynurenine metabolites in rat plasma.

It is highly beneficial to monitor the activity of the kynurenine pathway in a large series of samples with high accuracy and reliability in a single experimental protocol. We have developed a rapid specific solid-phase extraction (SPE)-liquid chromatography-electrospray ionization tandem mass spectrometry method for assaying tryptophan, kynurenine, kynurenic acid (KYNA), 3-hydroxyanthranilic acid (3OHAA), anthranilic acid and quinolinic acid (QA) in rat plasma. We also evaluated picolinic acid (PA) in this method, but it presented with unacceptable validation parameters. The assay involves pre-purification by SPE followed by chromatographic separation by C18 reversed phase chromatography. Mass spectrometric detection was performed using a mass spectrometer in positive and negative electrospray ionization; with a flow rate of 0.2 mL/min and an injection volume of 10 µL. Total run time including sample clean-up was 12 min. The assay method was found to be linear (R² > 0.95) and all the validation parameters were within acceptance range. The developed technique also demonstrated a significant elevation in plasma tryptophan, kynurenine, anthranilic acid and QA, and a significant decrease in KYNA, in rats subjected to post-weaning social isolation rearing, a putative animal model of relevance for depression and schizophrenia. This method can therefore be applied to measure metabolites of the kynurenine pathway in plasma accurately and precisely by LC-MS/MS, thereby helping to realize new opportunities in pharmacological and diagnostic research.

Social isolation rearing in rats alters plasma tryptophan metabolism and is reversed by sub-chronic clozapine treatment.

Schizophrenia is associated with increased oxidative stress, although the source of this redox disequilibrium requires further study. Altered tryptophan metabolism has been described in schizophrenia, possibly linked to inflammation and glutamate-directed excitotoxicity. Social isolation rearing (SIR) in rats induces various behavioural manifestations akin to schizophrenia, as well as altered frontal cortical glutamate N-methyl-d-aspartate (NMDA) receptor binding and increased oxidative stress, all reversed by antipsychotic treatment. Tryptophan is catabolized via the kynurenine pathway to kynurenine, 3-hydroxykynurenine, quinolinic acid (QA), kynurenic acid (KYNA), anthranilic acid and 3-hydroxyanthranilic acid (3-OHAA), ultimately contributing to neuronal integrity and redox balance in the brain. We studied tryptophan metabolism and neuroprotective-neurodegenerative balance in post-natal SIR rats, and its response to clozapine treatment. Male Sprague-Dawley (SD) rats (10 rats/group) were exposed to SIR or social rearing for 8 weeks, whereupon they received either sub-chronic vehicle or clozapine (5 mg/kg i.p) treatment. Plasma tryptophan metabolites were analysed by liquid-chromatography electrospray ionization tandem mass spectrometry. Plasma tryptophan, kynurenine, anthranilic acid, 3-OHAA and QA were significantly elevated in SIR vs. socially housed rats. KYNA and the neuroprotective ratio were significantly decreased. The latter implies a decrease in KYNA (neuroprotective) but an increase in QA (neurodegenerative) directed components of the pathway. Clozapine significantly reversed all the above alterations in SIR animals. Concluding, SIR in rats significantly disrupts tryptophan metabolism via the kynurenine pathway with increased risk for neurodegenerative changes in the brain. These changes are reversed by clozapine, emphasising the importance of these findings for the neurobiology and treatment of schizophrenia.

Cortico-striatal oxidative status, dopamine turnover and relation with stereotypy in the deer mouse.

The deer mouse presents with spontaneous stereotypic movements that resemble the repetitive behaviours of obsessive-compulsive disorder (OCD), and demonstrates a selective response to serotonin reuptake inhibitors. OCD has been linked to altered redox status and since increased dopamine signalling can promote stereotypies as well as oxidative stress, we investigated whether the severity of deer mouse stereotypy may be associated with altered dopamine turnover and cortico-striatal redox status. Deer mice were separated into high (HSB), low (LSB) and non-stereotypy (NS) groups. Frontal cortical and striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), as well as superoxide dismutase (SOD) activity, reduced (GSH) and oxidised (GSSG) glutathione and glutathione redox index, were analysed as markers for regional dopamine turnover and oxidative stress, respectively. Dopamine and its metabolites and SOD activity did not differ across the stereotypy groups. Significantly reduced GSH and GSSG and increased glutathione redox index were only observed in the frontal cortex of HSB animals. Frontal cortical GSH and GSSG were inversely correlated while glutathione redox index was positively correlated with stereotypy. Deer mouse stereotypy is thus characterised by a deficient glutathione system in the frontal cortex but not striatum, and provides a therapeutic rationale for using glutathione-active antioxidants in OCD. The evidence for a primary frontal lesion has importance for future OCD research.

Isolation rearing-induced deficits in sensorimotor gating and social interaction in rats are related to cortico-striatal oxidative stress, and reversed by sub-chronic clozapine administration.

Social isolation rearing (SIR) in rats induces behavioral and glutamatergic changes akin to schizophrenia. We studied the effects of 8 weeks SIR on cortico-striatal redox and social and cognitive behaviors in rats. SIR increased superoxide dismutase activity, decreased oxidized:reduced glutathione ratio and increased lipid peroxidation in both brain regions, and induced deficits in prepulse inhibition and social and self-directed interactive behaviors. Both behavioral and cortico-striatal redox disturbances were corrected by clozapine (5 mg/kg/day×11days). Behavioral changes evoked by SIR are associated with cortico-striatal oxidative stress that is reversed by clozapine treatment, providing novel insight into the neurobiology and treatment of schizophrenia.

Synthesis and transdermal permeation of novel N4-methoxypoly(ethylene glycol) carbamates of cytarabine.

BACKGROUND: Cytarabine is a deoxycytidine analogue commonly used in the treatment of hematological malignant diseases. Its clinical utility, however, is severely limited by its short plasma half-life because of the catabolic action of nucleoside deaminases. METHOD: In this study, N(4)-carbamate derivatives of cytarabine (1) were synthesized and evaluated for transdermal penetration because this mode of administration may circumvent its limitations. The synthesis of these compounds was achieved in a two-step process. First, the methoxypoly(ethylene glycol) was activated by p-nitrophenyl chloroformate. Second, the activated intermediates were reacted with cytarabine in the presence of N-hydroxysuccinamide to give the N(4)-methoxypoly(ethylene glycol) carbamate derivatives. The transdermal flux values of the N(4)-carbamates of cytarabine were determined in vitro by Franz diffusion cell methodology. Aqueous solubility and log D (pH 7.4) values were determined and assessed for correlation with transdermal flux values. RESULTS: The synthesized carbamates, particularly, (9)-(13), showed increased solubility in both aqueous and lipid media. Log D values decreased as the oxyethylene chain lengthened. CONCLUSION: Although none of the derivatives showed significantly higher transdermal penetration than cytarabine (1), it should be mentioned that the mean for cytarabine N(4)-methoxyethyleneoxycarbamate (8) was 10 times higher and the median was 2 times higher.