Jan du Preez - Academia.edu (original) (raw)
Papers by Jan du Preez
Journal of Pharmacy and Pharmacology, 2014
The aim of this study was to investigate the in-vitro permeation enhancement effects of the gel a... more 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. 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. 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. Of the selected aloe species investigated, A. vera gel material showed the highest potential as transdermal drug penetration enhancer across human skin.
International journal of pharmaceutics, Jan 27, 2016
The artemisinin derivative artemisone has antitumor activity. In particular when encapsulated in ... more 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 (62.632μg/mL) than the artemisone-niosomes (12.792μg/mL). Neither of the controls delivered artemisone into the stratum corneum-epidermis. In the epidermis-dermis, artemisone (13.404μg/mL) was only detected after application of the SLN ...
Pharmacognosy magazine, 2015
Honeybush extracts (Cyclopia spp.) can be incorporated into skin care products to treat condition... more 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. To formulate Honeybush formulations and test it for antioxidant activity, skin penetration, and skin hydrating effects. 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. 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 ...
Journal of Pharmaceutical Sciences, 2016
The aim of this study was to investigate the effect of different penetration enhancers, containin... more The aim of this study was to investigate the effect of different penetration enhancers, containing essential fatty acids (EFAs), on the transdermal delivery of flurbiprofen. Evening primrose oil (EPO), vitamin F, and Pheroid™ technology all contain fatty acids and were compared using a cream-based formulation. This selection was to ascertain whether EFAs solely, or EFAs in a Pheroid™ delivery system, would have a significant increase in the transdermal delivery of a compound. Membrane release studies were performed, and the results indicated the following rank order for flurbiprofen release from the different formulations: vitamin F > control > EPO > Pheroid™. Topical skin delivery results indicated that flurbiprofen was present in the stratum corneum-epidermis and the epidermis-dermis. The average percentage flurbiprofen diffused to the receptor phase (representing human blood) indicated that the EPO formulation showed the highest average percentage diffused. The Pheroid™ formulation delivered the lowest concentration with a statistical significant difference (p < 0.05) compared with the control formulation (containing 1% flurbiprofen and no penetration enhancers). The control formulation presented the highest average flux, with the EPO formulation following the closest. It could, thus, be concluded that EPO is the most favorable chemical penetration enhancer when used in this formulation.
![Research paper thumbnail of Chelation of 2,6-Bis(hydroxymethyl)pyridine in cis -Dichloro(triphenylphosphine- P )[2-(oxymethylene- O )-6-(hydroxymethyl)pyridine- N ]oxorhenium(V)–Water (2/1)](https://attachments.academia-assets.com/47150394/thumbnails/1.jpg)
](Acta Crystallographica Section C, Feb 15, 1997
Drug Development and Industrial Pharmacy, 2015
Various natural products, including oils, have been utilized as penetration enhancers due to thei... more Various natural products, including oils, have been utilized as penetration enhancers due to their "safety profiles". These oils contain fatty acids promoting skin permeability through lipid fluidization within the stratum corneum; and might therefore be able to effectively enhance transdermal drug delivery. We investigated possible penetration enhancing properties of selected oils, utilizing flurbiprofen as marker compound in emulgel formulations. The formulations were compared to a liquid paraffin emulgel and a hydrogel to establish any significant penetration enhancing effects. Gas chromatographic analysis of the natural oils was performed at ambient temperature to determine the fatty acid composition in each selected natural oils. Franz cell diffusion studies and tape stripping methods were employed to study delivery of the marker into, and through the skin. The following rank order for the emulgel flux-values was obtained: Hydrogel > olive oil > liquid paraffin > coconut oil > grape seed oil > Avocado oil ≥ Crocodile oil > Emu oil. Results suggested that oils containing predominantly mono-unsaturated oleic acid, on average increased the flux of the marker to a larger extent than oils containing an almost even mixture of both mono- and poly-unsaturated fatty acids. Oils comprising saturated fatty acids (SFAs) with alkyl chains between C12 and C14, increased the marker flux to a higher extent than oils containing C16-C18 SFAs. Effects observed for branched fatty acids, however, did not vary significantly from effects for unbranched fatty acids with the same carbon chain length. Natural oils possess penetration enhancing effects.
AAPS PharmSciTech, 2015
Drug delivery vehicles can influence the topical delivery and the efficacy of an active pharmaceu... more Drug delivery vehicles can influence the topical delivery and the efficacy of an active pharmaceutical ingredient (API). In this study, the influence of Pheroid™ technology, which is a unique colloidal drug delivery system, on the skin permeation and antimelanoma efficacy of 5-fluorouracil were investigated. Lotions containing Pheroid™ with different concentrations of 5-fluorouracil were formulated then used in Franz cell skin diffusion studies and tape stripping. The in vitro efficacy of 5-fluorouracil against human melanoma cells (A375) was investigated using a flow cytometric apoptosis assay. Statistically significant concentrations of 5-fluorouracil diffused into and through the skin with Pheroid™ formulations resulting in an enhanced in vitro skin permeation from the 4.0% 5-fluorouracil lotion (p<0.05). The stratum corneum-epidermis and epidermis-dermis retained 5-fluorouracil concentrations of 2.31 and 6.69 μg/ml, respectively, after a diffusion study with the 4.0% Pheroid™ lotion. Subsequent to the apoptosis assay, significant differences were observed between the effect of 13.33 μg/ml 5-fluorouracil in Pheroid™ lotion and the effects of the controls. The results obtained suggest that the Pheroid™ drug delivery system possibly enhances the flux and delivery of 5-fluorouracil into the skin. Therefore, using Pheroid™ could possibly be advantageous with respect to topical delivery of 5-fluorouracil.
Journal of the Chemical Society, Dalton Transactions, 1983
ABSTRACT
Journal of Pharmacy and Pharmacology, 2014
The aim of this study was to investigate the in-vitro permeation enhancement effects of the gel a... more 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. 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. 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. Of the selected aloe species investigated, A. vera gel material showed the highest potential as transdermal drug penetration enhancer across human skin.
Drug Delivery, 2014
Abstract Context: Viral and fungal cutaneous manifestations are regularly encountered in immunoco... more Abstract 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.
Physiology & Behavior, 2011
The deer mouse presents with spontaneous stereotypic movements that resemble the repetitive behav... more 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.
Neuropharmacology, 2012
Schizophrenia is associated with increased oxidative stress, although the source of this redox di... more 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, 3hydroxykynurenine, quinolinic acid (QA), kynurenic acid (KYNA), anthranilic acid and 3hydroxyanthranilic acid (3-OHAA), ultimately contributing to neuronal integrity and redox balance in the brain. We studied tryptophan metabolism and neuroprotective-neurodegenerative balance in postnatal 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 liquidchromatography 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.
Medicinal Chemistry, 2009
The objective of this study was to synthesize derivatives of the anti-HIV drug stavudine (d4T) wi... more The objective of this study was to synthesize derivatives of the anti-HIV drug stavudine (d4T) with more favourable physicochemical properties for transdermal delivery in an effort to increase transdermal penetration of stavudine and thus reduce the severe side effects associated with the dose-dependent oral therapy. The synthesis, hydrolytic stability, and in vitro human skin permeation flux of a series of novel methoxypoly(ethylene glycol) (MPEG) carbonates of stavudine are reported. The carbonates were synthesized in a two-step process by coupling the MPEG promoiety of various chain lengths to C-5' of d4T. In kinetic studies the carbonates proved to be markedly stable in weakly acidic phosphate medium (pH 5.0) with half-lives ranging from 16 to 58 days. The aqueous solubility increased as the ethylene oxide chain lengthened. However, there was no significant increase in the estimated solubility in octanol. In vitro in the phosphate buffer (200 mM; pH 5.0) almost all carbonates permeate the human skin. However, the most effective penetrant, the derivative with 3 ethylene oxide units in the side chain, exhibited a flux of 26.1 nmol/cm 2 /h as compared to 59.15 nmol/cm 2 /h of the parent drug stavudine. Thus, no permeation enhancement was observed during this study.
Journal of Coordination Chemistry, 1992
... Nico1ini.J. Cherii. Soc., Dalton Trans., 61 1 (1988). U. Abram, R. hluenze, J. Hartung, L. Be... more ... Nico1ini.J. Cherii. Soc., Dalton Trans., 61 1 (1988). U. Abram, R. hluenze, J. Hartung, L. Beyer, R. Kirmse, K. Koehler, J. Stach, H. Behm and PT Beurskens, Inorg. C/tent., 28, 834 (1989). ... Soc., 2614 (1964). G. Backes-Dahmann and JH Enemark, Inorg. Chi., 26, 3960 (1987). ...
Journal of Chromatography B, 2012
It is highly beneficial to monitor the activity of the kynurenine pathway in a large series of sa... more 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 L. Total run time including sample cleanup was 12 min. The assay method was found to be linear (R 2 > 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.
![Research paper thumbnail of The reactivity of the [Re≡O]3+ core toward aromatic 1,2-diamines: the formation of rhenium(V)-imido complexes](https://attachments.academia-assets.com/47150415/thumbnails/1.jpg)
](Inorganica Chimica Acta, 1998
The reaction of the aromatic diamines 1.2-¢lieuninobenzene, 2,3-diaminophenol (H:L), 2,3-diaminot... more The reaction of the aromatic diamines 1.2-¢lieuninobenzene, 2,3-diaminophenol (H:L), 2,3-diaminotoluene and 3,4-diaminobenzophenone (H~N=R=NH~) with trans-ReOCld PPh~): in an equimolar ratio in ethanol gave the products trans.[ Re(N-R-NH,)CId PPh~)~] in good yield. IR. ~H NMR and X-ray crystallographic resdts indicate that the diamine ligands c~rdinate to rhenium(V) in a dianionic monodentate imido form. The structure of mms-[ Re(L)Cl~( PPh~ ) ~ ] was determined and shows that only the deprolonated amino nitrogen in the 2-position ofthe potentially ambidenlate 2,~-diaminophenol mo!ecule is coordinated to the metal.
![Research paper thumbnail of The reaction of nitro-1,2-diaminobenzenes with the [ReO]3+ core: isolation of oxo-free rhenium(V) complexes](https://attachments.academia-assets.com/43943724/thumbnails/1.jpg)
](Inorganica Chimica Acta, 2000
The reaction of 2 equiv. of 3-nitro-1,2-diaminobenzene (H 2 L 1 ) with trans-ReOCl 3 (PPh 3 ) 2 i... more The reaction of 2 equiv. of 3-nitro-1,2-diaminobenzene (H 2 L 1 ) with trans-ReOCl 3 (PPh 3 ) 2 in ethanol gave the oxo-free rhenium(V) complex [ReCl(PPh 3 )(L 1 ) 2 ] (1) in good yield. IR, 1 H NMR and X-ray crystallographic results indicate that the diamine ligand L 1 coordinates in a dianionic bidentate diamido form to the metal, and that the complex has the unusual skew-trapezoidal bipyramidal geometry. With 4-nitro-1,2-diaminobenzene (H 2 L 2 ) as ligand the complex [Re(L 2 )Cl 3 (PPh 3 ) 2 ] (2) was characterized, in which L 2 coordinates in a dianionic monodentate imido form through one nitrogen only. Crystal data for 1·EtOH: C 32 H 31 ClN 6 O 5 PRe, monoclinic P2 1 /c, a=14.937 (11), b=15.017(8), c=15.394(12) A , , i = 112.12(6)°, V= 3198.7(38) A , 3 , Z = 4, D calc =1.728 g cm − 3 , structure solution and refinement based on 3151 reflections converged at R= 0.0807.
Inorganica Chimica Acta, 1998
Inorganica Chimica Acta, 1994
Inorganica Chimica Acta, 2001
The complex cis-[ReO 2 (Hdab)(py) 2 ] (1) (H 2 dab=1,2-diaminobenzene) has been prepared by react... more The complex cis-[ReO 2 (Hdab)(py) 2 ] (1) (H 2 dab=1,2-diaminobenzene) has been prepared by reacting trans-[ReO 2 (py) 4 ]I with H 2 dab in ethanol. This is the first example of a neutral hexacoordinate rhenium(V) complex with a cis arrangement of the two oxo groups. The compound also provides the first example of a bidentate monoanionic monoimino coordination mode of H 2 dab. Crystal data for 1·(H 3 dab)I·H 2 O: C 22 H 26 IN 6 O 2 Re·H 2 O, triclinic, space group P1( , a=9.570(2), b = 12.493(3), c= 12.851(3) A , , h= 61.60(3), i =70.56(3), k=78.68(4)°, V= 1273.1(4) A , 3 and Z = 2.
Journal of Pharmacy and Pharmacology, 2014
The aim of this study was to investigate the in-vitro permeation enhancement effects of the gel a... more 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. 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. 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. Of the selected aloe species investigated, A. vera gel material showed the highest potential as transdermal drug penetration enhancer across human skin.
International journal of pharmaceutics, Jan 27, 2016
The artemisinin derivative artemisone has antitumor activity. In particular when encapsulated in ... more 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 (62.632μg/mL) than the artemisone-niosomes (12.792μg/mL). Neither of the controls delivered artemisone into the stratum corneum-epidermis. In the epidermis-dermis, artemisone (13.404μg/mL) was only detected after application of the SLN ...
Pharmacognosy magazine, 2015
Honeybush extracts (Cyclopia spp.) can be incorporated into skin care products to treat condition... more 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. To formulate Honeybush formulations and test it for antioxidant activity, skin penetration, and skin hydrating effects. 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. 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 ...
Journal of Pharmaceutical Sciences, 2016
The aim of this study was to investigate the effect of different penetration enhancers, containin... more The aim of this study was to investigate the effect of different penetration enhancers, containing essential fatty acids (EFAs), on the transdermal delivery of flurbiprofen. Evening primrose oil (EPO), vitamin F, and Pheroid™ technology all contain fatty acids and were compared using a cream-based formulation. This selection was to ascertain whether EFAs solely, or EFAs in a Pheroid™ delivery system, would have a significant increase in the transdermal delivery of a compound. Membrane release studies were performed, and the results indicated the following rank order for flurbiprofen release from the different formulations: vitamin F &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; control &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; EPO &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; Pheroid™. Topical skin delivery results indicated that flurbiprofen was present in the stratum corneum-epidermis and the epidermis-dermis. The average percentage flurbiprofen diffused to the receptor phase (representing human blood) indicated that the EPO formulation showed the highest average percentage diffused. The Pheroid™ formulation delivered the lowest concentration with a statistical significant difference (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) compared with the control formulation (containing 1% flurbiprofen and no penetration enhancers). The control formulation presented the highest average flux, with the EPO formulation following the closest. It could, thus, be concluded that EPO is the most favorable chemical penetration enhancer when used in this formulation.
Acta Crystallographica Section C, Feb 15, 1997
Drug Development and Industrial Pharmacy, 2015
Various natural products, including oils, have been utilized as penetration enhancers due to thei... more Various natural products, including oils, have been utilized as penetration enhancers due to their &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;safety profiles&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;. These oils contain fatty acids promoting skin permeability through lipid fluidization within the stratum corneum; and might therefore be able to effectively enhance transdermal drug delivery. We investigated possible penetration enhancing properties of selected oils, utilizing flurbiprofen as marker compound in emulgel formulations. The formulations were compared to a liquid paraffin emulgel and a hydrogel to establish any significant penetration enhancing effects. Gas chromatographic analysis of the natural oils was performed at ambient temperature to determine the fatty acid composition in each selected natural oils. Franz cell diffusion studies and tape stripping methods were employed to study delivery of the marker into, and through the skin. The following rank order for the emulgel flux-values was obtained: Hydrogel &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; olive oil &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; liquid paraffin &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; coconut oil &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; grape seed oil &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; Avocado oil ≥ Crocodile oil &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; Emu oil. Results suggested that oils containing predominantly mono-unsaturated oleic acid, on average increased the flux of the marker to a larger extent than oils containing an almost even mixture of both mono- and poly-unsaturated fatty acids. Oils comprising saturated fatty acids (SFAs) with alkyl chains between C12 and C14, increased the marker flux to a higher extent than oils containing C16-C18 SFAs. Effects observed for branched fatty acids, however, did not vary significantly from effects for unbranched fatty acids with the same carbon chain length. Natural oils possess penetration enhancing effects.
AAPS PharmSciTech, 2015
Drug delivery vehicles can influence the topical delivery and the efficacy of an active pharmaceu... more Drug delivery vehicles can influence the topical delivery and the efficacy of an active pharmaceutical ingredient (API). In this study, the influence of Pheroid™ technology, which is a unique colloidal drug delivery system, on the skin permeation and antimelanoma efficacy of 5-fluorouracil were investigated. Lotions containing Pheroid™ with different concentrations of 5-fluorouracil were formulated then used in Franz cell skin diffusion studies and tape stripping. The in vitro efficacy of 5-fluorouracil against human melanoma cells (A375) was investigated using a flow cytometric apoptosis assay. Statistically significant concentrations of 5-fluorouracil diffused into and through the skin with Pheroid™ formulations resulting in an enhanced in vitro skin permeation from the 4.0% 5-fluorouracil lotion (p<0.05). The stratum corneum-epidermis and epidermis-dermis retained 5-fluorouracil concentrations of 2.31 and 6.69 μg/ml, respectively, after a diffusion study with the 4.0% Pheroid™ lotion. Subsequent to the apoptosis assay, significant differences were observed between the effect of 13.33 μg/ml 5-fluorouracil in Pheroid™ lotion and the effects of the controls. The results obtained suggest that the Pheroid™ drug delivery system possibly enhances the flux and delivery of 5-fluorouracil into the skin. Therefore, using Pheroid™ could possibly be advantageous with respect to topical delivery of 5-fluorouracil.
Journal of the Chemical Society, Dalton Transactions, 1983
ABSTRACT
Journal of Pharmacy and Pharmacology, 2014
The aim of this study was to investigate the in-vitro permeation enhancement effects of the gel a... more 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. 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. 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. Of the selected aloe species investigated, A. vera gel material showed the highest potential as transdermal drug penetration enhancer across human skin.
Drug Delivery, 2014
Abstract Context: Viral and fungal cutaneous manifestations are regularly encountered in immunoco... more Abstract 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.
Physiology & Behavior, 2011
The deer mouse presents with spontaneous stereotypic movements that resemble the repetitive behav... more 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.
Neuropharmacology, 2012
Schizophrenia is associated with increased oxidative stress, although the source of this redox di... more 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, 3hydroxykynurenine, quinolinic acid (QA), kynurenic acid (KYNA), anthranilic acid and 3hydroxyanthranilic acid (3-OHAA), ultimately contributing to neuronal integrity and redox balance in the brain. We studied tryptophan metabolism and neuroprotective-neurodegenerative balance in postnatal 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 liquidchromatography 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.
Medicinal Chemistry, 2009
The objective of this study was to synthesize derivatives of the anti-HIV drug stavudine (d4T) wi... more The objective of this study was to synthesize derivatives of the anti-HIV drug stavudine (d4T) with more favourable physicochemical properties for transdermal delivery in an effort to increase transdermal penetration of stavudine and thus reduce the severe side effects associated with the dose-dependent oral therapy. The synthesis, hydrolytic stability, and in vitro human skin permeation flux of a series of novel methoxypoly(ethylene glycol) (MPEG) carbonates of stavudine are reported. The carbonates were synthesized in a two-step process by coupling the MPEG promoiety of various chain lengths to C-5' of d4T. In kinetic studies the carbonates proved to be markedly stable in weakly acidic phosphate medium (pH 5.0) with half-lives ranging from 16 to 58 days. The aqueous solubility increased as the ethylene oxide chain lengthened. However, there was no significant increase in the estimated solubility in octanol. In vitro in the phosphate buffer (200 mM; pH 5.0) almost all carbonates permeate the human skin. However, the most effective penetrant, the derivative with 3 ethylene oxide units in the side chain, exhibited a flux of 26.1 nmol/cm 2 /h as compared to 59.15 nmol/cm 2 /h of the parent drug stavudine. Thus, no permeation enhancement was observed during this study.
Journal of Coordination Chemistry, 1992
... Nico1ini.J. Cherii. Soc., Dalton Trans., 61 1 (1988). U. Abram, R. hluenze, J. Hartung, L. Be... more ... Nico1ini.J. Cherii. Soc., Dalton Trans., 61 1 (1988). U. Abram, R. hluenze, J. Hartung, L. Beyer, R. Kirmse, K. Koehler, J. Stach, H. Behm and PT Beurskens, Inorg. C/tent., 28, 834 (1989). ... Soc., 2614 (1964). G. Backes-Dahmann and JH Enemark, Inorg. Chi., 26, 3960 (1987). ...
Journal of Chromatography B, 2012
It is highly beneficial to monitor the activity of the kynurenine pathway in a large series of sa... more 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 L. Total run time including sample cleanup was 12 min. The assay method was found to be linear (R 2 > 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.
Inorganica Chimica Acta, 1998
The reaction of the aromatic diamines 1.2-¢lieuninobenzene, 2,3-diaminophenol (H:L), 2,3-diaminot... more The reaction of the aromatic diamines 1.2-¢lieuninobenzene, 2,3-diaminophenol (H:L), 2,3-diaminotoluene and 3,4-diaminobenzophenone (H~N=R=NH~) with trans-ReOCld PPh~): in an equimolar ratio in ethanol gave the products trans.[ Re(N-R-NH,)CId PPh~)~] in good yield. IR. ~H NMR and X-ray crystallographic resdts indicate that the diamine ligands c~rdinate to rhenium(V) in a dianionic monodentate imido form. The structure of mms-[ Re(L)Cl~( PPh~ ) ~ ] was determined and shows that only the deprolonated amino nitrogen in the 2-position ofthe potentially ambidenlate 2,~-diaminophenol mo!ecule is coordinated to the metal.
Inorganica Chimica Acta, 2000
The reaction of 2 equiv. of 3-nitro-1,2-diaminobenzene (H 2 L 1 ) with trans-ReOCl 3 (PPh 3 ) 2 i... more The reaction of 2 equiv. of 3-nitro-1,2-diaminobenzene (H 2 L 1 ) with trans-ReOCl 3 (PPh 3 ) 2 in ethanol gave the oxo-free rhenium(V) complex [ReCl(PPh 3 )(L 1 ) 2 ] (1) in good yield. IR, 1 H NMR and X-ray crystallographic results indicate that the diamine ligand L 1 coordinates in a dianionic bidentate diamido form to the metal, and that the complex has the unusual skew-trapezoidal bipyramidal geometry. With 4-nitro-1,2-diaminobenzene (H 2 L 2 ) as ligand the complex [Re(L 2 )Cl 3 (PPh 3 ) 2 ] (2) was characterized, in which L 2 coordinates in a dianionic monodentate imido form through one nitrogen only. Crystal data for 1·EtOH: C 32 H 31 ClN 6 O 5 PRe, monoclinic P2 1 /c, a=14.937 (11), b=15.017(8), c=15.394(12) A , , i = 112.12(6)°, V= 3198.7(38) A , 3 , Z = 4, D calc =1.728 g cm − 3 , structure solution and refinement based on 3151 reflections converged at R= 0.0807.
Inorganica Chimica Acta, 1998
Inorganica Chimica Acta, 1994
Inorganica Chimica Acta, 2001
The complex cis-[ReO 2 (Hdab)(py) 2 ] (1) (H 2 dab=1,2-diaminobenzene) has been prepared by react... more The complex cis-[ReO 2 (Hdab)(py) 2 ] (1) (H 2 dab=1,2-diaminobenzene) has been prepared by reacting trans-[ReO 2 (py) 4 ]I with H 2 dab in ethanol. This is the first example of a neutral hexacoordinate rhenium(V) complex with a cis arrangement of the two oxo groups. The compound also provides the first example of a bidentate monoanionic monoimino coordination mode of H 2 dab. Crystal data for 1·(H 3 dab)I·H 2 O: C 22 H 26 IN 6 O 2 Re·H 2 O, triclinic, space group P1( , a=9.570(2), b = 12.493(3), c= 12.851(3) A , , h= 61.60(3), i =70.56(3), k=78.68(4)°, V= 1273.1(4) A , 3 and Z = 2.