The central nervous system has been identified as an anatomical reservoir for HIV due the difficu... more The central nervous system has been identified as an anatomical reservoir for HIV due the difficulties in delivering therapeutic agents into the brain and this complication results in HIV-associated neurocognitive disorder that persists in infected patients. The brain regions that are potentially exposed to tissue deficits due to HIV have been reported in previous reports; therefore, it is important to determine the drugs that can enter and localize in brain regions that are known to be susceptible to HIV neurodegeneration. Sprague-Dawley rats received intraperitoneal doses of zidovudine and lamivudine (50 mg kg-1). Mass spectrometry methods were used to determine the pharmacokinetics, of zidovudine and lamivudine, in the brain using liquid chromatography tandem mass spectrometry and mass spectrometry imaging (MSI), respectively. Zidovudine and lamivudine displayed complementary pharmacokinetic curves indicating a rapid absorption and blood-brain barrier penetration of both drugs reaching Cmax at 0.5 h after single dose. MSI of coronal brain sections showed that zidovudine and lamivudine are mostly distributed in corpus callosum, globus pallidus, striatum, and the neocortex region. Mass spectrometry techniques were used to demonstrate that zidovudine and lamivudine drugs are able to reach and localize in brain regions that are targets of HIV neurodegeneration in the brain.
Journal of Drug Delivery Science and Technology, 2019
Abstract The present study is aimed at the employment of novel fatty acid derived lipids for the ... more Abstract The present study is aimed at the employment of novel fatty acid derived lipids for the preparation of pH-responsive nanostructured lipid carriers (NLCs) for vancomycin (VCM) intravenous delivery against resistant and sensitive Staphylococcus aureus bacteria. Two branched lipids [stearic acid derived solid lipid and oleic acid derived liquid lipid] were synthesized, characterized and used to fabricate NLCs by hot homogenization technique. Particle size, polydispersity index, zeta potential and encapsulation efficiency were 225.2 ± 9.1 nm, 0.258 ± 0.02, −9.2 ± 2.7 mV and 88.7 ± 13.12%, respectively. An understanding of drug encapsulation efficiencies and formation of the NLCs were supported by in silico studies. In vitro antibacterial activity revealed that VCM loaded-NLCs had higher activity against methicillin-susceptible and resistant Staphylococcus aureus than the bare VCM. Cell viability study showed that NLCs had 2.5-fold better killing percentage than the bare drug at similar concentrations. Furthermore, the in vivo efficacy of VCM loaded-NLCs was assessed in a mouse model of MRSA skin infection. MRSA CFU load of the skin treated with NLCs was 37-fold lower than bare VCM (p
Tigecycline (TIG), a derivative of minocycline, is the first in the novel class of glycylcyclines... more Tigecycline (TIG), a derivative of minocycline, is the first in the novel class of glycylcyclines and is currently indicated for the treatment of complicated skin structure and intra‐abdominal infections. A selective, accurate and reversed‐phase high‐performance liquid chromatography‐tandem mass spectrometry (HPLC‐MS/MS) method was developed for the determination of TIG in rat brain tissues. Sample preparation was based on protein precipitation and solid phase extraction using Supel‐Select HLB (30 mg/1 mL) cartridges. The samples were separated on a YMC Triart C18 column (150 mm x 3.0 mm. 3.0 µm) using gradient elution. Positive electrospray ionization (ESI+) was used for the detection mechanism with the multiple reaction monitoring (MRM) mode. The method was validated over the concentration range of 150–1200 ng/mL for rat brain tissue. The precision and accuracy for all brain analyses were within the acceptable limit. The mean extraction recovery in rat brain was 83.6%. This valida...
Antimicrobial agents and chemotherapy, Jan 7, 2018
The anti-leprosy drug clofazimine was recently repurposed as part of a newly endorsed short-cours... more The anti-leprosy drug clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment-shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, clofazimine causes dose- and duration-dependent skin discoloration in patients, and the optimal clofazimine dosing strategy in the context of the first-line regimen is unknown. We utilized a well-established mouse model to systematically address the impact of duration, dose, and companion drugs on the treatment-shortening activity of clofazimine in the first-line regimen. In all studies, the primary outcome was relapse-free cure (culture-negative lungs) six months after stopping treatment, and the secondary outcome was bactericidal activity, , the decline in lung bacterial burden during treatment. Our findings indicate that clofazimine activity is most potent when co-administered with first-line ...
Journal of the South African Veterinary Association, 2017
Dry pelleted dog food in the South African market is available via supermarkets, pet stores (stan... more Dry pelleted dog food in the South African market is available via supermarkets, pet stores (standard brands [SBs]) and veterinary channels (premium brands [PBs]). For the purpose of this study, the supermarket channel included the cheaper quality foods and PBs were sold via the veterinary channel (n = 20). These feeds were analysed for four main mycotoxins (aflatoxins [AF], fumonisin [FB], ochratoxin A [OTA] and zearalenone [ZEA]) using standard welldescribed extraction, characterisation and quantitation processes. Irrespective of the brand or marketing channel, all foods were contaminated with fungi (mainly Aspergillus flavus, Aspergillus fumigatus and Aspergillus parasiticus) and mycotoxins (most prevalent being aflatoxins and fumonisins). This was observed in all 20 samples irrespective of the marketing channel or perceived quality. Also, many samples within each marketing channel failed the 10 ppb limit for aflatoxin set by regulations in South Africa. Although fumonisin was de...
Transdermal drug delivery is an attractive route of administration relative to other routes as it... more Transdermal drug delivery is an attractive route of administration relative to other routes as it offers enhanced therapeutic efficacy. However, due to poor skin permeability of certain drugs, their application in transdermal delivery is limited. The ultra-deformable nature of transferosomes makes them suitable vehicles for transdermal delivery of drugs that have high molecular weights and hydrophilicity. However, their low viscosity, which leads to low contact time on the surface of the skin, has restricted their application in transdermal delivery. Therefore, this study aimed to deliver transferosomes loaded with a highly water-soluble and high molecular weight vancomycin hydrochloride (VCM-HCl) via a bigel for systemic delivery and treatment of microbial infections. VCM-HCl-loaded transferosomal formulations (TNFs) were prepared using a reverse-phase evaporation method and then loaded into a bigel. Both the TNFs and TNFs-loaded bigel (TNF-L-B) were characterized by a range of in vitro and ex vivo techniques. TNFs and TNF-L-B were tested for biosafety via the MTT assay and found to be biosafe. Prepared TNFs had sizes, zeta potential and entrapment efficiency of 63.02±5.34nm, -20.93±6.13mV and 84.48±1.22% respectively. VCM-HCl release from TNF-L-B showed a prolonged release profile with 39.76±1.6% after 24hrs when compared to bare VCM-HCl loaded in the bigel (74.81± 8.84%). Ex-vivo permeation of prepared TNF-L-B showed a higher permeation flux of 0.56µg/cm2/h compared to the bare VCM-HCl-loaded bigel of 0.23µg/cm2/h, indicating superior permeation and bioavailability of the drug. Additionally, the prepared TNF-L-B demonstrated improved antimicrobial activity. The TNF-L-B showed minimum inhibitory concentrations (MIC) of 0.97μg/ml against Staphylococcus aureus (SA) and 1.95μg/ml against methicillin-resistant SA (MRSA), which were 2-fold lower MIC values than the bare drug. The time-kill assay showed that both TNFs and TNF-L-B systems caused a 5.6-log reduction (100%) in MRSA compared to bare VCM-HCl after 24 hrs of incubation. Furthermore, as opposed to the bare VCM-HCl solution, the degree of biofilm reduction caused by TNFs (55.72%) and TNF-L-B (34.58%) suggests their dominance in eradicating MRSA biofilm. These findings indicate that TNF-L-B is a promising system for transdermal delivery of hydrophilic and high molecular weight drugs.
The central nervous system has been identified as an anatomical reservoir for HIV due the difficu... more The central nervous system has been identified as an anatomical reservoir for HIV due the difficulties in delivering therapeutic agents into the brain and this complication results in HIV-associated neurocognitive disorder that persists in infected patients. The brain regions that are potentially exposed to tissue deficits due to HIV have been reported in previous reports; therefore, it is important to determine the drugs that can enter and localize in brain regions that are known to be susceptible to HIV neurodegeneration. Sprague-Dawley rats received intraperitoneal doses of zidovudine and lamivudine (50 mg kg-1). Mass spectrometry methods were used to determine the pharmacokinetics, of zidovudine and lamivudine, in the brain using liquid chromatography tandem mass spectrometry and mass spectrometry imaging (MSI), respectively. Zidovudine and lamivudine displayed complementary pharmacokinetic curves indicating a rapid absorption and blood-brain barrier penetration of both drugs reaching Cmax at 0.5 h after single dose. MSI of coronal brain sections showed that zidovudine and lamivudine are mostly distributed in corpus callosum, globus pallidus, striatum, and the neocortex region. Mass spectrometry techniques were used to demonstrate that zidovudine and lamivudine drugs are able to reach and localize in brain regions that are targets of HIV neurodegeneration in the brain.
Journal of Drug Delivery Science and Technology, 2019
Abstract The present study is aimed at the employment of novel fatty acid derived lipids for the ... more Abstract The present study is aimed at the employment of novel fatty acid derived lipids for the preparation of pH-responsive nanostructured lipid carriers (NLCs) for vancomycin (VCM) intravenous delivery against resistant and sensitive Staphylococcus aureus bacteria. Two branched lipids [stearic acid derived solid lipid and oleic acid derived liquid lipid] were synthesized, characterized and used to fabricate NLCs by hot homogenization technique. Particle size, polydispersity index, zeta potential and encapsulation efficiency were 225.2 ± 9.1 nm, 0.258 ± 0.02, −9.2 ± 2.7 mV and 88.7 ± 13.12%, respectively. An understanding of drug encapsulation efficiencies and formation of the NLCs were supported by in silico studies. In vitro antibacterial activity revealed that VCM loaded-NLCs had higher activity against methicillin-susceptible and resistant Staphylococcus aureus than the bare VCM. Cell viability study showed that NLCs had 2.5-fold better killing percentage than the bare drug at similar concentrations. Furthermore, the in vivo efficacy of VCM loaded-NLCs was assessed in a mouse model of MRSA skin infection. MRSA CFU load of the skin treated with NLCs was 37-fold lower than bare VCM (p
Tigecycline (TIG), a derivative of minocycline, is the first in the novel class of glycylcyclines... more Tigecycline (TIG), a derivative of minocycline, is the first in the novel class of glycylcyclines and is currently indicated for the treatment of complicated skin structure and intra‐abdominal infections. A selective, accurate and reversed‐phase high‐performance liquid chromatography‐tandem mass spectrometry (HPLC‐MS/MS) method was developed for the determination of TIG in rat brain tissues. Sample preparation was based on protein precipitation and solid phase extraction using Supel‐Select HLB (30 mg/1 mL) cartridges. The samples were separated on a YMC Triart C18 column (150 mm x 3.0 mm. 3.0 µm) using gradient elution. Positive electrospray ionization (ESI+) was used for the detection mechanism with the multiple reaction monitoring (MRM) mode. The method was validated over the concentration range of 150–1200 ng/mL for rat brain tissue. The precision and accuracy for all brain analyses were within the acceptable limit. The mean extraction recovery in rat brain was 83.6%. This valida...
Antimicrobial agents and chemotherapy, Jan 7, 2018
The anti-leprosy drug clofazimine was recently repurposed as part of a newly endorsed short-cours... more The anti-leprosy drug clofazimine was recently repurposed as part of a newly endorsed short-course regimen for multidrug-resistant tuberculosis. It also enables significant treatment-shortening when added to the first-line regimen for drug-susceptible tuberculosis in a mouse model. However, clofazimine causes dose- and duration-dependent skin discoloration in patients, and the optimal clofazimine dosing strategy in the context of the first-line regimen is unknown. We utilized a well-established mouse model to systematically address the impact of duration, dose, and companion drugs on the treatment-shortening activity of clofazimine in the first-line regimen. In all studies, the primary outcome was relapse-free cure (culture-negative lungs) six months after stopping treatment, and the secondary outcome was bactericidal activity, , the decline in lung bacterial burden during treatment. Our findings indicate that clofazimine activity is most potent when co-administered with first-line ...
Journal of the South African Veterinary Association, 2017
Dry pelleted dog food in the South African market is available via supermarkets, pet stores (stan... more Dry pelleted dog food in the South African market is available via supermarkets, pet stores (standard brands [SBs]) and veterinary channels (premium brands [PBs]). For the purpose of this study, the supermarket channel included the cheaper quality foods and PBs were sold via the veterinary channel (n = 20). These feeds were analysed for four main mycotoxins (aflatoxins [AF], fumonisin [FB], ochratoxin A [OTA] and zearalenone [ZEA]) using standard welldescribed extraction, characterisation and quantitation processes. Irrespective of the brand or marketing channel, all foods were contaminated with fungi (mainly Aspergillus flavus, Aspergillus fumigatus and Aspergillus parasiticus) and mycotoxins (most prevalent being aflatoxins and fumonisins). This was observed in all 20 samples irrespective of the marketing channel or perceived quality. Also, many samples within each marketing channel failed the 10 ppb limit for aflatoxin set by regulations in South Africa. Although fumonisin was de...
Transdermal drug delivery is an attractive route of administration relative to other routes as it... more Transdermal drug delivery is an attractive route of administration relative to other routes as it offers enhanced therapeutic efficacy. However, due to poor skin permeability of certain drugs, their application in transdermal delivery is limited. The ultra-deformable nature of transferosomes makes them suitable vehicles for transdermal delivery of drugs that have high molecular weights and hydrophilicity. However, their low viscosity, which leads to low contact time on the surface of the skin, has restricted their application in transdermal delivery. Therefore, this study aimed to deliver transferosomes loaded with a highly water-soluble and high molecular weight vancomycin hydrochloride (VCM-HCl) via a bigel for systemic delivery and treatment of microbial infections. VCM-HCl-loaded transferosomal formulations (TNFs) were prepared using a reverse-phase evaporation method and then loaded into a bigel. Both the TNFs and TNFs-loaded bigel (TNF-L-B) were characterized by a range of in vitro and ex vivo techniques. TNFs and TNF-L-B were tested for biosafety via the MTT assay and found to be biosafe. Prepared TNFs had sizes, zeta potential and entrapment efficiency of 63.02±5.34nm, -20.93±6.13mV and 84.48±1.22% respectively. VCM-HCl release from TNF-L-B showed a prolonged release profile with 39.76±1.6% after 24hrs when compared to bare VCM-HCl loaded in the bigel (74.81± 8.84%). Ex-vivo permeation of prepared TNF-L-B showed a higher permeation flux of 0.56µg/cm2/h compared to the bare VCM-HCl-loaded bigel of 0.23µg/cm2/h, indicating superior permeation and bioavailability of the drug. Additionally, the prepared TNF-L-B demonstrated improved antimicrobial activity. The TNF-L-B showed minimum inhibitory concentrations (MIC) of 0.97μg/ml against Staphylococcus aureus (SA) and 1.95μg/ml against methicillin-resistant SA (MRSA), which were 2-fold lower MIC values than the bare drug. The time-kill assay showed that both TNFs and TNF-L-B systems caused a 5.6-log reduction (100%) in MRSA compared to bare VCM-HCl after 24 hrs of incubation. Furthermore, as opposed to the bare VCM-HCl solution, the degree of biofilm reduction caused by TNFs (55.72%) and TNF-L-B (34.58%) suggests their dominance in eradicating MRSA biofilm. These findings indicate that TNF-L-B is a promising system for transdermal delivery of hydrophilic and high molecular weight drugs.
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