Peter Galettis

Bio: Peter Galettis is an academic researcher from University of Newcastle. The author has contributed to research in topics: Gemcitabine & Pharmacokinetics. The author has an hindex of 20, co-authored 55 publications receiving 1641 citations. Previous affiliations of Peter Galettis include University of New South Wales & Royal North Shore Hospital.

The pharmacokinetics and the pharmacodynamics of cannabinoids.

Abstract: There is increasing interest in the use of cannabinoids for disease and symptom management, but limited information available regarding their pharmacokinetics and pharmacodynamics to guide prescribers. Cannabis medicines contain a wide variety of chemical compounds, including the cannabinoids delta-9-tetrahydrocannabinol (THC), which is psychoactive, and the nonpsychoactive cannabidiol (CBD). Cannabis use is associated with both pathological and behavioural toxicity and, accordingly, is contraindicated in the context of significant psychiatric, cardiovascular, renal or hepatic illness. The pharmacokinetics of cannabinoids and the effects observed depend on the formulation and route of administration, which should be tailored to individual patient requirements. As both THC and CBD are hepatically metabolized, the potential exists for pharmacokinetic drug interactions via inhibition or induction of enzymes or transporters. An important example is the CBD-mediated inhibition of clobazam metabolism. Pharmacodynamic interactions may occur if cannabis is administered with other central nervous system depressant drugs, and cardiac toxicity may occur via additive hypertension and tachycardia with sympathomimetic agents. More vulnerable populations, such as older patients, may benefit from the potential symptomatic and palliative benefits of cannabinoids but are at increased risk of adverse effects. The limited availability of applicable pharmacokinetic and pharmacodynamic information highlights the need to initiate prescribing cannabis medicines using a 'start low and go slow' approach, carefully observing the patient for desired and adverse effects. Further clinical studies in the actual patient populations for whom prescribing may be considered are needed, to derive a better understanding of these drugs and enhance safe and optimal prescribing.

Role of lipophilicity in determining cellular uptake and antitumour activity of gold phosphine complexes.

Abstract: Purpose: The lipophilic cation [Au(I)(dppe)2]+ [where dppe is 1,2-bis(diphenylphosphino)ethane] has previously demonstrated potent in vitro antitumour activity. We wished to determine the physicochemical basis for the cellular uptake of this drug, as well as of analogues including the 1:2 adducts of Au(I) with 1,2-bis(di-n-pyridylphosphino)ethane (dnpype; n=2, 3 and 4), and to compare in vitro and in vivo antitumour activity. Methods and results: Logarithmic IC50 values for the CH-1 cell line bore a parabolic dependence on drug lipophilicity, as measured either by high-performance liquid chromatography or by n-octanol-water partition. Cellular uptake of drug, as measured by inductively coupled plasma mass spectrometry, varied by over three orders of magnitude over the series. Logarithmic uptake had a parabolic dependence on drug lipophilicity but a linear relationship to logarithmic IC50 values. Free drug concentrations were determined under the culture conditions and logarithmic free drug IC50 values and uptake rates were linearly related to lipophilicity. Uptake of drug in vivo in tissue from murine colon 38 tumours was approximately proportional to the dose administered. Host toxicity varied according to lipophilicity with the most selective compound having an intermediate value. This compound was also the most active of those tested in vivo, giving a growth delay of 9 days following daily intraperitoneal dosing (10 days) at 4 μmol kg−1 day−1. It was also significantly more active than another lipophilic cation, MKT-077. Conclusions: Alteration of lipophilicity of aromatic cationic antitumour drugs greatly affects cellular uptake and binding to plasma proteins. Changes in lipophilicity also affect host toxicity, and optimal lipophilicity may be a critical factor in the design of analogues with high antitumour activity.

Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs

Abstract: Previous work has shown platinum drugs to differ in their effects on the peripheral nervous system. To test whether their differential toxicity was due to differences in their partitioning into the peripheral nervous system, we correlated the hydrophobicity, reactivity, tissue accumulation and neurotoxicity of a series of eight platinum analogues. Neurotoxicity was detected by measuring sensory nerve conduction velocity (SNCV) in Wistar rats treated twice per week at the maximum tolerated dose. Tissue platinum concentrations were measured by inductively coupled plasma mass spectrometry. Hydrophobicity (log P) was measured using an octanol-aqueous shake-flask method. The half-life of platinum drug binding to plasma proteins in vitro was determined. The cumulative dose causing altered SNCV ranged from 15 to > 2050 micromol kg(-1). Ranking of the compounds by their neurotoxic potency in rats (oxaliplatin > R,R-(DACH)PtC4 > ormaplatin > S,S-(DACH)PtCl4 > S,S-(DACH)Pt oxalato > cisplatin > carboplatin > JM216) correlated with the frequency of neurotoxicity in patients (r> 0.99; P carboplatin > oxaliplatin > R,R-(DACH)PtCl4 = S,S-(DACH)PtCl4 and did not correlate with neurotoxicity. Log P ranged from - 2.53 to -0.16 but did not correlate with neurotoxicity. Log P correlated inversely with platinum accumulation in dorsal root ganglia (r2 = 0.99; P = 0.04), sural nerve (r2 = 0.85; P = 0.025), sciatic nerve (r2 = 0.98; P= 0.0012), spinal cord (r2 = 0.97, P= 0.018) and brain (r2 = 0.98, P= 0.001). Reactivity correlated with neurotoxicity potency in rats (r2 = 0.89, P = 0.0005) and with the frequency of neurotoxicity in patients (r2 = 0.99, P = 0.0002). The hydrophilicity of platinum drugs correlates with platinum sequestration in the peripheral nervous system but not with neurotoxicity. Differences in the reactivity of platinum complexes accounts for some of the variation in their neurotoxicity.

A randomised controlled trial of vaporised Δ9-tetrahydrocannabinol and cannabidiol alone and in combination in frequent and infrequent cannabis users: acute intoxication effects

Abstract: Access to cannabis and cannabinoid products is increasing worldwide for recreational and medicinal use. Two primary compounds within cannabis plant matter, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are both psychoactive, but only THC is considered intoxicating. There is significant interest in potential therapeutic properties of these cannabinoids and of CBD in particular. Some research has suggested that CBD may ameliorate adverse effects of THC, but this may be dose dependent as other evidence suggests possible potentiating effects of THC by low doses of CBD. We conducted a randomised placebo controlled trial to examine the acute effects of these compounds alone and in combination when administered by vaporisation to frequent and infrequent cannabis users. Participants (n = 36; 31 male) completed 5 drug conditions spaced one week apart, with the following planned contrasts: placebo vs CBD alone (400 mg); THC alone (8 mg) vs THC combined with low (4 mg) or high (400 mg) doses of CBD. Objective (blind observer ratings) and subjective (self-rated) measures of intoxication were the primary outcomes, with additional indices of intoxication examined. CBD showed some intoxicating properties relative to placebo. Low doses of CBD when combined with THC enhanced, while high doses of CBD reduced the intoxicating effects of THC. The enhancement of intoxication by low-dose CBD was particularly prominent in infrequent cannabis users and was consistent across objective and subjective measures. Most effects were significant at p < .0001. These findings are important to consider in terms of recommended proportions of THC and CBD in cannabis plant matter whether used medicinally or recreationally and have implications for novice or less experienced cannabis users. Trial registration: ISRCTN Registry Identifier: ISRCTN24109245.

Smart micro/nanoparticles in stimulus-responsive drug/gene delivery systems

Abstract: New achievements in the realm of nanoscience and innovative techniques of nanomedicine have moved micro/nanoparticles (MNPs) to the point of becoming actually useful for practical applications in the near future. Various differences between the extracellular and intracellular environments of cancerous and normal cells and the particular characteristics of tumors such as physicochemical properties, neovasculature, elasticity, surface electrical charge, and pH have motivated the design and fabrication of inventive “smart” MNPs for stimulus-responsive controlled drug release. These novel MNPs can be tailored to be responsive to pH variations, redox potential, enzymatic activation, thermal gradients, magnetic fields, light, and ultrasound (US), or can even be responsive to dual or multi-combinations of different stimuli. This unparalleled capability has increased their importance as site-specific controlled drug delivery systems (DDSs) and has encouraged their rapid development in recent years. An in-depth understanding of the underlying mechanisms of these DDS approaches is expected to further contribute to this groundbreaking field of nanomedicine. Smart nanocarriers in the form of MNPs that can be triggered by internal or external stimulus are summarized and discussed in the present review, including pH-sensitive peptides and polymers, redox-responsive micelles and nanogels, thermo- or magnetic-responsive nanoparticles (NPs), mechanical- or electrical-responsive MNPs, light or ultrasound-sensitive particles, and multi-responsive MNPs including dual stimuli-sensitive nanosheets of graphene. This review highlights the recent advances of smart MNPs categorized according to their activation stimulus (physical, chemical, or biological) and looks forward to future pharmaceutical applications.

Coinage Metal−N-Heterocyclic Carbene Complexes

Abstract: 2.3.5. Multi-NHCs Linked by Spacers 3568 2.4. The Ag2O Route 3570 2.4.1. Feasibility 3570 2.4.2. Complications 3571 2.4.3. Theoretical Consideration 3572 2.5. Applications 3572 2.5.1. Ag(I)-NHCs in NHC Transfer 3572 2.5.2. Ag(I)-NHCs in Catalysis 3572 2.5.3. Ag(I)-NHCs in Medicine 3572 2.5.4. Ag(I)-NHCs in Nanomaterials 3573 3. Au(I)and Au(III)-NHCs 3573 3.1. Historical Background 3573 3.2. General Synthetic Methods 3573 3.3. Formation of Au(I)and Au(III)-NHCs 3574 3.3.1. Neutral [Au(NHC)L] 3574 3.3.2. Ionic [Au(NHC)L][Anion] 3576 3.3.3. Multinuclear Au(I)-NHCs 3578 3.3.4. Other Classes of Au(I)-NHCs 3578 3.3.5. Au(III)-NHC Complexes 3579 3.4. Applications 3579 3.4.1. Au(I)and Au(III)-NHCs in Catalysis 3579 3.4.2. Au(I)-NHCs in Medicine 3580 4. Cu(I)and Cu(II)-NHCs 3581 4.1. Historical Background 3581 4.2. General Synthetic Methods 3582 4.3. Formation of Cu(I)and Cu(II)-NHCs 3583 4.3.1. Complexes Containing the Cu(NHC)2 Core 3583 4.3.2. [Cu(NHC)(Halide)] 3583 4.3.3. [Cu(NHC)(Ligand)] 3584 4.3.4. Multinuclear Cu(I)and Cu(II)-NHCs 3589 4.4. Catalysis 3591 4.4.1. Past Events 3591 4.4.2. Recent Advancements 3591 5. Photoluminescence 3592 6. Conclusions 3594 7. Abbreviations 3594 8. Acknowledgments 3595 9. References 3595

Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention.

Abstract: 1.1. Discovery of the Phospholipase A2 Superfamily Phospholipases represent one of the earliest enzyme activities to be identified and studied and the phospholipase A2 (PLA2) superfamily (see defining specificity1 in Figure 1) traces its roots to the identification of lytic actions of snake venom at the end of the 19th century. The enzyme was first purified and characterized from cobra venom and later from rattlesnake venom. As protein sequencing methodologies advanced in the 1970’s, it became apparent that these enzymes had an unusually large number of cysteines (over 10% of the amino acids) and as secreted enzymes, that they were all in the form of disulfide bonds. It was further recognized that in the case of PLA2, cobras and rattlesnakes had six disulfides in common, but one disulfide bond is located in distinctly different locations. This led to the designation of Type 1 and Type 2 for cobras (old world snakes) and rattlesnakes (new world snakes), respectively.2 During that same period, studies on the porcine pancreatic digestive enzyme that hydrolyzes phospholipids led to the determination that this mammalian enzyme (and also the human pancreatic enzyme) had the same disulfide bonding pattern as cobras and hence the designation as IB with the cobra enzyme as IA. Open in a separate window Figure 1 The specific reaction catalyzed by phospholipase A2 at the sn-2 position of the glycerol backbone is shown. X, any of a number of polar headgroups; R1, fatty acids, or alkyl, or alkenyl groups and R2, fatty acids or acyl moieties.