Causes and outcomes of at-risk underperforming pharmacy students: implications for policy and practice.

OBJECTIVE: This study aimed to understand the key determinants for poor academic performance of students completing a Bachelor of Pharmacy (BPharm), Bachelor of Pharmacy and Management (BPharmMgmt), or Master of Pharmacy (MPharm) degree. METHODS: Data were collected on pharmacy students who had not met academic progression requirements between 2008 and 2018 at The University of Sydney, Australia. This included: age at the start of pharmacy degree; gender; whether they transferred from another university; whether they were a domestic or international student; Australian Tertiary Admissions Rank upon entry, previous studies in biology, chemistry, or mathematics; show cause triggers (units of study failed); number of show causes; students' written show cause responses; weighted average mark at last show cause or graduation; whether they graduated and were a registered pharmacist; and, the number of years they spent studying the degree. Descriptive studies were used to analyse student characteristics using SPSS software, and student self-reported reasons for poor performance were analysed reflexively using thematic analysis procedures using NVivo. RESULTS: This study included 164 pharmacy students enrolled in a BPharm (79.3%, n = 130), BPharmMgmt (1.2%, n = 2), or MPharm (19.5%, n = 32). Of the students, 54% (n = 88) were men, 81% (n = 133) were domestic students, 15% (n = 24) transferred from another degree program, and 38% (n = 62) graduated from the course. Show cause students were less likely to graduate if they transferred from another degree program (P = 0.0002) or failed more than three units of study (UoS; P < 0.0001). The most commonly failed UoS were related to organic or pharmaceutical chemistry, and the top student self-reported reasons for poor performance was stress/anxiety, physical health, and depression. CONCLUSION: Pharmacy schools should aim to address student foundational knowledge in chemistry, identify at-risk students early using pre-subject testing, and provide better services to address student mental health.

Potential factors that can affect the performance of undergraduate pharmacy research students: a descriptive study.

OBJECTIVE: This descriptive study aimed to examine whether student past coursework performance, student or research supervisor characteristics, and the type of research project are related to the overall academic performance of a pharmacy student completing an honours research program. METHODS: Data on undergraduate honours students who completed a Bachelor of Pharmacy degree at The University of Sydney, Sydney, Australia, between Jan 2015 and Dec 2020 was collected. This included socio-demographic characteristics, type of project undertaken, and academic outputs. Data was also collected on each supervisor's academic role, level of experience, research area, and where they completed their PhD. Descriptive statistics were used to describe the study cohort and correlation analysis and unpaired t-tail analyses were conducted using SPSS software. RESULTS: This five year study included 130 students of which 67% were female and 60% were domestic students. Each student was supervised by one of 48 individual academics who were a mix of early- (31%), mid-career (29%), and experienced researchers (40%) for pharmaceutical science (50%), clinical (45%), and education (5%) projects. Just less than half (49%) of students published one peer-reviewed journal article. Female students outperformed male students (p = 0.031) with female students also twice as likely (15%) to receive a university medal eligible mark compared with male students (7.0%). Similarly, domestic students were twice as likely (15%) to receive a university medal eligible mark when compared with international students (7.7%). Students who undertook a pharmaceutical science-based project outperformed education-based project students (p = 0.0235). Students who had published at least one peer-reviewed journal article outperformed those who had not published (p = 0.0014). CONCLUSION: Factors that affected honours performance were student gender, residential status, type of project undertaken, and whether a student had published a peer-reviewed journal article.

The Effectiveness and Adverse Events of Cannabidiol and Tetrahydrocannabinol Used in the Treatment of Anxiety Disorders in a PTSD Subpopulation: An Interim Analysis of an Observational Study.

Background: Anxiety is a condition for which current treatments are often limited by adverse events (AEs). Components of medicinal cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC), have been proposed as potential treatments for anxiety disorders, specifically posttraumatic stress disorder (PTSD). Objective: To evaluate quality-of-life outcomes after treatment with various cannabis formulations to determine the effectiveness and associated AEs. Methods: An interim analysis of data collected between September 2018 and June 2021 from the CA Clinics Observational Study. Patient-Reported Outcomes Measurement Information System-29 survey scores of 198 participants with an anxiety disorder were compared at baseline and after treatment with medicinal cannabis. The data of 568 anxiety participants were also analyzed to examine the AEs they experienced by the Medical Dictionary for Regulatory Activities organ system class. Results: The median doses taken were 50.0 mg/day for CBD and 4.4 mg/day for THC. The total participant sample reported significantly improved anxiety, depression, fatigue, and ability to take part in social roles and activities. Those who were diagnosed with PTSD (n = 57) reported significantly improved anxiety, depression, fatigue, and social abilities. The most common AEs reported across the whole participant cohort were dry mouth (32.6%), somnolence (31.3%), and fatigue (18.5%), but incidence varied with different cannabis formulations. The inclusion of THC in a formulation was significantly associated with experiencing gastrointestinal AEs; specifically dry mouth and nausea. Conclusions: Formulations of cannabis significantly improved anxiety, depression, fatigue, and the ability to participate in social activities in participants with anxiety disorders. The AEs experienced by participants are consistent with those in other studies.

Opioid exposures in children under 5 years of age (2004-2019): A retrospective study of calls to Australia's largest poisons information centre.

AIM: To describe time trends in opioid exposures in children under 5 years, and to describe patient demographics, the medicines involved, the reasons for exposure and disposition. METHODS: A retrospective analysis of paediatric (<5 years of age) opioid exposure calls to the New South Wales Poisons Information Centre (NSWPIC, Australia's largest poison centre), 2004-2019. Joinpoint regression analysis was used to examine temporal trends. RESULTS: There were 4807 cases of paediatric opioid exposure during the 16 year study period, with an average of 300 exposures per year. Exposures increased, 2004-2007, with an annual percentage change (APC) of 14.6% (95% CI = 4.3 to 26.0%), then decreased, 2007-2016, APC -3.4% (95% CI = -5.3 to -1.3%). A steeper decrease was observed after 2016, APC -14.1% (95% CI = -21.8 to -5.6%). The overall APC was -2.3% (95% CI = -4.7 to 0.2%), 2004-2019. Accidental exposures accounted for 86% of calls (4137). The majority of calls were from family members regarding exposures that happened at home, highlighting the need for safety initiatives. The preparations most frequently involved were paracetamol/opioid combination products (primarily codeine), 53% (2566) and ibuprofen/opioid combinations 14% (650). Twenty-two percent of cases were referred to a hospital (1062), and a further 15% (719) of calls originated from hospital staff. CONCLUSION: Opioid exposures in young Australian children continue to occur; however, the rate has declined since 2007. Safe storage and parent education initiatives could further reduce the burden of paediatric opioid poisoning in Australia.

An Analysis for Adulteration and Contamination of Over-the-Counter Weight-Loss Products.

Six Australian and five overseas complementary medicines (CM) and meal replacement shake products were analysed for potential adulteration with two common active pharmaceutical ingredients, caffeine and sibutramine, using thin-layer chromatography and mass spectrometry. The declared amount of caffeine in each product was also reviewed. Finally, the products were examined for heavy metal contamination using inductively coupled plasma-mass spectrometry. The results showed that there was no detected adulteration of either caffeine (for those products that did not list caffeine as an ingredient) or sibutramine in the 11 products; however, based on the product labels, one Australian and one overseas (two in total) CM product contained more than the maximum daily safety limit (400 mg) of caffeine. Potentially excessive lead and/or chromium was detected in six products, including four Australian products and two products purchased online. One Australian CM product appeared to contain these heavy metals at concentrations at, or exceeding, the safety limits specified in the United States Pharmacopeia or set by the World Health Organization. The overconsumption of caffeine and heavy metals has the potential of causing significant health effects in consumers.

Can we Predict Drug Excretion into Saliva? A Systematic Review and Analysis of Physicochemical Properties.

BACKGROUND AND OBJECTIVES: Saliva is a patient-friendly matrix for therapeutic drug monitoring (TDM) but is infrequently used in routine care. This is due to the uncertainty of saliva-based TDM results to inform dosing. This study aimed to retrieve data on saliva-plasma concentration and subsequently determine the physicochemical properties that influence the excretion of drugs into saliva to increase the foundational knowledge underpinning saliva-based TDM. METHODS: Medline, Web of Science and Embase (1974-2023) were searched for human clinical studies, which determined drug pharmacokinetics in both saliva and plasma. Studies with at least ten subjects and five paired saliva-plasma concentrations per subject were included. For each study, the ratio of the area under the concentration-time curve between saliva and plasma was determined to assess excretion into saliva. Physicochemical properties of each drug (e.g. pKa, lipophilicity, molecular weight, polar surface area, rotatable bonds and fraction of drug unbound to plasma proteins) were obtained from PubChem and Drugbank. Drugs were categorised by their ionisability, after which saliva-to-plasma ratios were predicted with adjustment for protein binding and physiological pH via the Henderson-Hasselbalch equation. Spearman correlation analyses were performed for each drug category to identify factors predicting saliva excretion (α = 5%). Study quality was assessed by the risk of bias in non-randomised studies of interventions tool. RESULTS: Overall, 42 studies including 40 drugs (anti-psychotics, anti-microbials, immunosuppressants, anti-thrombotic, anti-cancer and cardiac drugs) were included. The median saliva-to-plasma ratios were similar for drugs in the amphoteric (0.59), basic (0.43) and acidic (0.41) groups and lowest for drugs in the neutral group (0.21). Higher excretion of acidic drugs (n = 5) into saliva was associated with lower ionisation and protein binding (correlation between predicted versus observed saliva-to-plasma ratios: R2 = 0.85, p = 0.02). For basic drugs (n = 21), pKa predicted saliva excretion (Spearman correlation coefficient: R = 0.53, p = 0.02). For amphoteric drugs (n = 10), hydrogen bond donor (R = - 0.76, p = 0.01) and polar surface area (R = - 0.69, p = 0.02) were predictors. For neutral drugs (n = 10), protein binding (R = 0.84, p = 0.004), lipophilicity (R = - 0.65, p = 0.04) and hydrogen bond donor count (R = - 0.68, p = 0.03) were predictors. Drugs considered potentially suitable for saliva-based TDM are phenytoin, tacrolimus, voriconazole and lamotrigine. The studies had a low-to-moderate risk of bias. CONCLUSIONS: Many commonly used drugs are excreted into saliva, which can be partly predicted by a drug's ionisation state, protein binding, lipophilicity, hydrogen bond donor count and polar surface area. The contribution of drug transporters and physiological factors to the excretion needs to be evaluated. Continued research on drugs potentially suitable for saliva-based TDM will aid in adopting this person-centred TDM approach to improve patient outcomes.

Hospitalised poisonings in Australian children: a 10-year retrospective study.

INTRODUCTION: Paediatric poisoning is a major cause of childhood injury, and most poisonings are preventable. We aimed to describe hospitalisations resulting from poisoning and envenomation in Australian children, including demographics, cause of the exposure, hospital length of stay, rates of intensive care unit admission and in-hospital deaths. We also aimed to describe risk factors for increased length of stay and intensive care unit admission. METHODS: A retrospective analysis was performed of hospitalised poisoning and envenomation cases of children (<15 years) in Australia from 1 July 2009 to 30 June 2019. A nationwide hospital admissions database was used for this study. RESULTS: During the 10-year study period 33,438 children were admitted to hospital due to a pharmaceutical or non-pharmaceutical poisoning/envenomation; an average of 74.8 cases per 100,000 population per year. Approximately 10 children were admitted to hospital each day for poisoning. Over 70% of these cases were due to pharmaceuticals (n = 23,628), most frequently non-opioid analgesics, anti-pyretics and anti-rheumatics (n = 8759, 37.1% of pharmaceutical exposures). The most common non-pharmaceutical exposure was contact with venomous animals and toxic plants (n = 4578, 46.7% of non-pharmaceuticals). Intentional self-harm occurred in 7833 (23.4%) of cases. Intensive care unit admission was required in 519 cases (2.5% of the 20,739 cases where this information was available), while 200 (0.96% of 20,739) needed ventilator support. Ten children (0.03%) died. Older age, female sex, poisoning with pharmaceuticals and metropolitan hospital location were associated with increased length of stay. Older age and poisoning with pharmaceuticals were also associated with intensive care unit admission. CONCLUSION: Approximately 10 children were admitted to hospital with poisoning every day in Australia. Most poisonings were due to pharmaceuticals, particularly simple analgesics that are found in most Australian homes. Severe outcomes (intensive care unit admissions and deaths) were rare.

Medicinal cannabis for patients with chronic non-cancer pain: analysis of safety and concomitant medications.

OBJECTIVES: This study aimed to explore the incidence of adverse events (AEs) reported by patients when initiating medicinal cannabis treatment for chronic pain, and the association of cannabis constituents, dose and concomitant medicines with AE incidence. METHODS: Patient demographics, cannabis products and AE data were collected as part of the Cannabis Access Clinics Observational Study, and concomitant medicines were obtained from patient health summaries provided by referring doctors. Cannabis products were grouped by their constituents as either cannabidiol-only or containing both cannabidiol and Δ-9-tetrahydrocannabinol. KEY FINDINGS: From a total of 275 patients, each had a median of six concomitant medicines, with opioids (n = 179; 65%) the most common. A total of 35.6% patients took 10 or more other medicines, and they were associated with a 3.6 times higher likelihood to report the AE of fatigue (P = 0.048). Patients who received concomitant gabapentinoids were 2.4 times more likely to report dizziness (P = 0.036), patients on tricyclic antidepressants were 1.8 times more likely to report somnolence (P = 0.034) and 3.4 times more likely to report anxiety (P = 0.04), when compared with patients who were not prescribed those classes of medications. Those patients who were prescribed products containing both cannabidiol and Δ-9-tetrahydrocannabinol were 1.5 times more likely (P = 0.004) to have experienced an AE when compared with those prescribed only cannabidiol. CONCLUSIONS: These findings show that certain concomitant medications and cannabis constituents may be associated with AE incidence when initiating medicinal cannabis. These potential pharmacokinetic and pharmacodynamic interactions require further study to develop guidance for prescribers and pharmacists.

Medicinal cannabis for Australian patients with chronic refractory pain including arthritis.

Objectives: To examine the tolerability and effectiveness of medicinal cannabis prescribed to patients for chronic, refractory pain, with a subset analysis on arthritis. Methods: This was an interim analysis of the CA Clinics Observational Study investigating self-reported adverse events (AEs) and changes in health-related quality of life (HRQoL) outcomes over time after commencing medicinal cannabis. Patients were prescribed medicinal cannabis by a medical practitioner, containing various ratios of Δ9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD). Results: The overall chronic pain cohort, and specifically the balanced CBD:THC products, were associated with significantly reduced pain intensity scores (p = 0.003, p = 0.025), with 22% of patients reporting a clinically meaningful reduction in pain intensity. Patients in the arthritis subset (n = 199) reported significantly reduced pain intensity scores (p = 0.005) overall, and specifically for those taking CBD-only (p = 0.018) and balanced products (p = 0.005). Other HRQoL outcomes, including pain interference and pain impact scores were significantly improved depending on the CBD:THC ratio. Products that contained a balanced ratio of CBD:THC were associated with improvements in the most number of PROMIS-29 domains. Approximately half (n = 364; 51%) of the chronic pain cohort experienced at least one AE, the most common being dry mouth (24%), somnolence (19%) or fatigue (12%). These findings were similar in the arthritis subset. Discussion: Medicinal cannabis was observed to improve pain intensity scores and HRQoL outcomes in patients with chronic, refractory pain, providing real-world insights into medicinal cannabis' therapeutic potential.

Microneedle-enabled therapeutics delivery and biosensing in clinical trials.

Microneedles (MNs) are micron-sized protrusions attached to a range of devices that are used in therapeutic delivery and diagnosis. Because MNs can be self-applied, are painless, and can carry multiple therapeutic agents, they have received extensive attention, and have been widely investigated, for local and systemic therapy. Many researchers are currently working to extend the use of MNs to clinical applications. In this review, we provide an update and analysis on MN-based clinical trials since their inception in 2007. The MNs in clinical trials are classified into five types based on their appearance and properties, including: hollow MNs, MN patches, radiofrequency MNs, MN rollers, and other MNs. The various aspects of MN trials are summarized, such as MN types, clinical trial time, and trial regions. This review aims to present an overview of MN development and provide insights for future research in this field. To our knowledge, this is the first review focused on MN clinical trials which showcases the latest applications of this advanced technology in medicine.

Cisplatin-tethered gold nanoparticles that exhibit enhanced reproducibility, drug loading, and stability: a step closer to pharmaceutical approval?

Gold nanoparticles (AuNPs) can be used as delivery vehicles for platinum anticancer drugs, improving their targeting and uptake into cells. Here, we examine the appropriateness of different-sized AuNPs as components of platinum-based drug-delivery systems, investigating their controlled synthesis, reproducibility, consistency of drug loading, and stability. The active component of cisplatin was tethered to 25, 55, and 90 nm AuNPs, with the nanoparticles being almost spherical in nature and demonstrating good batch-to-batch reproducibility (24.37 ± 0.62, 55.2 ± 1.75, and 89.1 ± 2.32 nm). The size distribution of 25 nm AuNPs has been significantly improved, compared with a previous method that produces polydispersed nanoparticles. Attachment of platinum to the AuNP surface through a poly(ethylene glycol) (PEG) linker exhibits an increase in the drug loading with increasing particle size: 25 nm (815 ± 106 drug molecules per AuNP), 55 nm (14216 ± 880), and 90 nm (54487 ± 15996). The stability of the naked, PEGylated, and platinum-conjugated nanoparticles has been examined over time under various conditions. When stored at 4 °C, there is minimal variation in the diameter for all three AuNP sizes; variation after 28 days for the 25 nm AuNPs was 2.4%; 55 nm, 3.3%; and 90 nm, 3.6%. The 25 nm AuNPs also demonstrate minimal changes in UV-visible absorbance over the same time period.

A chemical perspective on the clinical use of platinum-based anticancer drugs.

Platinum drugs have been a mainstay of cancer chemotherapy since the introduction of cisplatin in the 1970s. Since then, carboplatin and oxaliplatin have been approved world-wide and nedaplatin, lobaplatin, heptaplatin, dicycloplatin, and miriplatin have been approved in individual countries. The three main platinum drugs are not used in isolation but are combined in chemotherapy protocols from a range of 28 drugs that include: anthracyclines, alkylating agents, vinca alkaloids, antimetabolites, topoisomerase inhibitors, taxanes, and monoclonal antibodies. Interestingly, they are not yet used in combination with tyrosine kinase inhibitors or proteasome inhibitors. How platinum drugs are formulated for administration to patients is important to minimise aquation during storage and administration. Cisplatin is typically formulated in saline-based solutions while carboplatin and oxaliplatin are formulated in dextrose. Pharmacokinetics are an important factor in both the efficacy and safety of platinum drugs. This includes the quantity of protein-bound drug in blood serum, how fast the drugs are cleared by the body, and how fast the drugs are degraded and deactivated. Attempts to control platinum pharmacokinetics and side effects using rescue agents, macrocycles, and nanoparticles, and through the design of platinum(IV)-based drugs have not yet resulted in clinically successful outcomes. As cancer is predominantly a disease of old age, many cancer patients who are administered a platinum drug may have other medical conditions which means they may also be taking many non-cancer medicines. The co-administration of non-cancer medicines to patients can potentially affect the efficacy of platinum drugs and/or change the severity of their side effects through drug-drug interactions.

Poisonings with ADHD medication in children under the age of 5 years in Australia: a retrospective study, 2004-2019.

OBJECTIVE: To describe the temporal relationships in attention-deficit hyperactivity disorder (ADHD) medication poisoning exposures in children; describe patient demographics, medications involved, poisoning exposure reasons and disposition. DESIGN: A population-based, retrospective cohort study of calls to Australia's largest Poisons Information Centre. Poisoning exposure counts and dispensing-adjusted rates were modelled with Poisson, quasi-Poisson and negative binomial regression where appropriate. SETTING: Calls to the New South Wales Poisons Information Centre and dispensings on the Pharmaceutical Benefits Scheme. PATIENTS: Children under the age of 5 years. RESULTS: There were 1175 poisoning exposures to ADHD psychostimulants, 2004-2019; averaging 73 per year. Accidental poisonings accounted for 94% of cases. Methylphenidate was most frequently implicated (63%). Thirty-four per cent of cases were referred to hospital and a further 21% of calls were made by hospital staff. Poisoning exposure counts for all ADHD psychostimulants increased by 2.7% (95% CI=0.42% to 4.9%) per year; however, this differed by agent. Methylphenidate poisoning exposures increased by 5.2% per year (95% CI=4.3% to 6.1%), lisdexamfetamine increased by 62% per year (95% CI=48% to 76%), while dexamphetamine poisoning exposures decreased by 5.5% per year (95% CI=-9.5% to -1.4%). These trends are reflected in the number of dispensings; however, dispensings increased at a faster rate than exposures. When poisoning exposures were expressed as dispensing-adjusted rates, there was a 16% decrease (95% CI=-20% to -13%) per year. CONCLUSIONS: ADHD medication use has increased, associated with an increased number of paediatric poisoning exposures. However, poisoning exposures per dispensed prescription has decreased. The majority of cases required hospitalisation, indicating the need for further poisoning prevention strategies.

Gold nanoparticles for the improved anticancer drug delivery of the active component of oxaliplatin.

The platinum-based anticancer drugs cisplatin, carboplatin, and oxaliplatin are an important component of chemotherapy but are limited by severe dose-limiting side effects and the ability of tumors to develop resistance rapidly. These drugs can be improved through the use of drug-delivery vehicles that are able to target cancers passively or actively. In this study, we have tethered the active component of the anticancer drug oxaliplatin to a gold nanoparticle for improved drug delivery. Naked gold nanoparticles were functionalized with a thiolated poly(ethylene glycol) (PEG) monolayer capped with a carboxylate group. [Pt(1R,2R-diaminocyclohexane)(H(2)O)(2)]2NO(3) was added to the PEG surface to yield a supramolecular complex with 280 (+/-20) drug molecules per nanoparticle. The platinum-tethered nanoparticles were examined for cytotoxicity, drug uptake, and localization in the A549 lung epithelial cancer cell line and the colon cancer cell lines HCT116, HCT15, HT29, and RKO. The platinum-tethered nanoparticles demonstrated as good as, or significantly better, cytotoxicity than oxaliplatin alone in all of the cell lines and an unusual ability to penetrate the nucleus in the lung cancer cells.

Synthesis, processing and solid state excipient interactions of cucurbit[6]uril and its formulation into tablets for oral drug delivery.

The synthesis, processing, and solid state excipient interactions of cucurbit[6]uril (CB[6]) and its formulation into oral tablets has been examined using a range of physical chemistry techniques. Rapid precipitation from HCl by the addition of water yields microcrystalline CB[6] with smaller and more consistent particle size (30-165 µm) compared with the sieved CB[6] (50-540 µm) produced from large crystals grown by slow evaporation from HCl. The microcrystalline particles also contain fewer water molecules in the crystal compared with the sieved particles: 10 and 16% respectively. Microcrystalline CB[6] can be formulated into tablets suitable for oral delivery with a CB[6] content of 1-50% w/w, with the other excipients including lactose, talc, Avicel, magnesium stearate and Ac-Di-Sol. In the solid state microcrystalline CB[6] does not interact significantly with the talc, Ac-Di-Sol or Avicel, but significant interactions are observed when mixed or ground with either magnesium stearate or lactose, resulting in the lowering of the melting points of both excipients. This work represents the first study of the physical processing and solid state chemistry of CB[n]s for pharmaceutical formulation and represents an important development step in the use of CB[n]s as drug delivery vehicles.

Solid state stabilisation of the orally delivered drugs atenolol, glibenclamide, memantine and paracetamol through their complexation with cucurbit[7]uril.

The inclusion of the cardiovascular beta-blocker drug atenolol, the antidiabetic drug glibenclamide, the Alzheimer's NMDA glutamate receptor drug memantine and the analgesic/antipyretic drug paracetamol by cucurbit[7]uril (CB[7]) has been studied by (1)H nuclear magnetic resonance spectroscopy, electrospray ionisation mass spectrometry, molecular modelling, fluorescence displacement assays and differential scanning calorimetry. All four drugs form 1 : 1 host-guest complexes with CB[7], but the exchange kinetics and location of the binding is different for each drug. Atenolol is bound over the central phenyl ring with a binding constant of 4.2 x 10(4) M(-1), whereas glibenclamide is bound over the terminal cyclohexyl group with a binding constant of 1.7 x 10(5) M(-1), and memantine is totally bound within the CB[7] cavity. Paracetamol is bound in two locations, over the central phenyl ring and over the methyl group, with the CB[7] molecule shuttling quickly between the two sites. Inclusion by CB[7] was shown by differential scanning calorimetry to physically stabilise all four drugs, which has applications preventing drug degradation and improving drug processing and formulation.

Diffusion-based studies on the self-stacking and nanorod formation of platinum(II) intercalators.

Pulsed gradient spin-echo nuclear magnetic resonance diffusion measurements have been used to show that platinum(II)-based intercalating agents self-stack in solution and form nanorods 0.45-3.9 nm in length (at 25 mM); their lengths are dependent on metal complex concentration, salt concentration and solution temperature.

Degradation of bidentate-coordinated platinum(II)-based DNA intercalators by reduced L-glutathione.

We have examined the interaction of [(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)] (2+) (1, 56MESS), [(5-methyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)] (2+) (2, 5MESS), [(5,6-dimethyl-1,10-phenanthroline)(1R,2R-diaminocyclohexane)platinum(II)] (2+) (3, 56MERR), and [(5,6-dimethyl-1,10-phenanthroline)(ethylenediamine)platinum(II)] (2+) (4, 56MEEN) with reduced L-glutathione and L-methionine. Both thiols degrade all four complexes, mainly by displacing the ancillary ligand and forming a doubly bridged dinuclear complex. The degradation half-life of all the complexes with methionine is >7 days, indicating that these reactions are not biologically relevant. The rate of degradation by glutathione appears to be particularly important and shows an inverse correlation to cytotoxicity. The least active complex, 4 (t 1/2 glutathione: 20 h), degrades fastest, followed by 3 (31 h), 2 (40 h), and 1 (68 h). The major degradation product, [bis-mu-{reduced L-glutathione}bis{5,6-dimethyl-1,10-phenanthroline}bis{platinum(II)}] (2+) (5, 56MEGL), displays no cytotoxicity and is excluded as the source of the anticancer activity. Once bound by glutathione, these metal complexes do not then form coordinate bonds with guanosine. Partial encapsulation of the complexes within cucurbit[n]urils is able to stop the degradation process.

Examination of cucurbit[7]uril and its host-guest complexes by diffusion nuclear magnetic resonance.

The self-diffusion of cucurbit[7]uril (CB[7]) and its host-guest complexes in D2O has been examined using pulsed gradient spin-echo nuclear magnetic resonance spectroscopy. CB[7] diffuses freely at a concentration of 2 mM with a diffusion coefficient (D) of 3.07 x 10(-10) m(2) s(-1). At saturation (3.7 mM), CB[7] diffuses more slowly (D = 2.82 x 10(-10) m(2) s(-1)) indicating that it partially self-associates. At concentrations between 2 and 200 mM, CsCl has no effect on the diffusion coefficient of CB[7] (1 mM). Conversely, CB[7] (2 mM) significantly affects the diffusion of 133Cs+ (1 mM), decreasing its diffusion coefficient from 1.86 to 0.83 x 10(-9) m(2) s(-1). Similar changes in the rate of diffusion of other alkali earth metal cations are observed upon the addition of CB[7]. The diffusion coefficient of 23Na+ changes from 1.26 to 0.90 x 10(-9) m(2) s(-1) and 7Li+ changes from 3.40 to 3.07 x 10(-9) m(2) s(-1). In most cases, encapsulation of a variety of inorganic and organic guests within CB[7] decreases their rates of diffusion in D2O. For instance, the diffusion coefficient of the dinuclear platinum complex trans-[[PtCl(NH3)2}2mu-dpzm](2+) (where dpzm is 4,4'-dipyrazolylmethane) decreases from 4.88 to 2.95 x 10(-10) m(2) s(-1) upon encapsulation with an equimolar concentration of CB[7].