Cisplatin induced arrhythmia; electrolyte imbalance or disturbance of the SA node?

Since its approval in 1979 cisplatin has become one of the most extensively used chemotherapeutics in the clinic and although cell resistance and toxicity hinder its efficacy it continues to be a gold standard regimen. Cisplatin's side effects primarily include nephrotoxicity, gastrointestinal toxicity, neurotoxicity and ototoxicity. Cardiotoxicity is generally not defined as a side effect of cisplatin. However, over the past decade there has been a surge in the amount of clinical cases reporting a vast array of cardio-toxic events occurring during or shortly after cisplatin infusion, these range from angina to cardiac ischemia and chronic heart failure. This review intends to discuss the clinical cardiac manifestations of cisplatin specifically tachycardia and bradycardia which can be lethal and the possible mechanisms of action

The ex vivo neurotoxic, myotoxic and cardiotoxic activity of cucurbituril-based macrocyclic drug delivery vehicles

The cucurbituril family of drug delivery vehicles have been examined for their tissue specific toxicity using ex vivo models. Cucurbit[6]uril (CB[6]), cucurbit[7]uril (CB[7]) and the linear cucurbituril-derivative Motor2 were examined for their neuro-, myo- and cardiotoxic activity and compared with β-cyclodextrin. The protective effect of drug encapsulation by CB[7] was also examined on the platinum-based anticancer drug cisplatin. The results show that none of the cucurbiturils have statistically measurable neurotoxicity as measured using mouse sciatic nerve compound action potential. Cucurbituril myotoxicity was measured by nerve-muscle force of contraction through chemical and electrical stimulation. Motor2 was found to display no myotoxicity, whereas both CB[6] and CB[7] showed myotoxic activity via a presynaptic effect. Finally, cardiotoxicity, which was measured by changes in the rate and force of right and left atria contraction, was observed for all three cucurbiturils. Free cisplatin displays neuro-, myo- and cardiotoxic activity, consistent with the side-effects seen in the clinic. Whilst CB[7] had no effect on the level of cisplatin's neurotoxic activity, drug encapsulation within the macrocycle had a marked reduction in both the drug's myo- and cardiotoxic activity. Overall the results are consistent with the relative lack of toxicity displayed by these macrocycles in whole animal acute systemic toxicity studies and indicate continued potential of cucurbiturils as drug delivery vehicles for the reduction of the side effects associated with platinum-based chemotherapy

The ex vivo neurotoxic, myotoxic and cardiotoxic activity of cucurbituril-based macrocyclic drug delivery vehicles

The cucurbituril family of drug delivery vehicles have been examined for their tissue specific toxicity using ex vivo models. Cucurbit[6]uril (CB[6]), cucurbit[7]uril (CB[7]) and the linear cucurbituril-derivative Motor2 were examined for their neuro-, myo- and cardiotoxic activity and compared with β-cyclodextrin. The protective effect of drug encapsulation by CB[7] was also examined on the platinum-based anticancer drug cisplatin. The results show that none of the cucurbiturils have statistically measurable neurotoxicity as measured using mouse sciatic nerve compound action potential. Cucurbituril myotoxicity was measured by nerve-muscle force of contraction through chemical and electrical stimulation. Motor2 was found to display no myotoxicity, whereas both CB[6] and CB[7] showed myotoxic activity via a presynaptic effect. Finally, cardiotoxicity, which was measured by changes in the rate and force of right and left atria contraction, was observed for all three cucurbiturils. Free cisplatin displays neuro-, myo- and cardiotoxic activity, consistent with the side-effects seen in the clinic. Whilst CB[7] had no effect on the level of cisplatin’s neurotoxic activity, drug encapsulation within the macrocycle had a marked reduction in both the drug’s myo- and cardiotoxic activity. Overall the results are consistent with the relative lack of toxicity displayed by these macrocycles in whole animal acute systemic toxicity studies and indicate continued potential of cucurbiturils as drug delivery vehicles for the reduction of the side effects associated with platinum-based chemotherapy

Cucurbit[7]uril encapsulated cisplatin overcomes cisplatin resistance via a pharmacokinetic effect

The cucurbit[n]uril (CB[n]) family of macrocycles has been shown to have potential in drug delivery where they are able to provide physical and chemical stability to drugs, improve drug solubility, control drug release and mask the taste of drugs. Cisplatin is a small molecule platinum-based anticancer drug that has severe dose-limiting side-effects. Cisplatin forms a host–guest complex with cucurbit[7]uril (cisplatin@CB[7]) with the platinum atom and both chlorido ligands located inside the macrocycle, with binding stabilised by four hydrogen bonds (2.15–2.44 A ˚ ). Whilst CB[7] has no effect on the in vitro cytotoxicity of cisplatin in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant sub-lines A2780/cp70 and MCP1, there is a significant effect on in vivo cytotoxicity using human tumour xenografts. Cisplatin@CB[7] is just as effective on A2780 tumours compared with free cisplatin, and in the cisplatin-resistant A2780/cp70 tumours cisplatin@CB[7] markedly slows tumour growth. The ability of cisplatin@CB[7] to overcome resistance in vivo appears to be a pharmacokinetic effect. Whilst the peak plasma level and tissue distribution are the same for cisplatin@CB[7] and free cisplatin, the total concentration of circulating cisplatin@CB[7] over a period of 24 hours is significantly higher than for free cisplatin when administered at the equivalent dose. The results provide the first example of overcoming drug resistance via a purely pharmacokinetic effect rather than drug design or better tumour targeting, and demonstrate that in vitro assays are no longer as important in screening advanced systems of drug delivery

The status of platinum anticancer drugs in the clinic and in clinical trials

Since its approval in 1979 cisplatin has become an important component in chemotherapy regimes for the treatment of ovarian, testicular, lung and bladder cancers, as well as lymphomas, myelomas and melanoma. Unfortunately its continued use is greatly limited by severe dose limiting side effects and intrinsic or acquired drug resistance. Over the last 30 years, 23 other platinum-based drugs have entered clinical trials with only two (carboplatin and oxaliplatin) of these gaining international marketing approval, and another three (nedaplatin, lobaplatin and heptaplatin) gaining approval in individual nations. During this time there have been more failures than successes with the development of 14 drugs being halted during clinical trials. Currently there are four drugs in the various phases of clinical trial (satraplatin, picoplatin, LipoplatinTM and ProLindacTM). No new small molecule platinum drug has entered clinical trials since 1999 which is representative of a shift in focus away from drug design and towards drug delivery in the last decade. In this perspective article we update the status of platinum anticancer drugs currently approved for use, those undergoing clinical trials and those discontinued during clinical trials, and discuss the results in the context of where we believe the field will develop over the next decade

An implantable hydrogel for the delivery of cisplatin and the ex vivo neurotoxic, neuromyopathic and cardiotoxic activity of platinum-based anticancer drugs and macrocyclic drug delivery systems

Cisplatin is currently a leading anticancer drug used in the treatment of various cancers. Its clinical use, however, is limited by its poor bioavailability, its undesirable toxic side effects profile and by the ability of certain tumours to develop cisplatin resistance. A method that may overcome these problems is the reversible encapsulation of cisplatin within the cavity of a macro cyclic container such as cucurbit[7]uril; a macrocycle formed by the acid condensation of glycoluril and formaldehyde, which has been shown to overcome acquired resistance in an in vivo human tumour xenograft model via a pharmacokinetic effect. In the first section of this thesis an implantable hydrogel based system was developed for the delivery of cisplatin and cisplatin@CB[7]. First, cisplatin was encapsulated within cucucrbit[7]uril (CB[7]) to form the host-guest complex: cisplatin@CB[7]. This was then incorporated into gelatin and 0-4% w/v polyvinyl alcohol (PVA)-based hydrogels as slow release drug delivery systems. In vitro studies of the hydrogels demonstrated predictable yet not significant swelling and disintegration dependent on their PVA concentration. The hydrogel with the highest PVA content was slower to swell and release drug compared with hydrogels containing lower concentrations of PVA. The effect of the hydrogel's PVA concentration on in vitro cytotoxicity was examined using A2780/CP70 ovarian cancer cells with results showing a significant reduction in cytotoxicity as the hydrogel's PVA concentration increased which indicated that a slow release system was achieved. Over the 24 hours of drug exposure time used, hydrogels containing 4% PVA loaded with 1mM of cisplatin@CB[7] showed a 19 ± 0.01% (p = 0.004) decrease in viable cells compared to the control, whereas hydrogels containing 0% and 2% PVA induced an 81.2 ± 0.003% (p = 0.0005) and 42 ± 0.02% (p = 0.0002) inhibition of cell growth, respectively. Finally, the in vivo efficacy of a 2% PVA hydrogel implanted under the skin of nude mice bearing A2780/CP70 xenografts showed that low dose hydrogels containing cisplatin@CB[7] (30 μg equivalent of drug) was just as effective as an intraperitoneal high dose administration of free cisplatin (150 μg) at inhibiting tumour growth. Overall, the results suggest an ability of implantable hydrogels to treat cancers with much lower doses of drug, thereby reducing the severity of the toxic side effects induced. In the second section of this thesis, cisplatin, CB[7] and cisplatin@CB[7] were tested and compared for their ex vivo neurotoxic, neuromyopathic and cardiotoxic activity amongst other platinum-based drugs (K₂PtCl₄, 56MESS and PHENEN) and macrocyclic drug delivery systems (CB[6], β-cyclodextrin, Motor2 and pentamer) using electrophysiological methods. The neurotoxic activity of the drugs was studied using mouse desheathed sciatic nerve preparations. Both cisplatin and CB[7] administered at a concentration of 300 μM decreased the amplitude of the nerve compound action potential (nCAP) by 13 ± 4.7% ( p = 0.3) and 4 ± 0.2% ( p = 0.8), respectively over an 80 minute period. Neuromyopathic activity was studied using the chick biventer cervicis nerve muscle preparation. Results showed that incubation of the nerve-muscle tissue with 300 μM of cisplatin caused statistically significant muscle paralysis to occur by decreasing the electrically stimulated muscle twitch response by 96 ± 4% (p = 0.001), through interference in the presynaptic neuron. Whereas, CB[7] caused a statistically significant muscle paralysis by decreasing the electrically stimulated muscle twitch response by 84 ± 9% (p = 0.001) through interference with the postsynaptic muscle membrane. Cardiotoxic activity was examined using the rat right and left heart atria. Results show that incubation of the atria tissue with 300 μM of cisplatin reduced the contraction rate of the right atria by 68.8 ± 1% (p = 0.001) and in the left atria by 1 ± 1% (p = 0.4) by the end of the two hour period study. When incubated with 300 μM of CB[7], the contraction rate in the right atria increased by 31 ± 13.6% (p = 0.3) and decreased in the left atria by 10 ± 3.5% (p = 0.3) Finally, the effect of the encapsulation of cisplatin by CB[7] on its neurotoxic, neuromyopathic and cardiotoxic activity was investigated. Results show that while the encapsulation had no effect on the neurotoxic activity of cisplatin, the encapsulated complex reduced the extent of cisplatin's neuromyopathic activity by reducing the muscle paralysis induced by cisplatin by 60%. When encapsulated by CB[7], the cardiotoxicity of cisplatin on the contraction rate of the right atria was also significantly decreased from 65.8% to 11%. In conclusion, these results suggest that CB[7] could exhibit neuromyopathy and cardio protective properties as it reduced the neuromyopathic and cardiotoxic activity of the encapsulated cisplatin.Cisplatin is currently a leading anticancer drug used in the treatment of various cancers. Its clinical use, however, is limited by its poor bioavailability, its undesirable toxic side effects profile and by the ability of certain tumours to develop cisplatin resistance. A method that may overcome these problems is the reversible encapsulation of cisplatin within the cavity of a macro cyclic container such as cucurbit[7]uril; a macrocycle formed by the acid condensation of glycoluril and formaldehyde, which has been shown to overcome acquired resistance in an in vivo human tumour xenograft model via a pharmacokinetic effect. In the first section of this thesis an implantable hydrogel based system was developed for the delivery of cisplatin and cisplatin@CB[7]. First, cisplatin was encapsulated within cucucrbit[7]uril (CB[7]) to form the host-guest complex: cisplatin@CB[7]. This was then incorporated into gelatin and 0-4% w/v polyvinyl alcohol (PVA)-based hydrogels as slow release drug delivery systems. In vitro studies of the hydrogels demonstrated predictable yet not significant swelling and disintegration dependent on their PVA concentration. The hydrogel with the highest PVA content was slower to swell and release drug compared with hydrogels containing lower concentrations of PVA. The effect of the hydrogel's PVA concentration on in vitro cytotoxicity was examined using A2780/CP70 ovarian cancer cells with results showing a significant reduction in cytotoxicity as the hydrogel's PVA concentration increased which indicated that a slow release system was achieved. Over the 24 hours of drug exposure time used, hydrogels containing 4% PVA loaded with 1mM of cisplatin@CB[7] showed a 19 ± 0.01% (p = 0.004) decrease in viable cells compared to the control, whereas hydrogels containing 0% and 2% PVA induced an 81.2 ± 0.003% (p = 0.0005) and 42 ± 0.02% (p = 0.0002) inhibition of cell growth, respectively. Finally, the in vivo efficacy of a 2% PVA hydrogel implanted under the skin of nude mice bearing A2780/CP70 xenografts showed that low dose hydrogels containing cisplatin@CB[7] (30 μg equivalent of drug) was just as effective as an intraperitoneal high dose administration of free cisplatin (150 μg) at inhibiting tumour growth. Overall, the results suggest an ability of implantable hydrogels to treat cancers with much lower doses of drug, thereby reducing the severity of the toxic side effects induced. In the second section of this thesis, cisplatin, CB[7] and cisplatin@CB[7] were tested and compared for their ex vivo neurotoxic, neuromyopathic and cardiotoxic activity amongst other platinum-based drugs (K₂PtCl₄, 56MESS and PHENEN) and macrocyclic drug delivery systems (CB[6], β-cyclodextrin, Motor2 and pentamer) using electrophysiological methods. The neurotoxic activity of the drugs was studied using mouse desheathed sciatic nerve preparations. Both cisplatin and CB[7] administered at a concentration of 300 μM decreased the amplitude of the nerve compound action potential (nCAP) by 13 ± 4.7% ( p = 0.3) and 4 ± 0.2% ( p = 0.8), respectively over an 80 minute period. Neuromyopathic activity was studied using the chick biventer cervicis nerve muscle preparation. Results showed that incubation of the nerve-muscle tissue with 300 μM of cisplatin caused statistically significant muscle paralysis to occur by decreasing the electrically stimulated muscle twitch response by 96 ± 4% (p = 0.001), through interference in the presynaptic neuron. Whereas, CB[7] caused a statistically significant muscle paralysis by decreasing the electrically stimulated muscle twitch response by 84 ± 9% (p = 0.001) through interference with the postsynaptic muscle membrane. Cardiotoxic activity was examined using the rat right and left heart atria. Results show that incubation of the atria tissue with 300 μM of cisplatin reduced the contraction rate of the right atria by 68.8 ± 1% (p = 0.001) and in the left atria by 1 ± 1% (p = 0.4) by the end of the two hour period study. When incubated with 300 μM of CB[7], the contraction rate in the right atria increased by 31 ± 13.6% (p = 0.3) and decreased in the left atria by 10 ± 3.5% (p = 0.3) Finally, the effect of the encapsulation of cisplatin by CB[7] on its neurotoxic, neuromyopathic and cardiotoxic activity was investigated. Results show that while the encapsulation had no effect on the neurotoxic activity of cisplatin, the encapsulated complex reduced the extent of cisplatin's neuromyopathic activity by reducing the muscle paralysis induced by cisplatin by 60%. When encapsulated by CB[7], the cardiotoxicity of cisplatin on the contraction rate of the right atria was also significantly decreased from 65.8% to 11%. In conclusion, these results suggest that CB[7] could exhibit neuromyopathy and cardio protective properties as it reduced the neuromyopathic and cardiotoxic activity of the encapsulated cisplatin

The need for mandatory academic laboratory sustainability training – a fume cupboard case study

While scientific research is paramount to understanding the solar system, ecosystem, human disease and cures (etc) it continues to contribute to human-caused climate change. Scientists are becoming increasingly aware of the carbon footprint associated with their research and recognise the need to work more efficiently with their resource use and laboratory operations. University laboratories are spaces that allow for research to be carried out safely, however, they consume five times more energy per square meter than office buildings. Fume cupboards are amongst the most energy intensive equipment and thus are a dominant factor when working towards creating safer and greener laboratories. In this paper, we report on the gas, electricity, carbon and financial savings derived by upgrading 105 constant air volume fume cupboards to variable air volume systems. We also report on the frequency of fume cupboard use by research staff, postgraduate students, and their overall understanding of fume cupboard best practice operations. The results reflect that while savings were achieved, they were lower than predicted. A factor to this may be poor student and staff understanding of how fume cupboards work resulting in their incorrect usage, therefore hampering sustainable progression. This study highlights that a major gap exists between laboratory technical upgrades and researcher awareness of proper and safe equipment use and operation. To overcome this, we propose that in addition to health and safety training, mandatory laboratory sustainability operations training should be provided to all laboratory users

A cisplatin slow-release hydrogel drug delivery system based on a formulation of the macrocycle cucurbit[7]uril, gelatin and polyvinyl alcohol

The anticancer drug cisplatin was encapsulated within the cucurbit[7]uril macrocycle to form the host-guest complex: cisplatin@CB[7]. This was then incorporated into gelatin and 0–4% w/v polyvinyl alcohol (PVA)-based hydrogels as slow release drug delivery vehicles. The hydrogels demonstrated predicable swelling and disintegration dependent on the PVA concentration. The hydrogel with the highest PVA content was slower to swell and release drug compared with lower concentrations of PVA. The effect of the hydrogel PVA concentration on in vitro cytotoxicity was examined using A2780/CP70 ovarian cancer cells. Over the 24 h drug exposure time used, hydrogels containing 4% PVA showed a 20% decrease in viable cells compared to the control, whereas hydrogels containing 0% and 2% PVA induced an 80% and 45% inhibition of cell growth, respectively. There was no measurable difference in the in vitro cytotoxicity of free cisplatin and cisplatin@CB[7] containing hydrogels. Finally, the in vivo effectiveness of a 2%-PVA hydrogel implanted under the skin of nude mice bearing A2780/CP70 xenografts showed that low dose hydrogels containing cisplatin@CB[7] (30 μg equivalent of drug) was just as effective as an intraperitoneal high dose administration of free cisplatin (150 μg) at inhibiting tumour growth