Search

I am blessed to be in a unique situation. Being born in the late 80s, I am fortunate to toe the line in our industry: I have enough experience and [...]

Located within the Hajar Mountains, the first rock-driven traffic tunnel currently being constructed in the United Arab Emirates, will form an integral link for a new highway project between Sharjah [...]

In drug discovery it is essential that one of the parameters tested for any new chemical entity is its affinity for human efflux systems, most notably P-glycoprotein (P-gp). These efflux systems affect not only rates of oral absorption but also rates of excretion through the liver, blood–brain barrier, and accumulation in potential target cells that upregulate efflux systems. Current methods to determine drugs’ P-gp transport potential include in vitro bidirectional transport studies, and the two most common cell lines used are Caco2 and MDR1-transfected MDCK models. Caco2 cells are human but slow growing and require more than 3 weeks to mature, while MDCK cells are canine, but when transfected with human P-gp become a rapid model of P-gp affinity. Our laboratory has generated a Caco2 subclone called CLEFF4 that is fully human, yet now approaches the rapid nature of the MDCK model. No special medium is required. We have shown, in as little as 5 days postseeding, high transepithelial electrical resistance values of more than 1000 Ω·cm2plus P-gp expression more than threefold higher than that of 21-day-old cells. Currently tested drugs included rhodamine 123 (Rh123), vinblastine, and doxorubicin, and all drugs exhibited P-gp-mediated efflux that was inhibited by PSC833. By day 6, bidirectional transport of Rh123 was as potent as that of mature Caco2 cells, for use in comparative P-gp affinity studies. We now have a human P-gp model that is rapid and works without any need for special accelerating medium. We believe this could be a welcome addition to the testing regime of new chemical entities.

Invasive alien species (IAS) are one of the most severe threats to biodiversity and are the subject of varying degrees of surveillance activity. Predictive early warning systems (EWS), incorporating automated surveillance of relevant dataflows, warning generation and dissemination to decision makers are a key target for developing effective management around IAS, alongside more conventional early detection and horizon scanning technologies. Sophisticated modelling frameworks including the definition of the ‘risky’ species pool, and pathway analysis at the macro and micro-scale are increasingly available to support decision making and to help prioritise risks from different regions and/or taxa. The main challenges in constructing such frameworks, to be applied to border inspections, are (i) the lack of standardisation and integration of the associated complex digital data environments and (ii) effective integration into the decision making process, ensuring that risk information is disseminated in an actionable way to frontline surveillance staff and other decision makers. To truly achieve early warning in biosecurity requires close collaboration between developers and end-users to ensure that generated warnings are duly considered by decision makers, reflect best practice, scientific understanding and the working environment facing frontline actors. Progress towards this goal will rely on openness and mutual understanding of the role of EWS in IAS risk management, as much as on developments in the underlying technologies for surveillance and modelling procedures.

This study was conducted to determine the rate of P-glycoprotein (P-gp)–mediated efflux of digoxin analogues and metabolites and to assess the effects of macrolide antibiotics on this efflux. Bidirectional transport studies were conducted using our Caco-2 sub clone with high P-gp expression (CLEFF9). HPLC methods were employed to measure drug transport. All digoxin metabolites were P-gp substrates, although digoxin had the greatest efflux ratio. Erythromycin had no effect on the transport of digoxin, maintaining a basolateral to apical efflux ratio of 14.8, although it did reduce the efflux ratio of dihydrodigoxin and digoxigenin by 34% and 43%, respectively. Azithromycin also had little effect on the transport of digoxin or any of its metabolites. In contrast, clarithromycin and roxithromycin almost eliminated basolateral targeted efflux. Using paclitaxel as a known P-gp substrate, erythromycin demonstrated only partial P-gp inhibitory capacity, maintaining an efflux ratio over 100. In contrast, clarithromycin and roxithromycin were 10-fold greater P-gp inhibitors. Clarithromycin and roxithromycin are likely to exhibit drug interactions with digoxin via inhibition of efflux mechanisms. Azithromycin appears to have little influence on P-gp–mediated digoxin absorption or excretion and would be the safest macrolide to use concurrently with oral digoxin.

Background:Breastfeeding-related adverse drug reactions (ADRs) are thought to be uncommon as reported cases are globally low. The nonspecific nature of these reactions and a lack of awareness and difficulty in identification of ADRs by mothers and clinicians may result in these ADRs being underreported.Aims:This study hypothesized that breastfeeding-related infant ADRs are more frequent than reported. As a first-hand account of breastfeeding mothers, this study aimed to evaluate the impact of the perceived ADRs on the continuation of breastfeeding and maternal treatment.Methods:Women currently breastfeeding or having breastfed in the last 12 months were invited to complete an online survey. The survey comprised 42 questions in 5 sections to obtain data from breastfeeding mothers, including their use of medicines during lactation, perceptions of infant adverse reactions attributable to maternal medication use and its potential impact on breastfeeding.Results:This online survey was completed by 339 women, 42% of whom reported taking at least one medication during breastfeeding. ADRs were reported in 23 infants where a possible or probable causal relationship indicated by a Naranjo score of 1–8 was established in 16 (11.3%). Antibiotics (n= 12) and opioids (n= 2), including tramadol and oxycodone were identified as the most common adverse reaction-causing drugs. The average age of infants at the time of the perceived ADR was 25.6 days (95% confidence interval; 4–85 days; median age 17.5 days).Conclusion:Suspected ADR reporting in this study was significantly greater than those reported to the regulatory body, the Australian Therapeutics Goods Administration, which shows that common breastfeeding-related infant ADRs are underreported.

Abstract: Environmental lead intoxication, which frequently causes neurological disturbances, and iron deficiency are clinical problems commonly found in children. Also, iron deficiency has been shown to augment lead absorption from the intestine. Hence, there is evidence for an interaction between lead and iron metabolism which could produce changes in lead and iron uptake by the brain and other tissues. These possibilities were investigated using 15-, 21-, and 63-old rats with varying nutritional iron and lead status. Dams were fed diets containing 0 or 3% lead-acetate and 0.2% lead-acetate in the drinking water. After weaning, 0.2% lead-acetate in the drinking water became the sole source of dietary lead. Measurements were made of tissue lead and nonheme iron levels and the uptake of59Fe after intravenous injection of transferrin-bound59Fe. Iron deficiency was associated with increased intestinal absorption of lead as indicated by blood and kidney lead levels in rats exposed to dietary lead. However, iron deficiency did not increase lead deposition in the brain, and in all rats brain lead levels were relatively low (<0.1 μg/g). Lead concentrations in the liver were below 2 μg/g, whereas kidneys had almost 20 times this concentration. Animals with iron deficiency had lower liver iron levels and had increased brain59Fe uptake in comparison to control rats. However, iron levels in brain and kidneys were unaffected by lead intoxication regardless of the animal's iron status.59Fe uptake rates were also unaffected by lead, but increased rates of uptake were apparent in iron-deficient rats. Lead did increase liver iron levels in all iron-adequate rats, but iron deficiency had little effect. It is concluded that, compared with other tissues, the blood-brain barrier largely restricts lead uptake by the brain and that the uptake that does occur is unrelated to the iron status of the animal. Also, the level of lead intoxication produced in this investigation did not influence iron uptake by the brain and kidneys, but liver iron stores could be incresed if iron levels were already adequate.

Little is known regarding the interactions between iron and cadmium during postnatal development. This study examined the effect of altered levels of dietary iron and cadmium loading on the distribution of cadmium and iron in developing rats ages 15, 21, and 63 days. The uptake of iron, transferrin, and cadmium into various organs was also examined using59Fe, [125I]transferrin, and109Cd. Dietary cadmium loading reduced packed cell volume and plasma iron and nonheme iron levels in the liver and kidneys, evidence of the inducement of an iron deficient state. Dietary iron loading was able to reverse these effects, suggesting that they were the result of impaired intestinal absorption of iron. Cadmium loading resulted in cadmium concentrations in the liver and kidneys up to 20 μg/g in rats age 63 days, while cadmium levels in the brain reached only 0.16 μg/g, indicating that the blood–brain barrier restricts the entry of cadmium into the brain. Iron loading had little effect on cadmium levels in the organs and cadmium feeding did not lower tissue iron levels in iron loaded animals. These results suggest that cadmium inhibits iron absorption only at low to normal levels of dietary iron and that at high levels of intake iron and cadmium are largely absorbed by other, noncompetitive mechanisms. It was shown that109Cd is removed from the plasma extremely quickly irrespective of iron status and deposits mainly in the liver. One of the most striking effects of cadmium loading on iron metabolism was increased uptake of [125I]transferrin by the heart, possibly by disrupting the process of receptor-mediated endocytosis and recycling of transferrin by heart muscle.

Purpose. To compare the intestinal absorption and active efflux protein susceptibility of a new immunosuppressive agent (SDZ-RAD) with that of its analog rapamycin. Methods. Caco-2 cell monolayers were used to examine bidirectional transport of the two compounds at low micromolar concentrations. Single pass rat intestinal perfusion was also used to examine steady state permeability. Results. Rapamycin and SDZ-RAD showed a distinct preference for transport in the basolateral to apical direction of Caco-2 monolayers as efflux was >20 times greater than apical to basolateral transport. Efflux of SDZ-RAD was completely inhibited by verapamil while efflux of rapamycin was mostly inhibited by verapamil and partially inhibited by probenecid. Passive permeability was shown to be 20 × 10−6cm/sec for SDZ-RAD and 10 × 10−6cm/sec for rapamycin. In siturat studies also showed the permeability of rapamycin to be half that of SDZ-RAD with permeabilities of 12.6 × 10−6for rapamycin and 24.8 × 10−6cm/sec for SDZ-RAD. Conclusions. SDZ-RAD and rapamycin are strong substrates for P-gp-like mediated efflux. Rapamycin is also partially removed from cells by a second efflux system that is not responsive to SDZ-RAD. When these efflux pumps are inhibited SDZ-RAD is likely to be absorbed across the intestine at a faster rate than rapamycin.

ABSTRACTBidirectional transport of four novel antimalarial compounds was determined using Caco-2 cell monolayers. P glycoprotein-mediated efflux was greatest for pyronaridine (5 to 20 μM) and low for naphthoquine (5 μM). With 20 μM naphthoquine, net efflux was blocked, suggesting saturation of the transporter. Piperaquine and dihydroartemisinin were not transported by the system.

The poem "Little Rabbit, Run" by Andrew Crowe is presented. First Line: Run, run, little rabbit, Last Line: at least in the garden.

The article presents the poem "State and Union," by Andrew Crowe. First Line: When streets cross; Last Line: And the lamps that will always light them.

Presents the concrete poem "Crowe Poetry Graph," by Andrew Crowe. First Line: Description: Last Line: a - apex (climax).