A Potential Role for Creatine in Drug Abuse?

Supplemental creatine has been promoted for its positive health effects and is best known for its use by athletes to increase muscle mass. In addition to its role in physical performance, creatine supplementation has protective effects on the brain in models of neuronal damage and also alters mood state and cognitive performance. Creatine is found in high protein foods, such as fish or meat, and is also produced endogenously from the biosynthesis of arginine, glycine, and methionine. Changes in brain creatine levels, as measured using magnetic resonance spectroscopy, are seen in individuals exposed to drugs of abuse and depressed individuals. These changes in brain creatine indicate that energy metabolism differs in these populations relative to healthy individuals. Recent work shows that creatine supplementation has the ability to function in a manner similar to antidepressant drugs and can offset negative consequences of stress. These observations are important in relation to addictive behaviors as addiction is influenced by psychological factors such as psychosocial stress and depression. The significance of altered brain levels of creatine in drug-exposed individuals and the role of creatine supplementation in models of drug abuse have yet to be explored and represent gaps in the current understanding of brain energetics and addiction.     

Predictive Modeling of Drug Response in Non-Hodgkin’s Lymphoma

We combine mathematical modeling with experiments in living mice to quantify the relative roles of intrinsic cellular vs. tissue-scale physiological contributors to chemotherapy drug resistance, which are difficult to understand solely through experimentation. Experiments in cell culture and in mice with drug-sensitive (Eµ-myc/Arf-/-) and drug-resistant (Eµ-myc/p53-/-) lymphoma cell lines were conducted to calibrate and validate a mechanistic mathematical model. Inputs to inform the model include tumor drug transport characteristics, such as blood volume fraction, average geometric mean blood vessel radius, drug diffusion penetration distance, and drug response in cell culture. Model results show that the drug response in mice, represented by the fraction of dead tumor volume, can be reliably predicted from these inputs. Hence, a proof-of-principle for predictive quantification of lymphoma drug therapy was established based on both cellular and tissue-scale physiological contributions. We further demonstrate that, if the in vitro cytotoxic response of a specific cancer cell line under chemotherapy is known, the model is then able to predict the treatment efficacy in vivo. Lastly, tissue blood volume fraction was determined to be the most sensitive model parameter and a primary contributor to drug resistance.     

Multiscale Modelling of Fluid and Drug Transport in Vascular Tumours

A model for fluid and drug transport through the leaky neovasculature and porous interstitium of a solid tumour is developed. The transport problems are posed on a micro-scale characterized by the inter-capillary distance, and the method of multiple scales is used to derive the continuum equations describing fluid and drug transport on the length scale of the tumour (under the assumption of a spatially periodic microstructure). The fluid equations comprise a double porous medium, with coupled Darcy flow through the interstitium and vasculature, whereas the drug equations comprise advection–reaction equations; in each case the dependence of the transport coefficients on the vascular geometry is determined by solving micro-scale cell problems.     

Multi Drug and Other Forms of Drug Resistant Tuberculosis Are Uncommon among Treatment Na?ve Tuberculosis Patients in Tanzania

Background

Surveillance and effective management of drug resistance is important to sustaining tuberculosis (TB) control efforts. We aimed to determine resistance rates to first line anti tuberculosis drugs and to describe factors associated with the resistance to any of the first line anti tuberculosis drugs in Dar es Salaam Tanzania.

Materials

Newly diagnosed, TB patients with neither history of tuberculosis treatment nor isoniazid prophylaxis were included into the study. Sputum specimens were cultured on either mycobacteria growth indicator tube 960 (MGIT 960) or Lowenstein Jenstein (LJ) medium supplemented with either glycerol (GLJ) or pyruvate (PLJ). Drug susceptibility for isoniazid, rifampicin, streptomycin and ethambutol was determined by either Lowenstein–Jensen (LJ) medium or mycobacteria growth indicator tube 960 (MGIT 960).

Results

A total of 933 newly diagnosed TB patients, were included into the study. Multi drug resistance (MDR) tuberculosis was detected among 2 (0.2%) patients. Resistance to any of the four tested drugs was detected among 54 (5.8%) patients. Mono-resistance to isoniazid, rifampicin, streptomycin and ethambutol were 21(2.3%), 3 (0.3%), 13 (1.4%), 9 (1.0%) respectively.

Conclusion

Primary resistance to first line anti tuberculosis drugs is still low in this setting. Continued vigilance including periodic national surveillance of anti-tuberculosis resistance is recommended.     

Turning a Drug Target into a Drug Candidate: A New Paradigm for Neurological Drug Discovery?

The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a completely new paradigm in which an established drug target can be re-engineered to serve as a new candidate therapeutic agent. The L-glutamate-gated chloride channels (GluCls) of invertebrates are absent from vertebrate genomes, offering the opportunity to introduce this exogenous, inhibitory, L-glutamate receptor into vertebrate neuronal circuits either as a tool with which to study neural networks, or a candidate therapy. Epileptic seizures can involve L-glutamate-induced hyper-excitation and toxicity. Variant GluCls, with their inhibitory responses to L-glutamate, when engineered into human neurons, might counter the excitotoxic effects of excess L-glutamate. In reviewing recent studies on model organisms, it appears that this approach might offer a new paradigm for the development of candidate therapeutics for epilepsy.     

Investigation of Need of Natural Bioenhancer for a Metabolism Susceptible Drug—Raloxifene,in a Designed Self-Emulsifying Drug Delivery System

Bioenhancers can increase the bioavailability of metabolism susceptible drugs. The present study was designed to understand the impact of bioenhancer on permeability and bioavailability of a biopharmaceutical drug disposition classification system (BDDCS) class II drug raloxifene (RLX). RLX undergoes extensive first pass metabolism by UGT enzymes in gastrointestinal tract (GIT) and has an oral bioavailability of about 2%. Self-emulsifying drug delivery system (SEDDS) of RLX was developed using a designed approach and this formulation was loaded with reported bioenhancers: quercetin and piperine. These formulations were tested for improvement in permeability and bioavailability of the RLX. The apparent permeability using everted gut sac (P _app) for SEDDS (5.26?±?1.10?×?10^?8 cm/s) was found to be similar to that of SEDDS with bioenhancers (5.11?±?1.05?×?10^?8 cm/s). In oral bioavailability study in rat, SEDDS demonstrated a 4-fold and 2.5-fold higher AUC_0–∞ than RLX suspension (control) and marketed product, respectively. No additional improvement in permeability and bioavailability was offered by inclusion of piperine and quercetin (bioenhancers) in the SEDDS.     

Soluplus-Solubilized Citrated Camptothecin—A Potential Drug Delivery Strategy in Colon Cancer

Camptothecin (CPT), a potent antitumor drug, exhibits poor aqueous solubility and rapid conversion from the pharmacologically active lactone form to inactive carboxylate form at physiological pH. Solid dispersion of CPT in Soluplus®, an amphiphilic polymeric solubilizer, was prepared to increase the aqueous solubility of CPT and the resultant solid dispersion along with citric acid was formulated as hard gelatin capsules that were subsequently coated with Eudragit S100 polymer for colonic delivery. FTIR spectrum of the solid dispersion confirmed the presence of CPT. PXRD and DSC revealed the semicrystalline nature of solid dispersion. The solubility of the drug was found to increase ~40 times in the presence of Soluplus and ~75 times in solid dispersion. The capsules showed no drug release in 0.01 N HCl but released 86.4% drug in lactone form in phosphate buffer (pH 7.4) and the result appears to be due to citric acid-induced lowering of pH of buffer from 7.4 to 6.0. Thus the presence of citric acid in the formulation led to stabilization of the drug in its pharmacologically active lactone form. Cytotoxicity studies conducted with the formulation of solid dispersion with citric acid, utilizing cell cytotoxicity test (MTT test) on Caco-2 cells, confirmed cytotoxic nature of the formulation.     

Is DL-Fenfluramine a Potentially Helpful Drug Therapy in Overweight Adolescent Subjects?

We have studied the therapeutic effects of two different doses (30 mg and 60 mg, twice daily) of DL-fen-fluramine (DL-F) in, respectively, prepuberal (11–13 years old) and adolescent subjects (14–17 years old). Sixty-eight obese subjects were recruited for this study (22 boys, 36 girls, aged 10–17 years old) with body mass index ranging from 24.5 to 44.0 kg/m², absolute weight ranging from 37.0 to 119.5 kg and % over IBW ranging from 122% to 260%. Results were compared to a placebo treated group of obese adolescent patients (n=17), 6 boys and 11 girls, aged 10–17 years old, BMI ranging from 26–44 kg/m², absolute weight 53.1 to 96.5 kg, and with 129% to 253% over IBW. In the DL-F-treated subjects most patients (n=41) had a continuous weight loss during 12 months but 27 individuals were unable to lose any additional weight after the initial 6 months of the trial. Taken together 65% of all patients lost weight during DL-F treatment (12 months) whereas only 17.4% of the placebo group lost a significant (>10% BMI) amount of excess weight. Also the placebo group had a higher withdrawal rate (57%) as compared with the DL-F-treated group (24%). There was a significant (p<0.05) decrease of the mean & SD of the BMI (at 6 and 12 months of therapy). No significant change of the BMI was observed for control group. Minor adverse side effects consisted of a brief period of drowsiness and dry mouth. Our findings indicated that the continuous administration of DL-Fenfluramine might help obese adolescent subjects adhere to a diet and to maintain the weight loss achieved without major or harmful adverse effects .     

Temporal Variation in Drug Interaction Between Lithium and Morphine‐Induced Analgesia

The administration‐time‐dependent aspects of the drug interaction between lithium and morphine‐induced analgesia were studied using the mouse hot‐plate test at six different times of day, each scheduled at 4 h intervals. Lithium treatment alone, in doses of 1 to 10 mmol/kg administered intraperitoneally (i.p.) did not significantly alter test latencies compared to the corresponding clock‐time in saline‐injected controls. Basal pain sensitivity and morphine‐induced antinociceptive activity displayed significant circadian rhythms as assessed by the hot‐plate response latencies, with higher values occurring during the nocturnal activity than during the daytime rest span. Acute administration of lithium, in a dose of 3 mmol/kg, 30 min prior to morphine dosing did not influence morphine‐induced analgesia compared to all the clock‐time test‐matched morphine groups, except the 9 HALO (Hours After Lights On) one. There was a prominent potentiation of the morphine‐induced antinociception at this biological time during combined drug treatment. The latter finding demonstrates that administration‐time‐dependent differences in drug‐drug interactions need to be considered in both experimental designs and clinical settings.     

Trends in Antiretroviral Therapy and Prevalence of HIV Drug Resistance Mutations in Sweden 1997–2011

Objective

Describe trends in antiretroviral treatments and drug resistance mutations among Swedish HIV-patients over time 1997–2011.

Methods

Treatment histories, viral sequences, and demographic and clinical data were retrieved from the national database InfCareHIV. All ART-experienced patients were included (N = 6537), while resistance tests were restricted to those obtained ≥90 days after ART start. This cohort is fully representative for Sweden since the database covers virtually all diagnosed HIV-patients since the start of the epidemic. Patients were grouped according to the year of first ART, and treatments and mutations were analyzed by calendar year.

Results

The prevalence of major drug resistance mutations decreased dramatically over time, most rapidly between 2003 and 2007. Since then there has been a continued slow decrease for NRTI- and PI-associated mutations with an overall prevalence among all ART-experienced patients at 1.1% (NRTI) and 0.3% (PI) in 2011. NNRTI resistance reached the lowest level in 2007–2009 (0.6%), but is now increasing (0.9% in 2011). Patients with first ART exposure before 2001 are still highly overrepresented among those with PI and, to a lesser extent, NRTI resistance. In contrast, almost half of the patients with NNRTI mutations in 2011 initiated their first ART after 2007.

Conclusions

Tremendous improvements in ART options and knowledge have resulted in rapidly declining levels of resistance, and most of the current NRTI and PI mutations are found among patients with a history of suboptimal treatments. However, NNRTI resistance is increasing and is primarily found in patients infected in low- and middle-income countries who initiated ART in recent years. It is plausible that these patients were infected with resistant strains and it is therefore suggested that resource-rich countries like Sweden should test for resistance in minor quasispecies or use PI-based first-line regimens in patients who are at increased risk of carrying resistant virus.     

Drug inhibition profile prediction for NFκB pathway in multiple myeloma

Nuclear factor κB (NFκB) activation plays a crucial role in anti-apoptotic responses in response to the apoptotic signaling during tumor necrosis factor (TNFα) stimulation in Multiple Myeloma (MM). Although several drugs have been found effective for the treatment of MM by mainly inhibiting NFκB pathway, there are not any quantitative or qualitative results of comparison assessment on inhibition effect between different drugs either used alone or in combinations. Computational modeling is becoming increasingly indispensable for applied biological research mainly because it can provide strong quantitative predicting power. In this study, a novel computational pathway modeling approach is employed to comparably assess the inhibition effects of specific drugs used alone or in combinations on the NFκB pathway in MM and to predict the potential synergistic drug combinations.     

Abacavir-Reactive Memory T Cells Are Present in Drug Na?ve Individuals

BackgroundFifty-five percent of individuals with HLA-B*57:01 exposed to the antiretroviral drug abacavir develop a hypersensitivity reaction (HSR) that has been attributed to naïve T-cell responses to neo-antigen generated by the drug. Immunologically confirmed abacavir HSR can manifest clinically in less than 48 hours following first exposure suggesting that, at least in some cases, abacavir HSR is due to re-stimulation of a pre-existing memory T-cell population rather than priming of a high frequency naïve T-cell population.MethodsTo determine whether a pre-existing abacavir reactive memory T-cell population contributes to early abacavir HSR symptoms, we studied the abacavir specific naïve or memory T-cell response using HLA-B*57:01 positive HSR patients or healthy controls using ELISpot assay, intra-cellular cytokine staining and tetramer labelling.ResultsAbacavir reactive CD8+ T-cell responses were detected in vitro in one hundred percent of abacavir unexposed HLA-B*57:01 positive healthy donors. Abacavir-specific CD8+ T cells from such donors can be expanded from sorted memory, and sorted naïve, CD8+ T cells without need for autologous CD4+ T cells.ConclusionsWe propose that these pre-existing abacavir-reactive memory CD8+ T-cell responses must have been primed by earlier exposure to another foreign antigen and that these T cells cross-react with an abacavir-HLA-B*57:01-endogenous peptide ligand complex, in keeping with the model of heterologous immunity proposed in transplant rejection.     

Drug Users in Amsterdam: Are They Still at Risk for HIV?

Background and Aims

To examine whether drug users (DU) in the Amsterdam Cohort Study (ACS) are still at risk for HIV, we studied trends in HIV incidence and injecting and sexual risk behaviour from 1986 to 2011.

Methods

The ACS is an open, prospective cohort study on HIV. Calendar time trends in HIV incidence were modelled using Poisson regression. Trends in risk behaviour were modelled via generalized estimating equations. In 2010, a screening for STI (chlamydia, gonorrhoea and syphilis) was performed. Determinants of unprotected sex were studied using logistic regression analysis.

Results

The HIV incidence among 1298 participants of the ACS with a total follow-up of 12,921 person-years (PY) declined from 6.0/100 PY (95% confidence interval [CI] 3.2–11.1) in 1986 to less than 1/100 PY from 1997 onwards. Both injection and sexual risk behaviour declined significantly over time. Out of 197 participants screened for STI in 2010–2011, median age 49 years (IQR 43–59), only 5 (2.5%) were diagnosed with an STI. In multivariable analysis, having a steady partner (aOR 4.1, 95% CI 1.6–10.5) was associated with unprotected sex. HIV-infected participants were less likely to report unprotected sex (aOR 0.07, 95% CI 0.02–0.37).

Conclusions

HIV incidence and injection risk behaviour declined from 1986 onwards. STI prevalence is low; unprotected sex is associated with steady partners and is less common among HIV-infected participants. These findings indicate a low transmission risk of HIV and STI, which suggests that DU do not play a significant role in the current spread of HIV in Amsterdam.     

Cessation of Mass Drug Administration for Lymphatic Filariasis in Zanzibar in 2006: Was Transmission Interrupted?

BackgroundLymphatic filariasis (LF) is targeted for elimination through annual mass drug administration (MDA) for 4–6 years. In 2006, Zanzibar stopped MDA against LF after five rounds of MDA revealed no microfilaraemic individuals during surveys at selected sentinel sites. We asked the question if LF transmission was truly interrupted in 2006 when MDA was stopped.ConclusionsOur findings indicated ongoing transmission of LF on Pemba in 2012. Moreover, we presented evidence from previous studies that LF transmission was also active on Unguja shortly after stopping MDA in 2006. Based on these observations the government of Zanzibar decided to resume MDA against LF on both islands in 2013.     

The “Multi” of Drug Resistance Explained by Oscillating Drug Transporters,Drug–Membrane Physical Interactions and Spatial Dimensionality

Multi-drug resistance (MDR) can be explained by a drug handling-type activity. In this context it is also necessary to consider the multi-specificity between drugs and drug transporters in order to explain MDR. Accordingly, the efficiency of drug efflux in MDR has always been a conceptual problem in biochemistry. Indeed, how one protein can expel, from cells, hundreds of compounds with high specificity is still controversial today. To safeguard the notion of biochemical specificity, many studies have suggested alternative mechanisms to Pgp-mediated drug resistance, which do not involve the handling of drugs. However, none of these studies have definitively ruled out the possibility concept of drug handling. Thus, until now it was not possible to imagine MDR without drug-transporter affinity or specificity. However, drug-transporter affinity is not always needed to generate what appears to be a very efficient chemical reaction. Indeed, based on the fact that bi-dimensional diffusion properties (i.e. diffusion in the membrane) are paramount to explain drug pumping-mediated MDR, it is possible to suggest how specific mathematical properties of random motions can be used to construct a model of Pgp-MDR, providing that Pgp oscillates between open/drug-accepting and closed/drug-expelling conformations. This different viewpoint highlights the fact that the multi-specificity of drug transporters and the “vacuum cleaner” hypothesis may actually be two sides of the same coin, both explained by the diffusion properties of drugs in the membrane. After retrieving basic results, predictions will be highlighted. Finally, the coherence of this model in the context of cancer biology will be discussed further.     

Metabolism, Pharmacogenetics, and Metabolic Drug–Drug Interactions of Antipsychotic Drugs

1. Antipsychotic drugs are extensively metabolised by cytochrome P450 (CYP) enzymes.2. Dispositions of a number of antipsychotic drugs have been shown to cosegregate with polymorphism of CYP2D6.3. Metabolic drug–drug interactions have frequently been observed when antipsychotics are coadministered with other drugs.4. Many antipsychotic drugs are converted to active metabolites which can contribute to the therapeutic or side effects of the parent drug.5. Information concerning the individual CYP isoenzymes involved in the metabolism of antipsychotic drugs is important for the safe clinical use of this group of drugs.     

Drug resistance in parasites: can we stay ahead of the evolutionary curve?

The articles in this special issue of Trends in Parasitology document the current status of drug discovery in various helminth and protozoan parasitic infections. Parasitic diseases present a unique challenge to those who try to prevent or treat them. In most cases, the parasite has evolved to evade the human immune system, so the human host can control, but not eliminate, the parasite. Design of effective vaccines against these diseases presents daunting difficulties; therefore, drugs are currently the only way to prevent or treat parasitic diseases. Under these circumstances, selection of resistance to any effective, well-tolerated drug is inevitable; the question is not if, but when. The goal of this review is to try to draw general conclusions about the measurement and selection of resistance to drugs directed against a variety of very different parasites.