Total Drug Intake Research Articles

Drug Consumption and Hydration Status: Analysis of the Associations in an Elder Population.

Hydration status plays a key role in healthy ageing, and it is potentially affected by several factors, including drug consumption. However, research on this issue to date is scarce, especially in highly vulnerable groups, such as the elderly. We aimed to study the relationship linking hydration status, analysed by means of a validated questionnaire, 24 h urine analysis, body composition assessment, and drug consumption in a sample of old adults. A total of 144 elders were included in the study. Cardiovascular drug consumption was significantly associated with a lower water intake in men (β = -0.282, p = 0.029). Moreover, urinary analysis revealed that total drug intake as well as the consumption of diuretics and cardiovascular drugs were associated with poorer hydration status, whereas genito-urinary drugs were associated with an opposite effect, and these results were confirmed in terms of body composition. Hence, total drug consumption (β = -0.205), diuretic (β = -0.408), cardiovascular (β = -0.297), and genito-urinary drugs (β = 0.298) were significantly associated (p < 0.05) with total body water. The obtained results confirmed the impact of chronic treatment with certain drugs on hydration status. Nutritional interventions may be of great interest in certain population groups in order to prevent complications due to altered hydration status.

Early morpho-functional changes in patients treated with hydroxychloroquine: a prospective cohort study.

We aimed to find earlier morphological and functional alterations in the retinas of patients treated with hydroxychloroquine (HCQ). This was a prospective cohort study. We examined 33 patients (mean age, 57.14 [SD, 11.02]years) who were affected by various types of rheumatic diseases. The mean treatment period was 124.7 [SD, 99.4]months, and the mean total drug intake was 5.41 [SD, 3.34]g daily at baseline. The control group consisted of 28 subjects with a mean age of 61.25 [SD, 2.16years]. The set of tests encompassed best-corrected visual acuity (BCVA), a multifocal electroretinogram (mfERG), spectral-domain optical coherence tomography (SD-OCT), fundus auto fluorescence (FAF), the 10-2 automated visual field (VF) test (10-2 VF), and frequency-doubling technology (FDT). The mfERG P1 wave density amplitudes decreased in all the rings, from 31.10 to 28.02 (p = 0.008) in the first ring, and from 18.29 to 16.55 [p < 0.001], from 12.050 to 10.91 [p = 0.002], from 9.53 to 8.69 [p = 0.003], and from 8.25 to 7.48 [p = 0.001]nanovolts/degree2 in rings 2, 3, 4, and 5, respectively. A significant reduction was found also in the N1 wave in the second ring. The SD-OCT retinal thickness measurement revealed significant thinning in five sectors, including the outer and inner nasal sectors, the outer and inner temporal sectors, and the inner superior sector. The 10-2 VF mean deviation paradoxically improved, while minimal FAF alterations in the retinal pigment epithelium were found in eight eyes. mfERGs and SD-OCT were altered in our patients before significant retinal changes occurred.

Cocktail of Superoxide Dismutase and Fasudil Encapsulated in Targeted Liposomes Slows PAH Progression at a Reduced Dosing Frequency.

Currently, two or more pulmonary vasodilators are used to treat pulmonary arterial hypertension (PAH), but conventional vasodilators alone cannot reverse disease progression. In this study, we tested the hypothesis that a combination therapy comprising a vasodilator plus a therapeutic agent that slows pulmonary arterial remodeling and right heart hypertrophy is an efficacious alternative to current vasodilator-based PAH therapy. Thus, we encapsulated a cocktail of superoxide dismutase (SOD), a superoxide scavenger, and fasudil, a specific rho-kinase inhibitor, into a liposomal formulation equipped with a homing peptide, CAR. We evaluated the effect of the formulations on pulmonary hemodynamics in monocrotaline-induced PAH rats (MCT-induced PAH) and assessed the formulation's efficacy in slowing the disease progression in Sugen-5416/hypoxia-induced PAH rats (SU/hypoxia-induced PAH). For acute studies, we monitored both mean pulmonary and systemic arterial pressures (mPAP and mSAP) for 2 to 6 h after a single dose of the plain drugs or formulations. In chronic studies, PAH rats received plain drugs every 48 h and the formulations every 72 h for 21 days. In MCT-induced PAH rats, CAR-modified liposomes containing fasudil plus SOD elicited a more pronounced, prolonged, and selective reduction in mPAP than unmodified liposomes and plain drugs did. In SU/hypoxia-induced PAH rats, the formulation produced a >50% reduction in mPAP and slowed right ventricular hypertrophy. When compared with individual plain drugs or combination, CAR-modified-liposomes containing both drugs reduced the extent of collagen deposition, muscularization of arteries, increased SOD levels in the lungs, and decreased the expression of pSTAT-3 and p-MYPT1. Overall, CAR-modified-liposomes of SOD plus fasudil, given every 72 h, was as efficacious as plain drugs, given every 48 h, suggesting that the formulation can reduce the total drug intake, systemic exposures, and dosing frequency.

Relieving pain using dose-extending placebos: a scoping review.

Placebos are often used by clinicians, usually deceptively and with little rationale or evidence of benefit, making their use ethically problematic. In contrast with their typical current use, a provocative line of research suggests that placebos can be intentionally exploited to extend analgesic therapeutic effects. Is it possible to extend the effects of drug treatments by interspersing placebos? We reviewed a database of placebo studies, searching for studies that indicate that placebos given after repeated administration of active treatments acquire medication-like effects. We found a total of 22 studies in both animals and humans hinting of evidence that placebos may work as a sort of dose extender of active painkillers. Wherever effective in relieving clinical pain, such placebo use would offer several advantages. First, extending the effects of a painkiller through the use of placebos may reduce total drug intake and side effects. Second, dose-extending placebos may decrease patient dependence. Third, using placebos along with active medication, for part of the course of treatment, should limit dose escalation and lower costs. Provided that nondisclosure is preauthorized in the informed consent process and that robust evidence indicates therapeutic benefit comparable to that of standard full-dose therapeutic regimens, introducing dose-extending placebos into the clinical arsenal should be considered. This novel prospect of placebo use has the potential to change our general thinking about painkiller treatments, the typical regimens of painkiller applications, and the ways in which treatments are evaluated.

Low expression of D2R and Wntless correlates with high motivation for heroin.

Drug overdose now exceeds car accidents as the leading cause of accidental death in the United States. Of those drug overdoses, a large percentage of the deaths are due to heroin and/or pharmaceutical overdose, specifically misuse of prescription opioid analgesics. It is imperative, then, that we understand the mechanisms that lead to opioid abuse and addiction. The rewarding actions of opioids are mediated largely by the mu-opioid receptor (MOR), and signaling by this receptor is modulated by various interacting proteins. The neurotransmitter dopamine also contributes to opioid reward, and opioid addiction has been linked to reduced expression of dopamine D2 receptors (D2R) in the brain. That said, it is not known if alterations in the expression of these proteins relate to drug exposure and/or to the "addiction-like" behavior exhibited for the drug. Here, we held total drug self-administration constant across acquisition and showed that reduced expression of the D2R and the MOR interacting protein, Wntless, in the medial prefrontal cortex was associated with greater addiction-like behavior for heroin in general and with a greater willingness to work for the drug in particular. In contrast, reduced expression of the D2R in the nucleus accumbens and hippocampus was correlated with greater seeking during signaled nonavailability of the drug. Taken together, these data link reduced expression of both the D2R and Wntless to the explicit motivation for the drug rather than to differences in total drug intake per se.

Demand for food and cocaine in Fischer and Lewis rats.

Fischer and Lewis rat strains often serve as animal vulnerability models for drug abuse and addiction. When these strains respond for drugs of abuse, several measures, including total drug intake, response rate and progressive-ratio breakpoints, have been reported to be strain-dependent, a result suggesting genetic differences in drug reactivity and vulnerability. The present study extends these strain comparisons to a previously untested measure--demand analysis. In Experiment 1, four Fischer and four Lewis rats earned their daily food ration by lever pressing under a fixed-ratio schedule, the size of which was increased every three sessions from 3 to 1,000 in logarithmic steps. Consumption was plotted as a function of ratio size, and modeled by the exponential-demand equation (Hursh & Silberberg, 2008). Experiment 2 replicated Experiment 1 except that different rats were used, and cocaine reinforced lever pressing. A between-experiment comparison showed a commodity-by-strain interaction: Fischer rats defended consumption with greater vigor when cocaine served as the reinforcer than did Lewis rats; for food, this relation was reversed. However, for both strains, defense of consumption of food exceeded that of cocaine.

Optimal Switching In Structured Treatment Interruption For Hiv Therapy

This paper proposes ‘optimal switching control during structured treatment interruption,’ which switches RTI and PI to reduce medication and establish long-term immune response against HIV. The proposed method is compared with ‘optimized STI’ through numerical simulation. The proposed method results in a more rapid increase of CTLp, and thus total drug intake and the therapy period are reduced. HIV treatment simulation results are analyzed in terms of controllability. Due to the effect of PI, ‘optimal switching control during STI’ can achieve greater controllability more quickly than ‘optimized STI.’

Heroin self-administration: I. Incubation of goal-directed behavior in rats

This study used heroin self-administration to investigate incubation of goal-directed heroin-seeking behavior following abstinence. Male Sprague–Dawley rats self-administered heroin on a fixed ratio 10 (FR10) schedule of reinforcement with licking of an empty spout serving as the operant behavior during 14 daily 3 h sessions. After this acquisition period, all rats received a 90 min extinction session following either 1 day or 14 days of home cage abstinence. When the extinction session occurred after only 1 day of home cage abstinence, rats with a history of heroin self-administration divided their responses equally between the previously “active” and “inactive” spouts. However, when the extinction session occurred following 14 days of home cage abstinence, the rats exhibited marked goal-directed heroin-seeking behavior by licking more on the previously “active” than “inactive” spout. These findings demonstrate that heroin-seeking behavior incubates over time, resulting in goal-directed heroin-seeking behavior in rats following 14 days but not 1 day of abstinence. Moreover, this facilitatory effect occurred in response to a different training schedule, lower total drug intake, and shorter periods of daily access than previously reported with heroin.

Clonidine maintains intrathecal self-administration in rats following spinal nerve ligation

Clonidine is approved for spinal administration against neuropathic pain, and reverses both spontaneous and elicited pain in humans following spinal administration. Rodent studies that seek to model pharmacology in pain states have historically relied on reflexive withdrawal from noxious stimuli as the primary endpoint. Drug self-administration studies have face validity in the drug abuse field for modeling drug abuse in humans, however, this methodology has not been applied to address issues related to drug seeking behaviors that may be relevant for other human populations, such as patients with neuropathic pain. Rats without spinal nerve ligation (SNL) failed to acquire intrathecal clonidine self-administration over 10 days of access. Rats were found to self-administer intrathecal infusions of clonidine following SNL in a stable and dose-responsive manner, however, and clonidine was self-administered throughout the day with 66% of total drug intake occurring during the dark cycle. Substitution of clonidine with saline or with clonidine and the α2-adrenoceptor antagonist idazoxan resulted in extinction of responding in SNL animals. Food reinforcement was initially decreased in SNL rats self-administering clonidine compared to normal animals, however, tolerance developed to this effect of clonidine in SNL rats after 5 days. These data demonstrate that drug self-administration can be applied to questions other than drug abuse, and provides an additional measure for development of novel therapeutic strategies for chronic pain treatment.

Cocaine‐induced alterations in nucleus accumbens ionotropic glutamate receptor subunits in human and non‐human primates

Chronic cocaine and withdrawal induce significant alterations in nucleus accumbens (NAc) glutamatergic function in humans and rodent models of cocaine addiction. Dysregulation of glutamatergic function of the prefrontal cortical-NAc pathway has been proposed as a critical substrate for unmanageable drug seeking. Previously, we demonstrated significant up-regulation of NMDA, (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptor subunit mRNAs and protein levels in the ventral tegmental area (VTA), but not the substantia nigra, of cocaine overdose victims (COD). The present study was undertaken to examine the extent of altered ionotropic glutamate receptor (iGluR) subunit expression in the NAc and the putamen in cocaine overdose victims. Results revealed statistically significant increases in the NAc, but not in the putamen, of NMDA receptor subunit (NR)1 and glutamate receptor subunit (GluR)2/3 wit trends in GluR1 and GluR5 in COD. These results extend our previous finding and indicate pathway-specific alterations in iGluRs in COD. In order to determine that changes were related to cocaine intake and not to other factors in the COD victims, we examined the effects of cocaine intravenous self-administration in rhesus monkeys for 18 months (unit dose of 0.1 mg/kg/injection and daily drug intake of 0.5 mg/kg/session). Total drug intake for the group of four monkeys was 37.9 +/- 4.6 mg/kg. Statistically significant elevations were observed for NR1, GluR1, GluR2/3 and GluR5 (p < 0.05) and a trend towards increased NR1 phosphorylated at serine 896 (p = 0.07) in the NAc but not putamen of monkeys self-administering cocaine compared with controls. These results extend previous results by demonstrating an up-regulation of NR1, GluR2/3 and GluR5 in the NAc and suggest these alterations are pathway specific. Furthermore, these changes may mediate persistent drug intake and craving in the human cocaine abuser.

Common Drug Interactions

Summary Clinically significant interactions are most likely to occur between drugs that have potent effects, a narrow therapeutic range, and a steep dose-response curve.3 The treating oral and maxillofacial surgeon should know his or her patients' total drug intake (i.e., drugs prescribed by other practitioners, and all over-the-counter drugs, and, any herbal preparations). The effects of all drugs (including unwanted side effects) must be considered when a new medication is being added to a patients' existing regimen. The oral and maxillofacial surgeon should be cognizant that drug interactions may be the cause of an unexpected or unexplainable problem in his or her patient and be willing to address it. The authors have included several “quick reference tables” that provide useful information for clinical practice (Tables 1–12). The tables list drug interactions for medications with which the oral and maxillofacial surgeon may common into contact. These tables are by no means complete, and the reader who is interested in drug interactions should consult other sources: (1) Clinical Pharmacology Online: http://www.imc.gsm.com (select Drug Interactions) and (2) Medscape: http://www.medscape.com .

Within-session determination of dose-response curves for heroin self-administration in rats: comparison with between-session determination and effects of naltrexone

A procedure was employed in the present study to obtain dose-response curves for heroin self-administration within each experimental session. The data generated using this procedure were compared to dose-response data obtained using between-session dose manipulations. The dose of heroin (18, 30, 60 or 100 μg/kg/inf) was varied across 4-hourly segments separated by a 20-min time-out period during which heroin was not available. The within-session dose-response procedure yielded data similar to those obtained using between-session dose manipulations when the order of dose presentation was increasing or random. However, the dose-response curve for total drug intake was flat when the doses were presented in decreasing order. Further analysis of the dose-response curves in the within-session procedure demonstrated that the rate of heroin intake increased in the third and fourth hourly components compared to the first component, suggesting acute tolerance to the reinforcing and/or rate-suppressive effects of heroin. Furthermore, using a random order of dose presentation, administration of 3.0 mg/kg of naltrexone prior to the session shifted the dose-response curve for heroin self-administration 5-fold to the right in the within-session procedure. The data indicate that the within-session dose-response procedure can be used to investigate the pharmacology of heroin self-administration in rodents.

Effects of increasing response requirement on choice between cocaine and food in rhesus monkeys.

Rhesus monkeys were trained in a discrete-trials choice procedure and allowed to choose between intravenous injections of cocaine (0.01-1.0 mg/kg/injection) and food presentation (1 or 4 pellets; 1 g/pellet) during daily 7-h experimental sessions. When each reinforcer was available under a fixed-ratio (FR) 30 schedule, the frequency of cocaine choice and the total drug intake increased in a dose-related manner for all monkeys. When the FR for cocaine was differentially increased, the frequency of cocaine choice decreased, shifting the cocaine dose-response function to the right and/or downward. When the FR for cocaine was at least 480, cocaine preference could not be recovered up to doses of 1.0 mg/kg/injection. In a second experiment, when the response requirement for food was differentially increased, the frequency of cocaine choice increased. These results demonstrate that altering the response requirement for cocaine or for alternative reinforcers that are available can substantially affect cocaine self-administration.

Effects of increasing the magnitude of an alternative reinforcer on drug choice in a discrete-trials choice procedure

Rhesus monkeys were trained in a discrete-trials choice procedure and allowed to choose between food delivery (1-16 pellets; 1 g/pellet) and intravenous injections of cocaine (0.03-0.56 mg/kg/injection; N = 4) or procaine (1.0-10 mg/kg/injection; N = 4) during daily 3-h sessions. Injections were available as the alternative to food. When the amount of food available as the alternative to drug was held constant and dose of drug was varied, the frequency of drug choice and total drug intake increased in a dose-related fashion for both cocaine and procaine. For both drugs, when the amount of food available as the alternative to drug was increased and the dose of the drug was held constant, the frequency of drug choice and total drug intake decreased. Thus, increases in the magnitude of an alternative non-drug reinforcer decreased cocaine and procaine self-administration. Further, the results suggest that while increasing the magnitude of the alternative reinforcer decreased the potency of cocaine as a positive reinforcer, the reinforcing efficacy of procaine was decreased. Because drug use by humans typically occurs in a context in which other reinforcers are available, the present results are consistent with the hypothesis that drug self-administration by humans can be decreased by increasing the value of alternative positive reinforcers. In addition, these results suggest that the extent to which drug self-administration is sensitive to this manipulation varies across drugs.

Animal models of intravenous phencyclinoid self-administration

Phencyclidine (1-(1-phenylcyclohexyl)piperidine, PCP) self-administration has been demonstrated in rhesus monkeys, baboons, dogs and rats. Generally, an orderly inverted U-shaped dose-response curve for rates of self-injection has been observed. Total drug intake appears to increase slightly with increases in unit dose; however, this increase is much less than might be expected with other CNS depressants such as barbiturates or morphine. Additionally, several arylcyclohexylamine analogues of PCP and some members of the benzomorphan and dioxolane classes referred to collectively as “phencyclinoids” are self-administered by primates and dogs. New data are presented in this review profiling the self-administration of some of these drugs in rats, as well as a characterization of the self-administration of higher unit doses of PCP than previously reported. Also, preliminary results of the assessment of the reinforcing efficacy of some PCP analogues measured by the progressive ratio procedure are presented.

Role of noradrenergic and dopaminergic processes in amphetamine self-administration

Dogs were trained to intravenously self-administer d-amphetamine (0.05 mg/kg/infusion) until a stable intake per 4 hr daily session was achieved. When the dogs were given noncontingent infusions of d-amphetamine in varying amounts (0% to 100% of the baseline intake) immediately prior to the session, they decreased their self-administration response rate appropriately so that total drug intake remained constant. However, there were no changes in subsequent responding for d-amphetamine following pretreatment with either the noradrenergic agonist methoxamine (0.5–2.0 mg/kg) or the noradrenergic antagonist phenoxybenzamine (1–8 mg/kg). Additionally, responding was not maintained when methoxamine (0.05 mg/kg/infusion) was substituted for d-amphetamine. In contrast, pretreatment with either the dopaminergic antagonist pimozide (5–40 μg/kg) or chlorpromazine (0.25–2.0 mg/kg) produced dose-dependent increases in the number of self-administered d-amphetamine infustions. These data suggest that noradrenergic neurotransmission is not responsible for d-amphetamine self-administration, but an intact dopaminergic system does appear to be important.

Self-administration of CNS stimulants by dog

Drug-naive dogs were trained to respond for intravenous infusions of either d-amphetamine, phenmetrazine, or methylphenidate until a stable response rate per 4-hr daily session was achieved. The magnitude of reinforcement (i.e., mg/kg/infusion) was then varied systematically across a wide range for each drug. An inverse relationship between unit dose and number of self-administered infusions per session was seen. Thus, total drug intake per session remained relatively constant and was independent of unit dose. Using a parallel line bioassay design, the relative potencies of d-amphetamine, phenmetrazine, and methylphenidate to maintain self-administration were estimated. By comparing the unit doses of d-amphetamine which yielded the same rate of self-administration it was found that 1 mg of phenmetrazine is equivalent to 0.1 mg of d-amphetamine. It was also determined that 1 mg of methylphenidate is equivalent to 0.75 mg of d-amphetamine. These data indicate the dog can be used to assess the reinforcing properties of psychomotor stimulants.