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This study is concerned with dissecting out differences in the discriminative stimulus attributes between drugs from broader pharmacological categories such as sedative/hypnotics where generalization tests often indicate shared stimulus effects. To this end, the discriminative stimulus effects of three to five doses of either chlordiazepoxide (CDP), chlormethiazole (CMZ), ethanol (ETOH), and pentobarbital (P-barb) were studied with gerbils in a two-choice, T-maze task. When the discrimination was based upon the presence versus the absence of drug administration, speed of acquiring the discrimination increased dose-dependently for all four drugs with log of sessions to criterion being a linear function of log dose. The slopes of all four lines were similar. The acquisition of a discrimination based on different doses of the training drug was then examined. A two-to-one ratio of high to low doses was used. Discriminative control developed with CMZ, ETOH, and P-barb, but not with CDP. The side of the T-maze that correlated with the lower training dose was always selected in tests with saline. Gerbils were then trained to discriminate between two drugs using at least two different dose combinations. The CDP versus CMZ, CDP versus ETOH, CMZ versus P-barb, CMZ versus ETOH discriminations were acquired. The CDP versus P-barb discrimination was obtained across doses only after an additional training procedure was instituted such that the P-barb dose was incremented gradually from low to higher doses during discrimination training; the CDP training doses were 20 and 30 mg/kg in two different groups of gerbils, respectively and the dose of P-barb was incremented by 2.5 mg/kg until the final dose of 20 mg/kg was reached with the barbiturate. Thus, although often shown to share similar stimulus effects, members of the broad pharmacological class of CNS sedatives/hypnotics nonetheless were shown to be discriminable from one another. Non-drug tests (vehicle) were used to assess stimulus control between pairs of drugs, equal control being implicated when responding was evenly distributed across the two training conditions.
Conditioned stimuli (CSs) can control behavior either by activating responses when presented noncontingently or through their ability to maintain responding when presented contingently, that is, as conditioned reinforcers. In the present study, the extent to which drug-seeking behavior could be subject to these different types of stimulus control was studied by presenting to rats CSs that were either paired with each drug infusion or presented as discriminative stimuli (DSs) signaling the availability of drug. It was found that stimuli paired with either cocaine or heroin infusions increased drug seeking when presented contingent on responding, but not when presented noncontingently. By contrast, DSs that signaled cocaine availability increased drug seeking when presented either noncontingently or contingently. These results suggest that drug-seeking behavior can be influenced differentially by CSs and that conditioned reinforcers are especially important for maintaining prolonged sequences of drug-seeking behavior.
OBJECTIVE: Given the harms associated with injecting drug use to both individuals and community and the paucity of such data from rural areas, the study aimed to compare: patterns of drug use, harms, and service access and utilisation among rural and metropolitan injecting drug users (IDU). DESIGN: Cross-sectional survey, using interviewer-administered structured questionnaire. PARTICIPANTS: One hundred and sixty-four rural and 96 metropolitan IDU from seven different New South Wales Area Health Services, recruited through needle and syringe programs (NSPs), snowballing techniques and advertisement. RESULTS: Age, gender, education and employment were similar for rural and metropolitan participants. Both samples reported use of a range of drugs, but rural participants were less likely than metropolitan participants to report daily heroin use (2% vs 10%), but more likely to report having injected morphine (50% vs 21%) in the last six months. Similar proportions reported using a needle/syringe after another person. Rural participants were less likely to report use of NSPs (36% vs 80%) and reported a number of barriers to NSP access and also to drug treatment services. Rural participants reported a significantly longer period of time between blood-borne virus testing. CONCLUSION: Samples of rural IDU are similar to metropolitan, although report some differences in patterns of drug use. Service provision, including access to new injecting equipment, blood-borne virus testing and drug treatment was found to cause considerable problems for rural IDU. These issues warrant further consideration.
Confirmed opiate addicts (N = 78) were asked to associate three opiate names (heroin, morphine, and methadone) and six nonopiate names [pentobarbital, alcohol, Benzedrine, "goofballs" (barbiturates), cocaine, and "reefers" (marijuana)] to stages of addiction, steps in drug taking, and drug effects. It was believed that associations to opiates would represent a strong habit since most of the subjects had been addicted ("hooked") on one or more opiates and that associations to nonopiates would indicate a weak habit as most of the subjects had never been "hooked" on nonopiates. Weak and strong habits were alike in that , regardless of the drug, associations to "high" were given. Beyond this similarity, the patterns of associations were qualitatively and quantitatively different. For example, a strong habit was characterized by associations to advanced stages of addiction ("hooked" and "kicking a habit"), to steps in drug-taking ("preparing" and "fixing a shot"), and to drug effects (to "nod" or "scratch"). A weak habit was marked by associations to intermediate stages of addiction such as "chipping" (occasional use of drugs), as well as to beginning stages of addiction and to beginning steps in drug-taking, such as to "hustle."
The influence of movements of fluid from the blood into the bowel lumen (solvent drag) on absorption of drugs from the intestine was studied in conscious rats with surgically implanted duodenal tubes. The drugs were given to the rats by intraduodenal instillation either in isotonic saline or in solutions of mannite having twice or three times the osmotic pressure of the blood. The instillation of hypertonic mannite solutions leads to concentration-dependent exsorption of fluid. The drugs tested were atropine and azoniaspiro compound XVII (azoniaspiro[3alpha-benziloyloxy-nortropan-8,1'-pyrrolidine]-chloride), both of which are poorly absorbed, and phenobarbital and nicotine, both of which are well absorbed. The criteria used to assess the rate of entry of the drugs into the blood stream were "efficacy" and "toxicity". In the case of atropine, azoniaspiro compound XVII and nicotine mortality rate and survival time were measured, while in the case of phenobarbital the latent period between instillation of the solution and onset of the hypnotic effect was used. As the tonicity of the solution was raised, so the concentration-dependent "efficacy" and "toxicity" declined. This meant that the latent period after instillation of phenobarbital lengthened, while after instillation of atropine, azoniaspiro compound XVII and nicotine in solutions of increasing tonicity the mortality fell and survival was prolonged. The only exception to this generalization was found when azoniaspiro compound XVII was instilled in triple strength mannite solution. The reasons for this exception were not ascertained. From the results it is concluded that "solvent drag" is an important factor in the absorption of drugs from the intestine. A stream of fluid passing into the lumen interferes with absorption, and this is reflected in the diminished "efficacy" and "toxicity" of the drug. Another factor which may influence the absorption of the drugs tested is the fall in concentration resulting from the inflow of fluid into the bowel lumen. This tends to flatten the concentration gradient between the bowel lumen and the blood and therefore delays absorption.
We studied the influence of differences in strain, sex and drug administration time on physical dependence of morphine and phenobarbital in rats and also whether or not pole climbing avoidance is useful as an indicator of physical dependence. We then compared the behavioral characteristics seen with morphine-dependence with those of other CNS-affecting drugs. Withdrawal signs involving weight loss in morphine and phenobarbital groups were different in JCL-Wistar, SLC-Wistar, JCL-Sprague Dawley and HOS-Donryu strain rats. Withdrawal signs in males were generally more marked than in females. Withdrawal signs due to the difference of drug administration time were different with the sex and/or kinds of drugs. After administration of morphine-type and barbiturate-type drugs, withdrawal signs of sedation and weight loss, also excitability together with weight loss appeared 24 and 40 hours later, respectively. These signs were generally greatly increased by antagonist-induced withdrawal. Abrupt withdrawal of methamphetamine and cocaine caused no withdrawal signs. Rectal temperature was unchanged on abrupt withdrawal in the case of each drug, though temperatures did decrease with morphine-type drugs, and increased with phenobarbital and chlordiazepoxide groups, on antagonist-induced withdrawal. Inhibition of the avoidance was mild with the abrupt withdrawal of morphine, codeine, phenobarbital chlordiazepoxide and cocaine, but was marked on antagonist-induced withdrawal of morphine and codeine.
In Congo, urgent efforts are needed to help with the revision of the national antimalarial drug policy. Despite its high resistance level, chloroquine (CQ) is still extensively used as the first-line treatment for uncomplicated Plasmodium falciparum malaria. The study was conducted in children under 5 years with uncomplicated malaria in Pointe-Noire and Brazzaville, the two largest cities that contain approximately 60% of the population of Congo. We investigated by polymerized chain reaction and sequencing methods the frequency distribution of molecular markers for antimalarial drug resistance, including mutations in P. falciparum chloroquine resistance transporter (pfcrt) gene associated with CQ resistance and mutations in dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes conferring resistance to sulphadoxine/pyrimethamine (SP) among pre-treatment P. falciparum isolates, as well as assessing antimalarial drug use in the community. pfcrt (K76T) mutation was present in most isolates (96.4%, n = 138) and high frequency (69.2%, n = 133) of triple-mutant dhfr-S108N, N51I, C59R was observed. The quintuple mutant (dhfr-S108N, N51I, C59R and dhps-A437G or S436A, K540E) considered as molecular marker for SP treatment failure was not found because dhps-K540E mutation was absent in isolates tested; this is a clear evidence for the excellent efficacy of SP that we previously described in the same population. The complete absence of the dhps-K540E mutation is a deterrent component for using this molecular marker as an early warning tool for SP resistance testing in that population. Poor compliance issues related to the antimalarial drug use including inappropriate manufacturing practices reported in this study require intensive attention and should be taken into account when implementing drug policy change. If Congo changes its treatment policy from CQ to SP monotherapy, this will not last long. The strategy of combining SP with other affordable and effective antimalarial drugs such as the artemisinin derivatives to improve efficacy and to delay the development of parasite resistance is essential.
Our previous study suggested that hetero-oligomer formation of guinea pig liver UDP-glucuronosyltransferases (UGTs) 2B21 and 2B22 enhances UGT2B21-catalyzed morphine-6-glucuronidation. In this work, further evidence for a functional hetero-oligomer between UGT2B21 and UGT2B22 was provided by studies of the glucuronidation of chloramphenicol with dual expression in COS-7 cells. UGT2B21 expressed in COS cells was capable of glucuronidating the 3-hydroxyl group of morphine, 4-hydroxybiphenyl, borneol, testosterone, androsterone, and estriol, whereas it had some effect on chloramphenicol. On the contrary, UGT2B22 does not exhibit any significant activity toward these typical substrates tested in this study. When UGT2B21 and UGT2B22 were expressed simultaneously, the chloramphenicol glucuronidation was enhanced to 4.5-fold, whereas the activities toward other substrates were little affected except that for the 6-hydroxyl group of morphine. The protein expression level of UGT2B21 was comparable when UGT2B21 was expressed with or without UGT2B22. These results suggest that simultaneous expression of UGT2B21 and UGT2B22 enhances UGT2B21-catalyzed chloramphenicol glucuronidation. Hetero-oligomer formation of UGT2B21 and UGT2B22 may act by fine-tuning the catalytic glucuronidation of chloramphenicol.
It has become widely accepted that metabolic drug-drug interactions can be forecast using in vitro cytochrome P450 (CYP) data. For any CYP form-inhibitor pair, the magnitude of the interaction will depend on the potency of the inhibitor (inhibition constant, Ki) the concentration of the inhibitor available for inhibition ([I]), the fraction of the substrate dose metabolized by CYP (fm), and the fraction of the CYP-dependent metabolism catalyzed by the inhibited CYP form (e.g., fm,CYP3A4). While progress is being made toward our understanding of the factors necessary for predictions of [I]/Ki in vivo, it is evident that there is a need for quantitative databases that contain in vitro (e.g., Ki, fm,CYP3A4) and in vivo pharmacokinetic/absorption-distribution-metabolism-excretion (PK/ADME) data (e.g., fm) for a large number of marketed drugs. Ultimately, such databases would allow one to integrate all of the data necessary for the prediction of drug-drug interactions and permit the rational evaluation of new drug entities.
Fenozan B07, a 1,2,4-trioxane endoperoxide with potent blood schizontocidal activity against drug-sensitive and drug-resistant rodent malaria parasites, exerted a modest potentiating action when administered with chloroquine (CQ) to mice infected with parasites of the CQ-resistant P. yoelii ssp. NS, but not when given to mice infected with the CQ-sensitive P. berghei N strain. The reason why this potentiation may be of particular value in the treatment of severe falciparum malaria is discussed. Mefloquine and halofantrine displayed a similar level of potentiation with Fenozan B07 against the CQ-resistant parasites. However, antagonism was shown by combinations of Fenozan B07 with pyronaridine or the 8-aminoquinoline WR 238 605 when used against CQ-resistant parasites. Mefloquine with Fenozan B07 is also antagonistic against a highly mefloquine-resistant line of P. yoelii ssp. NS. The reasons behind such antagonism are not known. The importance is stressed of using carefully selected drug combinations of novel antimalarials, rather than single drugs, in order to impede the selection of drug-resistant parasites, but only after adequate, preclinical, toxicity testing.
Physicians who prescribe a new drug that has not been approved for a specific indication or a specific age group frequently find themselves in a quandary. Physicians who prescribe "old," time-honored drugs usually do not consult the package insert or search for US Food and Drug Administration (FDA) approval. This statement was written to clarify the legal and informational status of the package insert and the role of the FDA in approving or not approving drugs for specific indications or specific age groups. The unapproved use of approved drugs, or so-called "off-label" use, is extremely prevalent among physicians who care for children. It is important that such use of compounds be brought up to date with current FDA policies and to emphasize the responsibility of the prescribing physician in the use of these compounds.
The present study investigates the potential of therapeutic drug monitoring databases to document co-medication as a possible risk factor for subtherapeutic or excessively high concentrations of psychotropic drugs. Exposure was defined with respect to co-medication including one of five agents known for their capacity to induce (phenytoin, phenobarbital and carbamazepine) or to inhibit (thioridazine and levomepromazine) the metabolism of psychotropic drugs. 87 patients exposed to such co-medication were matched by sex, age and monitored psychotropic medication with 87 patients randomly selected from a pool of subjects whose co-medication did not include any substance known to interact. Outcome was defined with respect to dose-normalized concentrations being below or above therapeutic range. When taking all psychotropic drugs together, the estimated relative risk to reach concentrations above the therapeutic range was 7.8 for patients exposed to phenothiazine co-medication. The relative risk to remain at subtherapeutic level was 2.7 for patients with inducers. When considering the different psychotropic drugs separately, a coherent picture was observed, with increased risk ratios for all substances.
The effects of mixing solution volume (0.25-0.65 mL/g) on in vitro drug release from a self-setting bioactive calcium phosphate cement containing the anticancer agent 6-mercaptopurine (6-MP) as a model compound were investigated. The drug release profiles from isolated planar surfaces as well as the entire surfaces of cement systems containing 5% 6-MP were measured in simulated body fluid at pH 7.25 and 37.0 degrees C. The drug release rate from both cement system geometries increased with increasing mixing solution volume. Drug release profiles from the planar-release and entire-surface-release cement matrix systems were analyzed by and found to agree with the Higuchi and Cobby equations, and the kinetic parameters were estimated with a nonlinear least-squares computer program. Linear relationships were found between the mixing solution volume and the drug release rate constants or time required for 50% drug release for both cement release geometries. Furthermore, the total pore volume of the cements, as measured by mercury porosimetry, increased with increasing mixing solution volume.
Ten male N/Nih rats were trained to discriminate between the interoceptive cues produced by the purportedly dopaminergically-mediated drug d-amphetamine at 0.4 mg/kg intraperitoneally administered 20 min prior to training and those produced by the purportedly serotonergically-active agent norfenfluramine at 0.7 mg/kg. Once this discrimination was successfully acquired, the rats were tested with saline and with both drugs administered simultaneously and these manipulations were seen to produce random responding; indicating roughly equivalent cueing strength. Subsequently, various drugs thought to act upon serotonergic neurons, i.e., LSD and MDMA, were tested and shown to generalize in a dose-responsive manner to the norfenfluramine-appropriate lever. In contrast, the dopaminergically-active agent methcathinone and the D3 agonist 7-OH-DPAT produced generalization on the amphetamine-appropriate lever. Results are discussed in light of the increased specificity of behavioral testing available in a drug vs. drug discriminative paradigm using two drugs with different mechanisms of action.
PURPOSE: The purpose of this study was to investigate the pH-dependent passive and active transport of weakly basic drugs across the human intestinal epithelium. METHODS: The bidirectional pH-dependent transport of weak bases was studied in Caco-2 cell monolayers in the physiologic pH range of the gastrointestinal tract. RESULTS: A net secretion of atenolol and metoprolol was observed when a pH gradient was applied. However, the bidirectional transport of both compounds was equal in the nongradient system. Hence, at lower apical than basolateral pH a change in passive transport caused by an imbalance in the concentration of the uncharged drug species resulted in a "false" asymmetry (efflux ratio). Furthermore, a mixture of pH-dependent passive and active efflux was found for the P-glycoprotein (P-gp, MDR1, ABCB1) substrates, talinolol and quinidine, but not for the neutral drug, digoxin. However, the clinically important digoxin-quinidine interaction depended on the presence of a pH gradient. Hence, the degree of interaction depends on the amount of quinidine available at the binding site of the P-gp. CONCLUSIONS: Active efflux of weak bases can only be accounted for when the fraction of unionized drug species is equal in all compartments because the transport is biased by a pH-dependent passive component. However, this component may take part in vivo and contribute to drug-drug interactions involving P-gp.
Because methylphenidate (MPH) is currently the most widely prescribed medication for attention deficit hyperactivity disorder (ADHD), several studies have used this as the touch-stone for evaluating the efficacy of a newer stimulant, Adderall. In a parallel-groups study of MPH (n = 20), Adderall (n = 20), and placebo (n = 18), Pliszka et al. (2000) reported that both medications were superior to placebo in improving parent, teacher, and clinician ratings of ADHD and associated behaviors. Compared with MPH, Adderall led to significantly more improvements in teacher and clinician ratings. The present study extends these results by addressing the issue of clinical significance using drug-placebo and drug-drug response curve analyses of the same data. The goal of this method is to answer the following questions about drug-placebo or drug-drug differences: Is the effect clinically meaningful? What does the effect tell us about individual responses? Is the effect due to symptom improvement, the prevention of worsening, or both? Our results show that the efficacy of Adderall to improve functioning is seen throughout the full range of improvement scores. In contrast, MPH showed a substantial effect for "mildly" and "much improved" but not for "very much improved." Our analyses also show that both Adderall and MPH prevent worsening of symptoms. They further suggest that, compared with the Conners Teacher Rating Scale, the Clinical Global Impressions scale may be more sensitive to improvements at the "well end" of the spectrum of functioning.