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At least 19 recordsLinked to original sources
PubMed1992

The method of relative drug accumulation: a simple method for illustrating the effects of different drug dosing regimens and variability in drug elimination on time courses of drug concentrations.

A simple method is presented for graphically illustrating time courses of relative drug concentrations and accumulation during multiple dosing. This method is based on the drug amount ratio and requires knowledge of only the elimination half-life and the dosing interval. It involves the use of relative drug concentrations, where a concentration of unity is assigned to the time-averaged concentration at steady state in a reference subject for the dosing regimen(s) being evaluated. Examples of application of the method of relative drug accumulation involve simulations of the effects of different multiple-dose regimens and variability in drug elimination on time courses of drug concentrations and drug accumulation.

Computer Simulation↗
PubMed1976

[Cutaneous side effects of systemic drugs. Part 4 of a synopsis. 6/7. Drugs affecting the central nervous system. C. Drug-induced photosensitivity. D. Drug-induced changes of skin color].

This, the fourth part of a synopisis of cutaneous side effects of drugs, covers the drugs affecting the central nervous system: antiepileptics, hypnotics, narcotics and psychopharmaceutics; the myorelaxants and antiallergics follow, and lastly there is a section on drug addiction and placebo. The various cutaneous side effects are listed in chart form referring to more than 500 sources. A drug index is attached for handy reference. The reviews of certain drug induced skin disorders are continued with tables covering photosensitivity and changes in skin colour. Phototoxicity, photoallergy and light sensitivity by porphyria are differentiated. The various pigmentation disorders, colour changes due to metal deposits as well as different localisations are included.

Anticonvulsants↗
PubMed1992

Low molecular weight proteins as carriers for renal drug targeting. Preparation of drug-protein conjugates and drug-spacer derivatives and their catabolism in renal cortex homogenates and lysosomal lysates.

Low molecular weight proteins (LMWPs) are known to be reabsorbed and catabolized primarily by the proximal tubular cells of the kidneys. As such, LMWPs might serve as drug carriers that release drugs site-specifically in the kidney. We tested this concept in vitro by coupling different drugs to the LMWP lysozyme both directly (amide bond) and via different spacers: oligopeptides (amide bond), (poly-)alpha-hydroxy acids (ester bond), and a pH sensitive cis-aconityl spacer (amide bond). The capability of the kidney to release the parent drug from such drug-spacer derivatives and drug-LMWP conjugates by enzymatic or chemical hydrolysis of the bond was tested by incubation experiments in renal cortex homogenates and lysosomal lysates. Directly coupled conjugates of terminal carboxyl group containing drugs and lysozyme were catabolized to single amino acids, but did not result in release of the parent drug. The amide bond between the drug and the final amino acid (lysine) appeared to be stable in the incubation milieu. Different oligopeptide spacers coupled to the drugs showed similar results: the oligopeptide itself was cleaved but the amide bond between the drug and different single amino acids remained untouched. Only amide bonds of derivatives of carboxylic drugs with peptide structures themselves were cleaved. Some of the directly coupled conjugates of terminal amino drugs and oligopeptides showed clear release of the parent drug whereas others were stable. Terminal amino drugs were rapidly released from an acid-sensitive cis-aconityl spacer. Terminal carboxyl group containing drugs were enzymatically released from their glycolic and lactic ester spacers at different rates. These kinds of drugs were also released as parent drug from LMWP conjugates with ester spacers like L-lactic acid. Increasing spacer length by intercalating a tetra(L-lactic acid) molecular between the drug and the protein further increased the extent and rate of drug release, indicating increased accessibility of the bond to the enzymes. Terminal amino group containing drugs were rapidly generated as parent drug from LMWP conjugates using an acid-sensitive spacer. In addition the conjugates were found to be adequately stable in plasma, considering their rapid clearance from the bloodstream. It is concluded that LMWPs may indeed be of use as carriers for specific renal delivery of drugs, since renal cortex homogenates and lysosomal lysates are able to catabolize the protein and generate the parent drug from drug-LMWP conjugates bearing suitable spacers. The option of enzymatic release is limited by the narrow specificity of the lysosomal enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗
PubMed2026

Anti-psychotic drugs act synergistically in combination with antifungal drugs to inhibit drug-resistant Cryptococcus neoformans and Candida albicans.

UNLABELLED: Systemic fungal infections cause an estimated 3.8 million deaths annually, approximately 10% of which are caused by drug-resistant infections. With only five classes of antifungal drugs, treatment options are limited. Here, we explore synergistic drug combinations-when the efficacy of two drugs combined is greater than expected based on the sum of each individual drug's efficacy-to improve treatment of drug-resistant Cryptococcus neoformans and Candida albicans. Chlorpromazine acts synergistically with both amphotericin B and fluconazole against multiple fungal species, including azole-resistant C. neoformans and C. albicans. We then performed a genome-wide knockout mutant screen and found that ESCRT pathway mutants are resistant to chlorpromazine, while knockout mutants of genes involved in fatty acid biosynthesis are sensitive. Based on these data, we investigated sterol and fatty acid composition in chlorpromazine-treated cells and found only minor increases in sterol precursors, but a substantial increase in lipid droplet size and decreased lipid droplet numbers. This lipid droplet formation potentially sequesters lipid bioavailability and response to membrane stress. Together, these data suggest that chlorpromazine and its analogs are potentially promising treatments for systemic fungal infections that act via lipid homeostasis and stress response. IMPORTANCE: Fungal infections are a large and expensive health burden with high mortality rates. People with compromised immune systems from cancer, solid organ transplant, HIV infection, and other conditions are particularly affected. Systemic fungal infections are difficult to treat because there are few available drugs and treatment periods last months or years. Long treatment times increase the risk of treatment failure and can contribute to the rise of resistance. We identified an additional class of drugs, chlorpromazine and other phenothiazine drugs, that amplify the activity of existing antifungal drugs amphotericin B (AmB) and fluconazole (FLZ). AmB and FLZ act by targeting ergosterol, the fungal equivalent of cholesterol, which is required for a functional plasma membrane. Chlorpromazine increases the formation of lipid drops, which sequester lipids such as ergosterol. When chlorpromazine is combined with AmB, the fungal cell cannot respond to the plasma membrane damage caused by AmB, inhibiting the fungal cells. This work identifies new target processes and drugs that could treat deadly fungal infections.

antifungal resistance↗
PubMed1992

Drug use contexts and HIV-consequences: the effect of drug policy on patterns of everyday drug use in Rotterdam and the Bronx.

Epidemiological data on HIV seroprevalence has been essential in assessing the (future) extent of the AIDS epidemic. By coupling these data with quantifiable variables related to injection drug use (frequency of injecting, number of needle sharing partners) specific 'risk behaviors' could be determined, accounting for the rapid spread of the virus in the injecting drug user (IDU) population. Yet, such data give little information on the social mechanisms and setting generating such risk behaviors. In order to understand the transmission of HIV among the IDU population one needs to study the micro settings and social context of drug use. This paper describes and explores certain patterns of drug use, sharing, and natural support systems found amongst IDUs in two very different cities, Rotterdam (The Netherlands) and the Bronx, New York City (USA). By specifying details of the micro-settings of everyday drug use in both locales, it is possible to identify certain common elements and consequences of personal and social behavior driven by drug use per se (e.g. drug preference), and to differentiate these from behaviors and consequences determined by drug policy and the social context in which drug use actually occurs. These policies and the social context they create can in turn be shown to relate to risks for HIV transmission, e.g. the increased likelihood of sharing injection equipment. A more careful ethnographic approach, taking advantage of natural experimental opportunities, comparisons and controls, may be utilized to examine drug-related behaviors in their social context and to better assess their relevance to public health--especially to AIDS.

Cross-Cultural Comparison↗
PubMed1976

The relationship between drug education programs in the Greater New Haven schools and changes in drug use and drug-related beliefs and perceptions.

This study presents a broad epidemiological approach to evaluation of drug education. Data on adolescent drug use and on drug-related beliefs and perceptions, collected yearly over a three-year period in 33 schools in the Greater New Haven area, were analyzed in relation to information on drug education programs in these schools. Changes in the general prevalence rates for the study period (1970-1973) and with age were the background against which the effects of the independent variable--presence or absence of specific drug education activities in the various schools--were explored. While the overall evidence suggested that drug education does not have a strong, across-the-board influence on either drug use rates or beliefs and perceptions, more modest and specific effects were noted which have implications for drug education.

Adolescent↗
PubMed1979

Drug effects on the liver: a tabular compilation of drugs and drug-related hepatic diseases.

Geneic and chemical names of drugs and the possible adverse effects of these drugs on the human liver were tabulated. All drugs compiled in these tables have been approved by the Federal Drug Administration. They are currently available in the United States, and they are listed in the 1979 Physicians' Desk Reference. The tables include: (1) names of drugs that have caused a characteristic morphologic change, such as cholestatic lobular hepatitis; (2) morphologic diagnoses that have been documented after administration of each drug; and (3) references that can be matched to each drug and to its effects on the liver.

Chemical and Drug Induced Liver Injury↗
PubMed1992

Spectrum of drugs against atypical mycobacteria: how valid is the current practice of drug susceptibility testing and the choice of drugs?

The in vitro activity of 13 drugs against 552 clinical isolates of atypical mycobacteria representing 12 species was performed in 7H11 agar medium at the National Reference Laboratory for Mycobacteria, using the 1% proportion method. All the species tested were resistant to isoniazid and pyrazinamide. In general, clofazimine and D-cycloserine showed the widest spectrum of activity except in the case of Mycobactrium fortuitum and M. chelonei which were resistant to both drugs, and the M. szulgai and M. terrae complex which was resistant to D-cycloserine. The next broad-spectrum drug was ethionamide, followed by ansamycin, rifampin, capreomycin, kanamycin, streptomycin and ethambutol. Among the fluoroquinolones, both ciprofloxacin and ofloxacin were active against M. xenopi, M. gordonae and M. fortuitum whereas M. kansasii and M. gastri were sensitive to ofloxacin only. When the species were listed in respect of the number of drugs to which they were susceptible (less than 10% of resistant strains), they were classified as follows; 7/13 drugs for M. kansasii, M. gastri and M. xenopi; 6/13 for M. gordonae; 5/13 for M. marinum; 3/13 for M. szulgai; 2/13 for M. fortuitum; 1/13 for the M. avium, M. scrofulaceum, M. simiae, and M. terrae complex, and none of the 13 in the case of M. chelonei. These results are discussed in relation to the multiple drug resistance of atypical mycobacteria. We conclude that the critical concentrations of drugs established for M. tuberculosis are not appropriate for atypical mycobacteria.

Antitubercular Agents↗
PubMed1975

The relevance of the osmolarity of the instillation fluid to the effectiveness and toxicity of drugs given by the intraduodenal route--solvent drug influence on the intestinal absorption of drugs.

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.

Animals↗
PubMed1979

[Neuropharmacological studies on drug dependence (I). Effects due to the difference in strain, sex and drug administration time on physical dependence development and characteristics of withdrawal signs in CNS-affecting drug dependent rats (author's transl)].

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.

Animals↗
PubMed1976

Assessment of drugs in schizophrenia. Asessment of drug-induced extrapyramidal reactions and of drugs given for their control.

I have tried to bring out some of the important methodological problems found in examining the effectiveness of drugs used in the control of druginduced parkinsonism by referring mainly to studies in which I have taken part. I hope I have shown that the whole topic is far less well understood than is often assumed. The main points may be summarized as follows: there is doubt as to whether many of the drugs used in controlling drug-induced parkinsonism are really effective; the results of many studies are conflicting; many studies contain serious flaws in design; methods for assessing extrapyramidal signs are not well developed; we are ignorant of the way in which drug-induced extrapyramidal signs change spontaneously. There is a clear need for further research in this area to improve techniques of assessment, to provide basic information on drug-induced syndromes, and to rigorously examine the efficacy of the drugs used in controlling them.

Amantadine↗
PubMedDate not supplied

The metabolism of drugs in isolated rat hepatocytes. A comparison with in vivo drug metabolism and drug metabolism in subcellular liver fractions.

The metabolism of drugs in isolated rat hepatocytes has been investigated. Drugs which are metabolized by aromatic hydrolation, aliphatic hydroylation, N-demethylation, or glucuronidation have been used as substrates. With some substrates the rate of metabolism in isolated hepatocytes compares with that in hepatic 900g supernatant fraction or microsomes, but other substrates are metabolized at a slower rate in isolated hepatocytes. For example, the rate of butamoxane hydroxylation in isolated hepatocytes is slower than that in microsomes. However, the rate of hydroxylation is hepatocytes is identical to that in perfused liver. The metabolism of drugs in isolated hepatocytes correlates with in vivo drug metabolism better than does metabolism in the hepatic 9000g supernatant fraction or microsomes.

Animals↗