Citation for the 1998 Edwin B. Astwood Lecture Award of the Endocrine Society to Dr. Allen M. Spiegel

OBJECTIVE: To detect the spectrum of gestational exposure to illicit drugs and other xenobiotic agents in neonates by meconium analysis. METHOD: Meconium was collected from 98 neonates and analyzed for illicit drugs and other xenobiotic agents by high-performance liquid chromatography and gas chromatography/mass spectrometry. RESULTS: Eighty-one (82.7%) infants tested positive for xenobiotic agents, and each infant had from 1 to 9 drugs present. These included local anesthetics (30%) such as lidocaine and mepivacaine; food additives (25%) such as ionol (butylated hydroxytoluene); illicit drugs (11%), especially cocaine and morphine; analgesics (10%) such as meperidine; and fewer (< 10%) other drugs such as antihistamines, antidepressants, adrenergics, anticonvulsants, cough medications, analeptics, hypnosedatives, and cardiotonics. CONCLUSION: We demonstrated substantial exposure of neonates to xenobiotic agents, ranging from exposure to food additives, prescribed or over-the-counter medications, and drugs of abuse.     

Drugs inducing or aggravating parkinsonism: a review

Drug-induced parkinsonism (DIP) is frequent. The list of drugs able to induce parkinsonism is long and probably incomplete, because new drugs, with previously unknown antidopaminergic activity, are constantly being added. Not all the drugs have the same potency for inducing parkinsonism. We classify these drugs in three groups: (1) drugs with obvious antidopaminergic activity which regularly induce parkinsonism; (2) drugs able to induce parkinsonism in particular individuals and (3) drugs which may aggravate Parkinson's disease treated with levodopa. The reports of isolated cases of parkinsonism induced by widely-used drugs (drugs in group 2) may be the result of either an idiosyncratic side effect or a misdiagnosis of parkinsonism. The antidopaminergic activity of the drugs of this group is weak and not sufficiently demonstrated. Maybe, in these cases, the blockage of other neurotransmitters different from dopamine plays a role in the induction of parkinsonism. Probably, the number of patients with DIP is higher than reported or detected, because many patients suffer from weak symptoms that quickly disappear after drug withdrawal. One of the main points of interest is knowing the list, because all these drugs, specially those of group 1, should be avoided or used with caution in the treatment of some common symptomatic problems in patients with Parkinson's disease, such as depression, arterial hypertension, diabetes mellitus and cardiac disorders. The precautions should extent to other populations especially susceptible to suffer from DIP, such as the elderly or patients with other neurodegenerative disorders, such as Alzheimer's disease.     

Stepping through the drug use sequence: Longitudinal scalogram analysis of initiation and regular use.

Using a new technique for tracing the sequence of use over time, this study examined the pattern of drug involvement among 4,145 West Coast adolescents over the 4-yr span from Grades 7–20. During the period covered, the mid- to late 1980s, the authors found no evidence that cocaine has become a gateway drug. However, the data provided some support for treating cocaine initiation as a separate stage that precedes the onset of hard drugs other than pills. The analysis also showed that increased involvement with legal drugs constitutes an important step in the transition to hard drug use for most adolescents. Weekly alcohol use followed marijuana use and preceded use of all other illicit drugs for Hispanic, White, and Black youth. However, it followed use of hard drugs for Asians. Weekly smoking formed a distinct stage between initial use of pills and other hard drugs for non-Hispanic Whites. The results underscore the importance of prevention efforts aimed at curbing the transition to regular use of alcohol and cigarettes, as well as their initial use. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Nitric oxide synthesis inhibition retards surgical reversal of one-kidney Goldblatt hypertension in rats

We investigated the cellular drug resistance to aclarubicin (Acla), cytosine arabinoside (Ara-C), daunorubicin (Dau), doxorubicin (Dox), etoposide (Etop) and mitoxantrone (Mitox) using the MTT assay at time of disease presentation in 93 cases of acute myeloid leukaemia (AML). In 31 cases we concomitantly investigated MDR1 (multiple drug resistance 1 gene) expression (semi-quantitative competitive RT-PCR) of the leukaemic cells. Drug resistance towards Dau, Dox and Etop was correlated to the MDR1 expression of the AML cells (P<0.05) with high MDR1 expression being associated with high drug resistance towards these drugs. Although the data did not allow firm conclusions to be drawn on the correlation between MDR1 expression and drug resistance towards Ara-C and Mitox, the drug resistance towards Acla clearly was not correlated to, or dependent on, the MDR1 expression level of the AML blast cells. In addition, when examining the cross-activities among the six drugs distinct patterns emerged. Thus, high to very high degrees of cross-activity were found to exist between Dau, Dox, Etop and Mitox, whereas Ara-C had moderate cross-activity with the other drugs except Acla, which showed absent to moderate cross-activity with the other drugs. We conclude that MDR1 gene expression is of significance for cellular drug resistance towards specific (MDR1-related) drugs in AML, whereas it is not of significance regarding drug resistance towards other drugs, which is the case with the anthracycline Acla. We suggest that in the place of other more or less complicated ways to circumvent MDR1-mediated drug resistance, Acla may be used to replace Dau, Dox and other MDR1-related drugs if proven as potent as the drug it is to substitute.     

Influence of gender on the pharmacokinetics and pharmacodynamics of drugs

Historically, women, the elderly, and minorities were underrepresented in clinical drug trials. Information on possible gender-related differences in the pharmacokinetics of drugs is often lacking, although for some drugs significant differences could be demonstrated. In women, absorption, protein binding, volume of distribution, and metabolism of drugs may differ due to hormonal influences on physiological functions. Sex-related differences could be shown for phase I (cytochrome P450) as well as phase II (especially glucuronidation) reactions. Since many women world-wide take oral contraceptives, data should be provided to determine to what extent other drugs are influenced by estrogens and progestogens or to what extent the other drugs may attenuate the contraceptive efficacy. Moreover, estrogens interact with various enzymes and receptors, e.g. at the endothelial function as well as dopaminergic receptor sites, and may therefore attenuate or enhance drug effects or even drug side-effects. For a number of drugs it is well recognized, that women suffer more frequently from side-effects, however, it is often not clear, if this is due to gender differences in the pharmacokinetics or pharmacodynamics of the responsible drug. Very little is known about these gender-related differences and the possibility that women may show a different pattern of treatment response than men. As a result, drug approval authorities now require more data on the pharmacokinetics of novel drugs in women as well as a sufficient accrual of women in efficacy and outcome trials.     

Susceptibility of adult rats to lead-induced changes in NMDA receptor complex function

Sexual difficulties are highly prevalent in male patients with cardiovascular diseases, such as hypertension, atherosclerosis, and hypercholesterolemia. Recently, several studies have been conducted on the effects of cardiovascular diseases, as well as associated drug and nondrug treatments, on nocturnal penile tumescence (NPT) and other measures of sexual function. Although an overall trend has been observed toward decreased NPT in patients with chronic hypertension and other cardiovascular conditions, design and methodological difficulties have been noted in most studies, and results have been generally, inconclusive. Similarly, antihypertensive drugs such as beta-blockers and diuretics have been associated with diminished NPT in several studies, although methodological problems have again been noted. Furthermore, the mechanism of action of antihypertensive drugs on sleep-related erections has not been determined. Most recently, a positive effect of cholesterol-lowering drugs (pravastatin, lovastatin) on NPT has been observed in middle-aged males with chronic hypercholesterolemia. Additional studies of the effects of cardiovascular disease on NPT and other measures of sexual function are needed.     

Combined chemotherapy of patients with tuberculosis - new regimens and dosage forms

310 patients with pulmonary tuberculosis disseminating bacteria received isoniazid, rifampicin, streptomycin (ethambutol) and pirazinamid in different regimens and dosage forms. The drugs were administered in sequence or simultaneously, in single or divided doses. The best time and number characteristics as regards the discharge negativation were obtained in pirazinamid administration at a single dose daily or each other day irrespective of other drugs intake. 100 patients were given isoniazid, rifampicin and pirazinamid in multicomponent form tricox (Jemis, India). Tricox proved effective under additional administration of isoniazid in the same dose as was fixed in tricox.     

Hardiness, coping, and burnout in the nursing workplace

This article reviews the potential of a number of drug classes to produce or aggravate hypertension, with particular emphasis on older patients. Although little information is available regarding the hypertensive effects of mineralocorticoids in the elderly, glucocorticoids usually induce an increase in blood pressure (BP) that is dosage-dependent. Nonsteroidal anti-inflammatory drugs occasionally increase BP, but this effect is not usually clinically relevant. The alleged hypertensive potential of oral antihyperglycaemic agents has not yet been substantiated. In contrast, some antidepressants may be particularly dangerous in terms of their hypertensive complications. Although hypertension may be induced by monoamine oxidase inhibitors (MAOIs) given as monotherapy, severe hypertension is more likely to occur when MAOIs are combined with other sympathomimetic drugs. Several other drugs may also increase the risk of hypertension in elderly patients, but reliable data are lacking for most of these agents. Elderly people who are being treated with drugs that may increase BP should be closely monitored. This is particularly true for drugs that act on the CNS.     

Evaluation of antismoking advertising campaigns

BACKGROUND: Steroid acne is a folliculitis that can result from systemic or topical administration of steroid, and has been described as showing a similar clinical picture to Pityrosporum folliculitis, but there have been few reports about the incidence of Pityrosporum ovale and the effect of antimycotic drugs in steroid acne and other acneiform eruptions. Our purpose was to describe the association between steroid acne and P. ovale, and to confirm the superior efficacy of oral antifungal drugs over anti-acne drugs in the treatment of steroid acne. METHODS: The history, clinical features direct microscopy, histopathologic analysis, and therapeutic results of 125 cases with steroid acne or other acneiform eruptions were described and compared. RESULTS: Over 80% of patients with acneiform eruption receiving systemic steroid revealed significant numbers of P. ovale in the lesional follicle. Furthermore, oral antifungal drug (itraconazole) showed significantly better clinical and mycologic effects than any other group of medications used in this study. CONCLUSIONS: Steroid acne and other acneiform eruptions showing discrete follicular papules and/or pustules localized to the upper trunk and acneiform facial skin lesions associated with multiple acneiform lesions on the body in the summer period should be suspected as Pityrosporum folliculitis. In addition, oral antifungal drugs recommended for Pityrosporum folliculitis; however, it will require a larger case-control study to confirm the superiority of antifungal therapy over anti-acne treatment.     

Substance use and multiculturalism

This paper reviews intercultural variability of substance use behaviors, including availability of international statistics on consumption of alcohol and other drugs, as well as the use of drugs available locally only. Within a conceptual framework of intercultural relations, it considers the history of transcultural spread of substance use behaviors and possible reactions to the introduction of new drugs within a culture or jurisdiction, including illustrations of the "law of alien poisons." Although intercultural views of substance use have generally concentrated on majority groups' views of substance use in minority groups, minority and non-Western views of substance use need to be considered in the context of increasing international and intercultural communications that increase the rate at which substance use behaviors spread. Both Western and non-Western experiences with substance use and misuse must be taken into account so that better interventions can be developed to deal with addictions and other substance-related problems.     

Preclinical studies of water-insoluble camptothecin congeners: cytotoxicity, development of resistance, and combination treatments

Water-insoluble camptothecin (CPT) congeners are rapidly establishing themselves as promising anticancer drugs. In vitro, they have exhibited: (a) insensitivity to elevated levels of P-glycoprotein that confers multidrug resistance; (b) selective killing of malignant cells traversing the S-phase of the cell cycle, while leaving viable normal cells, which either are arrested at the S-G2 boundary or continue to divide; (c) no cross-resistance with several other anticancer drugs; and (d) potentiation or enhancement of cytotoxicity when appropriately used in combination with tumor necrosis factor, ionizing radiation, and hyperthermia. In addition, development of cell resistance to water-insoluble CPT congeners in vitro is accompanied by increased sensitivity to other anticancer drugs. Furthermore, water-insoluble CPT congeners have exhibited an unprecedented activity against a wide variety of human tumors xenografted in nude mice by inhibiting growth and inducing regression of carcinomas of the lung, breast, ovary, colon, stomach, pancreas, and prostate, as well as malignant melanoma, lymphoma, and leukemia. More importantly, oral administration of the water-insoluble CPT congeners in clinical studies with cancer patients makes other route(s) of administration unnecessary.     

Open hearts. The origins of direct-vision intracardiac surgery

This study attempts to clarify the drug problem of Japan in terms of images of illegal drugs (stimulants, marijuana, and volatile solvents) by comparing (1) different types of drugs and (2) differences between generations. Another objective of this research was to examine influence by the mass media reports with regard to drug incidents which influence upon image formation of illegal drugs among people. In this study 488 males from the city of Osaka were chosen by a random sampling method and a door to door survey was undertaken utilizing a self-administered questionnaire with a partial interview method. It was revealed that as a whole negative images such as "dangerous" and "terrible" were still widely prevailing and positive image such as "fashionable" was much less prevailing. Specially, stimulants were regarded more dangerous compared to marijuana and volatile solvents. In contrary, marijuana was regarded more fashionable compared to stimulants and volatile solvents. Volatile solvents were considered more "intimate" compared to other drugs. With regard to generation differences, it was the youth who possessed more positive images towards marijuana and more intimate feelings about volatile solvents than other generations. Findings show that with regard to news about illegal drug incidents, respondents' appraisal of the news of mass media primarily make significant influence, as compare to mere cognition, on images of illegal drugs. Furthermore, it was revealed that there was likely to result in positive images of illegal drugs due to lack of adequate information. From the aspects of education, it was suggested that dissemination of information at a vast range and maintenance of negative images might become a crucial task.     

The tertiary effect of psychotropic drugs. Results of an anthropologic study conducted in southwestern France among elderly consumers

This article presents part of the results of a research conducted in the South-west of France on consumption by elderlies of psychotropic drugs. Two institutions have been chosen. The author was seeking to measure the consumption of psychotropic drugs before and after institutionalization, based on a medical questionnaire distributed to doctors working in these institutions. The author then examines the impact of this consumption on social relations, at home and within institutions, from an anthropologic perspective. Elderlies, members of their families, as well as doctors and other parties concerned by this consumption have been questioned during semi-directed interviews. Other than the general consumption of psychotropic drugs in the two institutions which the author attempts to understand the extent, only modifications in family relationships after the taking of drugs at home are exposed in this article.     

Managing drug reactions to sulfonamides and other drugs in HIV infection: desensitization rather than rechallenge?

Drug reactions in patients with HIV infection, e.g. fever or rash, are a frequently occurring clinical problem. These side effects particularly are observed with sulfonamides; however, many other drugs have also shown to induce allergic reactions when given to patients with HIV infection. The production of hydroxylamines has been put forward as one of the explanations for these high incidence of reactions on drugs. Since sulfonamides are the first choice of therapy for the treatment and prophylaxis of Pneumocystis carinii pneumonia, several strategies have been developed to circumvent drug reactions. In general rechallenge or desensitization are recommended in literature. This article discusses the results and risks of rechallenge and desensitization with sulfonamides or other drugs, as mentioned in the literature. Furthermore preliminary results of rechallenge with a sulfonamide, which is not metabolized into hydroxylamines, are presented. From the data in the literature it is concluded that desensitization should be preferred to rechallenge.     

Systemic antifungal agents. Drug interactions of clinical significance

There are 3 main classes of systemic antifungals: the polyene macrolides (e.g. amphotericin B), the azoles (e.g. the imidazoles ketoconazole and miconazole and the triazoles itraconazole and fluconazole) and the allylamines (e.g. terbinafine). Other systemic antifungals include griseofulvin and flucytosine. Most drug-drug interactions involving systemic antifungals have negative consequences. The interactions of amphotericin B, flucytosine, griseofulvin, terbinafine and azole antifungals can be divided into the following categories: (i) additive dangerous interactions; (ii) modifications of antifungal kinetics by other drugs; and (iii) modifications of the kinetics of other drugs by antifungals. Amphotericin B and flucytosine mainly interact with other agents pharmacodynamically. Clinically important drug interactions with amphotericin B cause nephrotoxicity, hypokalaemia and blood dyscrasias. The most important drug interaction of flucytosine occurs with myelotoxic agents. Hypokalaemia can precipitate the long QT syndrome, as well as potentially lethal ventricular arrhythmias like torsade de pointes. Synergism is likely to occur when either QT interval-modifying drugs (e.g. terfenadine and astemizole) and drugs that induce hypokalaemia (e.g. amphotericin B) are coadministered. Induction and inhibition of cytochrome P450 enzymes at hepatic and extrahepatic sites are the mechanisms that underlie the most serious pharmacokinetic drug interactions of the azole antifungals. These agents have been shown to notably decrease the catabolism of numerous drugs: histamine H1 receptor antagonists, warfarin, cyclosporin, tacrolimus, digoxin, felodipine, lovastatin, midazolam, triazolam, methylprednisolone, glibenclamide (glyburide), phenytoin, rifabutin, ritonavir, saquinavir, nevirapine and nortriptyline. Non-antifungal drugs like carbamazepine, phenobarbital (phenobarbitone), phenytoin and rifampicin (rifampin) can induce the metabolism of azole antifungals. The bioavailability of ketoconazole and itraconazole is also reduced by drugs that increase gastric pH, such as H2 receptor antagonists, proton pump inhibitors, sucralfate and didanosine. Griseofulvin is an enzymatic inducer of coumarin-like drugs and estrogens, whereas terbinafine seems to have a low potential for drug interactions. Despite important advances in our understanding of the mechanisms underlying pharmacokinetic drug interactions during the 1990s, at this time they still remain difficult to predict in terms of magnitude in individual patients. This is because of the large interindividual and intraindividual variations in the catalytic activity of those metabolising enzymes that can either be induced or inhibited by various drugs. Notwithstanding these variations, increasing clinical experience is allowing pharmacokinetic interactions to be used to advantage in order to improve the tolerability of some drugs, as recently exemplified by the use of a fixed combination of ketoconazole and cyclosporin.     

New drugs of 1997

OBJECTIVE: To provide information regarding the most important properties of the new therapeutic agents marketed in 1997. DATA SOURCES: Published studies, drug information reference sources, and product labeling. DATA SYNTHESIS: A record-setting number of 45 new therapeutic agents were marketed in 1997. The indications and information on dosage and administration for each new agent are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. Where possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. CONCLUSION: A number of the new therapeutic agents marketed in 1997 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.     

Contents of lecithin and choline in crude drugs

The determination of lecithin and choline in crude drugs was established by a combination of high performance liquid chromatography (HPLC) with electrochemical detector (ECD) and enzyme reaction. Lecithin in crude drugs extracted with a mixture of chloroform-methanol (2:1) at room temperature was hydrolyzed by phospholipase D. The hydrolyzate was injected to HPLC, and choline was separated from impurities by reverse phase column. The choline was converted to betaine and hydrogen peroxide by passing through column packed with immobilized choline oxidase. This hydrogen peroxide was detected by ECD. The peak area of hydrogen peroxide derived from lecithin was proportional to the concentration of lecithin from 0.10 to 1.52 microgram/ml. Choline in crude drugs was extracted with ethanol under reflux and determined under the same HPLC conditions as lecithin. The peak area of hydrogen peroxide derived from choline was proportional to the concentration of choline from 0.01 to 0.45 microgram/ml. The contents of lecithin and choline in 31 kinds of crude drugs were determined by these established methods. The results showed that Cervi Parvum Cornu, Kokurozin, Foenigraeci Semen and Psoraleae Semen contained more lecithin than other crude drugs, while Angelicae Radix, Foenigraeci Semen, Psoraleae Semen, and especially Hippocampus were found to contain more choline than other crude drugs.     

In vivo studies on lysosubtilin. 3. Efficacy for treatment of mastitis and superficial lesions of the udder and teats in cows

Lysosubtilin is a broad-spectrum preparation of lytic enzymes from Bacillus subtilis designed for veterinary medicine. This study demonstrates its efficacy for the treatment of reproductive system diseases (mastitis, superficial lesions of the udder and teats) in cows. Prior to determination of optimal therapeutic doses, samples taken from the milk and udder skin of sick animals were examined microbiologically. The examinations revealed a high incidence of polymicrobial infections (26.9 and 84.9% for mastitis and superficial udder lesions, respectively) caused by various mixtures of bacteria (both Gram-positive and Gram-negative) and fungi/yeasts. Dose determination studies involved 115 cows with clinical signs of mastitis. The optimal dose for mastitis treatment was found to be 3.5 x 10(6) U lysosubtilin dissolved in 100 mL of distilled water, which was then administered into the mammary gland via the teat canal once daily until recovery. Such a dose yielded statistically significant decreases (P < 0.05) both in the length of time before clinical recovery (2 d versus 4 and 4.5 d with either of the two antibiotic-based traditional drugs) and in the percentage of animals who suffered relapses within a 2-month period following treatment (5% versus 60%, with one of the two drugs). A field experiment involving 106 cows was designed to compare the efficacy of 1% lysosubtilin water-glycerin solution (1:9 v/v) and other traditional medications for the topical treatment of superficial lesions of the udder and teats as well as its potential for mastitis prevention. All drugs used yielded a 100% cure rate, but lysosubtilin application made it possible to achieve a statistically significant decrease (P < 0.05) in the duration of the recovery period (2.5 d versus 4.5 to 5.5 d) when compared with any of the four other drugs tested. Its efficacy for mastitis prevention was at least 3.4 times higher than the efficacy of the other medications used (statistically significant, P < 0.05, with regards to two of the four drugs) as well. We therefore conclude that lytic enzyme preparations are prospective antimicrobial drugs and when used to combat animal diseases they may serve as a possible alternative to common antibiotics.     

Peroperative catheterization of the Eustachian tube

In general, patients who are malnourished tend to have prolonged effects from drugs metabolized by the MFOS. On the other hand, in obese patients, drugs that undergo phase II metabolism tend to be metabolized more rapidly, thus shortening their duration of action. Therefore, clinicians must remember that, in protein-calorie malnutrition, drugs metabolized in the liver may be more likely to cause toxic effects due to the decreased rate of hepatic metabolism. Dose reduction could eliminate these adverse effects. Alternatively, drugs that undergo phase II metabolism may need to be administered at higher doses in obese patients, since the desired clinical effect may not be seen at a normal dose due to the obesity-related increase in hepatic metabolism. This should be considered before discontinuing the drug as a result of its lack of effect.     

Breast cancer and benign breast disease patients evaluated in relation to oxidative stress

The 'WHO Analgesic Ladder' is a well validated approach for the selection of appropriate analgesic therapy for cancer pain as well as pain in AIDS. The mainstay of analgesic intervention for cancer and AIDS pain of moderate to severe intensity continues to be the appropriate use of opioid analgesics. There is, however, a growing appreciation for the role of adjuvant analgesics, such as antidepressants and other psychotropic medications, at each step of the WHO Analgesic Ladder, particularly in the treatment of neuropathic pain. Knowledge of the indications and usefulness of psychotropic analgesic drugs in cancer and AIDS pain populations will be most important to clinicians practicing in psycho-oncology/AIDS settings, particularly since these drugs are useful not only in the treatment of psychiatric complications of cancer and AIDS, but also as adjuvant analgesic agents in the management of pain. This paper reviews the literature on the use of antidepressants, psychostimulants, neuroleptics, anticonvulsants and other psychotropic analgesics in the management of cancer and AIDS pain. Mechanisms of analgesia, drug selection, and recommendations for clinical usage are discussed. The appropriate and timely use of psychotropic adjuvant analgesic drugs represents an opportunity for active psychiatric contribution to the multidisciplinary management of cancer and AIDS pain.