A new mechanism in serine proteases catalysis exhibited by dipeptidyl peptidase IV (DP IV)--Results of PM3 semiempirical thermodynamic studies supported by experimental results

There has been considerable interest and controversy over the potential clinical role of combination antiretroviral therapy, primarily in the treatment of patients with established HIV infection. In order to model the hematologic toxicity of high-dose combination antiretroviral therapy, the HL60 myeloid leukemia cell line was exposed to zidovudine, dideoxycytidine and/or didanosine. The results suggest that the myelotoxicity of high-dose combination antiretroviral therapy may be controlled by using very brief periods of drug exposure. Brief intense antiretroviral therapy may offer a useful approach, particularly in the treatment of patients with AIDS-related neoplasms who are also receiving myelotoxic antineoplastic drugs.     

Pulmonary toxicity of drugs used to treat systemic autoimmune diseases

A number of drugs used to treat systemic autoimmune diseases can cause respiratory complications. These include bronchospasm, noncardiac pulmonary edema, interstitial pneumonitis and fibrosis, hypersensitivity, and numerous other disorders. Additionally, some of these drugs increase the risk of infections, particularly with opportunistic organisms. This article reviews the clinical presentation and mechanism of toxicity of drug related pulmonary complications.     

Bioactive glass fiber/polymeric composites bond to bone tissue

Cancer cells genetically modified to secrete immunoregulatory cytokines offer great promise for human cancer treatment as tumor vaccines. However, in preclinical animal studies, large established cancer burdens have appeared difficult to eradicate with such vaccines. For example, lethally-irradiated GM-CSF-secreting CT26 colon carcinoma cell vaccine therapy tends to cure only animals bearing 1 x 10(5) wild-type CT26 cells or less. For many human cancers, antineoplastic chemotherapy can often significantly reduce systemic cancer burdens. Unfortunately, for most advanced metastatic solid organ cancers, such as cancers of the breast, colon, and prostate, antineoplastic drug treatments generally fail to effect cancer cures. Treatment regimens combining genetically-modified cancer cell vaccine therapy and antineoplastic chemotherapy have the potential to increase advanced cancer cure rates if antineoplastic drugs and drug combinations that do not inhibit vaccine-induced immune responses can be identified. To assess the potential immunomodulatory properties of commonly-used antineoplastic drugs that might be used in combination with cancer vaccine treatments, we studied the effects of the drugs on antitumor immune responses manifest by animals receiving lethally-irradiated GM-CSF-secreting CT26 cell vaccines. Immunomodulatory properties of the antineoplastic drugs were evaluated i) by monitoring drug effects on the generation of tumor-specific CD8+ cytotoxic T-lymphocytes (CTLs) in response to GM-CSF-secreting CT26 vaccine administration, ii) by determining drug effects on the resistance of vaccinated animals to subsequent challenge with lethal inoculac of CT26 cells, and iii) by evaluating combination drug and vaccine treatment efficacy against established CT26 tumors. Using this approach, doxorubicin was found to possess apparent immunostimulatory activities, depending on the dose and schedule of administration, while cyclophosphamide appeared immunosuppressive. The different immunomodulatory properties of doxorubicin and cyclophosphamide may be clinically relevant: combination doxorubicin and vaccine treatment of established CT26 cancers increased cure rates over that achieved with either agent alone, while combination cyclophosphamide and vaccine treatment of animals carrying CT26 tumors was no better in curing the animals than drug treatment alone.     

Patterns of drug-induced cardiovascular pathology in the beagle dog: relevance for humans

In toxicity studies, the examination of tissue sections for pathological changes is the principle method for the identification of organ toxicity and characterisation of the hazard of novel drugs for humans. Study of the patterns of pathological alterations also represents an important means of developing an understanding of the mechanism of toxicity. However as pathological change frequently represents a final common expression of diverse processes, additional functional information is often required for a clear understanding of the mechanisms of toxicity. This is exemplified in the evaluation of the effects of drugs on the beagle dog cardiovascular system where an understanding of mechanisms is crucial in the assessment of human risk. Particular patterns of drug-induced structural change in the myocardium or blood vessels are frequently linked to specific mechanisms of toxicity. However, assessment based on the interpretation of patterns of cardiovascular pathology alone may be misleading. Quite different changes in cardiac and vascular function or direct cellular toxicity may also be manifest by pathological features in common. Therefore, a clear understanding of mechanism frequently requires additional in vivo or in vitro physiological, pharmacological, biochemical or other mechanistic information. The beagle dog remains an important model for the study of cardiovascular toxicity because in this species, haemodynamic changes and pathological alterations can be related in a way that provides the basis for the safe study in humans of novel drugs with cardiovascular activity.     

Limitations in the use of gamma-glutamyl transferase estimations in alcohol-dependent subjects

OBJECTIVE: To investigate any relationship between the pathological features of amiodarone-induced pulmonary toxicity (APT) and clinical use of amiodarone in patients dying from acute respiratory distress syndrome (ARDS). DESIGN: Retrospective study. Review of clinical and pathological findings of patients dying from ARDS. SETTING: Intensive Care Unit (ICU) and Pathology Department of University hospital. SUBJECTS: Ten patients with clinical diagnosis of ARDS, who died in ICU and underwent post mortem examination. INTERVENTIONS: Case note review of clinical details; independent review of histological specimens. MEASUREMENT AND RESULTS: Over a 3-year period, ten patients underwent post mortem examination, of whom seven had received amiodarone. Three patients who received longer than 48 h of amiodarone had histological changes of widespread lipoid pneumonia, a recognised pattern of APT. CONCLUSIONS: Acute amiodarone pulmonary toxicity is a definite pathological entity in ICU patients. High oxygen concentrations may be a risk factor, while pre-existing pathology, e. g. ARDS, may mask its development. Amiodarone should be used with caution in this group of patients.     

Brain serotonin neurotoxicity and primary pulmonary hypertension from fenfluramine and dexfenfluramine. A systematic review of the evidence

OBJECTIVES: Obesity is an important clinical problem, and the use of dexfenfluramine hydrochloride for weight reduction has been widely publicized since its approval by the Food and Drug Administration. However, animal and human studies have demonstrated toxic effects of fenfluramines that clinicians should be aware of when considering prescribing the drugs. Our purpose was to systematically review data on brain serotonin neurotoxicity in animals treated with fenfluramines and the evidence linking fenfluramines to primary pulmonary hypertension (PPH). DATA SOURCES: Archival articles and reviews identified through a computerized search of MEDLINE from 1966 to April 1997 using "fenfluramine(s)," "serotonin," "neurotoxicity," "behavior," "anorexigens," "weight loss," and "primary pulmonary hypertension" as index terms. STUDY SELECTION: Reports dealing with long-term effects of fenfluramines on brain serotonin neurons, body weight, and pulmonary function in animals and humans. DATA EXTRACTION: Reports were reviewed by individuals with expertise in serotonin neurobiology, neurotoxicity, neuropsychiatry, and pulmonary medicine and evaluated for appropriateness for inclusion in this review. DATA SYNTHESIS: Fenfluramines cause dose-related, long-lasting reductions in serotonin axonal markers in all the animal species tested and with all the routes of drug administration used. Doses of fenfluramines that produce signs of brain serotonin neurotoxicity in animals are on the same order as those used to treat humans for weight loss when one takes into account known relations between body mass and drug clearance. However, no human studies have been conducted, and the pathological and clinical potential for neurotoxicity in humans is unknown. Appetite suppressants-most commonly fenfluramines-increase the risk of developing PPH (odds ratio, 6.3), particularly when used for more than 3 months (odds ratio, >20). CONCLUSIONS: Fenfluramine and dexfenfluramine have been demonstrated to damage brain serotonin neurons in animal studies. It is not known if such damage occurs in humans or if there are clinical consequences. Use of fenfluramines is associated with an increased risk of PPH. Future studies should address the long-term consequences of prolonged use of fenfluramines.     

Treatment of severe pulmonary embolism

Acute circulatory failure is the major complication of acute pulmonary embolism. It may be clinically silent, but sometimes leads to systemic hypotension, shock, or clinical manifestations of right ventricular failure. In these patients, oxygen, inotropic drugs, and fluid loading are indicated. Unless contra-indicated, thrombolytic therapy should be undertaken when clinical signs of circulatory failure occur. Surgical embolectomy is now undertaken in the very few patients not responding to maximal medical treatment. Vena cava interruption is not more often useful in massive pulmonary embolism than in non massive pulmonary embolism.     

Clinical applications of anticancer drugs targeted to topoisomerase II

Agents which 'poison' the enzyme topoisomerase II, have proven to be useful drugs for cancer treatment. Six antineoplastic drugs, which target topoisomerase II (doxorubicin, daunorubicin, idarubicin, mitoxantrone, etoposide and teniposide) are currently approved for clinical use in the United States. In this paper, the strategies and goals of cancer chemotherapy are summarized for the non-clinician. The use, pharmacology and toxicity of each of the six currently approved topoisomerase II inhibiting agents are reviewed.     

Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells. I. Comparative in vitro cytotoxicity of 27 drugs

Combined drug toxicity to HeLa cells was studied in vitro with use of the microtitre MIT-24 test system. Whether drug toxicity to HeLa cells is representative of drug toxicity to other cultivated cells was investigated by a comparison of the MIT-24 toxicity of 27 drugs to HeLa cells with their toxicity to various permanent cell lines and more differentiated primary cell cultures as reported in the literature, together with original recordings of the MIT-24 toxicity of 9 of the drugs to human fetal kidney cells. A similarity of drug toxicity to all cell types was found. Thus the MIT-24 recordings may be representative of a basal drug cytotoxicity, probably corresponding to local drug irritation and to causal systemic drug toxicity.     

Relationship between cognitive and social dysfunction in schizophrenia

Cytogenetic monitoring was carried out on a group of 38 nurses who reconstitute antineoplastic drugs in order to determine the extent of chromosomal damage. Genotoxic activities of antineoplastic drugs are studied by chromosome aberration assay, micronucleus assay, sister chromatid exchange (SCE) frequency high frequency cells (HFC) analysis, and mitotic activity of peripheral lymphocytes. Results confirmed that occupational exposure to a mixture of antineoplastic drugs may cause genome damages. The results of this study show that biomonitoring after exposure to a mixture of antineoplastic drugs which express clastogenic and aneugenic activity should involve a battery of cytogenetic methods.     

SR 4233 (tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours

SR 4233 (3-amino-1,2,4-benzotriazine 1,4-dioxide, WIN 59075, tirapazamine) is the lead compound in a new class of bioreductive anticancer drugs, the benzotriazine di-N-oxides. It is currently undergoing Phase I clinical testing. The preferential tumour cell killing of SR 4233 is a result of its high specific toxicity to cells at low oxygen tensions. Such hypoxic cells are a common feature of solid tumours, but not normal tissues, and are resistant to cancer therapies including radiation and some anticancer drugs. The killing of these tumour cells by SR 4233, particularly when given on multiple occasions, can increase total tumour cell killing by fractionated irradiation by several orders of magnitude without increasing toxicity to surrounding normal tissues. Topics covered in this review include the rationale for developing a hypoxic cytotoxic agent, the cytotoxicity of SR 4233 as a function of oxygen concentration, the mechanism of action of the drug and its intracellular target and the in vivo evidence that the drug may be useful as an adjunct both to radiotherapy and chemotherapy. Finally, the major unanswered questions on the drug are outlined.     

Nitric oxide, the biological mediator of the decade: fact or fiction?

Nitric oxide (NO), an atmospheric gas and free radical, is also an important biological mediator in animals and humans. Its enzymatic synthesis by constitutive (c) and inducible (i) isoforms of NO synthase (NOS) and its reactions with other biological molecules such as reactive oxygen species are well characterized. NO modulates pulmonary and systemic vascular tone through its vasodilator property. It has antithrombotic functions and mediates some consequences of the innate and acute inflammatory responses; cytokines and bacterial toxins induce widespread expression of iNOS associated with microvascular and haemodynamic changes in sepsis. Within the lungs, a diminution of NO production is implicated in pathological states associated with pulmonary hypertension, such as acute respiratory distress syndrome: inhaled NO is a selective pulmonary vasodilator and can improve ventilation-perfusion mismatch. However, it may have deleterious effects through modulating hypoxic pulmonary vasoconstriction. Inhibitors of NOS may be of benefit in inotrope-refractory septic shock, but toxicity of newly developed selective iNOS inhibitors have prevented clinical trials of efficacy. An expanding literature on the origins and measurement of NO in exhaled breath implicates NO as a potentially useful marker of disease activity in respiratory tract inflammation in the future. This report reviews some aspects of research into the clinical importance of nitric oxide.     

Treatment of concomitant illnesses in patients receiving anticonvulsants: drug interactions of clinical significance

As epilepsy often is a chronic condition requiring prolonged therapy with anticonvulsants, patients being treated for epilepsy can be at risk when they are prescribed other drugs for concomitant diseases. Pharmacokinetic interactions can occur at each step of drug disposition (absorption, distribution, metabolism and elimination). Although such interactions may occur frequently with some drugs, only some will be clinically relevant. Alterations in the hepatic biotransformation of metabolised drugs due to hepatic isoenzyme induction or inhibition is of particular concern. The consequences of pharmacokinetic interactions are either accumulation of the drug leading to toxicity, or lowering of plasma concentrations resulting in reduced efficacy. Clinically relevant interactions depend on the structure, dosage and duration of administration of interacting agents, and on the individual's genetic make-up. In the past, drug interactions have been analysed empirically. At present, at least for interactions between drugs that are biotransformed in the liver, the risk should be predicted by considering the individual cytochrome P450 isoforms involved in the metabolism of coadministered drugs. Although drug-drug interactions can be predicted, their extent cannot be due to large interindividual variability. Even if nearly all drug combinations could be used with close clinical surveillance and blood concentration determinations, drugs that are not metabolised and are not highly protein bound, as are several of the new anticonvulsants, such as gabapentin, lamotrigine and vigabatrin, have a clear advantage in terms of a lower interaction potential.     

Pulmonary infarcts can mimic pulmonary metastases from renal cancer

PURPOSE: Spontaneous regression of pulmonary metastases from renal cell carcinoma is a rare but well documented event. We present 2 recent cases that were radiographically consistent with pulmonary metastases from renal cell carcinoma but were pathologically shown to be pulmonary infarcts with no evidence of metastatic cells. Stable pulmonary infarcts can be misconstrued as metastatic disease in patients with renal cell carcinoma while resolving pulmonary infarcts may represent a subpopulation of patients with apparent spontaneous regression. Clinical implications of these findings are discussed. MATERIALS AND METHODS: Clinical and pathological data from 2 patients with large primary renal tumors, venous thrombi and lung masses were reviewed. Data from these cases, as well as pertinent urological and pathological literature, are presented. RESULTS: Although preoperative assessment was consistent with stage IV renal cell carcinoma, pathological examination of the lung masses in these patients showed no evidence of tumor cells. CONCLUSIONS: Pulmonary infarcts may mimic resolving or stable pulmonary metastasis in patients with renal cell carcinoma. Accurate clinical staging is crucial for the prognosis and treatment of renal cell carcinoma. Mistaking pulmonary infarcts for metastatic lesions can lead to inaccurate prognoses and inappropriate treatment.     

Place conditioning of mice with the NMDA receptor antagonists, eliprodil and dizocilpine

Leptomeningeal carcinomatosis (LC) occurs in solid tumors like breast, lung carcinoma and melanoma, rarely sarcoma and in leukemia and lymphoma. Clinical symptoms of LC often present with differential diagnostic problems. The most common presentation are multiple neuraxis syndromes which for didactic reasons are classically considered as central nervous system (CNS), spinal (SP) or cranial nerve (CN) symptoms and signs and appear isolated or more frequently in combinations. It is generally agreed that signs are usually more prominent than symptoms. Only few series focus on monolocular presentation at clinical manifestation. This overview describes the clinical symptoms and signs in patients with LC, the concept of multiple neuraxis lesions, CNS, CN and SP signs and symptoms. Also the problem of new symptoms and signs in patients treated with antineoplastic chemotherapy and radiation is addressed. The study is based on own results and a survey of the present literature.     

Psychopharmacotherapy in pregnancy and breast feeding

The primary purpose of this article is to review critically the literature on the use of psychotropic medications in pregnancy and during breast feeding in order to suggest strategies for the clinical management of these periods. Use of psychotropic medications during pregnancy may cause three complications: 1. teratogenicity, 2. perinatal syndromes (neonatal toxicity), and 3. postnatal behavioural sequelae (behavioural toxicity). The literature features few well-controlled studies concerning these points, so that the available information allows only few conclusions. Exposure to certain psychotropic drugs in utero may increase the risk for some specific congenital anomalies; there is mostly no strong evidence for behavioural toxicity in children exposed to psychotropic medications. Use of psychotropic drugs during pregnancy and breast feeding may be appropriate in many clinical situations and should include thoughtful weighing of risk of pre- and postnatal exposure versus risk of relapse following drug discontinuation. The authors try to present disorder-based guidelines for psychotropic drug use during pregnancy and breast feeding and for psychiatrically ill women who wish to conceive.     

Topotecan: a new topoisomerase I inhibiting antineoplastic agent

OBJECTIVE: To review the pharmacologic, pharmacokinetic, therapeutic, and safety aspects of irinotecan, a new antineoplastic agent, and to assess its role in the treatment of colorectal and lung cancer. DATA SOURCES: English-language articles from the MEDLINE database, January 1990-March 1998; Pharmacia & Upjohn Company; published articles and meeting abstracts. STUDY SELECTION: Studies in humans with cancer, clinical case reports, and open clinical studies were reviewed. Efficacy studies were limited to trials with at least 20 evaluable patients. DATA EXTRACTION: Relevant data were extracted from published reports and abstracts. DATA SYNTHESIS: Irinotecan is an effective agent for the treatment of advanced colorectal cancer. It demonstrates significant activity as a first-line agent and in patients with disease that is refractory to fluorouracil-containing regimens. Activity against lung cancer has also been demonstrated. Limited data indicate activity against cancers of the ovary, cervix, stomach, and in non-Hodgkin's lymphomas. Major toxicity consists of myelosuppression and diarrhea. CONCLUSIONS: Irinotecan is a useful addition to the antineoplastic drug family and offers significant efficacy for treatment of patients with fluorouracil-refractory colorectal cancer.     

Modulation of platinum-induced toxicities and therapeutic index: mechanistic insights and first- and second-generation protecting agents

Platinum-type drugs have proven to be valuable in the treatment of a variety of solid tumors, beginning with the commercial approval of cisplatin 18 years ago. There are several clinically important toxicities commonly associated with the administration of these drugs. Despite the extensive use of cisplatin and carboplatin, the fundamental chemical transformations and mechanisms that underlie their antitumor and toxic effects have not been fully characterized. Several first-generation protective thiols have been clinically studied in an attempt to reduce the toxicity of platinum-type drugs; while some of these agents appear to protect against certain toxicities, nearly all platinum-protecting drugs have their own intrinsic toxicities, which can be additive to the toxicity of platinum-type drugs. Tumor protection by platinum-protecting drugs is an additional untoward effect that is associated with certain types of agents and must be addressed with care. Recent advances in theoretical and laboratory methods and the use of supercomputers have extended our understanding of the possible major mechanisms underlying platinum drug antitumor activity and toxicity; we present strong evidence that there are two classes of chemical species of platinum drug. One class appears to predominantly account for the antitumor activity, and the other class of chemical species produces many of the toxic effects of platinum drugs. We have discovered a new nontoxic, second-generation platinum-protecting agent, known as BNP7787, which appears to selectively inactivate and eliminate toxic platinum species. BNP7787 has recently entered phase I clinical testing in cancer patients.     

Mucocutaneous reactions to antineoplastic agents

Mucocutaneous reaction patterns in patients receiving cancer therapy are not only variable, but in many instances identical patterns are produced by different pathologic mechanisms. For example, patients with leukemia or lymphoma may present with nodular skin lesions that may represent malignant infiltration, septic emboli, vasculitis, or a drug eruption. The most banal skin eruption may signal an impending or ongoing catastrophe. If one is able to make some clinical evaluation regarding the likelihood of a drug being responsible for the mucocutaneous eruption, it may help avoid further clinical or laboratory investigation and patient discomfort. Unfortunately, only a few antineoplastic agents have "characteristic" skin manifestations. If, however, these are kept in mind they may be helpful in the diffential diagnosis of mucocutaneous eruptions occurring in patients treated with cancer chemotherapeutic agents.     

QT interval: a measure of drug action

Historically, QT prolongation, occurring with or without drug therapy, has been considered primarily as a clinical marker for risk of arrhythmia. However, as understanding of cardiac repolarization improves and ability to measure accurately small changes in QT interval increases, the QT interval will be used as a marker for drug action as well. In addition, QT prolongation may prove to be a valuable tool for detecting and quantifying risk of arrhythmia due to drugs. This has been emphasized recently by the experience with terfenadine. Use of the QT interval as a marker for toxicity and efficacy will require sensitive and specific methods that are currently being developed and validated. The current methodologies for detecting small changes in the QT interval and the significance of those changes are discussed.