Development Of New Substances Research Articles

Anthrax--an old disease becomes topical: cutaneous anthrax and the eye

Anthrax disease and its eye manifestations were rare in the last 100 years, but the threat of terrorist actions has revived its topicality. After an introductory historical review, the pathogenesis of this disease with regard to the virulence of Bacillus anthracis is reported. On the basis of photos displaying the course of the disease, the symptoms particularly of the cutaneous form of this disease as well as the diagnostic possibilities are described. The current status of therapy and research for more effective treatment is discussed, with particular emphasis on the development of new substances with antitoxin properties and better vaccines. Bacillus anthracis is once again an actual threat, and therefore it is necessary for doctors to familiarize themselves with the current knowledge of this infection.

Chemotherapy for advanced non-small cell lung cancer (NSCLC)

Chemotherapy's role in the treatment of NSCLC has increased greatly over the last years. One of the main reasons for chemotherapy's increased acceptance has been the development of new substances with unique mechanisms of action and high single-agent activity, combined with favourable toxicity. Cytotoxic drugs are currently used as single agents or in combination for first- and second-line therapy to achieve palliation in locally advanced and metastatic disease.

Alcohol and the risk of myocardial infarction.

Epidemiological studies have repeatedly demonstrated a beneficial effect of moderate alcohol consumption on the incidence of coronary heart disease, myocardial infarction and overall mortality. The latter increases with excessive alcohol consumption. Although most epidemiological studies demonstrate a beneficial effect of alcohol consumption independent from the specific kind of alcoholic beverage, there is increasing evidence that wine and in particular red wine might contain pharmacological substances, which prevent atherosclerosis and myocardial infarction independent from the wine ethanol. Pathophysiological mechanisms mediating these beneficial effects include effects of wine phenols and tannins on LDL-cholesterol oxidation status, thrombocyte aggregation, endothelial function and smooth muscle cell proliferation. Identification and characterization of the pharmacologically active substances might provide the stage for the development of new substances to be used in the prevention of coronary artery disease and myocardial infarction.

Gemcitabine in non-small cell lung cancer (NSCLC).

The role of chemotherapy in the treatment of non-small cell lung cancer (NSCLC) has increased greatly in the past few years. While cytotoxic drugs are currently used both as single agents and in combination for palliation in locally advanced and metastatic disease, they have also been incorporated into multi-modality treatment strategies of Stage I to Stage III NSCLC. One of the main reasons for the increased acceptance of chemotherapy is the development of new substances. Among the most promising of these new drugs is the antimetabolite gemcitabine. Several single-arm gemcitabine Phase II studies involving more than 400 patients show validated response rates in more than 20% of the patients. These positive results have also been confirmed in randomized Phase II studies. Gemcitabine's unique mechanism of action, its lack of overlapping toxicity with other agents, and its favorable toxicity profile also define it as an ideal candidate for combination therapy. The activity seen with single-agent gemcitabine therapy can be compared with that of cisplatin-etoposide combination therapy. Gemcitabine-cisplatin combination response rates range from 31% to 54%, with a median survival time between 8.4 and 15.4 months and a 1-year survival rate between 30% and 59%. In addition to the clinical research of gemcitabine-cisplatin combinations, gemcitabine has also been tested in various double and triple combinations with carboplatin, paclitaxel, docetaxel, vinorelbine, and ifosfamide. Investigations combining gemcitabine with radiation therapy are on-going. The following review will summarize results from representative Phase I/II and III studies using gemcitabine for NSCLC patients.

New prospects for ultrasound contrast agents

Considering the several suggestions regarding the future developments of echocontrast agents, there is a striking difference between the few compounds actually available on the market and used in clinical practice and those undergoing experimental clinical trials. It is therefore difficult to predict what will be the actual impact of these agents in the next future. Future developments will probably go beyond color enhancement which was the end-point till a very short time ago. They can be schematically summarized as follows: (1) development of new substances which enhance both color and gray scales; (2) use of new-generation substances, such as BR1™ (Bracco, Milan, Italy) and EchoGen™ (Sonus, Bothell, WA), which use a gas other than air, such as perfluorate compounds which are more stable and gurantee longer and stronger effects; (3) use of more complex compounds acting at different levels. For example, SHU 536A (Sonovist) produces resonance phenomena with the second and third harmonics, and also stimulated acoustic emission which permits the morphological study of liver parenchyma. Other promising compounds are liposomes and aerosomes. Among the new possibilities in recording and observing phenomena, we can distinguish two main application fields: one is based on the physics of ultrasound and related to the presence of microbubbles in an acoustic field. These phenomena are generally obtained increasing the emission acoustic pressure, which eventually results in microbubble destruction and they are called nonlinear because there is no direct relationship between emission and return frequencies. These phenomena, which are detectable only with dedicated equipment, include: the resonance phenomenon with harmonic emission; intermittent harmonic emission and stimulated acoustic emission. The other application field is not strictly related to ultrasound physics and includes all the systems which can detect the presence of microbubles qualitatively or quantitatively. Other possible applications are related to the possibility of acquiring not only morphological but also functional data, especially in cardiology and neurology. Finally, targeted agents are potentially capable of demonstrating receptor sites or specific molecules, which may open very interesting therapeutic routes.

Viscoelastic-related glaucomas.

The routine surgical use of viscoelastic substances has revolutionized many anterior segment procedures. All of the currently available agents may be responsible for causing or exacerbating a transient, but occasionally significant, postoperative IOP elevation. In spite of differences in physical properties such as molecular weight, concentration, and viscosity, none of the various viscoelastics has consistently shown a decreased likelihood of producing ocular hypertension. Moreover, any newly introduced product must be evaluated carefully for this potential complication. Lavage of viscomaterial from the anterior chamber and administration of ocular antihypertensives may be helpful in averting or controlling the increased IOP. The surgeon should be cognizant of any pre-existing optic nerve damage and adjust the aggressiveness of postoperative glaucoma therapy accordingly. In the future, the development of new substances or simultaneous use of degrading enzymes may reduce or eliminate the incidence of viscoelastic-induced ocular hypertension.

Endocrine therapy of breast cancer. Status and perspectives

The modified therapeutic approach to metastatic breast cancer has been influenced by the realization that it cannot be cured even with the most aggressive chemotherapy. Consequently, quality of life and duration of remission have become more important parameters than judging therapeutic success only by rate of remission. The discovery of hormone receptors and of potent drugs with few side effects, which replaced ablative procedures, has led to an increased significance of endocrine therapy. Improved understanding of the endocrine mechanisms regulating malignant growth and their relationship to growth factors and tumor associated proteolysis have concurrently stimulated clinical research. Endocrine manipulation of malignant growth is based on competitive (antihormones), inhibitive (aromatase inhibitors, LHRH agonists), additive (gestagens) and ablative (ovarectomy) mechanisms. The knowledge of the optimal sequence and modality is mandatory for an individualized treatment, leading to significant advantages for the majority of patients. Premature induction of cytotoxic polychemotherapy may even cause disadvantages for subgroups of patients and should only be used as primary therapy in those situations, where urgent remission is mandatory. Only after all endocrine therapies have been tried and evaluated, one should turn to chemotherapy, whereby a trend towards "soft" chemotherapy, often as monotherapy, is favoured. The development of new substances, such as long acting LHRH analogues, "pure" antiestrogens with high receptor affinity, highly potent selective aromatase inhibitors and also the discovery of anti-progestins lead to further improvement of endocrine therapy in relation to efficacy as well as reduction of side effects. Adjuvant endocrine therapy with Tamoxifen correlates positively with the course of the disease and the survival rate in postmenopausal women. Unfortunately no effective adjuvant hormone therapy in premenopausal women exists to date.

Probes for double helical DNA sequence information: molecular mechanics study of a proposed model.

The biological activity of many molecules which bind to double helical DNA is related to the sequence specificity of their binding. The development of new substances of this type is challenging; a general solution to the problem does not exist. A new mechanism for small molecule-duplex DNA interaction termed intercalative displacement is proposed. The approach is promising for the design of new substances which will recognize sequence information on DNA. Molecular mechanics calculations in the absence of solvent and counterions predict that the proposed model is structurally and energetically closely related to the well known process of standard intercalation. The implications of these calculations for experimental studies are discussed.

Development of new drugs for endocrine tumour chemotherapy

The aim of our investigations is the development of new substances for endocrine treatment of hormone-dependent mammary carcinomas. Figure 1 shows in diagrammatic form some of the factors involved in the regulation by endocrine glands of hormone-dependent breast cancer and the different target points for endocrine treatment. Only the influence of oestrogens will be considered here and the co-operative effect of other hormones is excluded. There are three different possibilities of inhibiting the growth of mammary tumours and their metastases at a hormonal level: withdrawal ofoestrogens, administration of high doses of hormones, or antagonism of endogenous oestrogens. A decrease of the oestrogen level is accomplished by ablation; primarily by removal of still functioning ovaries, but also by adrenalectomy and or hypophysectomy. The biosyntheses of oestrogens can be inhibited first of all in the central nervous system. Presently, analogues of the gonadotropin releasing hormone that are active against tumours of the prostate are being tested for their activity against hormone-dependent breast cancer (3). In the periphery oestrogen synthesis in the adrenal gland is important since usually the ovaries have been removed or their function has ceased. Aminoglutethimide is known to inhibit the formation of pregnenolone in the adrenal gland and block the aromatization of androgens to oestrogens in the peripheral tissue. Its administration leads to remission of 50% of oestrogen receptor positive tumours. In the last few years, several inhibitors of the steroid aromatase have been synthesized (2,7) and their clinical value will have to be examined. Since the successful introduction of tamoxifen, the method of antagonizing oestrogens at a cellular level has become important. The advantages of the anti-oestrogen treatment are somewhat diminished however by the fact that every third patient does not respond to this therapy despite the presence of oestrogen receptors at the tumour tissue. The reasons for these failures are still unknown. Defects in cellular regulation can be