Sensitizer therapy

Disseminated gonococcal infections often respond quickly to antibiotics. Ceftriaxone 1 g/day for 7 to 10 days is the treatment of choice. After culture and sensitivity results are available and the organism is determined to be sensitive, therapy can be switched on the fourth day to oral amoxicillin or to doxycycline or tetracycline to complete the 7- to 10-day course. Clinical resolution of signs and symptoms usually is rapid. 

It is well known that diabetic patients undergoing coronary interventions have worse chnical and angiographic outcomes in comparison with nondiabetic patients. In the retrospective analysis of the PRESTO (Prevention of Restenosis with Tranilast and its Outcomes) trial the effect of different anti-diabetic treatment was analysed [40] in 1,110 diabetic patients who received non-sensitizer therapy (insulin and/or sulfonylureas) and in 887 patients who were treated with sensitizers (metformin with or without additional therapy). Compared with patients on non-sensitizer therapy, those on sensitizer therapy showed an adjusted OR of 0.72 p = 0.005 for any clinical event. The differences between the non-sensitizer therapy group and the sensitizer group were attributable mainly to decreased rates of death (OR = 0.39 p = 0.007) and myocardial infarction (OR = 0.31 p = 0.002). In this retrospective analysis, use of metformin in diabetics undergoing coronary interventions appeared to decrease adverse clinical events, especially death and myocardial infarction, compared with diabetic patients treated with non-sensitizer therapy. 

Bioluminescence in vitro chemosensitivity assays are now used to assess the sensitivity of tumor cells (obtained by surgical or needle biopsy) to different dmgs and combinations of dmgs. Cells are grown in microwell plates in the presence of the dmgs at various concentrations. If the tumor cells are sensitive to the dmg then they do not grow, hence total extracted cellular ATP, measured using the bioluminescence firefly luciferase reaction, is low. This method has been used to optimize therapy for different soHd tumors and for leukemias (306). 

Given stringent requirements for effective sensitizers and the desire to use wavelengths further to the red for therapeutic appHcations, definition of newer sensitizers has been a principal area of research since about 1987. Expanded theoretical and experimental understanding of photophysics has been a key element in identifying new classes of potential sensitizers (93—98). Research has focused on cationic derivatives of Nile Blue (93), metaHo-phthalocyanines (94), naphthalocyanines (95), chlorin-type compounds (96), expanded ring porphyrinoids (97), as well as porphyrins other than hematoporphyrin and its derivatives (98). This work has also been reviewed (10,91). Instmmentation for photodynamic therapy has been reviewed (99). 

Functional dyes (1) of many types are important photochemical sensitizers for oxidation, polymerization, (polymer) degradation, isomerization, and photodynamic therapy. Often, dye stmctures from several classes of materials can fulfiH a similar technological need, and reviewing several dye stmctures... 

Natural Sensitizing Dyes and Photodynamic Therapy. The chlorophylls are, of course, among the natural sensitizers for photosynthesis. Considerable iaterest exists ia chlorophyll and related pigments as photosensitizers ia biology and medicine (75), isomeric retinal chromophores as visual pigments (76,77), and the use of synthetic photosensitizers ia neurobiology (9), hematology (78), and photodynamic therapy (79). 

Naphthalocyanins, phthalocyanins, and porphyrins as sensitizers in photodynamic cancer therapy 98IZV836. 

Porphyrins, modified natural chlorophylls, chlorins, phthalocyanins, xanthenes, phenothiazine, and phenoxazine dyes as new sensitizers for photodynamic therapy 98MI50, 98MI51, 98MI52, 98MI53. 

The photophysical properties of porphycenes make these structures potential sensitizers for an application in Photodynamic Tumor Therapy (PDT). To improve the photophysical properties and to modify possible biological activity it is necessary to have porphycenes with an extended chromophore and/or with additional functional groups for further modifications. The Diels-Alder reaction of a vinyl porphycene allows for the preparation of benzoporphycenes with an extended chromophore9 and additional functional groups (cf. Section 1.1.2.4.). 

Many of the agents currently in use for the therapy of cancer can trigger apoptosis in cancer cells. Cancer-associated alterations of the genes that regulate apoptosis would therefore be predicted to affect sensitivity to these agents. 

NO-sensitive GC represents the most important effector enzyme for the signalling molecule NO, which is synthesised by NO synthases in a Ca2+-dependent manner. NO-sensitive GC contains a prosthetic heme group, acting as the acceptor site for NO. Formation of the NO-heme complex leads to a conformational change, resulting in an increase of up to 200-fold in catalytic activity of the enzyme [1]. The organic nitrates (see below) commonly used in the therapy of coronary heart disease exert their effects via the stimulation of this enzyme. 

Decreased activity of the thyroid gland results in hypothyroidism and, in severe cases, myxoedema. It is often of immunological origin and the manifestations are low metabolic rate, slow speech, lethargy, bradycardia, increased sensitivity to cold, and mental impairment. Myxoedema includes a characteristic thickening of the skin. Therapy of thyroid tumours is another cause of hypothyroidism. Thyroid deficiency... 

Treatment with specific antibodies (ALG, ATG, anti-CD3, anti-CD25) is indicated during the induction phase after transplantation and in the case of acute rejection for short time periods. Therapy with nonhuman antibodies may cause sensitization. Muromonab-CD3 might initiate a cytokine release syndrome (fever, chills, headache). 

There are few definitive data to substantiate the efficacy of LTRA therapy in refractory asthma, except for patients with aspirin-sensitive asthma. This is a fairly uncommon form of asthma that occurs generally in adults who often have no prior (i.e., childhood) history of asthma or atopy, may have nasal polyposis, and who often are dependent upon oral corticosteroids for control of their asthma. This syndrome is not specific to aspirin but is provoked by any inhibitors of the cycloxygenase-1 (COX-1) pathway. These patients have been shown to have a genetic defect that causes... 

LTRAs are extremely safe for patient use. However, the present generation of LTRAs is only modestly efficacious. Many patients show no clinically meaningful response, and current recommendations suggest a 1 month trial period to determine if patients will benefit from these drugs. With the exception of aspirin-sensitive asthmatics, there is currently no means for predicting which patients or under what circumstances antileukotrine therapies will be effective. 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

---