Systemic Agents

Other polyene antibiotics are in clinical use but no confirmed allergic reactions have been reported. 

The polycyclic antibiotic, griseofulvin, is derived from Penicillium griseofulvum and is perhaps the most important agent in the systemic treatment of dermatophyte infections (Fig. 2). It is used orally for the treatment of superficial fungal infections of nails, hair, and skin, increasing the resistance of keratin to infection. Side effects of therapy are usually mild most common are nausea, diarrhoea and headaches (Swartz 1962). 

Chang (1965) reported a case of cold urticaria and photosensitisation to griseofulvin, in which an attempt was made to demonstrate the presence of griseo-fulvin-specific antibodies. Positive reactions were obtained using rabbit passive cutaneous anaphylaxis in which a latent period of 4 h was allowed to elapse be- 

Some rashes have been reported during therapy of systemic mycoses with 5-fluorocytosine but it is not thought that these are allergic in origin (Doeglas 1978) 

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Cyclocondensation of the amine 151 with the ketoester 152 gave 153 that can be selectively alkylated to give 154 which upon benzylation and alkylation gave 155 as central nervous system agent (83EP90516) (Scheme 30). 

Among retinoids, 13-cis-retinoic acid is known to have not only anti-inflammatory but also sebostatic effects. Therefore it is one of the most potent topical and also systemic agents for therapy of acne. 

Bandarage, U.K., Kuehne, M.E., GUck, S.D. (2001) Chemical Synthesis and Biological Evaluation of 18-Methoxycoronaridine (18-MC) as a Potential Anti-Addictive Agent. Current Medicinal Chemistry Central Nervous System Agents, 1, 113-123. 

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Atkinson, F., Cole, S., Green, C., Van de Waterbeemd, H. Lipophilidty and other parameters affecting brain penetration. Curr. Med. Chem. Central Nervous System Agents 2002, 2, 229-240. 

Fowler, C.J. (2004) Curr. Med. Chem. Central Nervous System Agents 4, 161-174. 

Lopez-Rodriguez, M.L., Viso, A., Ortega-Gutierrez, S., Fernandez-Ruiz, J. and Ramos, J.A. (2002) Curr. Med. Chem Central Nervous System Agents 2, 129-141. 

Localized pain may be treated effectively with local topical therapy, whereas generalized pain may be treated best with systemic agents. 

Pharmacologic alternatives for psoriasis include topical agents, phototherapy, and systemic agents including the use of biologic response modifiers. 

UVA can be used with other systemic agents including oral retinoids (RePUVA) and methotrexate. This will be discussed later in greater detail. 

Sulfasalazine has variable efficacy and is of limited potency. However, its side-effect profile is better than other systemic therapies and it is sometimes tried as an initial systemic agent for moderate to severe psoriasis. Usual doses are 2 to 4 g/day in divided doses.10... 

Methotrexate has been used successfully with cyclosporine, either concurrently34 or in rotation. Rotational therapy is particularly effective since it minimizes the serious adverse effects of both agents hepatotoxidty from methotrexate and hypertension and nephrotoxicity from cyclosporine. Having an overlapping treatment period may not be necessary and patients have been successfully switched after a 1-week washout period.21,35 This is a very useful combination of systemic agents in the longterm management of this chronic disease. 

Vesicants are also systemic agents and readily pass through the skin to affect susceptible tissue including those that produce blood. For this reason they are often described as radio-mimetic poisons. In severe cases, systemic effects can include cardiovascular shock and multiorgan failure. Nitrogen vesicants can also cause central nervous system depression and cardiovascular shock. Both sulfur and nitrogen vesicants are carcinogenic. 

Urticants are also systemic agents and rapidly pass through the skin to affect susceptible tissue. Percutaneous absorption of liquids or solids can also produce pulmonary edema and blood clots in the lungs. 

If monotherapy with a systemic agent does not provide optimal outcomes, combining systemic therapies with other modalities may enhance benefit. The dose of each agent may often be reduced, resulting in lower toxicity. Combinations include ... 

Systemic agents that are considered safe in pregnancy include acyclovir, amoxicillin, azithromycin, cephalosporins, chlorpheniramine, cyproheptadine, dicloxacillin, diphenhydramine, erythromycin (except estolates), nystatin, and penicillin. 

Central nervous system agents (analgesics, anticonvulsants, sedative-hypnotics)... 

Prokai L, Zharikova A, Janaky T, Li X, Braddy AC, et al. 2001. Integration of mass spectrometry into early-phase discovery and development of central nervous system agents. J Mass Spectrom 36 1211. 

In a self-organizing system, agents pursue individual courses that are unpredictable. Reliable, reproducible structures emerge at the collective level from the interactions of those agents. Individual agents are literally out of control, but the system as a whole produces relatively stable results (see Kelly, 1994 for many interesting applications of this concept to economic life). 

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