Local Administration

The problem has been recognized by many of the developers concerned, who have consequently themselves adopted the environmental standards of other industrialized nations. In the absence of national controls this is a responsible and laudable approach. However, the piecemeal adoption of standards taken from elsewhere does not take account of local conditions. These conditions may either enhance or limit the ability of the environment to disperse and attenuate or assimilate pollutants (e.g. the occurrence of temperature inversions will limit the dispersion of air pollutants). Similarly, the use to which local resources are put may demand particularly high standards of environmental quality (e.g. the use of sea water or river water as the basis of potable water supply). The choice of standards must also take into account local practices and existing local administration. 

Leptin is a cytokine produced and secreted by adipose tissue in proportion to the body fat content [3]. Mice and humans lacking leptin or its receptor develop a severe hyperphagia and a dramatic degree of obesity which is considerably more pronounced than that of the NDRKO mouse. Thus, leptin is the key adiposity signal in rodents and humans. Leptin secretion appears to reflect the metabolic status of the adipocyte rather than the sheer size of triglyceride deposits, and leptin levels may transiently be dissociated from total body fat. Nonetheless, over the course of a day with unrestricted food supply, plasma leptin levels reliably reflect the amount of total body fat. Local administration of leptin into the brain results in reduced food intake. The vast majority of patients with obesity have elevated serum levels of leptin. Thus, it is believed that the polygenic obesity is due to leptin resistance rather than to inadequate leptin secretion, or to a reduced blood/brain transport of the cytokine. 

TNF was originally identified because of its cytotoxic activity against some tumor cell lines and its ability to induce hemorrhagic necrosis of solid tumors in various animal models. However, the clinical use of TNF as an anticancer drug has been so far limited by its severe cardiovascular side effects. Therefore, TNF treatment is limited to regional and local administration of high doses of TNF, often in combination with chemotherapy, as accomplished in isolated limb and isolated hepatic perfusion (ILP and IHP, respectively) [5]. In the case of ILP, typically metastases are treated, patients benefit from this procedure by salvage of limbs from a loss by amputation. 

The efforts so far made by the local administrations to convey refuse waters to treatment plants and to lower the percentage of phosphorus in... 

Pharmacologic management of thrombosis includes local administration of thrombolytic agents. Alteplase (2 mg per port) and reteplase (0.5 unit per port) are the two most commonly used agents today. Urokinase has been used in the past, but after its reintroduction to the United States market, the larger dosed vial size makes it less cost effective than the newer agents. 

IL-ip is a well documented sleep factor (reviewed by Obal Krueger, 2003). Its administration increases sleep, its blockade decreases sleep and sleep rebound, and its transcription increases during waking. IL-1 receptor knock-out mice sleep less. Local application of IL-1 p in POA also stimulates NREM sleep. We examined the effects of local administration of IL-1 p and an antagonist through microdialytic application adjacent to lateral POA neurons (Alam et at, 2004). Neuronal activity is recorded within 0.5-1.0 mm of a microdialysis membrane in unrestrained rats. IL-ip potently inhibited the activity of 79% of wake-active neurons. The inhibitory response to IL-ip of wake-active neurons could be blocked by pre-treatment with IL-lra, an IL-ip antagonist. IL-ip application also excited some sleep-active neurons, but this response was inconsistent. 

Histamine decarboxylase knockout mice are unable to produce histamine and these animals are unable to maintain wakefulness in a novel environment. Systemic or intraventricular administration of histamine or Hi receptor agonists induces wakefulness whereas systemic or intraventricular administration of Hi receptor antagonists induces sleep. Local administration of an H3 receptor agonist in the TMN induces sleep whereas local administration of an H3 receptor antagonist into the TMN induces wakefulness. 

Local administration of the Hi agonist 2-thiazolylethylamine (50 pg in 0.5 pi) into the pontine tegmentum increased wakefulness and reduced NREM sleep during the first 3 h after injection. In contrast, local application of mepyramine (5 pg in 0.25 pi) caused a decrease in wakefulness and an increase in NREM sleep. 

Reid M., Tafti M., Nishino S. et al. (1996). Local administration of dopaminergic drugs into the ventral tegmental area modulates cataplexy in the narcoleptic canine. Brain Res. 133, 83-100. 

Botulinum exotoxin impedes release of neurotransmitter vesicles from cholinergic terminals at neuromuscular junctions. Botulinum exotoxin is ingested with food or, in infants, synthesized in situ by anaerobic bacteria that colonize the gut. A characteristic feature of botulinum paralysis is that the maximal force of muscle contraction increases when motor nerve electrical stimulation is repeated at low frequency, a phenomenon attributable to the recruitment of additional cholinergic vesicles with repetitive depolarization of neuromuscular presynaptic terminals. Local administration of Clostridium botulinum exotoxin is now in vogue for its cosmetic effects and is used for relief of spasticity in dystonia and cerebral palsy [21]. 

Targeted delivery is critical to the success of future NO/donor drug discovery efforts. The goal must be to provide quantities of NO, through local administration... 

Local administration of NO to the lungs has been shown to reverse pulmonary hypertension in animal models [103], importantly with no systemic side effects. This is likely to be as a result of surplus NO being removed as nitrosyl-hemoglobin [104]. Such advantages of gaseous NO were first reported in 1991 [105, 106]. In 1999 and 2001 NO gas was approved as a drug in the USA and European Union, for treating hypoxemic respiratory failure in infants [107]. 

Gupta, P.K., Patel, J.P., and Hahn, K.R., Evaluation of pain and irritation following local administration of parenteral formulations using the rat paw lick model, /. Pharm. Sci. Technol., 48, 159, 1994. 

In the case of local administration, lipoplexes are generally retained at the site of injection, with poor dispersion (22). In contrast to small emulsions or neutral liposomes, which immediately appear in the venous outflow perfusate following intratumoral injection, the appearance of cationic liposomes is highly restricted to the injection zone (22). The authors deduced that the determining factor altering the pharmacokinetic properties is not the rate of transfer from the interstitial space to the vascular site but rather the rate of transfer from the injection site to the well-vascularized region (23). 

Lowering of pupillary sphincter tonus and pupillary dilation by local administration of homatropine or tropic-amide (mydriatics) allows observation of the ocular fundus. For diagnostic uses, only short-term pupillary dilation is needed. The effect of both agents subsides quickly in comparison with that of atropine (duration of several days). 

A major breakthrough in asthma therapy was the introduction in the 1970s of aerosol corticosteroids These agents (Table 39.3) maintain much of the impressive therapeutic efficacy of parenteral and oral corticosteroids, but by virtue of their local administration and markedly reduced systemic absorption, they are associated with a greatly reduced incidence and severity of side effects. The success of inhaled steroids has led to a substantial reduction in the use of systemic corticosteroids. Inhaled corticosteroids, along with 2-(tdreno-ceptor agonists, are front-line therapy of chronic asthma. 

Pharmacokinetics Absorbed through the cornea where the isopropyl esterprodrug is hydrolyzed to acid form to become biologically active. Highly lipophilic. The acid of latanoprost can be measured in the aqueous humor during the first 4 hours and in the plasma only during the first hour after local administration. In cornea, latanoprost is hydrolyzed to the biologically active acid. Metabolized in liver if it reaches systemic circulation. Metabolized to 1,2-dinor metabolite and 1,2,3,4-tetranor metabolite. Primarily eliminated by the kidneys. Half-life 17 min. 

Effect on eye Atropine produces mydriasis by blocking the cholinergic nerves supplying the smooth muscles of sphincter of the iris on local administration into the eye. It also produces paralysis of accommodation or cycloplegia (the condition in which, one can see things... 

Further clinical studies68 have shown that preparation 62 (i.v., i.m., per os and local administration) is active in painful polycystic mastopathies, probably by regeneration of breast connective tissue. In the course of treatment pain disappeared, the gland became supple again, the nodules diminished in size and there was often massive regression of macrocysts. 

The influence of these preparations on healing processes in wounds on subcutaneous, peroral or local administration as 5-10% ointments (Table 14) has been examined. 

Figure 2. Effects of local administration of TTX, alone and in combination with 10 pM imetit, on 100 mM potassium-evoked release of ACh from the cortex of freely moving rats. At 40 (Si) and 140 (S2) min the perfusion medium was changed from 4 to 100 mM KC1 for 10 min after equilibration. TTX was added 20 min, and imetit 10 min before S2 stimulation to the perfusion medium. Both remained throughout the S2 stimulation. Shown are means S.E. of (n) experiments. The presence of significant treatment effects was determined by one-way analysis of variance followed by Scheffe s test. P < 0.001 vs. control.

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