Enhancing drug influx

Enhancing Drug Influx in the Blood-Brain Barrier.594... 

Strategies to overcome these obstacles and enhance CNS drug delivery across the BBB can be divided into two principal groups enhancing drug influx and restricting drug efflux from BMVEC. 

ENHANCING DRUG INFLUX IN THE BLOOD-BRAIN BARRIER... 

Possible approaches for enhancing drug influx in the BBB include (i) modification of a drug chemical structure, (ii) drug solubilization in nano- or microcontainers, and (iii) transient increase of BBB permeability. 

Little is known about the nervous systems of cestodes and trematodes except that they probably differ from those of nematodes, since milbemycins and avermectins have no effect on them. However, a highly effective anti schistosomal and antitapeworm agent, praziquantel (see Chapter 54 Clinical Pharmacology of the Anthelmintic Drugs), is known to enhance Ca2+ influx and induce muscular contraction in those parasites, though it exerts no action on nematodes or insects. Some benzodiazepine derivatives have activities similar to those of praziquantel these activities are unrelated to the anxiolytic activities in the mammalian central nervous system. The nerves and muscles in schistosomes and tapeworms are thus interesting subjects for future chemotherapeutic studies. 

In that paper, we suggested for the first time that GA effects were related to inhibition of calcium uptake by smooth muscle and that indeed GA could be seen as a calcium channel blocker. This compoimd affected the contractile uterine responses in several species including human uterine smooth muscle [34]. GA also caused inhibition in the responses elicited by a number of spasmogenic compounds including acetylcholine, prostaglandins and even oxytocin "Fig. (5)." These drugs are known to enhance calcium influx by different but linked signal transduction pathways. 

The rather strong heterocyclic base, 4-aminopyridine 7.47) similarly blocks potassium channels thereby enhancing the influx of calcium ions during the depolarization of nerve terminals (Thesleff, 1980). Substances that can block calcium channels in muscle (e.g. verapamil, nifedipine) were introduced during the last decade as vasodilatory drugs (see Section 14.2). 

The 5-fluorouracil (5-FU) and NONOate conjugates (Fig. 1.7) were prepared and their cytotoxicity was tested [90]. The median effect doses of the conjugates for DU145 and HeLa cancer cell lines were 2-4-fold lower than that of 5-FU. In another study by Wink et al, the cytotoxicity of cisplatin was enhanced about 60-fold after NONOate pretreatment for 30 min [91]. The enhancement of cytotoxicity of 5-FU/NONOate conjugates and cisplatin-NONOate combination has shown that there is a synergistic effect between anticancer drugs and NO. Another study by Jia et al. demonstrated that the cytotoxicity of Taxol was enhanced by S-nitrosocaptopril (Fig. 1.7) [92]. This effect is primarily mediated via the increased influx of Taxol by NO into intracellular compartments, while NO-induced cytotoxicity cannot be excluded. 

Studies of sudden death in novice as well as experienced drug abusers found that cocaine causes vasoconstriction of the coronary arteries which seems to result from an enhancement of Ca2+ influx across myocardial membranes. However, remember that this class of drug affects other neurotransmitter systems. Cocaine inhbiits reuptake of NE and 5-HT as well as binds to the DA transporter. It increases catecholamine receptor sensitivity but does not seem to directly influence enkephalinergic receptors. In addition it also affects neurotransmission the H, Ach and phenylethylamine pathways. Activation of DA, NE or 5-HT neurons independently does not produce the euphoria associated with cocaine misuse. Euphoria seems to be related to simultaneous inteeraction between catecholamine and serotoninergic systems. 

Erythrocytes from ethanol-injected fish permeated more water than those from normal fish. Water permeation was significantly enhanced with Merc cor 30 and Nux vom 30 as compared to the control. RBCs from fish pretreated with Nux vom 30 inbibed more water in in vitro treatments than those from fish pre-treated with Ethanol 30. Since aquaporins are mainly responsible for water transport through the plasma membrane of red blood cells it is thought that potentized drugs such as Merc cor 30 and Nux vom 30 acted upon these proteins and facilitated water influx into the cells (Sukul et al., 2003). 

Q10 Sulfonylurea drugs enhance insulin secretion. They bind to the receptors on the /1-cells of the islets of Langerhans, causing a partial depolarization of the cell membrane, influx of calcium ions and a reduction in potassium efflux. The ultimate result is increased insulin secretion. These drugs also increase the sensitivity of the /1-cells to stimuli that cause insulin secretion, possibly by increasing the intracellular levels of a cyclic nucleotide second... 

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