Pharmacological results

Effect of paclitaxel-LCM and paclitaxel-cremophor on cell survival in vitro. (Taken from ref. 532.) 

The effect of paclitaxel on the morphology of C6 tumor cells was also examined in culture. C6 cells were treated with LCM alone, paclitaxel-CRE (6 pg/ml), or paclitaxel-LCM (6 pg/ml). Compared to the control (LCM alone), C6 tumor cells treated with either paclitaxel-CRE or paclitaxel-LCM for 24 hours resulted in contracted, rounded tumor cells (ref. 532). 

Similar morphological effects are obtained when the above experiment is repeated without cremophor (CRE), but in this case 

Earlier data with both Oil Red-0 staining and diO-labeled LCM indicated that 9L tumor cells have a much slower LCM uptake than do C6 tumor cells, both in vivo and in vitro (ref. 531). That difference might be a factor in how fast the paclitaxel is consumed and internalized by the tumor cells. A study by Sharma et al- (ref-605) also suggests that 9L tumor is somewhat paclitaxel-resistant. Accordingly, the daily dose of paclitaxel-LCM was adjusted to 960 pg/kg for subsequent 9L tumor-treatment experiments (ref. 532) (see below). 

Delayed tumor progression in rats receiving different treatments. (From ref. 532.) 

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Isotoma longiflora. This Peruvian plant contains an alkaloid, m.p. 190°, forming a hydrochloride, m.p. 160°. Pharmacological results are recorded and it is suggested that the alkaloid resembles lobeline of which it may be a derivative (Sanchez, Rev. Med. expU, (Peru), 1945, 4, 284 Chem. Abstr., 1948, 42, 1350). 

Sarracenia purpurea. According to Walti,i this pitcher plant on distillation with alkali yields a basic product from which on neutralisation by acid only ammonium salts could be isolated, which is said to be sufficient to account for the pharmacological results recorded for a neutralised distillate of the plant by Bates and Judovich ( (1) J. Amer. Chem. Soc., 1945, 67, 2271 (2) Ancesthesiology, 1942, 3, 663 Judovich, ibid., 1943, 4, 313). 

Pharmacological results (ED50 in mg/kg) obtained in rats from 17 reference neuroleptic compounds in the combined ATN test [48],... 

So far, we have reviewed the various ways in which complex dose-response curves in intact-tissue bioassays can be the result, the pharmacological resultant, of two or more interacting activities. Now, if all that these bioassays achieved was to blur and obscure the underlying activities, they would have to give way to the newer, analytically simpler assays based on chemistry and biochemistry. However, the beauty of intact-tissue bioassays is that they are analytically tractable by using families of dose-response curves and appropriate mathematical models, the complexity of intact hormone-receptor systems can, indeed, be interpreted. Bioassay allows them to be studied as systems in ways denied to simple biochemical assays. 

It will readily be seen in our series of w-fluorocarboxylic acids, that when n is odd, / -oxidation would yield the toxic fluoro-acetic acid, whereas when n is even, the compound would presumably be oxidized only as far as the non-toxic yff-fluoro-propionic acid.1 The pharmacological results obtained are in complete accord with this hypothesis, and provide verification, of a kind not hitherto achieved, of the process of / -oxidation in the living animal body. However, Weinhouse, Medes and Floyd2 have inoculated rat-liver slices with one or two fatty acids containing isotopic carbon, and have obtained some evidence for a process of /7-oxidation. 

The above-reviewed pharmacological results show some slight discrepancies specially with ciguatoxin. These discrepancies may be explained partly by the variability of the sample purity and partly by the presence in the extracts of secondary toxins. The complex description of the effects observed experimentally can explain the polymorphism of the clinical features. These pharmacological data can help the physician to improvise an appropriate treatment in ciguatera fish poisoning. 

The PGA salt of D AP has shown pharmacological results (peak timer shifted to a later time, increased Imax) corresponding to an increased contact time [12]. PGA consists of linear chains of D-galacturonic acid units (pyranose form), joined in a(l- 4)-glycosidic linkages, with a molecular weight ranging from 25 103 to 100 x 3. It formed a soluble salt or polyanionic complex with the... 

In accordance with the pharmacological results above, introduction of an additional methyl in the -position of the side chain as well as in the A -position of the imidazole drastically decreases the H3 receptor agonist potency of (/ )-a-methyl-histamine (12). In particular, (/ -a.A -dimethylhistamine (15) displays a pD2 value of 5.8 [19] and (f )-a,A -dimethylhistamine (16) a value of 4.3 [20],... 

Some preliminary pharmacological results have been obtained for 8,14-dihydronorsalutaridine and 8,14-dihydrosalutaridine (438). 8,14-Dihydronorsalutaridine has an antagonizing effect upon tetrabenazine which is a reserpine-like compound in its action on the central nervous system. 8,14-Dihydrosalutaridine (300 mg/kg) produces a moderate reduction of spontaneous motor activity in mice. 

In contrast to this investigation, in which pharmacological results from humans and dogs were comparable, a coating formulation with CAP showed no comparable results in humans, dogs, and pigs [62], The results in vitro, however, were comparable to the results found in vivo in humans. 

The design and the execution of safety pharmacology studies are focused upon the safety of human volunteers and patients in clinical trials. ICH S7A and may be soon S7B strive for effective integration of safety pharmacology results with those of the non-clinical (toxicology) and clinical safety databases. 

From pharmacology results and proposed clinical program, select route of administration (oral, pulmonary, intramuscular, subcutaneous, transdermal, ocular, vaginal, buccal, sublingual, etc.) and formulation type to be dosed (solution, suspension, tablet, capsule, granulation powder, microspheres, microemulsion, depot drug, etc.). 

The pharmacological results just presented have established the antimitotic activity of compound 140 to be 7 pg/mL [11 pM, Fig. (9)] in the sea urchin assay. A comparison between the antimitotic activitiy of synthetic analogue 140 with the naturally occurring products 1 and 3 determined thyrsiferol (1) to be the most potent substrate among the three compounds tested (Table 4). 

Pharmacological results show that Na, Cl", K channels and the Na /K pump seem to be involved in luminescence control of O. aranea. On the opposite, in the 2 other species, only clear results were observed for K channels. 

The University of Hawaii and Wayne State University licensed the natural and synthetic cryptophycin derivatives to the Lilly Company for advanced preclinical and clinical development. This led to the selection of cryptophycin 52 (LY355703) (76, Figure 13) as a phase I clinical candidate in the mid-1990s, with a single puhlication ° in late 2002 giving the phase I and pharmacological results from a variety of schedules, with an intermittent schedule being chosen for phase II studies. 

Although somewhat controversial and incomplete, the pharmacological results support the notion that the ChAc-containing system of septo-hippocampal fibres is cholinergic. 

In order to simplify subsequent interpretation of pharmacological results we went to considerable lengths to obtain the enantiomers of compounds I and II in states of absolute optical purity. That the enantiomers should be optically pure was important because, as will be shown shortly, the differences in the potency of the enantiomers of I and II in some tests was greater than 100 and consequently the presence of as little as 1 % of the active R-enantiomers as an impurity in the less active S-enantiomers... 

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