Search PubMed⌕ Search

Biomedical subjects

R S Jacobs

Publications and source records attributed to R S Jacobs.

At least 55 records · Page 3Linked to original sources
PubMed1984

In vitro inactivation of the neurotoxic action of beta-bungarotoxin by the marine natural product, manoalide.

The irreversible neurotoxic action of beta-bungarotoxin (beta-BuTx) can be prevented by preincubation of the toxin with manoalide, a non-steroidal anti-inflammatory agent. Manoalide was also found to inactivate purified phospholipase A2 and thus prevent hydrolysis of phosphatidylcholine. PLA2 is a component found in several neurotoxic venoms and is also a rate limiting enzyme important in phospholipid metabolism and prostaglandin synthesis in man.

Animals↗
PubMed1983

Quantal analysis indicates an alpha-toxin-like block by lophotoxin, a non-ionic marine natural product.

The effects of a structurally novel paralytic substance (lophotoxin) on quantal transmission parameters and the time course of synaptic potentials have been examined. This substance completely abolished potentials by reducing quantal size without affecting the release of quanta. Nerve conduction, membrane potential, and the passive electrical properties of the muscle end-plate remained unaffected. Lophotoxin appears to act directly on the acetylcholine receptor-channel complex, although perhaps not the cholinoreceptive site itself, as suggested by the unusual chemistry and onset kinetics of this toxin.

Animals↗
PubMed1983

A double-blind comparative trial with mianserin and amitriptyline in outpatients with major depressive disorders.

1 A double-blind trial with parallel treatment groups was conducted to compare the safety and efficacy of mianserin with amitriptyline. 2 This was a six week trial with weekly visits. Measurements at each visit included: 21 item Hamilton Depression (HAMD) Scale. Clinical Global Impression (CGI) Scale and Treatment Emergent Symptom Scale (TESS). 3 Mianserin and amitriptyline were comparable with respect to efficacy. 4 More adverse experiences were reported by amitriptyline patients. The predominant amitriptyline adverse experiences were of the anticholinergic type; the predominant mianserin adverse experience was drowsiness/fatigue. 5 The Efficacy Index (EI), a scale combining efficacy and adverse experiences, clearly demonstrated the superiority of mianserin over amitriptyline.

Amitriptyline↗
PubMed1983

Inhibition of bovine brain microtubule assembly in vitro by stypoldione.

Stypolidione, an orthoquinone derived from the brown seaweed Stypopodium zonale, inhibited the polymerization of three-cycle-purified bovine brain microtubule protein in vitro in a concentration-dependent manner. Fifty per cent inhibition of the extent of polymerization beginning under initiating conditions occurred at a stypoldione concentration of approximately 25 microM, and 50% inhibition of tubulin addition to the assembly ends of microtubules at steady state occurred at a concentration of approximately 8 microM. Only slight structural abnormalities could be detected by negative stain electron microscopy in some of the microtubules that did assemble in the presence of the drug, and no aberrant structural forms of microtubule protein were detected. Stypoldione inhibited the binding of [3H]colchicine to tubulin, with 50% inhibition of colchicine binding activity occurring at a stypoldione concentration of 12-15 microM. Inhibition of colchicine binding activity appeared noncompetitive and was at least partially reversible, suggesting that stypoldione and colchicine bind at separate sites. By assuming that the inhibition constant for the ability of stypoldione to prevent the binding of colchicine to tubulin was equivalent to the dissociation constant for the binding of stypoldione to tubulin, we calculated that approximately 62% of the tubulin present free in solution under initiating conditions and 35-37% of the soluble tubulin under steady-state conditions was complexed with stypoldione when polymerization was inhibited by 50%. These data are consistent with a mechanism in which stypoldione interacts with soluble tubulin and inactivates the tubulin so that it is unable to add to microtubule ends, although a colchicine-like mechanism involving an action of stypoldione at microtubule ends has not been eliminated.

Animals↗
PubMed1983

Effect of stypoldione on cell cycle progression, DNA and protein synthesis, and cell division in cultured sea urchin embryos.

We have found that stypoldione, a bright red o-quinone isolated from the brown alga Stypopodium zonale, inhibits the division of sea urchin embryos in a concentration-dependent manner (IC50 approximately 2.5 X 10(-6) M). Although previous studies have shown this marine natural product to inhibit beef brain microtubule assembly in vitro [Fed. Proc. 39:26-29 (1980); Mol. Pharmacol. 24:493-499 (1983)], we have found that stypoldione does not accumulate sea urchin embryos in mitosis and hence does not act like a mitotic spindle poison. We have also shown this marine natural product to inhibit both amino acid and nucleoside uptake. By preloading sea urchin embryos with nucleoside (i.e., [3H]thymidine) in order to dissociate effects on uptake from those on incorporation, we found that stypoldione in fact produces no significant inhibition of the M phase-independent S1 period of DNA synthesis, a result which suggests that stypoldione has no direct effect on DNA synthesis. In contrast, stypoldione did reduce the extent of amino acid incorporation in embryos preloaded with [3H]leucine. An inhibition of incorporation was apparent as early as 20 min after fertilization, and incorporation was reduced to 50% of control by 40 min postfertilization. This result suggests that stypoldione might inhibit cleavage via an inhibition of translation, although the existence of other inhibitory mechanisms cannot yet be ruled out. Cytological examination revealed that sea urchin embryos did not progress beyond-interphase or very early prophase when incubated in the presence of 1.0 X 10(-5) M stypoldione. The nuclear membranes remained intact, and chromatin did not condense into chromosomes in these arrested embryos. These results indicate that embryos exposed to stypoldione early in the cell cycle initiate and complete the M phase-independent S1 period of DNA synthesis, but stop cell cycle progression prior to the start of prophase of mitosis. The period between S phase and mitosis is referred to, by definition, as the "G2" phase of the cell cycle. The result therefore suggest that stypoldione blocks cell cycle progression (and, ultimately, cell division) by inhibiting progression through G2. This compound may represent a new class of G2-accumulating agents.

Animals↗
PubMed1981

Lophotoxin: a novel neuromuscular toxin from Pacific sea whips of the genus Lophogorgia.

A new neuromuscular toxin, lophotoxin, has been isolated from several pacific gorgonians of the genus Lophogorgia. The structure of lophotoxin was deduced by combined spectrochemical methods, and belongs to the well-known cembrene class of diterpenoid molecules. Lophotoxin contains furanoaldehyde and alpha, beta-epoxy-gamma-lactone functional groups, in sharp contrast to the cationic ammonium functional groups of the established neurotoxins.

Animals↗
PubMed1981

Effect of 4-aminopyridine on nerve terminal action potentials.

The effects of 4-aminopyridine (4AP) on the extracellularly recorded nerve terminal action potential (NTAP) and end-plate potential were studied at the frog neuromuscular junction. An in-depth analysis of the time course of the NTAP was performed in the presence and absence of extracellular Ca++. Low concentrations (5 X 10(-6) M) of 4AP produced no significant alterations in the time course of the NTAP, yet increased quantal content of the end-plate potential 2-fold. In contrast, high concentrations (5 X 10(-4) M) of 4AP prolonged the duration of the NTAP by selectively flattening the K+ slope of the NTAP and increased the quantal content of the end-plate potential. It is concluded that both potassium channel blockade and facilitation of transmitter release by 4AP can be demonstrated in this preparation, and that it is possible to separate these actions by varying the concentration of 4AP. Interpretation of these data suggests that there is a second site or mechanism of action by which 4AP potentials transmitter release. Possible mechanisms of action for 4AP are discussed.

4-Aminopyridine↗
PubMed1981

Selective compounds derived from marine organisms: effects on cell division in fertilized sea urchin eggs.

An investigation of the pharmacological selectivity of the fertilized sea urchin egg assay was undertaken with the view that this echinoderm may serve as a useful model for detecting new compounds that inhibit cell division and also may yield substantive information on biochemical events that may be sensitive to drug action. One hundred and thirty purified marine natural products were tested as well as 14 known antineoplastic agents. Nine active marine cytotoxins were identified and, based on in vitro studies of microtubule assembly, five compounds inhibited tubulin polymerization. Of the 14 antineoplastic agents tested thus far, the transcriptional inhibitor daunomycin has proven active as well as the microtubule assembly inhibitors Colcemid, podophyllotoxin, vinblastine, and vincristine.

Animals↗
PubMed1980

An inexpensive frequency-modulated (FM) audio monitor of time-dependent analog parameters.

The standard method for quantification and presentation of an experimental variable in real time is the use of visual display on the ordinate of an oscilloscope screen or chart recorder. This paper describes a relatively simple electronic circuit, using commercially available and inexpensive integrated circuits (IC), which generates an audible tone, the pitch of which varies in proportion to a running variable of interest. This device, which we call an "Audioscope," can accept as input the monitor output from any instrument that expresses an experimental parameter as a dc voltage. The Audioscope is particularly useful in implanting microelectrodes intracellularly. It may also function to mediate the first step in data recording on magnetic tape, and/or data analysis and reduction by electronic circuitary. We estimate that this device can be built, with two-channel capability, for less than $50, and in less than 10 hr by an experienced electronics technician.

Electronics↗
PubMed1979

Structure-activity relationships in the development of hypoxic cell radiosensitizers. I. Sensitization efficiency.

The efficiency of 35 nitroaromatic and nitroheterocyclic compounds in radiosensitizing hypoxic Chinese Hamster cells in vitro was determined. The concentration C of the compound required to achieve an enhancement ratio of 1.6 was measured, and the redox and partition properties were quantified as the one-electron reduction potential at pH 7, E, and the octanol: water partition coefficient, P, respectively. Most of the compounds studied were 2-nitroimidazoles, but some 4- and 5-nitromidazoles, 5-nitrofurans and nitrobenzenes were investigated for comparison. Together with data for nine nitroimidazoles previously reported, the results were fitted to a structure-activity relationship of the form -log C = b0 + b1E + b2 log P + b3 (log P)2 using multiple linear regression analysis. Statistical tests showed that the coefficients b2 and b3 were not significantly different from zero and the simpler equation, obtained by omitting the terms in log P, explained 85 per cent of the variance in log C. Earlier reports that the radiosensitization efficiency of nitro compounds in vitro largely depends on the reduction potential were confirmed. The conclusive demonstration that P is unimportant in vitro is valuable in interpreting the results of experiments in vivo, where P is expected to have a much greater influence on biological response.

Animals↗
PubMed1979

Structure-activity relationships in the development of hypoxic cell radiosensitizers. II. Cytotoxicity and therapeutic ratio.

This paper describes measurements of the aerobic cytotoxicity of 42 nitroaromatic and nitroheterocyclic compounds towards Chinese Hamster cells in vitro. The results of acute and chronic exposure were quantified, and the concentration C required to achieve a standard response estimated. Fitting the data to an equation of the form - log C = b0 + b1E, where E is the one-electron reduction potential, explained 47 and 71 per cent of the variance in the acute and chronic aerobic cytotoxicity respectively. The addition of further terms to the equation, quantifying partition properties, was not statistically significant. The coefficient b1 was similar for both acute and chronic exposure; the dependence of both cytotoxicity and radiosensitization efficiency on reduction potential was also similar. A therapeutic ratio derived from these in vitro measurements showed no dependence on redox or partition properties. The insensitivity of cytotoxicity and radiosensitization properties to variations in molecular structure, other than those which influence redox behaviour, offers exceptional flexibility in developing compounds of improved therapeutic ratio.

Animals↗
PubMed1978

Some examples of anomalous radiosensitizing behaviour of electron-affinic compounds in vitro.

Studies using V79 379A cells on about 50 nitroaromatic and nitroheterocyclic radisosensitizers have confirmed the relationship between sensitizing efficiency and electron affinity. Almost all the compounds studied behaved similarly by sensitizing hypoxic cells to X-irradiation in a dose-modifying manner whilst having no sensitizing effect on oxygenated cells. However, a small number of the radiosensitizers studied exhibited additional or atypical properties. A 4-nitroimidazole ring substituted with chlorine sensitized hypoxic cells much more efficiently than predicted from its redox potential. A 2-nitroimidazole substituted with a carboxylic acid side chain showed a low but constant level of sensitization over 5 decades of concentration. A 5-nitrofuran, in addition to sensitizing hypoxic cells by dose modification, sensitized oxygenated cells by a reduction in extrapolation number.

Cell Survival↗
PubMed1977

Motor nerve terminal facilitatory action of SQ 20009: an inhibitor of cyclic nucleotide phosphodiesterase.

Facilitatory effects of SQ 20009 [1-ethyl-4-(isopropylidenehydrazine)-1H-pyrazolo-(3,4-b)-pyridine-5-carboxylic acid, ethyl ester, HCl] were investigated at the frog sartorious neuromuscular junction. A dose-dependent increase in miniature end-plate potential frequency occurred without changes in miniature end-plate potential amplitude. Significant increases in the amplitude and the rate of rise of the end-plate potential and reduction in the incidence of end-plate potential failures were observed in magnesium blocked muscle. The increase in end-plate potential amplitude and rate of rise appeared calcium dependent. No significant changes in passive membrane resistance or muscle membrane sensitivity to acetylcholine were observed. Twitch studies employing direct and indirect stimulation of the rat diaphragm preparation demonstrated a preferential facilitation of the indirect response rather than a direct action on the muscle fiber. The facilitatory effect of SQ 20009 on evoked and spontaneous release were of approximately equal orders of magnitude, suggesting that the drug may affect a common mechanism in the two release processes.

Acetylcholine↗
PubMed1977

Lithium carbonate treatment in the syndrome of inappropriate secretion of antidiuretic hormone.

A case of a 76-year-old man with the syndrome of inappropriate secretion of antidiuretic hormone (ADH) is discussed. The patient was initially treated with fluid restriction followed by the administration of hypertonic saline. After failure to achieve rapid correction of the condition and continued lethargy and muscle weakness in the patient, a trial with lithium carbonate 300 mg three times daily via nasogastric tube was initiated. This resulted in a prompt reversal of the hyperosmolar state and improvement in electrolyte balance. However, despite the apparent success in treating his inappropriate ADH, the patient expired as a result of a massive cerebral vascular accident. The potential benefit of using lithium in the treatment of the syndrome of inappropriate secretion of ADH, and possible mechanisms of action, are reviewed.

Aged↗