Uses of streptomycin

Dr. Modell: The conference this afternoon was on the subject of the uses of streptomycin. The experiences with the sulfa drugs and penicillin have been put to good use in speeding up the steps necessary for the proper clinical evaluation of this new antimicrobial agent and now, only about three years after the first clinical reports on streptomycin, a formidable volume of information has accumulated concerning its actions and uses. The material is now available in a highly purified form. Since, however, it still contains some impurities, varying in amounts in different preparations, a biologic assay is applied to the different lots. It is less confusing to express dosage in units of weight rather than in biologic units and, therefore, the labels on the vials describe the contents in terms of Gm, of pure streptomycin base. Streptomycin is freely soluble in water. It is suitable for all the common routes of administration. Not enough is known about its absorption by oral administration and it does not seem to be useful for systemic action by the oral route. It is most commonly given by intramuscular injection in divided doses. A dose of 2 to 3 Gm. daily appears to be adequate for the majority of infections in which it is useful. Larger doses are likely to cause too high an incidence of toxic effects.Streptomycin is effective against most of the organisms which are inhibited by penicillin. In addition, however, it exerts a potent action against gram-negative organisms which are uninfluenced by penicillin. While bacteriologic experiments suggest a very wide field of usefulness for streptomycin, direct experience in the treatment of human diseases has greatly restricted the scope of its application. Experience thus far indicates that penicillin is preferable in those infections in which either of the drugs might be used because penicillin is non-toxic while streptomycin possesses toxic actions which are sometimes quite serious. There is also the fact that penicillin is administered in quantities measured in milligrams and streptomycin in quantities of grams and these large amounts of the drug are not practical for some of the special technics of administration such as suspension in wax and oil for delayed absorption. Thus far, streptomycin has been found especially useful in urinary infections caused by the Escherichia coli and some other, gram-negative bacterial infections of the urinary tract such as the Bacillus lactis aerogenes, Bacillus proteus and Bacillus pyocyaneus. It is highly effective in Friedländer's pneumonia, Hemophilus influenzae meningitis and tularemia. It has also been found effective in pneumonias, abscesses, peritonitis and other infections caused by the gram-negative bacteria frequently found in the urinary tract. It appears to be without value in virus infections. One of the most stirring aspects of streptomycin action is the observation that it cures certain forms of animal tuberculosis and the now well established clinical experience showing that it may check some forms of human tuberculosis, especially those in the exudative stage. There was considerable discussion in the conference concerning the details of its rôle in the therapy of human tuberculosis.Two other phases of streptomycin therapy received special consideration. There is some indication that different members of the same bacterial species show wide differences in susceptibility to streptomycin and it is now well established that for most infections, resistance to streptomycin is acquired quite rapidly, in a matter of days to weeks. This limits the application of the drug to brief courses of treatment and necessitates the use of fully effective doses, from the outset. The next point is the matter of toxicity. Streptomycin is not an innocuous drug. In addition to the various allergic drug reactions such as skin rash and fever, it may produce serious renal damage, it may affect the blood-forming organs and it exerts an action on the central nervous system involving the vestibular apparatus and the eighth nerve causing vertigo, tinnitus and impaired hearing, some of the effects becoming permanent. These effects are apt to occur after prolonged use of the drug, after three or four weeks. They are more frequent with the larger doses, doses larger than those usually necessary. One needs to keep them in mind, however, for the full scope of the applications of streptomycin has not yet been established and a good deal of exploration is still necessary to establish the full potentialities of streptomycin in human infections. In the present state of our knowledge, there is justification in giving streptomycin a trial in serious bacterial infections in which the other specific anti-microbial agents have failed. It is suggested that an in vitro test of the sensitivity of the organism may help to establish the indication for its trial in such cases.     

Do Electrode and Lead Design Differences for Permanent Cardiac Pacing Translate into Clinically Demonstrable Differences? (Comparison of Sintered Platinum and Activated Vitreous and Porous Carbon Electrodes)

A randomized prospective study was undertaken to compare the electrical performances of three permanent, endocardial, tined pacing leads with different electrode designs--sintered platinum, vitreous carbon, and porous carbon. Ninety-nine patients received one of the leads (S80 31; 423S 32; S100 36). Acute R wave amplitude and ST elevation of the native endocardial electrogram, voltage threshold, impedance, and current flow at four pulse durations (0.25-1.0 msec) were measured. Voltage thresholds were measured noninvasively at each of four pulse durations at 2 days and 1, 3, and 6 months after implantation. No significant differences were found in sensing properties, or current flow at threshold at 0.5 msec pulse duration. The 423S lead had a significantly higher impedance at threshold and both a higher impedance and lower current flow at 5 V. No significant differences in threshold voltages were found between the three leads at any pulse duration, at any of the assessed times after implantation. Six-month thresholds for the S80, 423S, and S100 leads were 1.18 +/- 0.35, 1.17 +/- 0.29, and 1.06 +/- 0.38 V respectively at 0.5 msec pulse duration. Differences between 'high performance' pacing leads need to be of a greater order of magnitude before they can be exploited to give any real clinical advantage to patients.     

Atrioventricular Node Ablation for Optimization of Pacemaker Treatment in Hypertrophic Obstructive Cardiomyopathy

Dual chamber pacing is a new indication for the treatment of drug resistant hypertrophic obstructive cardiontyopathy (HOCM) in patients with normal atrioventricular (AV) conduction. In sinus rhythm, the efficacy of the treatment is mainly related to the ability to bypass the normal AV conduction system in order to obtain a complete and permanent right ventricular (RV) capture. This is achieved by programming short AV delays. On the other hand, patients with HOCM frequently have co-existing left ventricular diastolic dysfunction, and the atrial contribution to left ventricular filling is critical. The lack of improvement, rarely encountered, is probably due to incomplete RV capture andlor to the deleterious effect of short AV delay. Instrumental AV node prolongation may he indicated in this situation. This procedure should be undertaken when previous drug-induced AV prolongation has failed. In theory, AV node modulation (i.e., creating a I ± AV block) seems ideal. However, this technique remains difficult, with disappointing chronic results. Most authors hence perform "conventional" AV node ablation. Particular attention is taken in order to perform a proximal node ablation, resulting in a complete AV block with narrow QRS escape rhythm. The reported incidence of AV node prolongation ranges from 7.5%-37.5%. The efficacy of the procedure on symptoms is explained by improved left ventricular filling and/or a further reduction in the systolic gradient evoked by complete RV capture. Another indication for AV node ablation in HOCM is the occurrence of atrial fibrillation, in order to restore adequate and permanent RV capture .     

Dose-Related Effects of the Hepatocarcinogen, Wy-14,643, on Peroxisomes and Cell Replication

Dose-Related Effects of the Hepatocarcinogen, Wy-14,643, onPeroxisomes and Cell Replication. WADA, N., MARSMAN, D. S.,AND POPP, J. A. (1992). Fundam. Appl. Toxicol. 18, 149–154. The dose and time dependency of peroxisome proliferation andhepatocyte replication was evaluated in the liver of rats fedthe peroxisome proliferator and hepatocarcinogen, Wy-14,643.Male F344 rats were fed NIH07 diet blended with Wy-14,643 at0, 5, 10, 50, 100, or 1000 ppm for 1, 3, 6, or 13 weeks. Hepatomegalywas induced by Wy-14,643 at all doses and at all time points.Peroxisome proliferation was present in rats fed 5 ppm Wy-14,643as early as 1 week, as determined by the peroxisome-specificNAD⁺ reduction of palmitoyl CoA (PCO) and the peroxisome-associatedactivity of carnitine acetyltransferase (CAT) (5-and 11-foldover control, respectively). The elevations of PCO and CAT weredose-dependent from 5 to 50 ppm and then plateaued from 50 to1000 ppm throughout the treatment period. Hepatocellular replication,evaluated by nuclear histoautoradiography ([³H]thymidine labeling,6-day infusion), was increased in all Wy-14,643 dose groupsafter 1 week of treatment (5 ppm, 4-fold; 10 ppm, 5-fold; 50ppm, 13-fold; 100 ppm, 12-fold; and 1000 ppm, 13-fold over controls).However, in 5 and 10 ppm groups this cell replication returnedto control levels by 3 weeks. In contrast, 50, 100, and 1000ppm groups had sustained increases in cell replication up to13 weeks (13 weeks: 6-, 7-, and 9-fold over controls, respectively).We have demonstrated that Wy-14,643 can induce peroxisome proliferationat 5 ppm, a dose 200 times lower than the dose shown to be highlyhepatocarcinogenic in rats (100% incidence by 60 weeks). Incontrast, 50 ppm was identified as the minimal dose which inducedsustained cell replication in rat liver. These data show thatperoxisome proliferation can be dissected from sustained cellreplication for correlating either peroxisome induction or cellreplication with tumor formation. These results provide importantinformation that can be used to design carcinogenicity experimentsto test if peroxisome proliferation and/or chronic enhancementof cell replication predictive risk factors for hepatocarcinogenieity.     

Interaction of glucagon with artificial lipid bilayer membranes

The enhancement of fluorescence emission from the tryptophan residue of glucagon, the quenching of that emission with acrylamide and with 5-doxyl and 16-doxyl stearic acid, circular dichroism spectra, the release of 6-carboxytluorescein, and polarized infrared attenuated total reflection (IR-ATR) spectra were used to study the interaction of glucagon with intact lipid vesicles and flat bilayers. Dimyristoylphosphatidylcholine bound the peptide only below the main transition temperature, thus confirming earlier results of Epand et al. (1977). However, the peptide is also bound by vesicles of unsaturated lipids above their transition temperature, suggesting an influence of lipid area on the binding process. Circular dichroism showed that binding to such vesicles also increases the helix content of glucagon. The IR-ATR study and a comparison with dynorphin-A-(I-13)-tridecapeptide revealed profound differences in orientation of the two peptides. The dichroic ratios and the derived order parameters indicated an isotropic orientation of the helical segments of glucagon, but did not exclude a principal orientation of the molecules lying flat on the nienibrane surface. In contrast, the axis of the dynorphin helix is clearly oriented normal to the interface. The two peptides also differ in their rates of 6-carboxyfluorescein release, suggesting a deeper penetration of the primary amphiphilic helix of dynorphin A-(I-13) than of the secondary amphiphilic helix of glucagon.