Wide Therapeutic Range Research Articles

Cost-effective aminoglycoside therapy in surgical patients

There is a risk that the current pressures for hospital cost containment may result in inappropriately restrictive administrative measures. A failure to take into account all factors in estimating the cost of antibiotic therapy yields a greatly distorted view of the importance of acquisition costs. Higher-priced drugs may actually be more cost-effective if they have greater efficacy, wider therapeutic range, and/or are less costly to prepare and administer. Simple microcomputer modeling techniques may be easily employed to examine the economic consequences of therapeutic decisions.

Single-dose ceftriaxone kinetics in liver insufficiency.

The disposition profile of ceftriaxone was studied in eight normal subjects and in 15 subjects with various degrees of chronic liver damage (alcoholic fatty liver [FL] and cirrhosis without [C] and with [CA] ascites) who received bolus injections of ceftriaxone, 1 gm iv. Plasma protein binding fell in all. As a result, mean free fraction in plasma rose between 140% (FL) and 320% (CA). An exceptionally large rise (1270%) occurred in one subject with CA when the condition was aggravated by renal impairment. Fourteen of 15 subjects had renal clearance of unbound drug of the same order as that in healthy adults. In chronic liver disease, mean nonrenal clearance of unbound drug fell with severity of liver damage. Kinetic parameters with reference to total drug differed in normal subjects and subjects with CA. Kinetic changes in the latter were such that elimination t 1/2 beta did not differ (9.7 and 8.4 hr). Because of the wide therapeutic range of ceftriaxone, subjects with chronic liver disease would require no dose adjustments, whereas dose reductions are envisaged for subjects with cirrhosis (C,CA) on the basis of increased unbound drug concentrations.

The toxicology of brotizolam.

Acute studies. Following oral or intraperitoneal administration, toxicity was very low (LD50 in rodents greater than 10,000 and greater than 900 mg/kg, respectively). Subacute and chronic studies in rodents. Signs of toxicity were seen only at doses of 400 mg/kg or more. Histopathological changes were found only in the 78-week study. Subacute studies in dogs (intravenous) and primates (oral). In dogs, doses of 0.1 and 0.3 mg/kg produced ataxia, salivation, and diarrhoea. In monkeys doses of 7 mg/kg or higher produced ataxia, increased appetite, hyperreflexive muscular spasms, increase in liver weight, and lipid depletion of the adrenal cortex. Reproductive studies in the rat and rabbit. Repeated doses of up to 30 mg/kg were not associated with any disturbance in fertility; nor were any embryotoxic or teratogenic effects observed. When dams wer treated with 400 mg/kg, litter mortality was markedly increased. Mutagenicity studies. The four different tests performed gave no indication of any mutagenic effect. Local tolerance tests in the rabbit. Brotizolam was well tolerated when administered intramuscularly, intra-arterially, or intravenously. Carcinogenicity studies in rodents. The mouse study showed no evidence of a tumourigenic effect. The rat study is still being evaluated. The toxicological studies demonstrate that brotizolam has an unusually wide therapeutic range. Findings of toxicological significance, most of which were reversible, were first recorded at doses of 7-10 mg/kg, i.e. at more than 100-times the intended human therapeutic dose.

High hopes for 'third generation' cephalosporins

A wide therapeutic range, low toxicity, and strong clinical efficacy against previously hard-to-treat, antibiotic-resistant infections are the main advantages of what is now being called the third generation of cephalosporin antibiotics. Scores of papers covering the drugs' microbiologic, pharmacologic, and clinical performance were presented at the 12th International Congress of Chemotherapy in Florence, Italy. What is intriguing about these relatively new cephalosporins and their relatives is that they are able to destroy many of the Gram-negative microorganisms that are not affected by or have become resistant to the first-generation cephalosporins. In addition, through chemical modification of the basic cephalosporin molecular structure, the third-generation drugs are able to sidestep most of the β lactamase enzymes, which have allowed microorganisms to neutralize the effects of many of the first- and second-generation agents. Currently, the only member of the new cephalosporin family on the American market is cefotaxime, developed by Hoechst-Roussel Pharmaceuticals, Inc,

Therapeutic value of anticholinergic agents in chronic obstructive pulmonary diseases

Anticholinergic agents have proved to be powerful bronchodilating drugs in various types of chronic obstructive pulmonary disease. Atropine given as an aerosol had a stronger bronchodilating effect, even in low doses not producing side-effects, than after peroral or intramuscular administration. Sch 1000, a new quater-nized atropine derivative had a stronger and more prolonged bronchodilator effect, even in significantly lower doses, and no side effects were observed. Because of its adventageous characteristics, Sch 1000 seems to be the anticholinergic agent to be preferred in clinical practice. It shows a wider therapeutic range than the beta adrenergic agent orciprenaline. A vagus-mediated reflex mechanism may be involved in histamine-induced bronchoconstriction. Experimental results show that a cholinergic mechanism and increased parasympathetic tone are important factors in the pathological mechanism of chronic airways obstruction.

Clinical investigations of a long-acting oestriol (polyoestriol phosphate).

ABSTRACT A description is given of experimental investigations and preliminary clinical experience with the long-acting oestriol compound polyoestriol phosphate – a water-soluble polymere of oestriol and phosphoric acid. The compound seems to exert all the physiologically important effects of oestriol. Even with high doses the hormone causes no proliferation of the endometrium and no withdrawal bleeding. It has no untoward effect on metabolism. It decreases slightly the cholesterol concentration (to the extent of ⅓–⅕ of the effect produced by long-acting oestradiol esters). The compound has a wide therapeutic range. No side-effects have been observed. Doses of 10 mg or more have a prolonged duration. Additional prolongation of the effect is largely dependent on dosage. To ensure an effect lasting for 4 weeks 40 mg polyoestriol phosphate (corresponding with 30 mg oestriol) is required – an amount which roughly corresponds with physiological quantitative data. The compound, which involves an interesting new principle of prolongation, was most effectively used in the treatment of menopausal symptoms and genital organic disorders. For these indications it can be recommended without reservation.

Experimental investigations of the effect of a polycarboxylic acid preparation on coagulation

After a general survey concerning the formation of blood-clots and recent theories regarding intravascular coagulation, the most important anticoagulants are mentioned and their effect briefly described. In the experimental section which describes the mechanism of action of the polycarboxylic acid preparation “Thrombo-Holzinger”, the possibility of another point of attack in the process of coagulation is assumed. The evaluation of the thrombelastographic findings confirms the changes already described by a number of other authors. In addition, the influence of high concentrations of Thrombo on the solidity of blood-clots as well as the possibility to administer the preparation intramuscularly are covered. No side-effects were observed even when high concentrations were administered. The preparation has a wide therapeutic range. Laboratory controls are not necessary even when the preparation is applied for considerable periods. A report concerning results achieved using high concentrations of Thrombo solutions therapeutically follows in the clinical section, which will be published in the near future.

Therapeutic and toxic indexes of digitalis: a comparative study of gitalin and digitalis leaf.

IN recent years considerable interest has been aroused in the therapeutic-toxic ratios possessed by various digitalis preparations; among those evoking special interest is gitalin, the water-extractable substance of digitalis purpurea that was first studied by Kraft1 in 1912 and later by others in this country.2 3 4 More recent reports dealing with gitalin have indicated a wider therapeutic range as compared with other preparations such as digitoxin, digitalis leaf and Digoxin.5 6 7 8 9 10 It has been stated, for example, that the therapeutic dose of amorphous gitalin is approximately 40 per cent of the toxic dose, whereas other glycosides (digitoxin, digitalis leaf and Digoxin) studied . . .

Gitalin therapy of congestive heart failure in the aged

1. 1. Gitalin was used successfully in the treatment of congestive heart failure of seventy-seven patients with an average age of 78.4 years. 2. 2. The initial gitalinizing dose in 155 trials ranged from 2.5 to 22.5 mg., averaging 7.0 mg. The daily maintenance dose ranged from 0.5 to 2.5 mg., averaging 0.92 mg. 3. 3. Gitalin was generally well tolerated. Fifteen of seventeen patients refractory to other glycosides were adequately controlled with gitalin. Nausea, anorexia, and occasional ventricular premature contractions were the earliest indications of toxicity. No serious toxic effects occurred. No paroxysmal arrhythmias developed in this series despite doses calculated to produce toxicity. 4. 4. Some differences between the problems of treating young and older patients with congestive heart disease are discussed. 5. 5. Gitalin is a very useful cardiac glycoside for the treatment of congestive heart failure in elderly patients because of its wide therapeutic range and efficacy.

Intrathecal chloramphenicol in staphylococcal meningitis resistant to penicillin and streptomycin.

Chloramphenicol, an antibiotic first isolated from Streptomyces venezuelae (Ehrlich et al, 1948), has recently been prepared synthetically (Olive, 1949). It is a crystalline chemical substance with a wide thera peutic range. It is soluble in water to a concentration of 2.5 mg. per ml. at 25? C, and solutions withstand boiling for five hours without measurable loss of potency. The antibiotic shows considerably more acti vity against Gram-negative organisms than against Gram-positive and acid-fast species. It is seven to thirty times as active as penicillin against tested Gram-negative species, but much less active against Staphylococcus aureus. The range of inhibiting con centration for the organism appears to lie between 1 and 16 ju,g. per ml. The drug may be administered orally or rectally. A review of the literature reveals no record of the use of intrathecal chloramphenicol in the treatment of pyogenic meningitis. We believe this to be the first record of the administration of chlor

Aureomycin, chloramphenicol, and penicillin in treatment of bacterial pneumonia.

The efficacy of penicillin administered parenterally in the treatment of many types of bacterial pneumonia is well established. Likewise, aureomycin, chloramphenicol, and oral penicillin have been successfully employed in this disease. Unfortunately, the wide therapeutic range of these agents has resulted in a failure in most instances, both in home and hospital practice, to do careful diagnostic studies. Usually, the necessary laboratory work is reserved for cases failing to respond to therapy. For this reason, accurate figures dealing with the treatment of large groups of pneumonia patients are becoming increasingly difficult to assemble, and, as a consequence, data regarding the use of the newer antibiotics are limited. Hence, confusion exists in the minds of many as to the antibiotic of choice in the initial treatment of bacterial pneumonia. Of considerable interest, therefore, are data collected in a single hospital where these antibiotics have been employed during the same pneumonia season.