Daily Dose Of Drug Research Articles

Drugs in human milk. Clinical pharmacokinetic considerations.

Drugs ingested by a lactating mother would be expected to appear in human milk to some extent and be ingested by a breast-feeding infant. Drugs pass from maternal plasma into milk by passive diffusion and are distributed within the aqueous, protein and lipid phases of milk. Distribution into milk will be affected by physiochemical characteristics of the drug: acid-base characteristics, relative protein binding in plasma and milk, and lipid solubility, as well as milk composition. The milk-to-plasma concentration ratio is the most commonly quoted index of drug distribution into human milk. However, calculation of the daily infant dose of drug ingested in milk, and from this the dose in milk relative to the maternal dose on a weight-adjusted basis, is a more relevant indicator of infant exposure to a drug. This is particularly true for drugs with a high volume of distribution, for which only a small proportion of the mother's dose is contained within the plasma and available for distribution into milk. A better indication of infant exposure to a drug is the steady-state plasma drug concentration in a breast-feeding infant, the major determinants of which are the dose rate (via milk) and the oral availability and clearance in the infant. Although in neonates the rate of absorption may be different from adults, there is little evidence that its extent is significantly different. Clearance, however, is impaired in very young infants, particularly if premature. The decreased clearance would result in a proportional increase in steady-state plasma concentrations in the breast-feeding infant. Consideration of the dose ingested in milk and the approximate clearance in infants of different ages allows estimation of likely steady-state plasma concentrations in breast-feeding infants. From these considerations, recommendations regarding the safety of drugs during breast-feeding can be made. Drugs which are very toxic or have dose-independent toxicity should be considered separately. Recommendations regarding 'social' drugs such as nicotine, alcohol, caffeine and theobromine are particularly difficult, as doses are uncontrolled and vary variable.

Effect of plasma metformin concentrations on serum lipid levels in type II diabetic patients.

In this study we evaluated the relationships between plasma metformin levels, measured by reverse-phase high-performance liquid chromatography, and serum lipid levels in 20 metformin-treated, type II diabetic patients. Mean fasting plasma metformin concentration was 490 +/- 188 ng/ml. No correlation was found between daily dose of drug and lipid parameters. A significant correlation emerged between circulating metformin concentration and serum triglycerides (r = -0.574, p less than 0.01), HDL-cholesterol (r = 0.583, p less than 0.01) and HDL2-cholesterol (r = 0.670, p less than 0.05). Multiple linear regression analysis showed that the correlation between plasma metformin concentration and serum triglycerides still remained significant after correction for other clinical and metabolic parameters. Total cholesterol and HDL3-cholesterol were not correlated with metformin concentrations. These results demonstrate the clinical usefulness of measuring plasma metformin concentrations and indicate that some effects of metformin on lipid metabolism depend on the drug plasma levels.

Effects of congestive heart failure on the pharmacokinetics and pharmacodynamics of antiarrhythmic agents

Changes in the pharmacokinetics of antiarrhythmic agents should be expected in patients with congestive heart failure (CHF). The direction of the changes, however, is not always predictable. The volume of distribution is often decreased by as much as 40%, and loading doses should, therefore, be appropriately reduced. Drug clearance may also be diminished due to decreased blood flow to the liver and kidneys, as well as decreased hepatic drug-metabolizing activity. Infusion rates should similarly be lowered to avoid toxicity. However, decreases in both volume of distribution and clearance may result in little, if any, change in elimination half-life, despite higher plasma concentrations. On the other hand, the elimination half-life of antiarrhythmic agents that have a large volume of distribution and are highly cleared by the liver may be twice as long in patients with CHF compared with normal subjects. Thus, the total daily dose of drug should also be lower in these patients. In addition, the time necessary to reach steady state is longer, so that premature dose escalation may lead to excessive drug accumulation. In terms of their pharmacodynamic effects, all antiarrhythmic agents have the potential to manifest a degree of negative inotropy, which must be anticipated as a possible side effect in patients with CHF. Some of the newer agents, such as tocainide and encainide, appear to cause only minimal myocardial depression. Other potential complications of all antiarrhythmic therapy include proarrhythmia and possible drug interactions with digitalis and diuretics.

Hormonal modulation in systemic lupus erythematosus. Preliminary clinical and hormonal results with cyproterone acetate.

We prospectively studied the effects of hormonal modulation using the antigonadotropic drug, cyproterone acetate (CA), in 7 female patients who had moderately active systemic lupus erythematosus. CA was taken orally at a mean daily dose of 50 mg for 21-33 months by 6 patients (9 months by the seventh patient) without any side effects. The number of clinical lupus exacerbations during CA treatment was lower than that during the corresponding pretreatment period (15 of 170 patient-months versus 27 of 156 patient-months; P less than 0.05), despite a reduction in the daily maintenance dose of corticosteroids or antimalarial drugs. Mean plasma testosterone levels were low initially and remained unchanged (0.66 +/- 0.31 to 0.59 +/- 0.23 nmoles/liter), whereas plasma estradiol decreased markedly (from 0.6 +/- 0 38 to 0.11 +/- 0.03 nmoles/liter), resulting in a significant reduction in the estradiol:testosterone ratio (from 1.19 +/- 0.68 to 0.23 +/- 0.12) and in the plasma concentration of the sex hormone-binding protein. Thus, cyproterone acetate induced improvement in clinical lupus activity in parallel with the expected lower estradiol:testosterone balance.

The Vigor of Drug Treatment in the Control of Hypertension: Results from the Munich Blood Pressure Study

The strength of antihypertensive drug treatment was investigated in a representative sample of the population of Munich. The Munich Blood Pressure Study, a cross-sectional study (MBS I) with follow-up one year later (MBS II) of a random sample of 3,198 citizens aged 30-69 years (response rate 69.3 percent) served as the data base. Using an empirical scale of the relative potency of antihypertensive drugs, the vigor of drug therapy was estimated. One unit of vigor was defined as the equivalent of the recommended average daily dose of the specific drug for long-term treatment. This index of therapeutic vigor was then applied to two groups, treated but uncontrolled hypertensives and controlled hypertensives. We found that 85 percent of the treated uncontrolled hypertensives and 90 percent of those with controlled hypertension were taking only small amounts of medication (less than two units of vigor). Particularly striking was the result that approximately 50 percent of each group received less than one unit of vigor. Based on these data it is concluded that physicians failed to prescribe adequate doses of antihypertensive agents for uncontrolled hypertensives. Furthermore, since a large number of patients had their blood pressure controlled by only very small doses of antihypertensive agents, it may be assumed that at least some of them did not require drug treatment or could have their blood pressure controlled by nonpharmacologic measures alone.

Double-Blind Comparison of Ketanserin with Propranolol in Hypertensive Patients

This double-blind study, which is still in progress, aims to compare ketanserin (K) and propranolol (P) during long-term treatment of hypertensive patients in general practice. After a run-in period on placebo, active treatment was initiated with 20 mg K or 40 mg P, b.i.d., during a 2-week period, whereafter the daily dose of either drug was doubled. Presently, 331 patients have been randomized, two-thirds to the K group (n = 221) and one-third to the P group (n = 110). Both groups were similar at randomization, with blood pressure (BP) averaging 171/105 mm Hg. The presently available data concerning the initial 3 months of the trial show that up to the 2nd month after randomization, systolic BP was significantly (p less than 0.05) higher in the K than in the P group, whereas the differences in diastolic BP were mostly not significant. The change in BP after 3 months on K treatment was positively and independently related to both the initial BP and the concurrent changes in body weight. Heart rate was lower (p less than 0.001) during P, whereas body weight was not statistically different between both groups. Differences in complaints between the K and P group were small. However, in the K group dry mouth was transiently more frequently reported at 1 month (p = 0.02) and multiple complaints at 3 months (p = 0.03).

Pig ureter device as a carrier for drug delivery system.

Water-soluble Estracyt® and water-insoluble estradiol-17βwere charged into a pig ureter which was used as a device for drug delivery system. The devices containing drugs were implanted subcutaneously in the back of male Wistar rats for 8 weeks at maximum and the release profiles of drugs from the device were checked in both the in vitro and in vivo experiments. The daily doses of drugs released in vitro from the device were kept constant at rates of 0.054mg/day for Estracyt® and 0.029mg/day for estradiol-17β. However, the daily doses of drugs released in vivo from the same device significantly decreased with an increase in implantation period. This can be easily explained from the results described below. E. g., the cumulative amounts of Estracyt® released in vitro and in vivo from the device for a period of 4 week from start of the test were found to be 1.513 and 0.399mg, respectively, while those amounts released during the first 8 weeks period were to be 3.240 and 0.448mg, respectively, in the above order. In order to claer the cause of such a retardation of in vivo release, the mutual interaction between the rat tissue and the device was microscopically investigated.

Pharmacokinetics of ketoconazole and treatment evaluation in candidal infections.

Twenty six children with candidiasis, aged between 5 months and 14 years, were treated with different formulations and regimens of ketoconazole. Fifteen children had alimentary tract candidiasis, two had oesophagitis, one had urinary tract candidiasis, two vaginitis, two septicaemia, one endo-ophthalmitis, and three had chronic pulmonary illness with persistence of Candida albicans in sputum. Daily drug doses ranged from 3 to 13 mg/kg and duration of treatment from seven days to 18 months. Pharmacokinetic studies in 22 of the children are reported. A total of 3 mg/kg/day given in three divided doses did not yield sufficiently high concentrations, which were achieved with a daily dose of 8 to 10 mg/kg. The effectiveness of treatment was proved by negative mycological tests (cultures or specific antibodies, or both) in 88%, by cure in 73%, and improvement in 11%. In three patients evaluation was not possible due to an insufficiently proved diagnosis. Nausea and pyrosis in four patients were the only side effects noted and no laboratory abnormalities were found. To achieve therapeutic concentrations of ketoconazole in children we suggest a daily dosage of 7 to 10 mg/kg in two or three divided doses.

Effects of Salicylates and Other Nonsteroidal Anti-inflammatory Drugs on Articular Cartilage

According to in vivo experimental data, salicylates and several other nonsteroidal anti-inflammatory agents suppress proteoglycan biosynthesis in normal and degenerating articular cartilage. Therapeutic levels of aspirin in vivo had a similar adverse effect on degenerating cartilage, as noted in two canine models of osteoarthritis and cartilage atrophy. Because the effective daily antirheumatic dose of nonsteroidal anti-inflammatory drugs is lower than that of salicylates, these drugs may have less negative effects on degenerating articular cartilage. However, clinical significance cannot be extrapolated from these experimental data.

The influence of dose frequency and agent toxicity on the cost of parenteral antibiotic therapy.

The influence of the number of daily doses on the overall cost of antibiotic therapy is examined in a general surgery patient population. Patients receiving a single first-generation cephalosporin are compared with patients receiving two or three antibiotics (including an aminoglycoside) in terms of (1) the cost of the drug and the supplies, (2) time required for nursing and pharmacy personnel to prepare and administer the doses, and (3) the influence of agent toxicity (renal function) on physician-ordered laboratory tests. On the whole, combination therapy including an aminoglycoside was four times as expensive as single-agent (first-generation cephalosporin) therapy. If future studies demonstrate that single-agent antibiotic therapy is as effective as traditional combination therapy for specific infectious diseases, the influence of the number of daily doses of drug and agent toxicity may support the cost-effective use of the newer agents.

Isolation and identification of spirorenone metabolites from the monkey (Macaca fascicularis)

The plasma level of spirorenone was determined 3 h after 1, 8, 22 and 46 daily oral administrations of 20 mg/kg to two female and two male monkeys ( Macaca fascicularis ). A fifth animal, female, was treated with eight daily doses of tritium-labelled drug and was completely bled from the carotid vein 4 h after the last administration in order to isolate and identify plasma metabolites. After repeated daily doses of spirorenone the mean plasma level of unchanged drug was 711 ± 213 ng/ml. In the plasma of the fifth animal four radioactively labelled compounds could be detected after extraction and subsequent HPLC separation. Mass spectrometric identification of three of the substances indicated 1,2-dihydrospirorenone, hydroxy-1,2-dihydrospirorenone and the unchanged drug itself.

Tocainide for refractory symptomatic ventricular arrhythmias

Tocainide, an oral form of lidocaine, was employed in 120 patients with recurrent malignant ventricular arrhythmia refractory to conventional antiarrhythmic drugs. After discontinuation of all antiarrhythmic agents, patients underwent control studies including 48 hours of ambulatory electrocardiographc monitoring and maximal symptom-limited exercise testing. One hundred patients had frequent as well as repetitive ventricular premature beats whereas in 20 patients, because of infrequency of ectopic activity, invasive electrophysiologic studies were carried out to provoke a repetitive ventricular response. Tocainide therapy was begun at 1,200 mg daily and increased to 2,400 mg daily guided by drug efficacy and the occurrence of adverse effects. After 48 hours of treatment with a fixed dose, drug action was evaluated by repeat monitoring and exercise stress testing or electrophysiologic testing. Fifty-five patients (46 percent) responded to tocainide. The average daily dose of drug and peak blood levels were equivalent in responders and nonresponders. Adverse effects occurred in 42 patients (35 percent) and were primarily related to the central nervous system. Lidocaine predicted the response to tocainide in 78 percent of patients. Thirty-four patients were continued on long-term maintenance therapy. After an average follow-up period of 16 months (range 2 to 39), treatment with the drug was discontinued in nine patients. The remaining 25 patients have had no adverse effects and no recurrence of ventricular arrhythmia.

Prolonged effect of nadolol on heart rate in hyperthyroidism.

There is extensive experience in the treatment of hyperthyroidism with beta-blockade. Because of the short half-life of propranolol the drug must be taken in divided doses. The effect of a single daily dose of a long-acting beta-blocking drug, nadolol, was investigated in 7 hyperthyroid patients. A satisfactory and prolonged reduction in heart rate was observed during continuous monitoring over a 24-hour period. Nadolol, therefore, is a possible alternative to propranolol in the treatment of hyperthyroidism with an advantage in the poorly-compliant patient.

Prevalence of persistent abnormal involuntary movements among patients in a Nigerian long-stay psychiatric unit.

226 patients in a Nigerian chronic psychiatric patients' unit were examined for the evidence of abnormal involuntary movements. 21 (9.3%) of the patients had the disorder. The prevalence rate was higher among the females (14.5%) than among the males (7%). All the 21 patients had the diagnosis of schizophrenia. Also, they were found to be of an older age group than the total population. In comparison with a control group, the development of persistent abnormal involuntary movement was found not to be related to the daily dose of neuroleptic drugs administered or to the duration of the illness. The disorder was thought to be an idiosyncratic reaction.

Accelerated appearance of neoplasms in female nzb/nzw mice treated with high‐dose cyclophosphamide

Prolonged immunosuppressive therapy with cyclophosphamide increases the prevalence of neoplasms in NZB/NZW mice, an animal model of systemic lupus erythematosus. The current study was designed to compare the oncogenic properties of high dose cyclophosphamide with a low dose therapeutic regimen. Female NZB/NZW mice received life-long therapy with "high dose" cyclophosphamide, 16 mg/kg/day, or "low-dose" cyclophosphamide, 5.7 mg/kg/day; control mice received saline. High dose therapy clearly accelerated appearance of neoplasms. Seventeen of 19 mice treated with high-dose cyclophosphamide developed neoplasms at the mean age of 61 weeks. Fifty-seven percent of these tumors were mammary carcinomas. Neoplasms appeared in all mice treated with low dose; mean longevity in this treatment group was 80 weeks (compared to high dose treated mice, P less than 0.001). Carcinomas, pulmonary adenomas, and lymphomas were the most common tumors in mice receiving low dose therapy. Positive tests for ANA were suppressed in high dose treated mice. AntiDNA antibody levels and glomerulonephritis were decreased significantly in both groups of cyclophosphamide-treated mice compared to controls. It was concluded that the high daily dose of immunosuppressive drug was related to early oncogenesis in autoimmune NZB/NZW mice.

Steady-state serum salicylate levels in hospitalized patients with rheumatoid arthritis

When the total daily drug dose was individualized to produce a steady-state serum salicylate concentration between 20 and 35 mg/dl, clinically acceptable fluctuations of serum concentrations occurred during both twice daily and three times daily administration. In 6 rheumatoid arthritis patients receiving choline magnesium trisalicylate, mean steady-state serum levels were the same, and the ranges of hourly mean concentrations during 8 and 12 hour dosage intervals were 19 to 27 mg/dl and 17 to 30 mg/dl, respectively. Changing the dosing interval from 8 to 12 hours required a 50% increase in the fractional doses, but resulted in an increase of only 3 mg/dl in mean peak concentration and a ddecrease of 1 mg/dl in mean minimum concentration.

Effect of treatment with certain flavonoids on Mengo virus-induced encephalitis in mice

Among the four flavonoids tested quercetin and morin proved to be significantly effective against lethal Mengo virus-induced encephalitis in mice when the drugs were adminsitered orally (p.o.). With subcutaneous (s.c.) administration all four drugs failed to prevent mortality in the infected mice. Quercetin produced maximum protective response in intraperitoneally (i.p.) or intranasally (i.nas.) infected mice when administered twice daily at doses of 20 mg/kg for a period of not less than four days. Single injections of the full daily dose of drug failed to prevent deaths in mice. Treatment must be begun at the time of, or prior to, virus inoculation. Delayed initiation of treatment was ineffective in preventing mortality.

Δ<sup>1</sup>-Tetrahydrocannabinol, Cannabidiol and Cannabinol Effects on the Immune Response of Mice

delta1-tetrahydrocannabinol (THC) elicited a dose-dependent (1, 5, 10 mg/kg) depression of the immune response, of immature mice, stimulated with sheep red blood cells. The impairment of humoral immunity was specific for THC but not for cannabidiol at 25 mg/kg or cannabinol at 25 mg/kg. The mice were given four daily doses (i.p.) of either drug or vehicle (Tween 80-propylene glycol in 1% saline) or a single injection (i.p.) of sheep red blood cells in addition to four daily doses (i.p.) of drug or vehicle. Suppression of the antigenic response by THC was reflected as a reduction of splenic weight, reduction in the number of splenic antibody-forming cells, lowered hemagglutination titer and reduction in the percentage of splenic white pulp of total spleen volume.

The oral 100-day LD50 index of phenacetin in guinea pigs

The oral LD50 (100 days) of phenacetin in young, male guinea pigs (the daily intragastric dose which killed 50% of animals over a period of 100 days of administration) was 0.228 ± 0.081 g/kg/day. The oral 100-day LD50 index, or oral LD50 (100 days) expressed as a percentage of the acute, oral LD50 (1 dose), was 8.6 ± 3.1. At the oral LD50 (100 days) there occurred growth inhibition, increase in food and water intake and urinary volume, slowing of the respiratory rate, ataxia, dacryorrhea, loss of weight, some hydration of body tissues, extensive capillary-venous congestion, degenerative changes and infection of certain body organs. Part of the toxicity syndrome at the LD50 (100 days) was similar to that reported for several other chemical agents. Higher daily doses produced signs which approached those at the oral LD50 (1 dose). Compared with corresponding published data on other drugs, the results indicate that the oral 100-day LD50 index could be a useful single relative index of the effects of giving repeated large daily doses of drugs. Since the oral 100-day LD50 index of phenacetin in guinea pigs was lower than that in albino rats, species of animal would appear to be a factor in evaluating the significance of the index.

Primaquine sensitivity. Glucose-6-phosphate dehydrogenase deficiency: an inborn error of metabolism of medical and biological significance.

The potential danger of hemolysis from use of the 8-aminoquinoline antimalarial drug, pamaquine (Plasmoquine), has been known since 1926.¹Earle,²in 1948, reported that pamaquine caused hemolysis in 5%-10% of American Negroes, but rarely in Caucasians. Similar observations were made in 1952 by Hockwald³during an evaluation of the related, but less toxic drug, primaquine; it was further noted that the severity of hemolysis was determined by the amount of drug administered. In 1954, Dern⁴discovered that the susceptibility to hemolysis by primaquine is due to an intrinsic abnormality of the erythrocyte. Dern, Beutler, and Alving⁵reported that the hemolysis is self-limited in that clinical recovery occurs even if the daily dose of drug is continued. Many drugs can precipitate hemolysis.⁶This hypersusceptibility to hemolysis by drugs is a genetically transmitted inborn error of metabolism.⁷The first biochemical abnormality to characterize drug-sensitive cells,