Oral and intravenous bretylium disposition.

To compare the oral and intravenous disposition of bretylium tosylate in man, 10 normal male subjects were randomly assigned single doses of 5 mg/kg bretylium tosylate either orally or intravenously and crossed over 2 wk later to the opposite route (20 studies). Each experiment included sampling for drug in serum and urine over 48 hr. Bretylium tosylate was assayed by gas chromatography. Kinetic analysis provided the following mean [coefficient of variation] results: 100FPo, 22.6% [40.2%]; ClrIV, 300 ml/min [27.8%]; ClrPo, 1.268 mg/min [54.8%]; ClBIV, 299 ml/min [31.9%]; f, 101% [8.7%]; Vdss, 3.37 l/kg [30.5%]; lambda lIV 0.0510 [12.8%]; lambda lPG, 0.115 [52.7%]hr-1; elimination half-life (t 1/2) after intravenous bretylium tosylate, 13.6 hr, and after oral bretylium tosylate, 6.0 hr (harmonic means). Bretylium tosylate binding to plasma proteins in normal volunteer samples was found to be negligible. The results indicate extensive tissue binding of bretylium tosylate. Oral doses of bretylium tosylate are only partially absorbed. Bretylium tosylate is eliminated entirely by the kidneys as unchanged drug. The greater renal clearance after oral than intravenous bretylium tosylate, and the greater elimination rate constant and shorter oral bretylium tosyulate t 1/2 are of interest but no explanation is available.

Parabolic equation relating free and total drug concentrations in cases of nonlinear plasma protein binding.

In many cases of nonlinear drug-protein binding, investigators have fitted data to the classical Langmuir model with two classes of binding sites involving four parameters. For human serum albumin binding of tolmetin and salicylate, a simple two-parameter parabolic equation relating free to total concentrations fitted the binding data better. Thus, the free fraction corresponding to the serum or plasma drug concentration in the blood sample taken from a subject can be estimated directly from the parabolic model. This is not the case when the Langmuir model is used to describe nonlinear binding data since the positive root of a cubic equation must be obtained to estimate the free from the total concentration. The direct relationship between free and total drug concentrations would be useful in many clinical situations.

Free fraction change with differing volume ratios in equilibrium dialysis: cases of non-linear drug-protein binding.

When equilibrium dialysis is used to measure drug-protein binding, an increase in the volume ratio (buffer solution/protein solution) causes a decrease in the total drug concentration at equilibrium. When binding is non-linear, this decrease in total drug-concentration also causes a decrease in the free fraction. By use of the same volume ratio (3:1) binding curves were obtained for the binding of prednisolone to plasma proteins, and for the binding of salicylic acid and tolmetin to human serum albumin (HSA). When the volume ratio was changed, the observed free fractions were appreciably different from those expected by taking into account only the changes in the total equilibrium drug concentration. There is evidence that this phenomenon is the result of competition for binding sites between the drug and an impurity in the HSA. The effects are not the result of the presence of free fatty acids.

Socio-economic determinants of mortality in Latin America.

PIP: The characteristics and sources of socioeconomic differentials of mortality in Latin America, in so far as they are currently known, are examined in an attempt to clarify the present situation and its perspectives. Mortality in a population is a function of the frequency of illness (incidence) and the probability of dying of the sick individual (lethality). Information on the socioeconomic differentials of mortality in Latin America is systematically reviewed with attention directed to the following: differentials among Latin American countries, regional differences within countries, urban-rural contrasts in mortality, mortality and income level and level of education, and mortality and ethnic groups. Latin America shows considerable heterogeneity with respect to the risk of dying, which varies from 202/1000 births in Bolivia to 38/1000 in Uruguay. It is estimated that more than 1/2 of the children born in Latin America are exposed to a mortality rate of over 120/1000. A study of the urban and rural populations of 12 Latin American countries revealed that the risk for rural populations exceeds that for urban populations by 30-60%. There is extensive evidence showing that mortality is higher in the working class and is associated with lower levels of education and income. Mortality was also higher in certain indigenous groups. Socioeconomic differentials of mortality are more marked in Latin America than in the developed nations. The mother's level of educational attainment is the variable most significantly associated with infant and child mortality. The prospect of reducing the current mortality levels is dependent primarily upon the implementation of policies aimed at a more egalitarian distribution of the benefits of socioeconomic development among the population.^ieng

Demographic growth and health needs in Latin America.

The net effect of the rapid population growth in Latin American countries is an increase in the needs for health services. Nevertheless, the demographic factor is not the only nor the most important consideration in determining how to satisfy these demands in the region. The main contradiction lies between the magnitude of needs for services generated by the adverse living conditions prevalling among the majority of the population, together with a restricted supply of health services, the availability of which varies according to social class. The problem of the increasing demand for medical care, generated by the rapid population growth, should be recognized as originating in the socioeconomic structural conditions prevailing in Latin American countries today which determine, simultaneously, low health levels, deficiencies in the provision of health services, and rapid population growth.

PIP: Unfavorable living conditions prevailing in Latin America are exacerbated by rapid population growth. Where the socioeconomic level is very low the need for health care services is very severe. 71% of the high per capita income population in Chile (1.00 and more) satisfied their demand for annual medical visits, compared to 39% of the low income (.0-.19) in 1968. A health policy which delivers medical services to the population sector which most needs them and does not discriminate by social class would reduce the present high rates of population growth. Population projections by the Latin American Demographic Center anticipate increases by an average of 50% between 1975-1990. Estimated growth will exceeded 60% in Honduras, Nicaragua, Mexico, and the Dominican Republic. Since life expectancy is lowest in Nicaragua and Honduras, demographic increase will occur where health needs are the greatest. By contrast, Argentina and Uruguay, where life expectancy is the highest, anticipate 20% growth.

[Economic and social determinants of mortality in Latin America]. / Determinantes economicas y sociales de la mortalidad en America Latina.

PIP: It is estimated that more than half of the infants born in Latin America are exposed to a mortality rate higher than 120/1000. Social indicators, such as number of hospital beds, protein consumption, literacy level, and type of housing are highly related to life expectancy at birth. More important yet is the relation of mortality with the socioeconomic characteristics of a given country within Latin America. Geographical differences of mortality are the result of national policies especially in regard to urban and rural population. For example, probability of death in Ecuador is 98/1000 in urban areas, and 145/1000 in rural areas; data are similar for other countries. The socioeconomic contradictions of the capitalist system create differences in mortality rates by concentrating in the few cities most of the health services, and by providing better living conditions for the urban population. Mortality, especially infant, is inversely related to income and to educational status and age of the mother. The many indigenous ethnic groups still existing in many Latin American countries have even higher mortality rates than the rest of the population. Respiratory dysfunctions, infectious diseases, malnutrition and accidents are the main causes of infant mortality in all groups of people, but with much higher rates for the working classes, and lower rates for the higher income classes. As a final analysis, not only is it important to use modern medical knowledge and technology to lower mortaltiy rates, but, and above all, it is imperative to modify social and economic structures.^ieng

Empirical findings on the association between education and child health status: discussion.

PIP: In this discussion of the empirical findings on the association between education and child health status, it is important to note the important contributions of Cochrane and Caldwell. Most of the evidence comes from aggregate studies, and it shows certain facts significant from the perspective of policies. The association between education and child mortality is found in a variety of conditions, and mother's education appears to have a stronger effect than father's education. This finding warrants a discussion of the mechanism of this effect. It is also relevant for intervention programs. It is clear that despite much research the exact nature of the association between education and child mortality is not well known, and the mechanism should not be oversimplified. The errors in basic data may be impressive, and at times it is unknown how much the real "effect" of education on mortality is overestimated or underestimated. Selecting and operationalizing variables is an important step in the attempt to understand the nature of the relationship between education and mortality. When dealing with population censuses or other sources of systematic information, efforts are restricted to available information. Operational variables are usually proxies to the real theoretical variables of interest, and sometimes they are rather poor indicators. The theoretical frame of analysis is more important when the researcher designs the collection of information. The point that must be emphasized is that both the changes in mortality and education are occurring in the 3rd world countries within a historic transition from precapitalistic modes of production to relatively advanced, dependent, capitalistic development. Examples are included which show the importance of considering the contextual, historical conditions which, to a certain extent, are determining both parents' education and child mortality as well as the association between them. Another point to be considered is that both the magnitude of mortality and the low educational levels are shocking in several underdeveloped countries with avoidable deaths running to the order of several million each year. The final point concerns informal education. Recently, the idea of extending health services through primary health care has received important consideration. Those programs emphasize health education and certain community participation in health programs, but these facts are not reflected in the usual years of schooling index. In sum, the study of the association of parents' education and child mortality must be understood in the historic perspective of the different and complex social changes that are taking place in the societies of the 3rd world.^ieng

[Socioeconomic differentials in the decline of fertility in Costa Rica, 1960-1970 (author's transl)]. / El descenso de la fecundidad en Costa Rica y sus diferencias socioeconomicas, 1960-1970.

PIP: Principal source for investigation on fertility are birth registrations, a source which is very often deficient by omission in Latin America. This situation has prompted the development of more specific methods which use other, and more reliable, information. One of these is the own-children method, which allows estimations based on population censuses. This article presents an investigation on the process of fertility decline in Costa Rica between 1960 and 1970, using the own-children method applied to data from the 1973 census. Costa Rica was selected to evaluate this method since the country's birth registers are relatively reliable. Total fertility rate was higher than that estimated through birth registration; in certain rural regions it was 10-15% higher, possibly because, in those particular regions, omission of birth registration was higher than the national level. Towards the end of the 1950s, half of the women in fertile age were using contraception; the decline in fertility began in the middle and high social classes, and in urban areas. Later, at the end of the 1960s, the decline in fertility reached urban proletarian groups, and the illiterate rural population. It seems obvious that these fertility changes are due to the insertion of families into the system of production, meaning that modernization and education have created a climate favorable to smaller families. These findings are consistent with available information on changes of attitude toward family planning, heavily promoted by the National Family Planning Program begun in 1968. In 1970 the steepest decline in fertility was noted in those groups which, despite the decline, still had the highest fertility rate; by 1977 a tendency toward stabilization was registered.^ieng

Errors in interpretation of data from equilibrium dialysis protein binding experiments.

In equilibrium dialysis protein binding experiments, the fraction of free or bound drug determined at equilibrium by dialysis of a patient plasma sample does not correspond to the drug concentration in the initial plasma sample, but to the drug concentration inside the plasma compartment of the dialysis apparatus at equilibrium. That fraction of free or bound drug corresponds to a lower total drug concentration than that in the initial plasma sample because of loss of drug due to passage of free drug into the buffer compartment in the equilibrium dialysis experiment. The magnitude of the difference between the initial drug concentration and the equilibrium drug concentration depends on the extent of drug binding and experimental conditions. If the initial total drug concentration in the plasma or serum sample as well as the fraction of drug bound at equilibrium as determined by radiotracer methods are known, then, using methods given in the text, the equilibrium drug concentration, the binding parameters corresponding to equilibrium conditions, and the free drug concentration in the initial plasma sample may be estimated.

[Infant and child mortality in Latin America].

PIP: High mortality rates persist in Latin America, and data collection is made very difficult because of the lack of reliable statistics. A study was initiated in 1976 to measure the probability of mortality from birth to 2 years of age in 12 Latin American countries. The Brass method was used and applied to population censuses. Probability of mortality is extremely heterogeneous and regularly very high, varying between a maximum of 202/1000 in Bolivia, to a minimum of 112/1000 in Uruguay. In comparison, the same probability is 21/1000 in the U.S., and 11/1000 in sweden. Mortality in rural areas is much higher than in urban ones, and varies according to the degree of education of the mother, children being born to mothers who had 10 years of formal education having the lowest risk of death. Children born to the indigenous population, largely illiterate and living in the poorest of conditions, have the highest probability of death, a probability reaching 67% of all deaths under 2 years. National health services in Latin America, although vastly improved and improving, still do not meet the needs of the population, especially rural, and structural and historical conditions hamper a wider application of existing medical knowledge.^ieng

Binding of tolmetin and salicylic acid to human serum albumin as a function of temperature.

When drug-protein binding data are evaluated thermodynamically standard free energy (delta G0), standard enthalpy (delta H0) and standard entropy (delta S0) are usually estimated from association constants (Ka) derived from binding data obtained at only two temperatures. Estimation of delta H0 involves the assumption of its constancy in the temperature range studied and linearity of a van't Hoff plot of ln Ka versus 1/T. Sometimes the assumption of such linearity is invalid for theoretical reasons and data obtained at only two temperatures contain no information concerning linearity of this plot. We present data for the binding of both tolmetin and salicylic acid to human serum albumin as a function of temperature which make doubtful the validity of using association constants of these drugs to derive thermodynamic constants other than delta G0 values.