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[Special pharmacokinetic aspects in newborns and young infants].

The safety of drug therapy in the newborn period and early infancy is endangered for two main reasons: 1. The relative distribution volume of drugs during maturation and in pathological states varies greatly and thus makes conventional dosage in short-term therapy ineffective. 2. During early childhood, the rate of elimination of many drugs is slow hence there is a risk of overdosage in long-term therapy with doses considered safe in older children. The example of two drugs demonstrates, that the course of blood levels is not only dependent on the elimination half life and on the relative distribution volume, but may also be modified to a large extent by the process of invasion. This increases the risk of iron-dextrane but contributes to the safety of Cephalexine. If drug therapy is to be safe and effective in childhood at least the basic elements of a most simple pharmacokinetical model consisting of Invasion, Volume of Distribution and Elimination must be known as can be shown by the mathematical extrapolation of blood level curves gained from single applications for long-therm therapy.

Age Factors↗

Protein bound radioactivity in neuronal and glial fractions following intra-carotid 3H-leucine perfusion.

Brain proteins in one cerebral hemisphere were labeled by means of intracarotid perfusion with 3H-leucine by a 40 s pulse. Recirculating precursor contributed little to the protein bound radioactivity. This radioactivity reached a peak level 30 min after perfusion. Fractions enriched in neuronal perikarya and glial cells showed a similar time course of labeling, but the neuronal fraction demonstrated the highest level of protein bound radioactivity. Subcellular fractions from whole brain were studied by the same system. The highest protein bound radioactivity was observed in the nuclear and microsomal fractions. The brain entry of the precursor by means of a controlled intracarotid pulse of short duration offers particular advantages in short-term experiments since the systemic metabolism of the labeled precursor is largely avoided. The easily achieved high labeling of proteins facilitates assay of the radio-activities in different cellular and subcellular fractions and also allows analyses of relative turnover rates in electrophoretically separated proteins.

Animals↗

[Certain hemodynamic indicators during rest and after intensive physical exercise at high altitude].

For 5 years 364 normal males, aged 19--25, were studied at the altitude of 3800--4200 m, along with local inhabitants of the mountain region; the hemodynamic shifts and arterial blood oxygenation were studied with the base metabolism conditions preserved both at rest, and after intensive physical exercises performed according to the step-test method with the maximum tempo of the work (cardiological motion test, WHO, 1967). The initial reaction of the cardiovascular system to the high altitude conditions manifested itself in an increased stroke volume and cardiac output, of the volume speed of blood ejection, of the cardiac index in a decrease of the total peripheral resistance and oxygen saturation of the arterial blood. This reaction was interpreted as a compensatory one. In the course of acclimatizing, the cardiac output and the pulse amplitude of the arterial pressure gradually decreased, and the total peripheral resistance increased. These hemodynamic changes must be of an adaptative nature. The maximum physical workload caused a distinct intensification of the circulatory reactions, especially in those living for considerable periods of time at high altitude and in local inhabitants. The general state of the examined remained good. Hence, these persons have a considerable reserve of functional capacities of their cardiovascular system, and can perform hard muscle work at high altitude. Individuals staying at high altitude for only short periods of time react to intensive physical workloads by a less distinct intensification of the contractile capacity of the heart and by a sharp decrease of blood oxygenation, considerable acceleration of the heart rate and respiration rate, as well as by a deterioriation of their general state. Such muscular efforts cause overloading of the heart only in persons with a short-term acclimatizing.

Acclimatization↗

Effect of short-term administration of cyproterone acetate on the reproductive tract histology, ovarian and serum cholesterol contents of female monkey (Presbytis entellus entellus).

Short courses of cyproterone acetate, a compound with progestational and antiandrogenic activities were administered to normally cycling female monkeys to investigate into the effects of cyproterone acetate on the reproductive tract. In little earlier follicular stage 20 mg of the drug daily for 30 days increased the cholesterol contents in the gonads. Serum cholesterol contents were slightly increased. When the reproductive tract was examined histologically, the gonads showed reduction in size, along with widespread degeneration of the young follicles as well as other growing follicles. Uterus showed progestational endometrial proliferation and sloughing of the vaginal productive tract.

Animals↗

Marital discord and early child development.

As part of a prospective study on the neuropsychiatric development of children born at varying degrees of organic and psychosocial risk, the effect of marital discord on the cognitive and social-emotional development of 315 first-born children into two parent households was investigated. Both the children and the quality of the parental relationship were evaluated when the children were 3 months and 2 years of age. The findings show that marital discord at 3 months does not affect child performance at 3 months, or at 24 months. Marital discord at 2 years does affect the emotional well-being of the 2 year olds, i.e. it is accompanied by a significant rise in psychopathological symptoms. When the effect of the stability of marital strife from the first assessment to the second was studied, a significant increase of behaviour problems and decrease in cognitive performance was found in the group of children whose parents' marital situation had deteriorated and failed in the meantime but surprisingly not in the group with chronic discordant relationships. Conversely, poor child performance and emotional adjustment improved with a positive change in the parental relationships. Analysis shows that negative marital change goes hand in hand with a decrease in parenting skills which affect children more adversely than their counterparts whose parents had a history of marriage and child-rearing problems. Further study of the course of marital relationships and child development at the next research waves (4.5 and 8 years) will show which results are of long-term versus short-term relevance.

Adolescent↗

[Modification of the body's resistance to acute ionizing radiation by synthetic beta-carotene].

Radiomodifying efficiency of short-term and chronic medicinal and treatment-prophylactic enrichment of rations with artificial beta-carotene, administered at single doses of 0.1-10.0 mg, were studied after acute external gamma-irradiation of adult nonlinear and Wistar rats (0.029 Gy/s) or female SBA mice (0.0037 Gy/s), where the absorbed dose was equal to 8-3 Gy or 9.9-9.5 Gy, respectively. Suspension of beta-carotene paste in olive oil accelerated death of rats irradiated at doses of 8 and 7 Gy (P = 0.04), and shortened their lifespan. At a dose of 6 Gy single and long-term enrichment of rations with beta-carotene decreased the rate of rat death within 30 days from 33.3% to 16.7% (P = 0.14) and 3.3% (P = 0.01), while their life time was increased from 48 days to 67 days (P = 0.05) and 508 days (P = 0.01). beta-Carotene was found to affect favourably the radiation-induced (5 Gy) leukocytopenia, and decreased thymus mass (6 Gy) and body weight (8 Gy). In treatment-prophylactic enrichment with beta-carotene of mice (9.9 Gy) ration their survival was increased from 15% to 30% and lifespan from 14.4 days to 28.9 days (P = 0.05). During medicinal or treatment-prophylactic courses of beta-carotene death of mice (9.7 Gy) was decreased from 75% to 35% (P = 0.01) or 60% and life time was increased from 16.7 days to 22.17 days or 39.9 days (P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Echocardiographic evaluation of left ventricular wall motion before and after heart transplantation.

Forty transplanted hearts were retrospectively investigated before, immediately after, and 15 +/- 12 months after heart transplantation by two-dimensional echocardiography for the presence and course of left ventricular myocardial wall motion abnormalities. Fourteen heart donors who were brain dead because of subarachnoid hemorrhage formed group 1 (mean age, 35 years); 21 heart donors who were brain dead because of head injury formed group 2 (mean age, 29 years), and five heart donors who were brain dead because of head injury with an additional chest trauma formed group 3 (mean age, 28 years). Myocardial wall motion was examined in six different myocardial segments (inferior, septal, anterior, posterior, posterolateral, apical) and was quantitatively assessed by a modified score index system (score index 0 = normal wall motion; score index 1 = diffuse hypokinesia). Overall, 27 of the 40 heart donors showed mild to severe (9 of the 40) wall motion abnormalities, which improved shortly after heart transplantation (score index: 0.36 vs 0.18, p < 0.01), and remained improved 15 months after heart transplantation (score index: 0.15). Among the different study groups, a significant improvement occurred in the myocardial wall motion score index on a short-term and long-term basis in all the groups, except for group 2, regarding the long-term follow-up. This study concluded that brain-dead, potential heart donors often reveal mild-to-severe left ventricular wall motion abnormalities, which are readily detected and semiquantitated by two-dimensional echocardiography.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

[Serial testing of antiarrhythmic agents using programmed stimulation in recurrent ventricular tachycardia].

Serial testing of drugs (STL) by means of programmed electric stimulation (PES) was implemented in 41 patients with relapsing monomorphic persisting ventricular tachycardia (S-KT) of varying aetiology and severity. To reduce underrating of the action of antiarrhythmics, milder criteria were used for evaluation of the short-term and long-term effectiveness of therapy. By STL a total of 137 drugs and their combinations were tested. S-KT was not induced by 60 of them (44%) and in 35 patients (85%). In the remaining 6 patients STL could not be completed because of non-adherence of the patients to the method or because of serious proarrhythmic action of therapy. In the course of long-term follow up (mean 21 months) in positive therapy an arrhythmic episode did not occur during the first year in any of the patients, in the course of two years it occurred in 14%, in three years in 29% and in the course of four years in 33% of the patients. Treatment preventing S-KT had to be abandoned because of serious side-effects in four patients. In all of these four patients later an arrhythmic episode developed. Long-term treatment with antiarrhythmics selected by means of STL by programmed stimulation is a rational approach to pharmacotherapy of serious ventricular arrhythmias. In cases leading to combined treatment with amiodarone and antiarrhythmics class I it would be, however, better in view of the high incidence of serious effects of this treatment to use implantation of a defibrillator.

Adult↗

[Postoperative infections and antibiotic prophylaxis in radical hysterectomy. Retrospective study].

Radical hysterectomy is associated with a high risk of postoperative infectious morbidity. A series of 73 patients who underwent abdominal radical hysterectomy with pelvic lymphadenectomy is presented. Hospital charts were reviewed to determine the influence of surgical characteristics and of different antibiotic prophylaxis regimens on postoperative septic complications. The overall incidence of postoperative infections was 31.5%; in 13 patients had urinary tract infections (17.7%), 3 surgical site-related infections (4.1%) and 6 febrile morbidity (8.2%). There were also 3 cases of phlebitis and 3 infectious events at distant sites. No interaction was observed between the examined risk factors and the overall infectious morbidity. Time of surgical procedure and average blood transfusion show a trend toward increased values in patients with complications compared to patients with regular postoperative course. The most important current controversy about the use of prophylaxis in radical hysterectomy concerns the duration of postoperative treatment. In this series the major part of the subjects received a long-term antibiotic prophylaxis regimen (greater than 72 hours), and only 18% received a perioperative prophylaxis. Women without postoperative complications were more frequently treated with a long-term antibiotic prophylaxis (82%) compared to women with infectious morbidity (65%). Moreover, in patients with complications, the proportion of cases who needed an additional antibiotic therapy was lower in the group receiving long-term prophylaxis (20%) compared to the short-term group (83%).

Anti-Bacterial Agents↗

Blood pressure reduction as a preventive treatment of diabetic nephropathy.

Arterial hypertension is present in 10-80% of newly diagnosed Type 2 diabetics, and in 30-50% of Type 1 diabetics after some years. In patients with overt nephropathy, correction of hypertension is associated with a reduction in the rate of decline of glomerular filtration rate. In most patients without clinical diabetic nephropathy, arterial pressure remains within normal limits as defined by usual criteria, whether or not microalbuminuria is present. Short-term studies of Type 1 diabetics with microalbuminuria suggest that angiotensin-converting enzyme inhibitors result in a fall in urinary albumin excretion rate more than calcium antagonists and diuretics. Additional studies assessing the long-term effect of different antihypertensive agents on the evolution of early diabetic nephropathy are needed before the superiority of any drug can be claimed. In addition, non pharmacological approaches, including optimal glycemic control as well as modification of dietary sodium and serum lipid profile, may alter the progressive course of elevation in arterial pressure and decline in renal function. The optimal level of blood pressure for diabetic patients remains to be determined.

Albuminuria↗

[Short-term ceftriaxone treatment of typhoid fever in children].

Ten children, diagnosed as having typhoid fever, were enrolled in this study between April and September, 1989. Ceftriaxone was administered intravenously, in two dosages adding to 50-100 mg/kg/day over as short a period as five days. The mean period of defervescence was 3.2 days. No adverse reactions to the drug occurred; all those fulfilling the prescribed course were cured. To date, no relapse has been reported nor has any patient become a chronic carrier. Shortterm use of Ceftriaxone had the advantages of rapid response, abscence of serious side effects, and low failure rate in treating children with typhoid fever.

Adolescent↗

[The late results of short-term chemotherapy in benign forms of tuberculosis in children].

The study included 359 cases of primary tuberculosis (benign forms) in children aged 0-14 years, out of which 181 non-complicated and 178 complicated forms. The therapeutical regimens were: 3HEZ2/3HE2 (study subgroup) and 6HE2/3H2 (control) for non-complicated forms, and 3HRZ2/3HR2 (study subgroup) and 3HES2/3HE2/3H2 (control) for complicated ones. Late results (5 years after treatment end) were very good (from clinical, radiological, bacteriological points of view) in 100% of cases. Thus, short-course regimens are preferable to longer ones (over 6 months) in the chemotherapy of the benign forms of pulmonary tuberculosis in children.

Adolescent↗

Long-term management of panic disorder.

The high-potency benzodiazepines have been effective in short-term treatment of panic disorder, but systematic investigation of their long-term efficacy and safety is necessary. In a 1-year follow-up study of patients continuing treatment with clonazepam, 90% maintained a positive response without developing significant tolerance. In a 2.5-year follow-up study of alprazolam therapy, little evidence of tolerance emerged and initial therapeutic gains were maintained, even among patients who decreased or discontinued medication. As with antidepressants, many patients remain on high-potency benzodiazepine medication after short-term treatment; the choice of maintenance agent should reflect side effects of treatment as well as the ease of discontinuation. The high-potency benzodiazepines are a reasonable alternative to antidepressants, which involve problems of morbidity, noncompliance, and risk for overdose. Discontinuation may be less difficult with the longer-acting high-potency benzodiazepines, which thus may be advantageous for long-term treatment. It is necessary to determine the contributions of all aspects of treatment, both behavioral and pharmacologic, to the longitudinal course of patients with panic disorders.

Alprazolam↗

The clinical course and long-term management of generalized anxiety disorder.

Evidence suggests that generalized anxiety disorder (GAD) has a fairly chronic course marked by significant long-term distress and comorbidity. Research has focused on short-term treatment of GAD, and long-term outcome studies after either short- or long-term treatment have been relatively neglected. The authors discuss the benefits and risks of various drug and nondrug therapies used in the long-term management of generalized anxiety disorder and suggest avenues for future research.

Anti-Anxiety Agents↗

The effect of moderate non-hemolytic jaundice and phototherapy on newborn behavior.

To study the effects of moderate non-hemolytic jaundice and phototherapy (PT) on newborn behavior, initially 29 full-term infants with serum bilirubin (SB) 12-15 mg/dl were randomly assigned to PT (n = 14) or non-PT (n = 15) group. PT was done until SB less than 12 mg/dl. One infant in the PT group was excluded because of G-6-PD deficiency and evidence of hemolysis. Four infants in the non-PT group were excluded because their serum bilirubin concentrations finally exceeded 15 mg/dl and they were put on phototherapy for ethical concern. Two more infants were then added to the non-PT group to make a total number of 13. Additional 14 infants with serum bilirubin levels less than 12 mg/dl were studied as controls. Neonatal Behavioral Assessment Scales (NBAS) were performed 4 times: just before PT, right after termination of PT, 24 hrs after termination of PT and at 2 wks of age in PT group, and at comparable ages with the non-PT and control groups. The course of jaundice was measured in terms of SB levels at entry into study, peak SB levels, duration from entry into study to the time when SB levels dropped below 12 mg/dl and age when SB levels dropped below 12 mg/dl. The values did not differ significantly between the PT and non-PT groups. Therefore, phototherapy did not change the clinical course of jaundice in the majority of infants with bilirubin levels between 12 and 15 mg/dl. The 7 cluster scores of 1st NBAS did not differ significantly among the 3 groups of infants. On the 2nd and 3rd examinations, the infants in the PT group performed poorer in some of the orientation items than the infants in the non-PT and control groups (p less than 0.05) whereas the non-PT groups showed similar performance as the control group. At 2 wks of age, no significant differences of the NBAS scores were found in 3 groups. We conclude that moderate non-hemolytic jaundice (serum bilirubin 12-15 mg/dl) does not affect the behavior of full-term infants in this study. Phototherapy has some short-term adverse effects on visual, auditory orientation and alertness of the infants which may impair infant-caregiver interaction.

Female↗

[Follow-up study of short course chemotherapy of pulmonary tuberculosis complicated with diabetes mellitus].

A retrospective analysis was made for 644 patients with pulmonary tuberculosis newly diagnosed during the time of 1977 to 1985 to evaluate the influence of diabetes mellitus (DM) on the drug response rate and the long-term relapse rate in the treatment of tuberculosis. These patients were divided into four groups: (1) 123 patients with DM on 9- to 12-month short course regimens; (2) 79 with DM on 13- to 36-month long-term regimens; (3) 379 nondiabetic patients on short-term regimens; and (4) 63 nondiabetics on long-term regimens. Bacteriological relapse after chemotherapy was defined as positive cultures growing at least 20 or more colonies. 1) Bacteriological negative conversion rates were similar in both diabetic and nondiabetic patients who had received combination regimens including INH and RFP. The degree of control of DM did not affect the conversion rate. 2) Of 297 patients who had received short-course chemotherapy and the information for analysis were available as of August 1989, 8 (10.3%) had relapses in 78 diabetic, and patients 23 (10.5%) in 219 non-diabetic patients; the difference was not statistically significant. There were also no discernible differences in the relapse rates between patients on the short-course regimens and those on the long-term regimens. 3) Most of the relapses occurred around 6 months and 30 months after completing the short-course chemotherapy. Similar pattern of relapses was observed also in the long-term therapy group. 4) Pretreatment radiographic findings and quantity of the acid-fast bacilli in the sputum, and the presence of cavitary lesions at the completion of therapy bore no significant relation to the development of relapse. 5) In the diabetic patients the degree of control of DM contributed little to the development of recurrence. 6) Although most of the patients without DM relapsed with sensitive strains and achieved a good response to retreatment, diabetic patients frequently relapsed with resistant strains and had a grave prognosis. 7) Of 41 patients who died after having been on the short-course regimens, two were attributed to tuberculosis. Only one was attributed to tuberculosis of 25 patients who died after receiving the long-term regimens. 8) The data obtained here confirmed that the 12-month regimen for diabetic patients could achieve favorable results in the response rate and the long-term relapse rate, as that for nondiabetic patients. However the cases of tuberculosis complicated with DM frequently showed a poor prognosis once the relapse took place. These results suggest that pyrazinamide-containing 4-drug combination regimens in an initial intensive phase is the preferred treatment for the patients with DM.

Adult↗

Catamnestic study of cases with tardive decompensated hydrocephalus.

One hundred patients with decompensated hydrocephalus (60 operated, 40 nonoperated) were studied both retrospectively and prospectively at 3 moments of the disease course. The indicators were clinical: neurologic, psychic and social, and paraclinical: results of pneumoencephalography, encephalography, radioisotope cisternography. The effects of surgical treatment (ventriculocardiac derivation) and of medical treatment were evaluated at short and long term. In surgical treatment, favourable short-term outcome (headache, gait and micturition disorders, improved consciousness, psychomotor activity, social behaviour) was found in 88% of the patients; long-term favourable outcome was present in 60% of the patients and implied only the psychic and social indicators. In medical treatment the favourable short-term outcome was nonsignificant and the long-term outcome was favourable in only 32% of the patients. In the remaining cases evaluated as unfavourable, the cognitive disorders increased progressively. The predictors for favourable therapeutic outcome were: early diagnosis, early surgical intervention, the clinical form of hydrocephalus, the sequelae and short-term effects of surgical treatment.

Adult↗

Long-term graft survival.

1. Long-term graft survival is characterized by failure rates that are essentially constant after about a year or 2. The rate has not varied appreciably among cohorts defined in terms of transplant year. 2. Transplants with an excellent clinical course throughout the first 3 months (about 2-thirds of cadaver-donor first transplants) have substantially better long-term graft survival than those with a less favorable early course. 3. Having an excellent early clinical course did not remove the effects of the several factors related to long-term survival. 4. Use of cyclosporine did not relate to long-term survival. 5. Factors related to short-term graft survival (1 year), generally related to long-term survival and in the same direction. Cyclosporine use was a major exception. 6. The dominant factor for long-term survival was tissue matching as reflected in donor categories: HLA-identical sibling, parent, and cadaver. 7. Black recipients had a decidedly poorer long-term survival than recipients of other races/ethnicities. 8. Transplant center was a dominant factor in long-term graft survival. 9. Multivariable analysis did not materially alter the findings obtained from factors considered separately. This was attributable to the sensitivity associated with small standard errors resulting from the large number of cadaver-donor transplants and the combination of smaller numbers and longer survival of living-related transplants.

Age Factors↗