Quinine pharmacokinetics in young children with severe malaria

In this study, we determined selenium concentrations in serum samples of healthy women (146 pregnant and 74 nonpregnant) living in the Mediterranean area of the coast of Granada (southeast Spain). The subjects were distributed in two groups: group A (pregnant women), divided into three categories according to the trimester of pregnancy, and group B (nonpregnant women). No significant differences were observed in the selenium levels either among pregnant women according to the trimester of pregnancy or in the group of nonpregnant women. No other significant differences were determined as regards the age of pregnant women (P > 0.05). Serum selenium levels are slightly lower during pregnancy. Considering that serum selenium levels affect the body selenium status, the concentrations determined establish the non-existence of selenium problems in the daily dietary intake with respect to maternal and fetal necessities during pregnancy.     

The pharmacokinetics of teniloxazine in healthy subjects and patients with hepatic cirrhosis

The single-dose and steady-state pharmacokinetics of teniloxazine, an investigational drug with antidepressant and anti-anoxic properties, were compared in 12 healthy volunteers and 12 cirrhotic patients, following oral administration of 80 mg teniloxazine maleate every 12 h for 7 days. In healthy volunteers, an increase in oral clearance, CLo (from a mean (s.d.) value of 14.6 (3.9) to 18.0 (6.6) ml min-1 kg-1; mean % ratio between the two values (95% CI), 123 (94-151)) and a significant shortening of t 1/2 (from 6.2 (2.7) to 4.8 (1.4) h; mean % ratio (95% CI), 78 (58-98)) were observed upon repeated administration, suggesting autoinduction of teniloxazine metabolism. In cirrhotic patients, the pharmacokinetic parameters of teniloxazine remained essentially invariant with time. Compared with normal subjects, CLo was about halved in cirrhotic patients, whereas t 1/2 was more than doubled. As a consequence of these modifications, the multiple-dose regimen resulted in a two-fold mean drug accumulation in cirrhotic patients, compared with virtually no accumulation in healthy volunteers. Although no adverse events were noted in either study group, it is suggested that maintenance doses for patients with liver dysfunction should initially be at the lower end of the therapeutic range.     

Quinine and mefloquine in the treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy

Between 1991 and 1996, 372 pregnant women with uncomplicated, multidrug-resistant Plasmodium falciparum malaria, living on the western border of Thailand, were treated with either mefloquine (N = 194), quinine (N = 93) or both drugs (N = 85). Antimalarial treatment was generally well tolerated; the most common side-effects were dizziness (42%) and tinnitus (35%) following quinine, and anorexia (23%) and dizziness (36%) following mefloquine. In the patients treated for primary infections with melfloquine, 6% failed to clear their parasitaemia by day 7 and 28% failed by day 42. The corresponding figures for quinine were 4% and 23%, respectively. The failure rates in the 117 women treated for recrudescent infections were higher, the increase being significant for quinine (38%; P = 0.03) but not for mefloquine (37%). The percentage of pregnant women who had patent gametocytaemia on presentation ranged from 4%-19%. Over 50% of the patients were anaemic (haematocrit < 30%) on presentation and 52% of those not anaemic on enrolment developed anaemia during follow-up. Mefloquine and quinine, the only antimalarials generally available for the treatment of highly drug-resistant P. falciparum in pregnancy, give unsatisfactory treatment responses when used as single agents. New, safe and effective regimens are needed for the treatment of pregnant women with multidrug-resistant falciparum malaria.     

Efficacy and pharmacokinetics of a new intrarectal quinine formulation in children with Plasmodium falciparum malaria

The O-2A progenitor cell, which serves as a stem cell for the myelinating oligodendrocyte, has been implicated as a major target for radiation-induced spinal cord injury. In an attempt to increase the number of O-2A cells in the spinal cord, we applied an ex vivo gene therapy procedure for delivering platelet derived growth factor (PDGF). Recombinant fibroblasts expressing PDGF A chain were injected into the cisterna magna of adult rats, which resulted in cell seeding of the subarachnoid space of the cervical spinal cord. The number of O-2A progenitors in the cervical spinal cord was then assessed with an in vitro clonogenic assay. O-2A cells were found to be increased 8 days after recombinant cell injection, and they remained elevated up to at least 14 days. Analysis of O-2A colonies indicated that the implantation of PDGF-expressing cells increased the number of O-2A progenitors without affecting their in vitro proliferation potential or differentiation capacity. These data suggest that implantation of PDGF-expressing cells in the subarachnoid space of the cervical spinal cord may influence a stem cell population critical to the repair of demyelinated lesions.     

Polycardiographic evaluation of cardiotoxic effects of rubidomycin in patients with acute leukemia

In 6 out of 11 patients treated with rubidomycin deterioration of haemodynamic indices was observed including prolongation of the pressure rise subperiod, isometric contarction subperiod and reduction of mechanical index. These changes appeared already after the first administration of the drug and were followed in 4 cases by signs of circulatory failure.     

The effects of cardiotoxic chemotherapy on blood pressure in patients with lymphoma

A retrospective study was carried in 1500 patients submitted to elective laparoscopic cholecystectomy to ascertain its feasibility in patients with previous abdominal surgery. In 411 patients (27.4%) previous infraumbilical intraperitoneal surgery had been performed, and 106 of them (7.06%) had 2 or more operations. Twenty five patients (1.66%) had previous supraumbilical intraperitoneal operations (colonic resection, hydatid liver cysts, gastrectomies, etc.) One of them had been operated 3 times. In this group of 25 patients the first trocar and pneumoperitoneum were performed by open laparoscopy. In 2 patients a Marlex mesh was present from previous surgery for supraumbilical hernias. Previous infraumbilical intraperitoneal surgery did not interfere with laparoscopic cholecystectomy, even in patients with several operations. There was no morbidity from Verres needle or trocars. In the 25 patients with supraumbilical intraperitoneal operations, laparoscopic cholecystectomy was completed in 22. In 3, adhesions prevented the visualization of the gallbladder and these patients were converted to an open procedure. In the 2 patients Marlex mesh prevented laparoscopic cholecystectomy because of adhesions to abdominal organs. We conclude that in most instances previous abdominal operations are no contraindication to laparoscopic cholecystectomy.     

Identical effects of indomethacin on renal function in healthy uninephrectomized subjects and in healthy control subjects

1. Animal studies have shown that prostaglandins are important for renal function after unilateral nephrectomy. In order to investigate the importance of prostaglandins for renal function in the fully adapted remnant kidney in healthy uninephrectomized subjects, the acute effects of indomethacin on renal haemodynamics, lithium clearance, urinary excretion rates of prostaglandin E2, sodium and water, and plasma levels of angiotensin II, aldosterone, atrial natriuretic peptide and arginine vasopressin were measured in 14 healthy uninephrectomized subjects (median time after nephrectomy 1.7 years) and in 14 matched healthy control subjects. In addition, nine healthy control subjects were studied without indomethacin and served as a time-control group. 2. Before indomethacin ingestion there was a significantly higher single-kidney urinary excretion rate of prostaglandin E2 in the uninephrectomized group (uninephrectomized group, 349.2 fmol/min; control group, 76.6 fmol/min; time-control group, 96.3 fmol/min). 3. Indomethacin ingestion resulted in equal changes in all parameters in both groups. These were significant decreases in glomerular filtration rate (-11.3% versus -14.6%), renal plasma flow (-6.5% versus -13.0%), urinary flow rate (-49.8% versus -49.4%), fractional sodium excretion (-44.5% versus -47.4%), lithium clearance (33.2% versus -23.8%) and urinary excretion rate of prostaglandin E2 (-93.8% versus -86.7%) (uninephrectomized versus control subjects, values are medians). In the time-control group no changes were observed in these parameters. 4. It is concluded that healthy uninephrectomized subjects with a fully adapted remnant kidney have a normal renal response to acute indomethacin-induced inhibition of prostaglandin synthesis.     

Biapenem pharmacokinetics in healthy volunteers and in patients with impaired renal function

Biapenem (CAS 120410-24-4) is a new broad spectrum antibiotic agent from the group of carbapenem antibiotics. Results of a pharmacokinetic study in eight volunteers, 17 patients with variant degrees of renal impairment and in addition 13 haemodialysis patients, both on (n = 8) and off dialysis (n = 5), are reported. A single dose of 500 mg biapenem was administered i.v. over 30 min; blood and urine samples were collected up to 24 h post infusion in volunteers and up to 48 h in patients. Concentrations were determined by microbiological assay using the cup plate method. The tolerance was good. The renal function in patients was determined using single shot 51chromium-EDTA clearance. The calculation of pharmacokinetic parameters was performed non-compartmentally as well as based on an open two-compartment model. Although the compound is eliminated extrarenally in considerable amounts (approximately 46% in volunteers), an important prolonged elimination in renal dysfunction was found. This was mainly due to decreased renal elimination but also partly due to decreased extrarenal clearance. A dose reduction factor (DRF) is calculated derived from the ratio of the areas under the serum concentration curve (AUC), in normal and impaired renal function. Dosage suggestions are made. The compound is eliminated considerably by haemodialysis. It is therefore recommended that biapenem is given after haemodialysis or in double the dose on haemodialysis days.     

Evaluation of atovaquone in the treatment of patients with uncomplicated Plasmodium falciparum malaria

The activity of atovaquone in patients with oligosymptomatic Plasmodium falciparum malaria was assessed in an open, non-comparative clinical study. The patients showed a good clinical response, but there was a high rate of recrudescence. The activity of atovaquone in combination with another antimalarial agent should be investigated.     

Subacute Plasmodium falciparum malaria in 43 patients returning from areas with chloroquine in Africa

PURPOSE: To identify clinical and biological features of subacute falciparum malaria, risk factors, and to evaluate the efficacy of curative treatment. PATIENTS AND METHODS: Diagnostic criteria were the association of apyrexia, anemia, little or no parasitemia and a high titer of anti-Plasmodium antibodies. Forty-three cases were observed in subjects returning from chloroquine-resistant areas in Africa. They were matched with controls for age, country of residence and duration of stay. Controls were missionaries who attended our unit for a routine medical check-up during the study period. RESULTS: The clinical presentation and biological features were similar to "malarial cachexia", a condition mainly described in non-immune children in endemic areas. Splenomegaly was present in 58% of the patients. Biological features included little or no parasitemia, an overall decrease in the blood cell count, an increased erythrocyte sedimentation rate and a high titer of anti-Plasmodium antibodies. This syndrome was not correlated with the frequency of chloroquine resistance, the area of stay (urban or rural) or to the kind of chemoprophylaxis. CONCLUSIONS: This study describes subacute resistant falciparum malaria in patients who had prolonged stay in chloroquine-resistant areas of Africa associating splenomegaly, cytopenia and a low or absent parasitemia. Subacute chloroquine-resistant malaria could be due to host factors which remained to be determined by prospective immunological studies. Curative treatment with mefloquine is effective.     

Digitalis effects on the electrocardiogramm: ergometric studies in healthy subjects and patients with coronary artery disease (author's transl)

Therapeutically effective doses of beta-acetyldigoxin in healthy subjects produced no or only minor S-T depression both at rest and under maximal cycle-ergometry, in individual instances the S-T segment never being depressed by more than 0.1 mV. On the other hand, similar exercise in patients with latent coronary insufficiency produced marked, significantly and dose-dependent S-T segment depressions under increasing digitalisation within the therapeutic range, and in some of the patients there was also decreased exercise tolerance before anginal symptoms. It is concluded that the so-called digitalis effect is definitely of diagnostic significance in the recognition of latent coronary insufficiency, contrary to previously held belief.     

The haemodynamic effects and pharmacokinetics of intravenous nicorandil in healthy volunteers

Psychotherapy research with children is based mainly on adult methodologies. Common issues include bias in recruitment of subjects, demographics, developmental concerns, and control group considerations. The advantages and drawbacks of various types of control groups, such as wait-list controls, and placebo conditions are discussed along with ethical issues. Instrument choice, validity and reliability, and standardization of procedures in conducting research are addressed. Finally, the therapist as a variable is reviewed, including selection and assignment of therapists, and therapist bias.     

Zatebradine: pharmacokinetics of a novel heart-rate-lowering agent after intravenous infusion and oral administration to healthy subjects

Although high-frequency low-intensity transcutaneous electric nerve stimulation (TENS) has been extensively used to relieve low back pain, experimental studies of its effectiveness have yielded contradictory findings mainly due to methodological problems in pain evaluation and placebo control. In the present study, separate visual analog scales (VAS) were used to measure the sensory-discriminative and motivational-affective components of low back pain. Forty-two subjects were randomly assigned to 1 of 3 groups: TENS, placebo-TENS, and no treatment (control). In order to measure the short-term effect of TENS, VAS pain ratings were taken before and after each treatment session. Also, to measure long-term effects, patients rated their pain at home every 2 h throughout a 3-day period before and 1 week, 3 months and 6 months after the treatment sessions. In comparing the pain evaluations made immediately before and after each treatment session, TENS and placebo-TENS significantly reduced both the intensity and unpleasantness of chronic low back pain. TENS was significantly more efficient than placebo-TENS in reducing pain intensity but not pain unpleasantness. TENS also produced a significant additive effect over repetitive treatment sessions for pain intensity and relative pain unpleasantness. This additive effect was not found for placebo-TENS. When evaluated at home, pain intensity was significantly reduced more by TENS than placebo-TENS 1 week after the end of treatment, but not 3 months and 6 months later. At home evaluation of pain unpleasantness in the TENS group was never different from the placebo-TENS group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Angiotensin-converting enzyme activity in stools of healthy subjects and patients with celiac disease

Angiotensin-converting enzyme (ACE) is a dipeptidylcarboxypeptidase that occurs in three types of cells: endothelial, epithelial, and neuroepithelial. ACE activity is present in plasma, urine, and vascular endothelium. High levels of ACE are found in the brush border of human small bowel. The aim of this study was to evaluate ACE activity in human stools and to find a correlation with the intestinal loss of epithelial cells. Fifteen healthy subjects (HS) (8 males, 7 females; age range 6-56 years), 20 patients with celiac disease (CD) (11 males, 9 females; age range 15-53 years), and 18 patients with CD in remission after a gluten-free diet (CD-GFD) (8 males, 10 females; age range 14-54 years) were enrolled in the study. The fecal ACE activity was measured in all groups. Fecal samples were kept at -20 degrees C for a subsequent test. In HS, fecal ACE activity was 21.03 +/- 16.17 nmol/min/100 g (mean +/- SD). In patients with CD with subtotal mucosa atrophy, ACE activity was significantly higher (113 +/- 88.94) than in HS and CD on GFD (36.65 +/- 23.9). We have demonstrated ACE activity in human stools. ACE activity in stools seems to derive from the microvilli of the intestinal mucosa, thus suggesting the potential usefulness of ACE determination as an index of enterocyte damage.     

Pharmacokinetics of mefloquine, when given alone and in combination with artemether, in patients with uncomplicated falciparum malaria

The pharmacokinetics of mefloquine at a single oral dose of 750 mg, when given alone or 24 hours after a single oral dose of artemether (300 mg) was investigated in 27 Thai patients with acute uncomplicated falciparum malaria (17 with mefloquine alone, 10 with the combination). The oral bioavailabiiity of mefloquine was significantly decreased when administered 24 hours after an oral dose of artemether. This was evident by the significantly lower values of Cmax, AUC[0-24 h], AUC[0-48 h], AUC[0-72 h], as well as total AUC[Cmax: 1,290 (827-2,619) vs 1,820 (1,283-2,531) ng.ml-1; AUC[0-24 h]: 0.99 (0.64-1.41) vs 1.33 (1.07-1.95) micrograms.day.ml-1; AUC[0-48 h]: 1.78(1.23-2.58) vs 2.67 (2.09-3.84) micrograms.day.ml-1; AUC[0-72 h]: 2.74 (1.63-3.6) vs 4.54 (2.88-5.38) micrograms.day.ml-1; AUC: 11.11 (6-20.96) vs 15.29 (9.3-36.71) micrograms.day.ml-1]. Tmax was also delayed with the combination regimen [14 (5-24) vs 6 (4-16) h]. Terminal elimination half-lives were comparable [t1/2z: 11.1 (6.8-14.3) vs 13.4 (10.5-19.1) h].     

Carotid-vertebral artery blood transit time: results in healthy subjects and patients with schizophrenia and brain disease

Estimation of blood transit time in the neck and the extension of this into the head was made by a method of electrical impedance, over a wide age range, in 159 healthy subjects, 160 schizophrenic patients, and 199 patients with organic brain disease. In each case, the distance between the electrocardiogram and the next succeeding pulse-volume impedance wave was measured and averaged over 30 serial wave forms. Chronological age proved a significant variable, transit times lengthening progressively with the age, but only for measurements extending into the head. Sex and hemispheric laterality played no significant role. With age held constant, mean transit times into the head were significantly prolonged in both groups of patients as compared with controls. No significant differences were found however between means of psychiatric andneurological patients. It is suggested that these results reinforce the organic etiology of schizophrenia.     

Late feedback effects of hypothalamic-pituitary-adrenal axis hormones in healthy subjects

The main aims of the present study were to establish an in vitro/in vivo correlation for multiple-unit capsules of paracetamol by means of statistical prediction models and to investigate the effect of a number of in vitro variables on the discussion rate of paracetamol from the formulation. A fractional factorial screening design was used to investigate the effects of the variables agitation, pH, osmolality, viscosity, and the presence of bile salt on the dissolution rate of paracetamol. The effects were evaluated in two separate partial least-squares models, in which the responses were expressed as the cumulative percentage of paracetamol dissolved at specified time-points (model I) and as the shape (beta) and scale (eta) parameters according to the Weibull function (model II). It was concluded that agitation and viscosity had significant effects on the dissolution rate of paracetamol. Statistical models based on the responses from models I and II were then used to predict the in vitro conditions most closely correlated with the in vitro dissolution of paracetamol after administration of the formulation to 10 healthy volunteers. The predicted optimal in vitro conditions were similar for the two models and not too far from what is expected from the gastrointestinal tract. The experimental verification of the in vitro conditions showed that both models were equally good, and contributed to high degrees of correlation with the in vivo dissolution behavior of the formulation during 9 hr. The relationships obtained when plotting the percentage dissolved in vitro versus in vivo were y = 1.1x (r2 = 0.98) and y = 1.1x (r2 = 0.94) for models I and II, respectively. Based on these results, it is difficult to state a preference for one of the models. Finally, the use of statistical prediction models to develop critical in vitro tests is a successful approach in the establishment of associations between dissolution behavior in vitro and in vivo for oral extended-release systems.     

Regulation of hepatic glucose production in healthy subjects and patients with non-insulin-dependent diabetes mellitus

The regulation of endogenous glucose production is central to the control of blood glucose concentrations. In non-insulin-dependent diabetes mellitus (NIDDM), increased endogenous glucose production contributes to fasting hyperglycaemia. Gluconeogenesis appears to be exaggerated in NIDDM, and it may be hypothesized that an enhanced release of gluconeogenic precursors is responsible for increased total glucose output. However, it would appear that substrate-induced stimulation of gluconeogenesis fails to increase total glucose production in healthy humans and NIDDM patients. This autoregulation of endogenous glucose production may be attained by inhibition of glycogenolysis and/or gluconeogenesis from endogenous substrate. It has also been observed that stimulation of intrahepatic disposal of neoformed glucose (mainly as glycogen synthesis) contributes to autoregulation. These observations support the concept that intrahepatic disposal of glucose-6-phosphate plays a major role in the control of endogenous glucose production.