Investigation of L-type Ca(2+) current in the aganglionic bowel segment in Hirschsprung's disease.

BACKGROUND: Studies on animal models of Hirschsprung's disease (HD) suggest that L-type Ca(2+) channels are down-regulated in the aganglionic bowel segment, however, this has yet to be confirmed in HD patients. The objective of this study was to test the hypothesis that L-type Ca(2+) current density is decreased in smooth muscle cells (SMC) obtained from the aganglionic bowel segment of patients with HD in comparison with those from the ganglionic segment. METHODS: Smooth muscle cells were freshly isolated from colon samples obtained from HD patients undergoing pull-through surgery. L-type Ca(2+) currents were recorded using the perforated patch configuration of the whole cell voltage clamp technique and the expression levels of CACNA1C transcripts (which encode L-type Ca(2+) channels) in the ganglionic and aganglionic bowel segments were compared using real-time quantitative PCR. KEY RESULTS: All SMC displayed robust currents that had activation/inactivation kinetics typical of L-type Ca(2+) current, were inhibited by nifedipine and enhanced by the L-type Ca(2+) channel agonists FPL 64176 and Bay K 8644. Moreover, FPL 64176 activated currents were also inhibited by nifedipine. However, there was no significant difference in L-type Ca(2+) current density, CACNA1C subunit expression or sensitivity to the pharmacological agents noted above, between SMC isolated from the ganglionic and aganglionic regions of the HD colon. CONCLUSIONS & INFERENCES: In contrast to studies on genetic animal models of HD, L-type Ca(2+) currents are not down-regulated in the aganglionic bowel segment of HD patients and are therefore unlikely to account for the impaired colonic peristalsis observed in these patients.

Survey of the fatty acid composition of retail milk differing in label claims based on production management practices.

Consumers are becoming increasingly health conscious, and food product choices have expanded. Choices in the dairy case include fluid milk labeled according to production management practices. Such labeling practices may be misunderstood and perceived by consumers to reflect differences in the quality or nutritional content of milk. Our objective was to investigate nutritional differences in specialty labeled milk, specifically to compare the fatty acid (FA) composition of conventional milk with milk labeled as recombinant bST (rbST)-free or organic. The retail milk samples (n=292) obtained from the 48 contiguous states of the United States represented the consumer supply of pasteurized, homogenized milk of 3 milk types: conventionally produced milk with no specialty labeling, milk labeled rbST-free, and milk labeled organic. We found no statistical differences in the FA composition of conventional and rbST-free milk; however, these 2 groups were statistically different from organic milk for several FA. When measuring FA as a percentage of total FA, organic milk was higher in saturated FA (65.9 vs. 62.8%) and lower in monounsaturated FA (26.8 vs. 29.7%) and polyunsaturated FA (4.3 vs. 4.8%) compared with the average of conventional and rbST-free retail milk samples. Likewise, among bioactive FA compared as a percentage of total FA, organic milk was slightly lower in trans 18:1 FA (2.8 vs. 3.1%) and higher in n-3 FA (0.82 vs. 0.50%) and conjugated linoleic acid (0.70 vs. 0.57%). From a public health perspective, the direction for some of these differences would be considered desirable and for others would be considered undesirable; however, without exception, the magnitudes of the differences in milk FA composition among milk label types were minor and of no physiological importance when considering public health or dietary recommendations. Overall, when data from our analysis of FA composition of conventional milk and milk labeled rbST-free or organic were combined with previous analytical comparisons of the quality and composition of these retail milk samples, results established that there were no meaningful differences that would affect public health and that all milks were similar in nutritional quality and wholesomeness.

Hot topic: Enhancing omega-3 fatty acids in milk fat of dairy cows by using stearidonic acid-enriched soybean oil from genetically modified soybeans.

Very long chain n-3 fatty acids such as eicosapentaenoic acid (EPA; 20:5n-3) are important in human cardiac health and the prevention of chronic diseases, but food sources are limited. Stearidonic acid (SDA; 18:4n-3) is an n-3 fatty acid that humans are able to convert to EPA. In utilizing SDA-enhanced soybean oil (SBO) derived from genetically modified soybeans, our objectives were to examine the potential to increase the n-3 fatty acid content of milk fat and to determine the efficiency of SDA uptake from the digestive tract and transfer to milk fat. Three multiparous, rumen-fistulated Holstein cows were assigned randomly in a 3 x 3 Latin square design to the following treatments: 1) control (no oil infusion); 2) abomasal infusion of SDA-enhanced SBO (SDA-abo); and 3) ruminal infusion of SDA-enhanced SBO (SDA-rum). The SDA-enhanced SBO contained 27.1% SDA, 10.4% alpha-linolenic acid, and 7.2% gamma-linolenic acid. Oil infusions provided 57 g/d of SDA with equal amounts of oil infused into either the rumen or abomasum at 6-h intervals over a 7-d infusion period. Cow numbers were limited and no treatment differences were detected for DMI or milk production (22.9+/-0.5 kg/d and 32.3+/-0.9 kg/d, respectively; least squares means +/- SE), milk protein percentage and yield (3.24+/-0.04% and 1.03+/-0.02 kg/d), or lactose percentage and yield (4.88+/-0.05% and 1.55+/-0.05 kg/d). Treatment also had no effect on milk fat yield (1.36+/-0.03 kg/d), but milk fat percentage was lower for the SDA-rum treatment (4.04+/-0.04% vs. 4.30+/-0.04% for control and 4.41+/-0.05% for SDA-abo). The SDA-abo treatment increased n-3 fatty acids to 3.9% of total milk fatty acids, a value more than 5-fold greater than that for the control. Expressed as a percentage of total milk fatty acids, values (least squares means +/- SE) for the SDA-abo treatment were 1.55+/-0.03% for alpha-linolenic acid (18:3n-3), 1.86+/-0.02 for SDA, 0.23 +/- <0.01 for eicosatetraenoic acid (20:4n-3), and 0.18+/-0.01 for EPA. Transfer efficiency of SDA to milk fat represented 39.3% (range=36.8 to 41.9%) of the abomasally infused SDA and 47.3% (range=45.0 to 49.6%) when the n-3 fatty acids downstream from SDA were included. In contrast, transfer of ruminally infused SDA to milk fat averaged only 1.7% (range=1.3 to 2.1%), indicating extensive rumen biohydrogenation. Overall, results demonstrate the potential to use SDA-enhanced SBO from genetically modified soybeans combined with proper ruminal protection to achieve impressive increases in the milk fat content of SDA and other n-3 fatty acids that are beneficial for human health.

Differences in nitrergic innervation of the developing chick cloaca and colorectum.

The intrinsic innervation of the developing gut has long been a subject of investigation, but little is known regarding that of the embryonic cloaca. The cloaca, like the rest of the gastrointestinal tract, is intrinsically innervated by the enteric nervous system. Nitrergic neurons and fibres make up a large part of this system, thus, their distribution provides us with a useful insight into its development. Cloacal and colorectal tissue specimens were removed from chick embryos at embryonic days 11 (E11), E15 and E19. NADPH-diaphorase (NADPH-d) histochemistry was carried out using whole mount tissue preparations. Ganglia density, the number of NADPH-d-positive cells per ganglia in the myenteric plexus and cell size were calculated and statistical analysis was performed to compare both regions of the gut (P<0.001). There were significant differences in the ganglia density in the cloaca compared to the colorectum at E11 (P<0.05) and E15 (P<0.01), with the colorectum having a much denser network. In both the cloaca and the colorectum, ganglia density significantly decreased with age (P<0.001), while significant differences were observed in the number of NADPH-d-positive cells per ganglia in both regions through development. Total cell size was similar in both the cloaca and colorectum at each stage and increased in both regions through development, predominantly due to an increase in the cytoplasm. Results reveal striking differences in innervation between the chick embryo cloaca and colorectum. The sparse network of innervation evident within the cloaca in contrast to the dense network within the colorectum emphasizes the individuality of both regions. These results highlight the need for a further in-depth analysis of the enteric nervous system's development within the embryonic cloaca.

Adriamycin induces notochord hypertrophy with conservation of sonic hedgehog expression in abnormal ectopic notochord in the adriamycin rat model.

BACKGROUND/PURPOSE: The Adriamycin rat model (ARM) is a well-established model of the Vertebral, Anorectal, Cardiac, Tracheoesophageal, Renal, Limb (VACTERL) association. The notochord, which expresses Sonic Hedgehog (Shh), has been found to be grossly malformed with ventral ectopic branches in the foregut region of embryos in the ARM. The authors designed this study to test the hypothesis that Shh-expressing ectopic notochord could contribute to an increased volume of notochord relative to total embryo volume, resulting in an increased concentration of Shh in the notochord of affected embryos. METHODS: Adriamycin was administered intraperitoneally to rats on days 7 (E7), E8, and E9 of gestation and saline to control animals. Embryos recovered at E12 and E14 were examined immunohistochemically for Shh expression. Quantitative morphology using the Cavalieri technique was performed to determine embryo and notochord volume. RESULTS: Embryos in both Adriamycin and control groups at E12 and E14 showed comparable levels of Shh expression in notochord at all locations. The percentage of notochord per embryo was significantly increased in Adriamycin embryos at E12 and E14 compared with equivalent controls. CONCLUSIONS: These data suggest that Adriamycin induces notochord hypertrophy. With all regions of the notochord secreting Shh, this could result in a higher concentration gradient of Shh in close abnormal proximity to the foregut, possibly contributing to the malformations found in the VACTERL association.

Increased fibronectin expression in developing embryos is associated with abnormal notochord in the Adriamycin rat model.

BACKGROUND: The VACTERL association is a spectrum of clinical conditions, including esophageal atresia (EA) and tracheoesophageal fistula (TEF), which affects approximately 1 in 5,000 live human births. The administration of intraperitoneal Adriamycin to pregnant rats reliably induces anomalies, such as EA and TEF, in their offspring, in what is known as the Adriamycin rat model (ARM). In affected embryos the presence of gross notochord abnormalities is commonly found, with typical features being ectopic ventral branches and adherence of the notochord to the foregut. Fibronectin (FN) is an extracellular matrix (ECM) glycoprotein present on most cell surfaces, in extracellular fluids and in plasma. FN is involved in various functions, including cell adhesion, cell motility and wound healing. Previous studies in rats have shown that a single dose of Adriamycin can produce an appreciable rise in FN levels in various organs such as kidney and heart. We hypothesised that Adriamycin administration could promote upregulation of FN expression contributing to increased gut-notochord adherence and the development of abnormal ventral notochordal branching in the ARM. This study was designed to investigate FN expression in ARM embryos. METHODS: Adriamycin (1.75 mg/kg) was administered intraperitoneally to pregnant rats on days 7,8 and 9 of gestation (E7, E8 and E9 respectively). Control animals were given saline. Embryos recovered on E10-E14 were fixed, embedded in paraffin and sectioned. Immunohistochemistry using an anti-FN rabbit polyclonal antibody was performed. RESULTS: FN expression in both Adriamycin and control embryos on E10, E11 and E12 was comparable. However, the levels of FN expression in Adriamycin embryos on E13 and E14 were significantly greater in embryos with abnormal notochords than in equivalent control embryos. CONCLUSION: Adriamycin-induced increased expression of FN, in the ARM, may contribute to abnormal notochord development leading to the VACTERL association.

The timing of enteric neural crest cell colonisation of the chick embryo cloaca.

Neural crest cell (NCC) migration and formation of the enteric nervous system (ENS) is an essential process in the development of the normal human gut. Abnormalities of the ENS lead to a number of neurochristopathies. In avian embryos, the cloaca acts as a common chamber into which gastrointestinal, urinary and genital tracts emerge. Previous studies have elucidated the specific timeframes at which NCCs reach the various regions of the developing chick gut but, to date, none have looked at NCC colonisation of the cloaca. The aim of our study was to investigate the exact timing of the appearance of NCCs in the cloaca of chick embryos. Chicken embryos were harvested on embryonic days (E) 8-12. Whole embryos were fixed, embedded in paraffin and sectioned. Fluorescent immunohistochemistry, using an anti-HNK-1/N-CAM monoclonal antibody, was performed and images were obtained by confocal microscopy. There was no evidence of NCCs in the cloaca of embryos from E8 to E11. Intense immunoreactivity to HNK-1 first appeared in the cloaca of E12 embryos, demonstrating a profuse circumferential colonisation by NCCs at this time. Our study is the first to show the exact timing of enteric NCC colonisation of the chick embryo cloaca. Further studies, involving quail-chick chimeras, are required to establish the true origin of cloacal NCCs and to establish the relationship between NCCs and persistent cloaca.

Distribution and chemical coding of orphanin FQ/nociceptin-immunoreactive neurons in the myenteric plexus of guinea pig intestines and sphincter of Oddi.

Longitudinal muscle-myenteric plexus preparations of guinea pig intestines and sphincter of Oddi (SO) were immunostained for orphanin FQ/nociceptin. Orphanin FQ-immunoreactive (OFQ-IR) neurons and nerve fibers were relatively abundant in the SO, duodenum, ileum, cecum, and distal colon, with fewer neurons and nerve fibers observed in the proximal colon. Double staining with antibodies directed against the neuron-specific RNA binding protein Hu revealed that while the numbers of OFQ-IR neurons per ganglion decreased along the gut tube, similar proportions (7-9%) of neurons in these regions were OFQ-IR, whereas <1% of the neurons in the proximal colon were OFQ positive. In the ileum, where 8% of the myenteric neurons were OFQ-IR, all OFQ-IR neurons expressed choline acetyltransferase. In addition, multiple-label immunohistochemistry demonstrated that 58% of the OFQ-IR neurons were calretinin-IR, 52% were substance P-IR, and 28% were enkephalin-IR. Nitric oxide synthase immunoreactivity was observed in about 5% of OFQ-IR neurons, or 0.4% of the total population, and a similar proportion of the OFQ-IR neurons was positive for vasoactive intestinal peptide. No OFQ-IR neurons were immunoreactive for calbindin, somatostatin, or serotonin. These results, combined with previous studies of chemical coding and projection patterns in the guinea pig myenteric plexus, indicate that OFQ-IR is expressed preferentially in excitatory motor neurons projecting to the longitudinal and circular muscle layers, as well as a small subgroup of descending interneurons. Because OFQ is expressed by excitatory motor neurons, and because this peptide inhibits excitatory neurotransmission in the guinea pig ileum, it is likely that OFQ acts through a feedback autoinhibitory mechanism.

Unstructured cases in case-based learning benefit students with primary care career preferences.

BACKGROUND: The impact of instructional method on students with opposing surgical career orientations was investigated in a prospective study. METHODS: Students were randomly assigned to structured or unstructured case-based discussions. Clinical reasoning (OSCE and a diagnosis exercise), subject knowledge (multiple choice test [MCT]), method preference, and pre-third year career preference were compared. RESULTS: Twenty-two students listed a surgical career high (Surgical) and 20 low (Primary). Surgical MCT scores were higher than Primary regardless of instructional method. Surgical diagnosis exercise scores were higher than Primary with the structured method (22.0+/-2.3 versus 15.1+/-3.0, P <0.08). Unstructured scores on this exercise were similar (19.7+/-1.8 Surgical versus 20.3+/-3.5 Primary). Analysis of variance suggested an interaction on the diagnosis exercise between method and career (P = 0.16). Students preferred the unstructured method. CONCLUSIONS: The improved diagnosis exercise performance implies that unstructured cases positively influence surgical domain specific reasoning for nonsurgical career students. These method effects increase our understanding of case-based methods in surgical education.

Preventing iron deficiency in infants and preschool children in Argentina.

This paper summarizes the results of most major studies of iron deficiency and anemia in infants and children in Argentina. Possible reasons for high prevalences of iron deficiency and anemia in certain population groups are given, and plans for future interventions, based on these data, are discussed.

Role of case structure and prior experience in a case-based surgical clerkship.

BACKGROUND: As case-based methods replaced lectures in a surgical clerkship, the influences of case structure and prior experience on learning were investigated. METHODS: Early and late third-year students randomly received different cases. "Structured" cases had data presented and summarized. "Unstructured" cases required questions to faculty for information. Multiple choice tests and differential diagnosis activities were administered. An attitudinal questionnaire gauged student perceptions. RESULTS: In both multiple choice and differential diagnosis activities, the late rotation, "unstructured" group scored higher than the "structured" group. Conversely, the early rotation, "unstructured" group scored lower than the "structured" group. Combined, rotation, and structure significantly affected both multiple choice and differential diagnosis activities (ANOVA, P < or = 0.02). Early rotation, "unstructured" students described a more enjoyable experience, despite lower evaluation scores. CONCLUSIONS: Surgical clerkship case-based learning is profoundly affected by case structure and prior clinical experience. Case-based curriculum should be tailored to accommodate these interactions.

Estudio de ciertos factores de riesgo de la salud y de la situación nutricional de adolescentes urbanos / Health risk factors and nutritional status of urban adolescents

Se estudiaron 386 adolescentes (58 por ciento hombres y 42 por ciento mujeres) de la población que concurrió espontáneamente al Servicio de Adolescencia del Hospital Argerich. Se realizaron encuestas de hábitos de vida, alimentaria, socioeconómica y estudios bioquímicos. El 69 por ciento de los adolescentes no utilizaba ningún método anticonceptivo. La mitad de la población consumía alcohol regularmente especialmente en los NSE más bajos; 8.1 por ciento fumaba regularmente y se demostró desconocimiento de los riesgos vinculados con el tabaquismo. 7.6 por ciento presentó colesterolemias elevadas (especialmente en el NSE alto) 6 por ciento LDL elevado y 10 por ciento HDL bajo. El 18 por ciento de los varones y 52 por ciento de las mujeres no practicaba ninguna forma de actividad física sistemática (p<0.01) y los adolescentes del NSE bajo destinaron significativamente menos energía a la actividad física (541 Kcal/día ñ 660 Kcal/día)comparados con sus pares del NSE medio (855 Kcal/día ñ 1088 Kcal/día) y alto (948 Kcal/día ñ 1044 Kcal/día) (p<0.05). El 30 por ciento pasaba más de 4 horas mirando TV, 6 por ciento presentó retraso crónico de crecimiento, 19.1 por ciento de las mujeres y 13.3 por ciento de los varones eran obesos. La ingesta energética media fue 2697 ñ 1099 Kcal/día, (grasas 32 por ciento ñ 10 por ciento, grasas saturadas 13 por ciento ñ 5 por ciento)...

Evidence of alkaline phosphatase interference in a zidovudine radioimmunoassay.

Phosphorylated zidovudine (ZDV) concentrations may provide a link between drug exposure and clinical efficacy since these would include the active, intracellular form of the drug, ZDV triphosphate. Many groups are investigating the optimal methodology that can be used to accomplish this goal. The initial purpose of the present studies was to examine the effect of the inclusion of cell wash steps on the quantitation of intracellular ZDV. Ten milliliters of whole blood collected from healthy volunteers was spiked with increasing ZDV concentrations (0.187, 0.375, 1.87, and 3.75 microM), allowed to equilibrate at room temperature for 1 h, and separated into whole-blood components by a density gradient procedure. A mononuclear cell pellet was obtained, reconstituted with 2 ml of phosphate-buffered saline (PBS), and split into two aliquots, one of which was not washed at all and the other of which was washed four times with 1 ml of PBS. All samples were analyzed by ZDV radioimmunoassay (RIA) after a 1:1 dilution with either 1 mg of alkaline phosphatase (type 1-S; Sigma) per ml or PBS. Parent ZDV was measured in those samples which were not treated with the enzyme, while total ZDV was measured in those samples which were exposed to alkaline phosphatase (21 degrees C for 1 h). The result of the difference between the two samples is total phosphorylated ZDV. During the experiment, evidence of alkaline phosphatase interference with the RIA became apparent, confusing interpretation of intracellular ZDV concentrations. This evidence was based on three sets of data. First, wash samples showed increases in ZDV concentrations of as great as 0.127 microgramM after exposure to alkaline phosphatase, even though on microscopic inspection the wash samples were acellular. Second, the sum of total ZDV recovered from the four wash samples plus the washed cell pellet was as much as 14-fold greater than the total ZDV measured in the unwashed cell pellet. Theoretically, at least, these two entities should be equal. Finally, control samples of alkaline phosphatase in PBS (0.5 mg/ml) run directly through the assay measured false ZDV levels ranging from 0.002 to 0.075 microgramM (0.6 to 20 ng/ml). Alkaline phosphatase is frequently used to measure phosphorylated anabolites of ZDV in peripheral blood mononuclear cells. These data show that the particular form of alkaline phosphatase used may interfere with the ZDV RIA and may confuse the interpretation of phosphorylated anabolite concentrations of ZDV.

In vitro protein-binding characteristics of atevirdine and its N-dealkylated metabolite.

The in vitro protein-binding characteristics of atevirdine (ATV), a non-nucleoside reverse transcriptase inhibitor with activity against HIV-1, and its N-dealkylated metabolite (N-ATV) were studied using equilibrium dialysis. ATV and N-ATV were studied at concentrations of 5, 10, 20, and 30 microM in five protein-containing solutions [albumin 4%, plasma, serum, immune globulin (IgG) 1.5%, alpha 1-acid glycoprotein (AAG)] for 5 h at 37 degrees C. All samples were analyzed by high-performance liquid chromatography. The free fraction of atevirdine in plasma, albumin, and serum was 0.01-0.02 over the range of drug concentrations studied. The fraction unbound (fu) in these protein solutions statistically differed from IgG and AAG (P < 0.05), where the fraction unbound averaged 0.96 and 0.53, respectively. N-ATV had a similar binding profile as ATV with a fraction unbound of 0.04, 0.03, 0.03 in albumin, plasma and serum, respectively. A difference existed in N-ATV binding when compared to IgG and AAG with an average fu of 0.87 and 0.59 (P < 0.05 vs. plasma). The potential clinical implications of the high degree of protein binding for ATV and N-ATV are discussed.

Puncture wounds of the foot: can infective complications be avoided?

The bacteriological flora of the foot and shoe was studied concurrently in 200 volunteers without foot injuries, and 80 patients with puncture wounds of the foot. Seven of 28 child patients developed clinical infections, three with Pseudomonas aeruginosa. Eleven of 52 adult patients also developed infections. No patients developed infection if oral antibiotics were given within the first 24 h after injury (P < 0.05). Oral antibiotic prophylaxis is recommended for puncture wounds of the foot.

Zalcitabine.

OBJECTIVE: To review the chemistry, intracellular metabolism, pharmacokinetics, and clinical trials of zalcitabine (2'3'-dideoxycytidine, ddC). DATA SOURCES: English-language articles and conference procedings. The indexing terms used were zalcitabine, 2'3'-dideoxycytidine, and ddC. STUDY SELECTION: In addition to the manufacturer's package insert, available Phase I and Phase I/II studies were reviewed. DATA EXTRACTION: Clinical experience with ddC has been limited to uncontrolled studies and an expanded-access program. Efficacy was evaluated solely on surrogate markers of HIV disease: CD4+ lymphocyte counts and p24 antigen determinations. Clinical endpoints, such as disease progression and survival rates, must be provided to the Food and Drug Administration (FDA) for continued approval. DATA SYNTHESIS: The FDA has approved use of ddC in combination with zidovudine (ZDV) as therapy of HIV infection for patients with CD4+ lymphocyte counts < or = 300 cells/mm3 who have experienced significant clinical or immunologic deterioration. Although ddC has the same mechanism of action as other nucleoside analogs, it is more potent on a molar basis. The drug is stable in gastric pH and has good bioavailability (approximately 70-90 percent), but is rapidly cleared from plasma (half life approximately 1-3 h). Intracellular concentrations of ddC triphosphate, the active form, are probably related to plasma concentrations, yet may persist in cells longer than the parent drug persists in plasma. When used as primary therapy in patients with CD4+ < or = 300 cells/mm3, ddC/ZDV increased CD4+ lymphocyte counts and reduced plasma p24 antigen concentrations. In comparison to ZDV monotherapy data taken from other studies, ddC/ZDV appeared to demonstrate a more pronounced and sustained increase in CD4+ cell counts; however, this observation cannot be confirmed until the results of ZDV-controlled comparisons are available. Overall, 17-31 percent of the patients receiving the currently recommended initial dosage of ddC experience peripheral neuropathy. CONCLUSIONS: In combination with ZDV, ddC appears to augment the CD4+ cell response of ZDV monotherapy in the treatment of HIV infection for ZDV-naive patients, although controlled studies and rigorous statistical analyses are lacking at present. The efficacy of ddC/ZDV in patients who received prior treatment with ZDV monotherapy is unclear at the present.

Comparative pharmacokinetics of antiviral nucleoside analogues.

The recent development of nucleoside analogues with antiviral activity has expanded the small but useful armamentarium for the treatment of certain viral diseases such as the human immunodeficiency virus, cytomegalovirus and others. Their intracellular site of action and need for sequential phosphorylation require that traditional pharmacokinetic parameters be used in conjunction with an understanding of intracellular metabolism when designing dosage regimens. This review summarises the available pharmacokinetic literature for zidovudine, didanosine, zalcitabine, aciclovir, ganciclovir, vidarabine and ribavirin. After oral administration, didanosine, aciclovir and ribavirin are < 50% bioavailable and ganciclovir is < 6% absorbed. In contrast, zidovudine and zalcitabine are > 60% bioavailable, although zidovudine undergoes considerable and variable first-pass hepatic glucuronidation while zalcitabine has no first-pass effect. Zidovudine, zalcitabine and didanosine are absorbed rapidly in the fasted state, with peak plasma concentrations exceeding their respective in vitro antiretroviral inhibitory concentrations. All reviewed agents except ribavirin have a relatively short plasma half-life (approximately 0.5 to 4h), with each agent demonstrating a different intracellular enzymatic activation scheme. For example, the rate-limiting step for formation of zidovudine triphosphate is the conversion of the monophosphate to the diphosphate, while didanosine is ultimately converted to dideoxyadenosine triphosphate which has the longest intracellular half-life (approximately 12 to 24h) among these agents. These drugs are not highly protein bound and they distribute into tissues with an apparent volume of distribution at steady-state ranging from 0.3 to 1.2 L/kg. They vary in the extent to which they enter cerebrospinal fluid, ranging from a low of < 25% for didanosine to a high of > 70% of a concurrent plasma concentration for ribavirin and vidarabine. These agents also vary with regard to degree of renal excretion of the parent drug, with the lowest noted for vidarabine (1 to 3%) and the highest for zalcitabine (approximately 75%) and ganciclovir (> 90%). With the increasing number of clinically useful nucleoside analogues, it is essential for the clinician to appreciate the subtle differences among these agents to ensure that optimal therapeutic outcomes may be attained with minimal toxicity.

Didanosine.

OBJECTIVE: To review the chemistry, intracellular metabolism, pharmacokinetics, and clinical experience with didanosine (2',3'-dideoxyinosine [ddI]). DATA SOURCES: English-language articles and conference proceedings (indexing terms were didanosine, 2',3'-dideoxyinosine, and ddI). STUDY SELECTION: Available Phase I studies and abstracts determined to have clinical significance were included. DATA EXTRACTION: Clinical experience with ddI is limited to uncontrolled Phase I studies and a large "expanded-access" program. The primary outcome parameters used to evaluate ddI were the HIV surrogate markers: CD4+ lymphocytes and p24 antigen. Thus, the clinical data reviewed here must be evaluated critically and be considered preliminary until the results of studies comparing ddI with zidovudine (ZDV) and combination studies are available. DATA SYNTHESIS: Didanosine has been approved for the treatment of HIV infection in patients who are unable to tolerate ZDV because of adverse effects (e.g., anemia and neutropenia) or who experience clinical or immunologic deterioration while receiving ZDV. Compared with ZDV, ddI has a long intracellular half-life and negligible bone-marrow toxicity. It also has in vitro activity against ZDV-resistant strains of HIV. Phase I studies indicate that ddI has a beneficial effect on the CD4+ cell counts and HIV p24 antigen concentrations. As a result of the acid-labile nature of ddI, oral formulations are buffered or must be mixed with antacid to neutralize gastric pH. Bioavailability then averages 20-40 percent, depending on the dose and formulation given. The plasma half-life, total body clearance, and volume of distribution of ddI are one to two hours, 0.7-1 L/kg/h, and 0.8-1 L/kg, respectively. Painful peripheral neuropathy and pancreatitis (dose-limiting toxicities of ddI) occurred in 34 and 9 percent of patients in Phase I studies, respectively. CONCLUSIONS: Didanosine has demonstrated preliminary efficacy in the treatment of late-stage HIV infection; however, its effect on patient survival, its efficacy relative to ZDV, and its utility in combination with other agents are still under evaluation.

Latin America: actions for the prevention and treatment of malnutrition.

The stagnation of the social and economic progress of Latin America in the 1980s is an aftermatch of its enormous external debt and of the drop in the international price of agricultural goods which are its main exports. Today in LA more people is malnourished and live under the line of poverty than in the 1970s. Programs for the prevention of malnutrition and for the rehabilitation of malnourished children have been enforced in most countries in order to mitigate the effects of the crisis. Such actions are briefly discussed.