Early dietary influence on later immunocompetence.
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Animals↗
Biomedical subjects
S Lundin
Publications and source records attributed to S Lundin.
Impaired endothelium-mediated vasodilatation in the peripheral vasculature of patients with acute pulmonary allograft rejection.
BACKGROUND: Experimental studies have provided evidence that, during acute pulmonary allograft rejection, endothelial dysfunction occurs not only in the transplanted lung but also in arteries of organs native to the transplant recipient. We therefore tested the hypothesis that allograft rejection leads to the release of factors into the circulation that could affect the endothelial function in lung transplant recipients. METHODS: Acetylcholine (10, 30, and 60 micrograms/min) and sodium nitroprusside (1, 3, and 6 micrograms/min) were infused into the brachial artery in nine transplant recipients (five single lung, one double lung, three heart-lung) 2 to 37 weeks after transplantation, during both acute rejection and rejection-free episodes. Changes in forearm blood flow were assessed with venous occlusion plethysmography. Plasma levels of interleukin-2, -6, and -8, endothelin-1, L-arginine, and asymmetric dimethylarginine were measured and correlated to rejection episodes. RESULTS: The vasodilatory response to acetylcholine was significantly reduced during acute rejection compared with rejection-free episodes (percentage increase from basal flow: 156% +/- 21%, 395% +/- 65%, and 585% +/- 87% during rejection versus 272% +/- 75%, 633% +/- 113%, and 933% +/- 158% during absence of rejection, p < 0.05). No statistically significant difference was found between vasodilatory responses to nitroprusside during acute rejection and rejection-free episodes. Plasma levels of L-arginine, asymmetric dimethylarginine, interleukin-6, and endothelin-1 were not significantly altered during lung rejection. CONCLUSIONS: These data indicate that a reversible peripheral decrease in endothelium-dependent vasodilatation occurs during acute rejection in lung transplant recipients. This result may be due to interactions among circulating cytokines and leukocytes activated by the rejection process and the endothelium.
Acetylcholine↗
The maturation of the immune system.
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Animals↗
Different properties of the paracellular pathway account for the regional small intestinal permeability to the peptide desmopressin.
The regional small intestinal permeability to the vasopressin analogue desmopressin (dDAVP) was further characterized in proximal jejunal and distal (ileocecal) segments of the rat. Administration of the peptide to closed small intestinal loops confirmed the existence of regional absorption differences also in vivo in rats. Thus, the extent of absorption was about 4 times as high from the ileocecal part of the small intestine. The mucosal to serosal passage of dDAVP was studied in small intestinal segments from rats, mounted in Grass diffusion chambers. Increasing the mucosal concentration of dDAVP 100-fold had no effect on permeability coefficients (Papp) and the regional permeability distal:proximal ratio was maintained. Excessive amounts of unlabeled dDAVP to reduce the passage of [3H]dDAVP had no effect either. These findings make the existence of an active, receptor-mediated transport mechanism unlikely, and dDAVP probably does not affect its own transport rate. The higher ileocecal permeability could either be due to the presence of more permeable or dynamic pores in this region, where the epithelial surface area is smaller, or to an increased capacity for paracellular water flux. These results may have relevance for drug transport in the small intestine, where site-specific delivery of drug or enhancing agents may be optimized.
Animals↗
Human leukocyte interferon-alpha in cream for the management of genital herpes in Asian women: a placebo-controlled, double-blind study.
This double-blind, placebo-controlled study examined the clinical efficacy and tolerance of human leukocyte interferon-alpha (2 x 10(6) IU/g) in hydrophilic cream to cure patients afflicted with first episodes of genital herpes. Sixty patients aged 18-40 years (mean 24.5) with culture-confirmed herpes simplex genitalis, bearing 755 lesions (mean 12.6) were randomized to active and placebo groups. Patients joined the study within 7 days (mean 4.1) of the manifestation of lesions. Each patient was given a precoded 40-g tube containing placebo/active preparation with instructions on self-application of the trial medication to their lesions three times daily for 5 consecutive days (max. 15 topical applications per week). Patients were examined three times a week to evaluate clinical efficacy and other beneficial effects. A reepithelialized lesion with some residual erythema was recorded as healed. Patients resolved during the active treatment period (1-4 weeks) were spared further therapy and were requested to visit us as scheduled for posttreatment control after 16 weeks. From the remaining patients empty tubes were collected, and similarly coded replacement tubes were given to continue the treatment (in total 160 tubes were used). Patients treated with leukocyte interferon-alpha cream had significantly shorter mean duration of viral shedding/healing than placebo recipients, (6.2 days vs. 15 days; P < 0.01); thus the number of healed patients was 25/30 (83.3%) vs. 5/30 (17%; P < 0.001. Of the 60 patients 49 (81.6%) complained no drug-related side effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Topical↗
Metabolism of vasopressin, oxytocin, and their analogues in the human gastrointestinal tract.
The bioavailability from the gastrointestinal tract of peptides as large as nonapeptides is very low, which may be attributed to extensive lumenal and mucosal degradation. The aim of the present study was to investigate the stability of the neurohypophyseal hormones arginine-vasopressin (AVP), oxytocin (OT), and their synthetic analogues in human intestinal contents, small intestinal brush-border membranes, and gastric, rectal, and colonic plasma membranes. Peptides were incubated in gastrointestinal contents from healthy volunteers and in human intestinal mucosa homogenates. The extent of degradation was determined by reversed-phase high performance liquid chromatography (HPLC). AVP was rapidly degraded in the ileum fractions of the intestinal contents whereas 50% of the analogue 1-deamino-8-D-arginine vasopressin (dDAVP) remained intact after 35 min. The degradation was pH dependent, and a concentration-dependent inhibition was observed when aprotinin, a proteinase inhibitor, was preincubated with contents from the ileum. No degradation of AVP, dDAVP, or oxytocin analogues was observed in the mucosa homogenate from the stomach. The peptides were found to be rather slowly degraded by intestinal microvilli membranes and colonic and rectal plasma membranes. This degradation occurred essentially when reduced glutathione 10(-4) M was added to the incubations. In conclusion, the major enzymatic barrier to intestinal absorption of OT, VP, and their analogues is present in the intestinal juice and not in the mucosa, which, however, constitutes a major physical barrier to peptide transport.
Adult↗
Absorption of an oxytocin antagonist (antocin) and a vasopressin analogue (dDAVP) through a standardized skin erosion in volunteers.
PURPOSE: Transdermal administration of the peptides [Mpa1, D-Tyr (Ethyl)2, Thr4, Orn8]-oxytocin (antocin) and [Mpa1, D-Arg8]-vasopressin (dDAVP) was studied in healthy volunteers. METHODS: A standardized skin erosion was formed preliminary by suctioning. The peptides were administered in plastic reservoirs through a 5 mm erosion and the absorption was followed for a six-day period with plasma concentration determinations on days 1, 3 and 6 with refilling the reservoirs daily with 15 microns and 10 mM solutions of dDAVP and antocin, respectively. Fourteen healthy non-smoking volunteers divided equally between the sexes, participated in the study. Plasma concentrations were measured using specific radioimmunoassays. Reservoir concentrations and metabolic stability of the peptides were determined using reverse-phase HPLC. RESULTS: Both antocin and dDAVP were absorbed across the skin erosion. The absorption pattern was biphasic with a high initial absorption during days 1 and 2 followed by a lower absorption on days 3 and 6. The absorption on day 1, which was estimated at more than 50% for both peptides during a 24 h period, corresponded to a simultaneous decrease in peptide concentration in the reservoirs. The extent of absorption for antocin on days 3 and 6 was 1/3 to 1/6, respectively, of that observed on day 1. Antocin was minimally degraded in the skin reservoir while dDAVP was intact. However, accumulation of cellular material appeared in the antocin reservoirs. The absorption of antocin was reduced by exposure to intact skin surrounding the skin erosion. No pain was experienced and no scar formation was observed. CONCLUSIONS: The observed biphasic absorption may be a consequence of the mild inflammatory response occurring subsequent to eroding the skin. The standardized skin erosion may provide a route for the short-term delivery of otherwise poorly absorbable peptide and protein drugs.
Absorption↗
Enhanced intestinal absorption of oxytocin peptide analogues in the absence of pancreatic juice in pigs.
PURPOSE: The present investigation was done to study the intestinal absorption of three oxytocin peptide analogues and to elucidate the role of pancreatic juice on their absorption. METHODS: In conscious chronically catheterized pigs (6-8 weeks of age) plasma concentration of the peptides, [Mpa, D-Tyr(Ethyl), Thr, Orn]-oxytocin (F314), [Mpa, D-Tyr(Ethyl), Val, D-Arg]-oxytocin (CAT), and [Mpa, D-Tyr(Ethyl), Thr, Orn, desGly, carba]-oxytocin (F327) after intraduodenal administration, during presence or diversion of the pancreatic juice via a pancreatic duct catheter, were determined by radioimmunoassay. The stability of the peptides to degradation was determined in vitro by incubation with activated pancreatic juice, chymotrypsin or trypsin, followed by reversed phase HPLC analyses. RESULTS: All peptides were absorbed with a bioavailability of about 0.5% in the presence of pancreatic juice, but increased to 1.0%, 2.1%, and 13.5% for F314, CAT, and F327, respectively, when the pancreatic juice was diverted from the intestine. After incubation with pancreatic juice 95% of F314, 98% of F327, and 100% of CAT was found intact. When incubated with trypsin CAT remained intact while F314 and F327 were degraded by 54% and 46%, respectively. Incubation with purified chymotrypsin did not degrade the test peptides. CONCLUSIONS: The results indicate that the increased absorption of peptides observed under conditions of diverted pancreatic juice cannot only be explained by the absence of pancreatic enzymes, but also by changed absorptive properties in the gastrointestinal tract.
Animals↗
Conversion of inhaled nitric oxide to nitrate in man.
1. Nitric oxide (NO) is potentially useful as a selective vasodilator drug in infants and adults with pulmonary hypertension. In vitro and in vivo observations demonstrate that NO may be converted to nitrate in the blood, to be further excreted into the urine. The aim of the present study was to assess quantitatively the importance of this pathway for inhaled NO in human subjects. 2. Healthy subjects inhaled 15NO (25 p.p.m.) for 1 h. The plasma and urine levels of 15NO3- were followed for 2 and 48 h, respectively. 3. The measured retention of 15NO in the lungs was 224 +/- 13 mumol, corresponding to 90 +/- 2% of the inhaled amount. Plasma 15NO3- increased during the inhalation of 15NO, to about 15 mumol l-1, and fell when inhalation of 15NO was terminated. 4. Urinary excretion of 15NO3- during the first 24 h after inhalation was 154 +/- 12 mumol. During the following 24 h another 8 +/- 2 mumol of 15NO3- appeared in the urine. 5. We conclude that conversion of inhaled NO to nitrate is a major metabolic pathway in man, covering more than 70% of its inactivation. The metabolic fate of the remaining NO inhaled requires further study.
Administration, Inhalation↗
Regional small intestinal passage in the rat to some commonly used permeability probes.
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Animals↗
Small intestinal absorption of polyethylene glycol 400 to 1,000 in the portacaval shunted rat.
Functional changes of the intestinal barrier that may occur after the creation of a portacaval shunt (PCS) were investigated. After chronic PCS in the rat, the intestinal absorption of and the jejunal permeability to the inert polymer marker polyethylene glycol (PEG) with molecular weight (Mw) ranging from 400 to 1,000 g/mol were investigated. The PEG mixture was orally fed to PCS and sham-operated rats, and urine was collected for 24 hours to obtain the urinary recovery of the different PEG polymers as a measure of intestinal absorption. To study the intestinal permeability, segments from the proximal small intestine were incubated in diffusion chambers with the PEG mixture on the mucosal side, and samples were withdrawn from the serosal side for analysis. The urinary recovery for the PEGs increased (P < .01) while the tissue permeability decreased (P < .001) in the PCS group rats in comparison with Sham-operated rats. The increased absorption in vivo was caused neither by altered renal clearance, nor by changed portal blood pressure. The decreased jejunal permeability in the PCS rats could be explained by a reduction of the mucosal area by shortening of the microvilli. This discrepancy indicates that changes in permeability and absorption may not be parallel during PCS. It is possible that these changes also may be affected by nutritional factors, drug therapy, as well as toxic substances.
Animals↗
Immunological mechanisms of the gut.
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Animals↗
Nitric oxide synthesis and metabolism in man.
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Chromatography, Liquid↗
Human leukocyte interferon-alpha in cream, for the treatment of genital warts in Asian women: a placebo-controlled, double-blind study.
The purpose of this double-blind, placebo-controlled study was to determine and compare the clinical efficacy and tolerance of human leukocyte alpha-interferon (incorporated 2 x 10(6) IU/g) in hydrophilic cream to cure genital warts. Preselected Asian female patients (n = 150) aged 18-40 years (mean 22.5), with the clinical and biopsy-confirmed diagnosis of genital warts (mean 2.64), predominantly flat vaginal condylomas, were randomly allocated to 3 parallel groups. Each patient was given a coded tube containing 80 g placebo/active preparation with a graduated applicator. Patients were instructed to inject 6 g of the either alloted placebo/active cream deep into the vagina thrice a day for 3 consecutive days (group A) or 4 consecutive days (group B) per week, and if not cured the same treatment was extended to 3 more weeks (maximum 4 weeks active treatment). To assess the clinical efficacy patients were examined on a week-to-week basis. A total clearance of warts (biopsy-confirmed) was evaluated as a complete cure. Patients cured during the treatment were spared further treatment and were requested to visit us after 16 weeks for relapse control. As for the remaining patients, empty tubes were collected, and similarly coded replacement tubes were given for further treatment (in total 588 tubes were used). By the end of the treatment 57.2% lesions (227/397) were eliminated in all the groups: 48% patients in group A, 90% patients in group B, and 10% patients in placebo groups taken as completely cured.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Gastrointestinal absorption and plasma clearance rates of [D-Arg8]vasopressin analogues in the rat.
The gastrointestinal absorption of a series of vasopressin (VP) analogues with enhanced enzymatic stability was determined in chronically catheterized, conscious rats. The following peptides were used: [Mpa1,D-Arg8]vasopressin (dDAVP), [Mpa1,Asn4,D-Arg8]VP, [Mpa1,Val4,D-Arg8]VP, [Mpa1,(CH3)3Ala4,D-Arg8]VP, [Mpa1,Tyr(ethyl)2,D-Arg8]VP, and [Mpa1,D-Tyr(ethyl)2,Ile3,Val4,D-Arg8]VP. The peptides were administered by gavage feeding and blood samples were taken repeatedly for 3 h. In another series of experiments, plasma clearance rates (Clp) were determined using the constant infusion method. Plasma concentrations were measured by use of a cross-reacting dDAVP antiserum in a radioimmunoassay method. The bioavailability of all peptides was below 0.1%. The Clp values differed sevenfold; the lowest was for [Mpa1,D-Tyr(ethyl)2,Ile3,Val4,D-Arg8]VP and the highest was for [Mpa1,Asn4,D-Arg8]VP. With the exception of dDAVP the Clp values of the analogues showed an inverse relationship with hydrophilicity. Incubations in relatively concentrated intestinal contents for 1 h showed extensive degradation of the analogues except for [Mpa1,D-Tyr(ethyl)2,Ile3,Val4,D-Arg8]VP. It can be concluded that, in the rat, the bioavailability of dDAVP is lower than in other animal species and in man. Increased resistance to peptide degradation by gastrointestinal contents did not improve absorption. Therefore, the permeability properties of the intestinal mucosa are likely to be a more important factor affecting the gastrointestinal absorption of this group of peptides, although postabsorption events, like hepatic extraction, may also play a role.
Amino Acid Sequence↗
Effects of atrial natriuretic peptide on renal function after cardiac surgery and in cyclosporine-treated heart transplant recipients.
The study investigated the effects of intravenous infusion of atrial natriuretic peptide (human ANP 99-126) on renal function and central hemodynamics after coronary artery bypass grafting (CABG), and the ability of ANP to reverse the acute nephrotoxic effects of cyclosporine after heart transplantation. Ten patients with an EF > 0.5 and normal renal function were studied 2 to 4 hours after CABG surgery. Furthermore, six heart transplant recipients receiving cyclosporine for immunosuppression who developed renal dysfunction 2 to 4 days after transplantation were studied. Standard urinary clearance of 51Cr-EDTA and PAH was used to study the effects of ANP on glomerular filtration rate (GFR) and renal blood flow (RBF). Baseline measurements were first performed during two 30-minute periods. Incremental infusion rates of ANP were then administered for three consecutive 30-minute periods (25, 50, and 100 ng/kg/min), followed by two 30-minute post-ANP control periods. Marked increases in urinary flow (UF), GFR, filtration fraction (FF), and fractional urinary excretion of Na+ were observed in the CABG patients with increasing doses of ANP, while RBF was unchanged. Mean arterial pressure decreased by around 15% at the highest ANP dose. In the heart transplant recipients, baseline GFR was markedly reduced compared to pretransplantation values (-65%). UF, GFR, and RBF increased 240%, 69%, and 53%, respectively, while renal vascular resistance decreased 45% during the highest dose of ANP infused. At this ANP dose level, circulating ANP concentrations were sixfold to eightfold higher than the preinfusion control level.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Transdermal administration of morphine to healthy subjects.
1. Twelve healthy subjects received 10 mg morphine HCl delivered transdermally from an occlusive reservoir applied to a small area of skin, painlessly de-epithelialised by vacuum suction. On a separate occasion, 10 mg morphine HCl was given as an i.v. infusion over 20 min. 2. Venous blood samples were collected serially for 72 h and assayed for morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) by h.p.l.c. Pupil size, salivation, and central nervous effects (nausea, fatigue, headache, feeling of heaviness and dysphoria/euphoria) were also measured. 3. After transdermal application morphine was absorbed by a first-order process to produce relatively constant plasma drug concentrations over 11 h. The absolute bioavailability of transdermal morphine was 75% (65-85%; 95% CI). The plasma concentrations of both M6G and M3G were lower after transdermal administration than after i.v. infusion, and a considerable delay (of up to 1 h) was observed before the metabolites were detectable. AUC ratios for M3G and M6G relative to morphine were similar after both modes of administration. 4. Non-analgesic effects were less pronounced at the lower plasma drug and metabolite concentrations observed after transdermal delivery than after the i.v. infusion of morphine. 5. Transdermal administration of morphine warrants investigation as an alternative route of morphine delivery.
Administration, Cutaneous↗
Topical 0.3% and 0.5% podophyllotoxin cream for self-treatment of molluscum contagiosum in males. A placebo-controlled, double-blind study.
BACKGROUND: Molluscum contagiosum is generally a self-limiting benign skin disease that affects mostly children and young adults. OBJECTIVE: The purpose of this multicenter, double-blind, placebo-controlled study was to compare the clinical efficacy and tolerance of 0.3% and 0.5% podophyllotoxin in a hydrophilic cream base to cure molluscum contagiosum in Asian males. METHODS: Preselected patients (n = 150), age range 10-26 years (mean: 15.4), harboring 1,125 lesions (mean: 7.5), with size ranging from 2 to 8 mm in diameter (mean spot size 3.2 mm) and biopsy-proven diagnosis of molluscum contagiosum, were randomly allocated to three parallel groups. Twenty-four (16%) patients had atopic dermatitis. Patients self-administered placebo, 0.3% or 0.5% podophyllotoxin cream, twice daily for 3 consecutive days, and if total elimination was not achieved with one trial (6 topical applications), the same treatment was extended to 3 more weeks (24 topical applications in 4 weeks). The duration of the study was 12 weeks with 6 months (on monthly basis) follow-up. By the end of the treatment 80 patients (52, 92 and 16% patients in the 0.3%, 0.5% and the placebo groups, respectively) were evaluated as completely cured. During the treatment 92 patients (61.3%) did not complain of any allergic or localized adverse symptoms. Tolerable moderate to mild frequent side effects were pruritus (20.6%) and erythema (18%), with no dropouts. No recurrence was seen after 9 months of follow-up. Response to the trial medications appeared to be directly proportional to the concentration of podophyllotoxin (p < 0.001). Self-medication was well accepted by all the patients. It was concluded that the 0.5% podophyllotoxin cream preparation was more efficacious than the 0.3% incorporation (p < 0.001) and can be considered a safe, home-based first line of therapy to cure molluscum contagiosum.
Adolescent↗