PubMed Health⌕ Search

Biomedical subjects

L Hendricks

Publications and source records attributed to L Hendricks.

18 recordsLinked to original sources
PubMed1999

Peak cyclosporine levels (Cmax) correlate with freedom from liver graft rejection: results of a prospective, randomized comparison of neoral and sandimmune for liver transplantation (NOF-8).

BACKGROUND: Despite two decades of use, there are limited data on the best way to administer and monitor cyclosporine (CsA) for liver transplantation. The present study was undertaken (1) to determine whether treatment with a new formulation of CsA, Neoral, would improve the results of liver transplantation; and (2) to study the relationships between pharmacokinetic parameters and clinical outcomes after transplantation. METHODS: A double-blind, randomized, comparison of Sandimmune (SIM) with Neoral (NEO) was conducted at five Canadian centers in 188 consecutive adults undergoing primary orthotopic liver transplantation. Patients were induced with intravenous CsA then switched to NEO or SIM. Dose adjustments were made daily, or as needed, to reach a target trough CsA level of 350 ng/ml in both groups. Pharmacokinetic studies were performed on days 5, 10, 15, and 16 weeks after transplantation. RESULTS: The NEO group was slightly younger, with a median age of 50 years (range: 23-70) versus 55 years (range: 24-71) for SIM (P = 0.007); otherwise the two groups were well balanced. The NEO group stopped intravenous CsA earlier (5.8+/-2.6 days vs. 8.7+/-4.7 days, P<0.0001). This group required a lower median daily oral dose (7.5 mg/kg vs. 9.0 mg/kg, P<0.01) to maintain comparable trough CsA levels. Five SIM patients, but no NEO patients, discontinued the study due to the inability to reach target trough levels of CsA within the prescribed time (P<0.05). At 4 months, there were no differences between the two groups with respect to patient survival (93% NEO vs. 91% SIM), graft survival (90% NEO vs. 86% SIM), and rejection-free survival (54.1% NEO, 51.8% SIM). The incidence of serious adverse events was also similar and did not correlate with CsA pharmacokinetic profiles. The NEO group had a higher area under the drug concentration curve for the first 6 hr after the dosing interval (AUC0-6) and peak CsA levels (Cmax). There was a strong correlation between freedom from graft rejection during the first month after transplantation and (a) AUC0-6 and (b) Cmax at days 5 and 10 after transplantation, but only in the NEO group did this reach statistical significance. In contrast, there was a poor correlation between trough CsA and graft rejection. In patients on NEO, the concentration of CsA 2 hr after dosing (C2) closely reflected AUC0-6 (r2 = 0.93), whereas there was a poorer correlation in patients on SIM (r2 = 0.73) CONCLUSIONS: Cmax and/or AUC0-6 may provide better markers than trough levels for monitoring CsA-based immune suppression after orthotopic liver transplantation. Prospective studies are underway to determine whether dosing to C2, which provides a good estimation of Cmax, can be used to take full advantage of NEO's improved absorption profile.

Adult↗
PubMed1998

Safety and tolerability of cyclosporine and cyclosporine microemulsion during 18 months of follow-up in stable renal transplant recipients: a report of the Canadian Neoral Renal Study Group.

BACKGROUND: There has been concern that the increased drug exposure associated with treatment with cyclosporine microemulsion (CsA-ME) would lead to an increase in adverse events. METHODS: The long-term safety and tolerability of conventional cyclosporine (CsA) and CsA-ME were compared in a randomized, multicenter, pharmacoepidemiologic study involving 1097 stable renal transplant patients after 18 months of follow-up. RESULTS: No significant difference was seen in change in serum creatinine or calculated creatinine clearance between the two groups. Episodes of deterioration in renal function (change in serum creatinine > or = 20%) were categorized with the following results for CsA-ME versus CsA, respectively: acute rejection, 4.5% vs. 4.5%; chronic rejection, 8% vs. 11%; CsA nephrotoxicity, 12% vs. 7% (P=0.008); transient changes, 17% vs. 12%; other causes, 4% vs. 6%. During the first 6 months of the study, a transient increase in the incidence of gastrointestinal and neurological adverse events was seen in the CsA-ME group compared with the CsA group. Up to 18 months, patients in the CsA group reported significantly fewer hearing and vestibular disorders, but more cardiovascular problems than those in the CsA-ME group (P=0.035). CONCLUSIONS: Tolerance to CsA and CsA-ME was similar. Renal function over 18 months was not adversely affected by the increased drug exposure with CsA-ME, although there was a transient increase in nephrotoxicity. The frequency of acute and chronic rejection did not change.

Administration, Oral↗
PubMed1998

[A comparative randomized prospective multicenter study of Sandimmune vs Neoral in liver transplantation].

Despite two decades of use, there are limited data on the best way to administer and monitor cyclosporine for orthotopic liver transplantation (OLT). The present study was undertaken: 1) to establish the safety of a new formulation of cyclosporine, Neoral, 2) to determine if treatment with Neoral will improve the results of liver transplantation and 3) to study the relationship between pharmacokinetic parameters and clinical outcomes after OLT. A double-blind, randomized, comparison of Sandimmune and Neoral was conducted at 5 Canadian centers in 188 consecutive adults undergoing OLT. Patients were induced with intravenous cyclosporine (CsA) then switched to Neoral or Sandimmune. Dose adjustments were made daily, or as needed, to reach a target trough CsA level (C0) of 350 ng/mL in both groups. Pharmacokinetic studies were performed on days 5, 10, 15 and 30 after transplantation. The Neoral group stopped intravenous CsA earlier (p < 0.0001), and these patients required a lower median daily oral dose (p < 0.01) to maintain comparable trough CsA levels. Five Sandimmune patients, but no Neoral patients discontinued the study because of the inability to reach target trough levels of CsA within the prescribed time (p < 0.05). At 4 months, there were no differences between the two groups with respect to patient survival, graft survival or rejection-free survival. The incidence of serious adverse events was also similar and did not correlate with CsA profiles. The Neoral group had a higher area under the drug concentration curve (AUC) and peak CsA levels (Cmax). There was a correlation between freedom from graft rejection and both AUC and Cmax at days 5 and 10 post-transplant. In contrast, there was a poor correlation between C0 and graft rejection. In summary, Neoral appears to be safe and well tolerated by patients. Cmax and/or AUC maybe better markers for monitoring cyclosporine based immunosuppression after liver transplantation.

Administration, Oral↗
PubMed1996

Degradation of aggrecan precursors within a specialized subcompartment of the chicken chondrocyte endoplasmic reticulum.

Chicken chondrocytes in culture synthesize aggrecan proteoglycan as a 370 kDa precursor that is glycosylated and secreted into the medium with a half-life of 30 min. In metabolic studies the 370 kDa precursor was shown to render a degradation intermediate of 190 kDa, which appeared with no measurable lag phase; it was dependent on temperature ( > 20 degrees C) and inhibited by certain serine and serine/cysteine protease inhibitors such as leupeptin and PMSF. By contrast, degradation was unaffected by treatment of the cells with brefeldin A or with lysosomotropic agents. Aggrecan precursors were detected by immunofluorescence analysis within a subcompartment of the endoplasmic reticulum (ER), previously characterized as a smooth-membrane-bound subregion [Vertel, Velasco, LaFrance, Walters and Kaczman-Daniel (1989) J. Cell Biol. 109, 1827-1836]. Analysis of the subcellular fractions derived from chondrocytes indicated that the degradation intermediate was concentrated in the ER subcompartment. Degradation was dependent on the Ca2+ concentration and the redox state in the ER. Treatment of the cells with agents or conditions that alter the degradation rate of aggrecan precursors, such as protease inhibitors, decreased temperature or dithiothreitol, also modified the retention of these molecules in the ER subcompartment, as seen by immunofluorescence. These results indicate that a fraction of the 370 kDa aggrecan precursor is targeted to a smooth ER subcompartment where it undergoes degradation.

Aggrecans↗
PubMed1995

Pharmacokinetics of the combination of fluvastatin and gemfibrozil.

High-risk patients with dyslipidemias resistant to diet and single-agent pharmacotherapy may require combination therapy to achieve target levels of low density lipoprotein, triglycerides, and high density lipoprotein. Combinations of fibrates and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are effective, but because of safety concerns related to myopathy and rhabdomyolysis, it is important to consider the possibility of pharmacokinetic interactions when such combinations are used. In this study, the area under the curve, maximum plasma concentration, and time to maximum concentration for fluvastatin and gemfibrozil are compared, when used alone and in combination, in patients with hyperlipidemia and either coronary or carotid atherosclerosis, or a family history of coronary artery disease. A total of 17 patients were studied in a random sequence, open-label, crossover study of fluvastatin at 20 mg twice daily, gemfibrozil at 600 mg twice daily, and the combination of the 2 drugs. No significant difference was observed in area under the curve, maximum plasma concentration, and time to maximum concentration when comparing the combination with each drug alone. These pharmacokinetic data add support to the clinical observations that the combination of fluvastatin and gemfibrozil is both effective and safe.

Anticholesteremic Agents↗
PubMed1995

"Sucrose analgesia" and diphtheria-tetanus-pertussis immunizations at 2 and 4 months.

In human newborns, small amounts of sucrose reduce crying with procedural pain by about 50%. To determine whether "sucrose analgesia" could be extended to painful procedures beyond the newborn period, 57 infants were randomly assigned to receive three 250-microliters doses of 50% sucrose solution (g/100 mL) or water before their diphtheria-tetanus-pertussis immunizations at 2 and 4 months of age. Crying during and after injection was measured separately to determine whether sucrose modified crying during the noxious stimulus, recovery from the stimulus, or both. Sucrose was effective in reducing crying only from 83 to 69%, and the reduction was limited to the postinjection period. We conclude that, although sucrose continues to have some effect beyond the newborn period, the effect is limited to recovery from the noxious stimulus, is clinically modest, and is probably smaller than in the newborn period.

Crying↗
PubMed1994

Evidence for different clinical subtypes of type 1 diabetes mellitus: a prospective study.

The purpose of this study was to determine whether the sex, age, severity of clinical presentation, presence of ICAs, IAs, and HLA-DR and DQ types could predict, in a cohort of newly-diagnosed diabetic children: (1) the duration of beta-cell function as measured by C-peptide response to a Sustacal meal; and (2) determine if those predictors could identify disease subtypes. A cohort of 170 consecutive patients was followed for 60 months after diagnosis. We found that age (0.0029), sex (0.0136), ICA (0.0001), presence of DKA (0.0070) and C-peptide peak at diagnosis (0.0000) significantly predicted the duration of residual beta-cell function over time. Furthermore, C-peptide secretion at diagnosis, presence of ICA, age and sex allowed the identification of three different prognostic groups with varying acceleration of beta-cell loss.

Adolescent↗
PubMed1993

Different rates of conversion to IDDM in siblings of type 1 diabetic children: the Montreal family study.

This study was undertaken to analyze the risk of developing insulin-dependent diabetes (IDDM) in siblings of type 1 diabetic children. Islet-cell antibodies (ICA) were tested in 568 subjects, siblings of type 1 diabetic children. The subjects were followed prospectively for the conversion to clinical diagnosis of IDDM. As a result siblings who were islet cell antibody (ICA)+ positive at the time of diagnosis of the diabetic sibling (index case) had a significantly higher risk of developing IDDM than those who were ICA-. However, of the 19 siblings who developed IDDM, only 10 were ICA+ at the time of the first test but, 17 became ICA+ before diagnosis of IDDM. The interval between a positive test and the clinical diagnosis of IDDM varied between subjects (6-44 months, mean = 18.4 +/- 4.2 S.E. months) but it was less than 1 year in one subject. In addition to the higher risk of developing IDDM when ICA was positive, male sex and younger age of the subjects as well as young age of the index case and multiplex pedigrees were significant predictors of conversion to IDDM. The Cox's regression tree constructed using RECPAM identified three groups of varying rates of conversion to IDDM: (1) a group with the slowest progression characterized by ICA- and age of index case > 5 years or female sex (relative hazard = 1); (2) an intermediate progression group consisting of subjects who are ICA- and have both < 5 years of age and male sex (relative hazard = 8.78); (3) a group with the fastest progression consisting of subjects who are ICA+ (relative hazard = 31.45). From these results our data suggest that in addition to ICA, clinical markers such as age, sex and multiple pedigrees are also significant predictors of the rate of conversion to IDDM. Furthermore, screening for ICA in family intervention studies will have to be done frequently, perhaps yearly, and will have to be continued into adult life, particularly in ICA- subjects in order to identify the 85-90% of subjects who become ICA+ at the clinical diagnosis of IDDM.

Adolescent↗
PubMed1993

Cell type-dependent variations in the subcellular distribution of alpha-mannosidase I and II.

alpha-mannosidases I and II (Man I and II) are resident enzymes of the Golgi complex involved in oligosaccharide processing during N-linked glycoprotein biosynthesis that are widely considered to be markers of the cis- and medial-Golgi compartments, respectively. We have investigated the distribution of these enzymes in several cell types by immunofluorescence and immunoelectron microscopy. Man II was most commonly found in medial- and/or trans- cisternae but showed cell type-dependent variations in intra-Golgi distribution. It was variously localized to either medial (NRK and CHO cells), both medial and trans (pancreatic acinar cells, enterocytes), or trans- (goblet cells) cisternae, or distributed across the entire Golgi stack (hepatocytes and some enterocytes). The distribution of Man I largely coincided with that of Man II in that it was detected primarily in medial- and trans-cisternae. It also showed cell type dependent variations in its intra-Golgi distribution. Man I and Man II were also detected within secretory granules and at the cell surface of some cell types (enterocytes, pancreatic acinar cells, goblet cells). In the case of Man II, cell surface staining was shown not to be due to antibody cross-reactivity with oligosaccharide epitopes. These results indicate that the distribution of Man I and Man II within the Golgi stack of a given cell type overlaps considerably, and their distribution from one cell type to another is more variable and less compartmentalized than previously assumed.

Animals↗
PubMed1989

Visceral leishmaniasis unresponsive to pentostam caused by Leishmania tropica in Kenya.

We report the characterization of 6 Leishmania tropica isolates from 2 patients with visceral leishmaniasis who were unresponsive to treatment with sodium stibogluconate. The Leishmania isolates, MHOM/KE/81/NLB-029A, -029XIB, and -029XIC and MHOM/KE/81/NLB-030I, -030B, and -030XXA, all from splenic aspirates, were characterized by cellulose acetate electrophoresis using 11 enzymes: malate dehydrogenase, malic enzyme, phosphogluconate dehydrogenase, glucose-6-phosphate dehydrogenase, superoxide dismutase, glutamate-oxaloacetate transaminase, adenylate kinase, nucleoside hydrolase, mannose phosphate isomerase, glucose phosphate isomerase, and phosphoglucomutase. Isozyme migration patterns were indistinguishable from those of 2 WHO reference strains of Leishmania tropica (MHOM/SU/60/LRC-L39, NLB-305 and MHOM/IQ/OO/LRC-L36, NLB-067). These are the first reported cases of visceral leishmaniasis (kala-azar) caused by L. tropica in Africa; these cases were refractory to sodium stibogluconate.

Animals↗
PubMed1988

Peripheral insulin sensitivity as modified by diet and exercise training.

To determine which component of a high-fat sucrose diet (HFS) caused insulin resistance and whether exercise training or fiber could prevent it, six dietary treatments were tested in rats: low-fat complex carbohydrate (LFCC); high-fat complex carbohydrate (HFCC); low-fat sucrose (LFS); high-fat sucrose (HFS); HFS plus fiber (HFS + F); and HFS plus exercise training (HFS + EX). After 10 wk rats were subjected to an intravenous glucose-tolerance test. The HFS and HFS + F groups developed glucose intolerance, as indicated by significantly greater areas under their glucose curves compared with the LFCC group's areas. The LFS, HFS, HFS + F, and HFS + EX groups developed insulin resistance, as indicated by significantly greater areas under their insulin curves compared with the LFCC and HFCC groups' areas. Either the presence of sucrose or the absence of complex carbohydrates, not high fat, was responsible for the insulin resistance and it was not improved by adding fiber to the diet or by exercise training.

Animals↗
PubMed1985

The use of athymic nude mice for the study of human keloids.

Keloid tissue has been implanted in the athymic nude mouse in order to develop an experimental animal model for the study of human keloids and hypertrophic scars. Untreated keloid tissues maintained essentially the same morphological patterns and glycosaminoglycan distributions for at least 60 days after implantation in the athymic mice. Normal human skin implanted in the same way was maintained without change in glycosaminoglycan distribution or morphologic characteristics. We suggest that this model may be useful for basic research of keloids and hypertrophic scars in that it will allow studies of morphologic, biochemical and therapeutic interrelationships under controlled conditions.

Animals↗
PubMed1984

Cutaneous leishmaniasis in Kenya: transmission of Leishmania major to man by the bite of a naturally infected Phlebotomus duboscqi.

One leishmanial stock was isolated from a Phlebotomus duboscqi female captured in Baringo District, Kenya, and others from papular lesions that developed at sites where this sandfly had fed on a man. When characterized by cellulose acetate electrophoresis (eight enzymes examined), these isolates proved to be identical to known Leishmania major strains from man and a rodent (Arvicanthis sp.) and different from L. donovani and L. adleri, which also occur in Baringo. This is the first case of human cutaneous leishmaniasis caused by L. major reported from Kenya.

Electrophoresis, Cellulose Acetate↗
PubMed1979

Diagnosis of cutaneous leishmaniasis by in vitro cultivation of saline aspirates in Schneider's Drosophila Medium.

A culture system was developed and evaluated as an improved diagnostic procedure for human infections of New and Old World cutaneous leishmaniasis. Needle aspirates of 55 suspect lesions from 40 human cases were made by injecting and withdrawing sterile saline from the outer margin of a lesion. Aspirates were inoculated and cultured in an insect cell culture medium, Schneider's Drosophila Medium, supplemented with 30% fetal bovine serum. Paralleled cultures in a blood-based medium, NNN, were used as a basis of comparison for sensitivity. Promastigotes were observed in 37 of 55 (67%) of the Schneider's Medium cultures on an average of 6.0 days, as compared to only 8 of 55 of the NNN cultures on an average of 11.6 days.

Biopsy, Needle↗
PubMedDate not supplied

Management of skin tears and stage II skin ulcers with two topical regimens: a study of cost minimization.

A health-economic study of newly formed skin tears and stage II ulcers used an unblinded, comparative, parallel-group design to evaluate two topical regimens as to time required for complete healing and assessment of cost minimization. Thirty-six elderly patients, at risk for developing indolent wounds of the skin and underlying tissues, were assigned to receive either a saline spray and a topical antibiotic ointment (TAM, n = 14) or Dermagran Spray and Dermagran Ointment (DSO, n = 22). The 76 wounds that appeared in these patients had comparable pretreatment surface areas of 3.73 +/- 0.96 cm2 in the DSO group versus 5.57 +/- 1.13 cm2 in the TAM group (P = NS). All wounds were treated twice daily, starting within 24 hours of their appearance, until complete healing. The 19 wounds in the TAM group healed within 48.0 +/- 25.3 days versus 15.4 +/- 1.9 days for the 57 wounds in the DSO group (P < .05). The cost of wound management for a given patient was calculated by adding the costs of nursing labor and the amount of product consumed to effect complete healing. To this end, the cost of the TAM regimen was $323.23 +/- 171.70 versus $104.75 +/- 12.92 for the DSO regimen (P < .05). Results are presented in light of the increasing pressure on long-term care facilities to provide effective and affordable treatment.

Administration, Topical↗