Biomedical subjects

J F Collins

Publications and source records attributed to J F Collins.

At least 19 recordsLinked to original sources

PubMed2001

Predisposition to nephropathy in Polynesians is associated with family history of renal disease, not diabetes mellitus.

AIMS: Familial clustering of diabetes and nephropathy suggests that either common environmental or inherited mechanisms are important in developing diabetic nephropathy. If an inherited mechanism is important, the albumin excretion rate might be increased in those at future risk. This study aimed to determine whether people with a family history of diabetes or people with a family history of renal disease were most at risk. METHODS: In a two-by-two factorial study of urinary albumin in non-diabetic Polynesians, 90 people with a first degree relative (FDR) with end-stage renal failure (ESRF) and diabetes (group 1) were compared with 90 people with a FDR with non-diabetic ESRF (group 2), with 90 people with a FDR with diabetes but no known nephropathy (group 3) and 90 people with no known relatives with either diabetes or nephropathy (group 4). Groups were matched for ethnicity and age. RESULTS: Subjects with a family history of ESRF (groups 1 and 2) had an increased mean albumin-creatinine ratio (1.25 vs. 1.00 mg/mmol, P = 0.01), but in subjects with a family history of diabetes (groups 1 and 3), the mean ratios were not significantly different from those without a family history of diabetes (1.06 vs. 1.17 mg/mmol; P = 0.2). In those with a family history of nephropathy, fasting blood glucose and systolic blood pressure were increased, while fasting insulin and 2 h insulin concentrations were lower. A family history of diabetes was associated with an increased fasting blood glucose and 2-h blood glucose. By multiple linear regression, the mean systolic blood pressure (P = 0.02), the 2-h glucose concentration (P = 0.05), a family history of renal failure (P = 0.04), female sex (P = 0.0001) and the total cholesterol (P = 0.01) were each independently associated with microalbuminuria, while a family history of diabetes was not (P = 0.09). CONCLUSIONS: These data suggest that among Polynesians there is no specific inherited tendency to diabetic nephropathy per se. The risk of nephropathy does not appear to be associated with the degree of familial risk of diabetes itself. Rather, the risk of diabetic nephropathy may be the result of a familial risk of nephropathy from any cause and is associated with diabetes through relative hypoinsulinaemia and hyperglycaemia.

Adult↗

PubMed2001

Regulation of the human sodium-phosphate cotransporter NaP(i)-IIb gene promoter by epidermal growth factor.

The intestinal sodium-phosphate cotransporter (NaP(i)-IIb) plays a major role in intestinal P(i) absorption. Epidermal growth factor (EGF) is involved in the regulation of P(i) homeostasis. However, the role of EGF in intestinal NaP(i)-IIb regulation is not clear. The current studies showed that EGF decreased NaP(i)-IIb mRNA abundance by 40-50% in both rat intestine and Caco-2 cells. To understand the mechanism of this regulation, we cloned the human NaP(i)-IIb gene and promoter region and studied the effect of EGF on NaP(i)-IIb gene transcription. The human NaP(i)-IIb gene has 12 exons and 11 introns. Two transcription initiation sites were identified by primer extension. Additionally, 2.8 kb of the 5'-flanking region of the gene was characterized as a functional promoter in human intestinal (Caco-2) and human lung (A549) cells. Additional studies showed that EGF inhibited promoter activity by 40-50% in Caco-2 cells and that actinomycin D treatment abolished this inhibition. EGF had no effect on promoter activity in lung (A549) cells. We conclude that the human NaP(i)-IIb gene promoter is functional in Caco-2 and A549 cells and that the gene is responsive to EGF by a transcriptionally mediated mechanism in intestinal cells.

Animals↗

PubMed2001

Transcriptional regulation of rat Na(+)/H(+) exchanger isoform-2 (NHE-2) gene by Sp1 transcription factor.

The rat Na(+)/H(+) exchanger isoform-2 (NHE-2) gene promoter lacks a TATA box and is very GC rich. A minimal promoter extending from bp -36 to +116 directs high-level expression of NHE-2 in mouse inner medullary collecting duct (mIMCD-3) cells. Four Sp1 consensus elements were found in this region. The introduction of mutations within these Sp1 consensus elements and DNA footprinting revealed that only two of them were utilized and are critical for basal transcriptional activation in mIMCD-3 cells. The use of Sp1, Sp3, and Sp4 antisera in electrophoretic mobility shift assays demonstrated that Sp1, Sp3, and Sp4 bound to this minimal promoter. We further analyzed the transcriptional regulation of NHE-2 by members of the Sp1 multigene family. In Drosophila SL2 cells, which lack endogenous Sp1, the minimal promoter cannot drive transcription. Introduction of Sp1 activated transcription over 100-fold, suggesting that Sp1 is critical for transcriptional regulation. However, neither Sp3 nor Sp4 was able to activate transcription in these cells. Furthermore, in mIMCD-3 cells, Sp1-mediated transcriptional activation was repressed by expression of Sp3 and Sp4. These data suggest that Sp1 is critical for the basal promoter function of rat NHE-2 and that Sp3 and Sp4 may repress transcriptional activation by competing with Sp1 for binding to core cis-elements.

Animals↗

PubMed2000

Molecular cloning of murine sodium-phosphate cotransporter type IIb (Na/P(i)-IIb) gene promoter and characterization of gene structure.

We report the cloning of the murine Na/P(i)-IIb cotransporter gene, which spans more than 18 kilobases and consists of 12 introns and 13 exons. Three promoter/reporter gene constructs, -159/+73, -429/+73 and -954/+73, showed significant luciferase activity (22-82-fold over background) when transfected into in rat intestinal epithelial (RIE-1) cells.

Animals↗

PubMed2000

Molecular cloning of the murine PHEX gene promoter.

We report the novel cloning of the murine PHEX promoter, the gene that is mutated in X-linked hypophosphatemic rickets (XLH). Four promoter/reporter gene constructs, -133/+104, -542/+104, -1061/+104, and -2866/+104, showed significant luciferase activity (4.9-13.2-fold over background) when transfected into rat osteogenic sarcoma (UMR-106) cells.

Animals↗

PubMed2000

Expression of rat, renal NHE2 and NHE3 during postnatal development.

The current studies were designed to characterize the expression of sodium-hydrogen exchangers NHE2 and NHE3 during rat, renal ontogeny. NHE2 mRNA and immunoreactive protein were more highly expressed at 2 and 3 weeks of age, with declining levels into adulthood. In situ hybridization of NHE2 mRNA localized the message to the renal inner cortex and outer medullary regions and suggested higher mRNA levels in suckling animals as compared to adults. Immunohistochemical analysis of rat kidney with the NHE2 antiserum showed specific staining of the distal convoluted tubules. In contrast, NHE3 mRNA expression was lowest in 2-week animals and higher in older rats, while NHE3 immunoreactive protein showed constant expression levels during development. Additionally uptake experiments utilizing HOE694 showed no change in NHE2 or NHE3 functional protein expression in 2-week-old rats versus adults. We conclude that the developmental increase in NHE2 mRNA and immunoreactive protein expression cannot be detected by functional assays, which suggests that NHE2 does not play a role in sodium absorption by the renal tubules (as has been previously suggested). Additionally, molecular changes seen in NHE3 mRNA expression do not affect functional protein activity, suggesting increased mRNA translational efficiency or protein stability in suckling rats.

Age Factors↗

PubMed2000

Biracial Japanese American identity: an evolving process.

This qualitative study explored the complexity of biracial identity development in Japanese Americans. It is based on the constant comparable method of analysis, or grounded theory. The study focused on how Japanese Americans perceived themselves in relation to other individuals, groups, and their environment. The data consisted of 15 extensive semistructured interviews with 8 men and 7 women (ages 20 to 40 years), each with 1 Japanese parent and 1 non-Asian parent. Findings relate to participants' initiating explorations of identity and perseverance in pursuing a biracial identity, which depended on the degree of support or negative experience within their social networks. Participants explored identity options attempting to develop their own meaning of identity, to develop a confident sense of themselves, and to secure a positive ethnic identity. Identity development among participants varied. It was a long-term process involving changes in the individual-environment relationship, which differed in the way individual participants influenced or selected from environmental opportunities, even creating or recreating some aspects. Within a given setting, as youths, the potential for social experiences were relatively fixed and changed only gradually. As adults, there were opportunities for participants to select their own social and geographic settings, providing opportunity for change. In their new environments, participants were exposed to new contacts and role models, acquired new behavioral repertoire, and underwent role transitions. Depending on this, new and different aspects of biracial identity developed. Participants indicated it was an emotional and conflictual process to positive assertion of identity. Before reaching this, all of the participants experienced periods of confusion. Most asserted biracial identity gradually, through a process of racial identity development consisting of the individual's changing or maintaining certain reference group perspectives, identifications, and allegiances as they passed through a series of life experiences. Instead of staying marginalized, they integrated both cultures, recognizing positive values of both, thus developing an integrated identity. Although the participants' experiences and perceptions were varied, the overarching themes of self-evaluation, confusion of categorization, belonging, infusion/exploration, situational use of identity, and resolution/acceptance/self-verification were presented. On the basis of the research, a model of ethnic identity for biracial individuals is proposed.

Adaptation, Psychological↗

PubMed2000

Age- and tissue-specific induction of NHE3 by glucocorticoids in the rat small intestine.

Of the two known apical isoforms of the Na(+)/H(+) exchanger (NHE) family, only the NHE3 gene is regulated by glucocorticoids. The aim of these studies was to investigate the mechanisms underlying the effects of methylprednisolone (MP) on expression of NHE3 in the proximal and distal small intestine of suckling and adult rats. Immunoblots showed that the glucocorticoid responsiveness in the proximal small intestine was greatest in suckling animals (NHE3/beta-actin: 0.43 +/- 0.09 control vs. 1.57 +/- 0.15 MP; P < 0. 001), and responsiveness decreased with age with no effect in adults (0.56 +/- 0.14 vs. 0.64 +/- 0.17). Distal small intestine was responsive only in adult rats (0.49 +/- 0.13 vs. 1.65 +/- 0.09; P < 0.001). This pattern was confirmed at the mRNA level and by (22)Na(+) uptake. Western blot and [(3)H]dexamethasone mesylate binding showed that the responsiveness of NHE3 to glucocorticoids is directly related to the expression of glucocorticoid receptor (GR) in the small intestine. These studies suggest that loss and gain of glucocorticoid responsiveness in the proximal and distal small intestine, respectively, are related to age- and segment-dependent expression of GR.

Aging↗

PubMed2000

Cloning and characterization of a type III Na-dependent phosphate cotransporter from mouse intestine.

Intestinal and renal absorption of inorganic phosphate (P(i)) is critical for phosphate homeostasis in mammals. We have isolated a cDNA that encodes a type III Na-dependent phosphate cotransporter from mouse small intestine (mPit-2). The nucleotide sequence of mPit-2 predicts a protein of 653 amino acids with at least 10 putative transmembrane domains. Kinetic studies, carried out in Xenopus oocytes, showed that mPit-2 cRNA induces significant Na-dependent P(i) uptake with an apparent Michaelis constant (K(m)) for phosphate of 38 microM. The transport of phosphate by mPit-2 is inhibited at high pH. Northern blot analysis demonstrated the presence of mPit-2 mRNA in various tissues, including intestine, kidney, heart, liver, brain, testis, and skin. The highest expression of mPit-2 in the intestine was found in the jejunum. In situ hybridization revealed that mPit-2 mRNA is expressed throughout the vertical crypt-villus axis of the intestinal epithelium. The presence of mPit-2 in the mouse intestine and its unique transport characteristics suggest that multiple Na-dependent cotransporters may contribute to phosphate absorption in the mammalian small intestine.

Animals↗

PubMed1999

Molecular cloning, functional characterization, tissue distribution, and chromosomal localization of a human, small intestinal sodium-phosphate (Na+-Pi) transporter (SLC34A2).

Phosphate plays a crucial role in cellular metabolism, and its homeostatic regulation in intestinal and renal epithelia is critical. Apically expressed sodium-phosphate (Na(+)-P(i)) transporters play a critical role in this regulation. We have isolated a cDNA (HGMW-approved symbol SLC34A2) encoding a novel human small intestinal Na(+)-P(i) transporter. The cDNA is shown to be 4135 bp in length with an open reading frame that predicts a 689-amino-acid polypeptide. The putative protein has 76% homology to mouse intestinal type II Na(+)-P(i) transporter (Na/Pi-IIb) and lower homologies with renal type II Na(+)-P(i) transporters. Northern blots showed a singular transcript of 5.0 kb in human lung, small intestine, and kidney. Computer analysis suggests a protein with 11 transmembrane domains and several potential posttranslational modification sites. Functional characterization in Xenopus laevis oocytes showed that this cDNA encodes a functional Na(+)-P(i) transporter. Furthermore, the gene encoding this cDNA was mapped to human chromosome 4p15.1-p15.3 by the FISH method.

Amino Acid Sequence↗

PubMed1999

Differential regulation of renal sodium-phosphate transporter by glucocorticoids during rat ontogeny.

The effects of chronic administration of methylprednisolone (MP) were studied on the ontogeny of the renal type II Na-P(i) transporter (NaPi-2). Immunoblot analysis showed that MP did not alter the expression of NaPi-2 protein levels in suckling and weanling rats; however, there was an approximately 50% decrease in adolescent and adult rats. There was no change in Na-dependent P(i) uptake in brush-border membrane vesicles in suckling rats, but there was an almost twofold decrease in adolescent rats induced by MP treatment. MP administration did not alter mRNA levels in suckling or adolescent rats. Dual injections with the glucocorticoid receptor blocker RU-486 (mifepristone) and MP did not reverse the downregulation of NaPi-2 immunoreactive protein levels in adolescent rats. To control for RU-486 antagonism efficiency, Na/H exchanger isoform 3 (NHE3) protein levels were also assayed after injection with RU-486 and MP. As expected, NHE3 protein levels increased after MP injection; however, the increase was blocked in adolescent rats by RU-486. We conclude that there is an age-dependent responsiveness to glucocorticoids and that the marked decrease in NaPi-2 immunoreactive protein levels and activity in adolescent rats is due to posttranscriptional mechanisms.

Actins↗

PubMed1999

Characterization of cis-elements required for osmotic response of rat Na(+)/H(+) exchanger-2 (NHE-2) gene.

The Na(+)/H(+) exchanger (NHE-2) has been implicated in osmoregulation in the kidney, because it transports Na(+) across the cell membrane and efficiently alters intracellular osmolarity. On hyperosmotic stress, NHE-2 mRNA increases in abundance in mouse inner medullary collecting duct (mIMCD-3) cells, suggesting possible transcriptional regulation. To investigate the molecular mechanism of potential transcriptional regulation of NHE-2 by hyperosmolarity, we have functionally characterized the 5'-flanking region of the gene in mIMCD-3 cells. Transient transfection of luciferase reporter gene constructs revealed a novel cis-acting element, which we call OsmoE (osmotic-responsive element, bp -808 to -791, GGGCCAGTTGGCGCTGGG), and a TonE-like element (tonicity-responsive element, bp -1201 to -1189, GCTGGAAAACCGA), which together are shown to be responsible for hyperosmotic induction of the NHE-2 gene. Electrophoretic mobility shift assays suggest that different DNA-protein interactions occur between these two osmotic response elements. However, both DNA sequences were shown to specifically bind nuclear proteins that dramatically increase in abundance under hyperosmotic conditions. Isolation of trans-acting factors and characterization of their specific interaction with these osmotic response elements will further elucidate the transcriptional mechanisms controlling NHE-2 gene expression under hyperosmolar conditions.

Animals↗

PubMed1998

Molecular cloning and characterization of the rat NHE-2 gene promoter.

To understand the molecular mechanisms underlying NHE-2 regulation in the mammalian kidney and intestine, we cloned and sequenced 5.6 kb of the 5'-flanking region of the rat NHE-2 gene. DNA sequence analysis revealed multiple putative cis-acting regulatory elements including SP1, CK, NFY-CBF, Tant, GCN4, and one progesterone and several retinoic acid response elements. The upstream sequence lacked TATA and CAAT boxes, but contained a high G/C rich region within the first 300 bp. A single transcriptional initiation site was identified by primer extension in rat kidney and small intestine, approximately 103 bp upstream of the previously identified 5'-end of the rat NHE-2 cDNA. Various regions of the promoter (from [-]5567 to [+]105 bp) were tested for their ability to drive expression of the luciferase reporter gene in transiently transfected murine Inner Medullary Collecting Duct (mIMCD-3) cells. Results demonstrated that [-]289, [-]1271 and [-]2630 bp constructs showed promoter activity that was significantly higher than the negative control construct (20-fold). These results also demonstrated that basal cis-acting elements are contained within [-]289 bp of the transcriptional start site. However, the functional activity of the [-]5567 bp construct was not significantly different from the negative control, suggesting that a negative regulatory element may be present between [-]2630 and [-]5567 bp of the promoter region.

Animals↗

PubMed1998

A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.

BACKGROUND AND METHODS: Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. RESULTS: Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. CONCLUSIONS: As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.

Aged↗

PubMed1998

Prevention and Treatment of Hypertension Study (PATHS): effects of an alcohol treatment program on blood pressure.

OBJECTIVE: To determine whether blood pressure is reduced for at least 6 months with an intervention to lower alcohol intake in moderate to heavy drinkers with above optimal to slightly elevated diastolic blood pressure, and whether reduction of alcohol intake can be maintained for 2 years. DESIGN: A randomized controlled trial. METHODS: Six hundred forty-one outpatient veterans with an average intake of 3 or more alcoholic drinks per day in the 6 months before entry into the study and with diastolic blood pressure 80 to 99 mm Hg were randomly assigned to a cognitive-behavioral alcohol reduction intervention program or a control observation group for 15 to 24 months. The goal of the intervention was the lower of 2 or fewer drinks daily or a 50% reduction in intake. A subgroup with hypertension was defined as having a diastolic blood pressure of 90 to 99 mm Hg, or 80 to 99 mm Hg if recently taking medication for hypertension. RESULTS: Reduction in average weekly self-reported alcohol intake was significantly greater (P<.001) at every assessment from 3 to 24 months in the intervention group vs the control group: levels declined from 432 g/wk at baseline by 202 g/wk in the intervention group and from 445 g/wk by 78 g/wk in the control group in the first 6 months, with similar reductions after 24 months. The intervention group had a 1.2/0.7-mm Hg greater reduction in blood pressure than the control group (for each, P = .17 and P = .18) for the 6-month primary end point; for the hypertensive stratum the difference was 0.9/0.7 mm Hg (for each, P = .58 and P = .44). CONCLUSIONS: The 1.3 drinks per day average difference between changes in self-reported alcohol intake observed in this trial produced only small nonsignificant effects on blood pressure. The results from the Prevention and Treatment of Hypertension Study (PATHS) do not provide strong support for reducing alcohol consumption in nondependent moderate drinkers as a sole method for the prevention or treatment of hypertension.

Adult↗

PubMed1998

Ontogeny of basolateral membrane sodium-hydrogen exchange (NHE) activity and mRNA expression of NHE-1 and NHE-4 in rat kidney and jejunum.

Na+/H+ exchange (NHE) activity varies with ontogenic state in rat intestinal basolateral membrane vesicles (BLMV). The current investigation sought to determine if these observations are due to differential expression of BLM NHE isoforms, NHE-1 and NHE-4. In rat kidney, BLMV sodium uptake levels were similar in 2, 3 and 6 week rats (13.28+/-0.68, 14.03+/-0.84, and 11.71+/-0.66 nmol Na+/mg protein/30 s, respectively), and lower in adults (5.53+/-0.24) (n=4; p<0.001 between 2 week rats and adults, and between 3 week rats and adults; p<0.01 between 6 week rats and adults). In rat jejunum, BLMV uptake was highest in adults (13.07+/-0.86 nmol Na+/mg protein/30 s), and decreased in 6, 3, and 2 week rats (4.48+/-0.75, 2.94+/-0.68, and 1.59+/-0.58, respectively) (n=4; p<0.001 between all groups and adults). Control immunoblot experiments with NHE-3 antiserum showed that BLMV preps were not contaminated with significant amounts of this brush-border membrane specific protein. Northern blots with isoform-specific probes showed highest renal NHE-1 hybridization intensities in 2 and 3 week rats (11.00+/-0.25 and 12.07+/-0.16 phosphorimage units, respectively), and lower intensities in 6 week and adult animals (4.30+/-0.95, and 4.40+/-1.40, respectively) (n=4; p<0.01 between 2 week animals and 6 week and adult animals, and between 3 week animals and 6 week and adult animals). NHE-1 probes in the intestine showed no hybridization intensity differences between groups: 2 week-7.09+/-1.10, 3 week-5.39+/-0.56, 6 week-8. 24+/-1.57, and adult-8.99+/-2.20 (n=3). NHE-4 specific probes in the kidney showed hybridization intensity levels of 9.22+/-0.35 in 2 week animals, 12.12+/-1.26 in 3 week animals, 5.63+/-0.81 in 6 week animals, and 3.52+/-0.57 in adults (n=4; p<0.05 between 2 week and adults; p<0.01 between 3 week and 6 week animals, and between 3 week and adults). No NHE-4 message was detected in rat jejunum by Northern blot analysis or by reverse transcriptase-PCR. These results suggest that ontogenic NHE activity at the jejunal BLM is not related to differential expression of NHE-1, while NHE activity at the renal BLM may in part be related to differential ontogenic expression of NHE-1 and NHE-4.

Animals↗

PubMed1998

Potency equivalency factors for some polycyclic aromatic hydrocarbons and polycyclic aromatic hydrocarbon derivatives.

Potency equivalency factors (PEFs) for cancer induction relative to benzo[a]pyrene have been derived for 21 polycyclic aromatic hydrocarbons (PAHs) and PAH derivatives based on a data preference scheme. PEFs have been derived only for PAHs with demonstrated carcinogenicity in bioassays. Cancer potency values and inhalation unit risks are presented for four additional carcinogenic PAHs based on expedited risk assessments conducted for California's Proposition 65. A much larger number of PAHs and PAH derivatives are considered mutagenic or genotoxic and may have limited evidence for carcinogenicity, but these compounds are not considered in this evaluation. New cancer bioassay data and possibly structure-activity analysis may indicate that additional PAHs are carcinogenic. Thus, additional PAHs may be identified as potential human carcinogens when such data become available. However, until that time the PEFs proposed for use in risk assessment were estimated only for PAHs currently classified as carcinogens.

Animals↗

PubMed1998

Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial.

AIMS: To evaluate the safety and efficacy of an 8 mg/day sublingual dose of buprenorphine in the maintenance treatment of heroin addicts by comparison with a 1 mg/day dose over a 16-week treatment period. As a secondary objective, outcomes were determined concurrently for patients treated with two other dose levels. DESIGN: Patients were randomized to four dosage groups and treated double-blind. SETTING: Twelve outpatient opiate maintenance treatment centers throughout the United States. PARTICIPANTS: Two hundred and thirty-nine women and 497 men who met the DSM-III-R criteria for opioid dependence and were seeking treatment. INTERVENTION: Patients received either 1, 4, 8 or 16 mg/day of buprenorphine and were treated in the usual clinical context, including a 1-hour weekly clinical counseling session. MEASUREMENT: Retention in treatment, illicit opioid use as determined by urine toxicology, opioid craving and global ratings by patient and staff. Safety outcome measures were provided by clinical monitoring and by analysis of the reported adverse events. FINDINGS: Outcomes in the 8 mg group were significantly better than in the 1 mg group in all four efficacy domains. No deaths occurred in either group. The 8 mg group did not show an increase in the frequency of adverse events. Most reported adverse effects were those commonly seen in patients treated with opioids. CONCLUSIONS: The findings support the safety and efficacy of buprenorphine and suggest that an adequate dose of buprenorphine will be a useful addition to pharmacotherapy.

Buprenorphine↗