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M J Peterson

Publications and source records attributed to M J Peterson.

At least 19 recordsLinked to original sources
PubMed1992

Genetic exchange in the evolution of the human MHC class II loci.

A total of 61 DNA sequences from human major histocompatibility class II loci were searched for statistical evidence of past genetic exchange (gene conversion or recombination). Among the 12 A-locus sequences (derived from DPA1 and DQA1), 4 clusters indicating potential exchange events were found. Among the 49 B-locus sequences (derived from DOB, DPB1, DPB2, DQB1, DRB1, DRB3, DRB4 and DRB5), 15 clusters were found. The clusters suggested short exchanges (less than 100 bp) within and between loci, and were concentrated in exon 2 (coding for the antigen binding site). The most striking feature of the results was the presence of an approximately 200-bp region in the middle of B-locus exon 2 which contained almost no locus-specific substitutions, which were abundant elsewhere. This suggests either strong selection for locus specificity in the other regions of the gene or a history of frequent between-locus exchange in this part of exon 2, which is involved in forming the antigen binding site.

Algorithms↗
PubMed1988

Spiro hydantoin aldose reductase inhibitors.

Sorbitol formation from glucose, catalyzed by the enzyme aldose reductase, is believed to play a role in the development of certain chronic complications of diabetes mellitus. Spiro hydantoins derived from five- and six-membered ketones fused to an aromatic ring or ring system inhibit aldose reductase isolated from calf lens. In vivo these compounds are potent inhibitors of sorbitol formation in sciatic nerves of streptozotocinized rats. Optimum in vivo activity is reached in spiro hydantoins derived from 6-halogenated 2,3-dihydro-4H-1-benzopyran-4-ones (4-chromanones). In 2,4-dihydro-6-fluorospiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5 '-dione, the activity resides exclusively in the 4S isomer, compound 115 (CP-45,634, USAN: sorbinil). This compound is currently being used to test, in humans, the value of aldose reductase inhibitors in the therapy of diabetic complications.

Aldehyde Reductase↗
PubMed1986

Applicability of red blood cell sorbitol measurements to monitor the clinical activity of sorbinil.

Increased flux of glucose through the polyol pathway with resultant resultant accumulation of tissue sorbitol is implicated in the pathogenesis of the chronic complications of diabetes. Sorbinil is a potent inhibitor of aldose reductase (the first enzyme in the polyol pathway) and has been shown to normalize sorbitol levels in relevant tissues (eg, nerve, kidney, lens) of experimentally-induced diabetic animals. The purpose of this study was to identify a relatively noninvasive method of monitoring the intrinsic (or biochemical) efficacy of sorbinil in diabetic man. Specifically, the objective was to identify a readily accessible tissue that would be reflective of polyol pathway activity and the activity of sorbinil in clinically relevant but less accessible tissues. Based on several previous studies, which demonstrated that sorbitol accumulation in human red blood cells (RBCs) was a function of ambient glucose concentrations, either in vitro or in vivo, our investigations were conducted to determine if RBC sorbitol accumulation would correlate with sorbitol accumulation in lens and nerve tissue of diabetic rats; the effect of sorbinil in reducing sorbitol levels in lens and nerve tissue of diabetic rats would be reflected by changes in RBC sorbitol; and sorbinil would reduce RBC sorbitol in diabetic man.

Animals↗
PubMed1986

Clinical experience with sorbinil--an aldose reductase inhibitor.

A considerable volume of animal pharmacologic data support the view that increased flux through the polyol pathway provides a unifying hypothesis for the major complications of diabetes. An extensive clinical program has been established to verify the extrapolation of the animal pharmacologic findings to man. Clinical data accumulated to date confirm the biochemical and electrophysiologic effects, and encouraging evidence of a drug effect in diabetic neuropathy and retinopathy has already been observed. In the large, controlled safety data base already available, the long-term clinical use of sorbinil is devoid of significant adverse effects in terms of both subjective side effects and laboratory parameters. The only clinically important adverse reaction reported to date has been a hypersensitivity reaction in the early weeks of therapy, which is similar to that seen with other hydantoins.

Aldehyde Reductase↗
PubMed1986

Sorbinil: a member of the novel class of spirohydantoin aldose reductase inhibitors.

A decade ago, we discovered that spirohydantoins are a novel class of aldose reductase inhibitors characterized by very potent in vivo activity. This important discovery resulted from a systematic screening effort for in vitro activity against aldose reductase isolated from bovine lens and subsequent testing of active compounds for in vivo activity in a streptozotocin-diabetic rat model, measuring inhibition of sorbitol formation in sciatic nerve. In this in vivo model, spirohydantoins were clearly more potent than all known carboxylic acid-type aldose reductase inhibitors. Structure-activity studies in the spirohydantoin class demonstrated that potent in vitro and in vivo activity were obtained when the spiro junction was adjacent to an aromatic ring and when this junction was part of a 5- or 6-membered ring system fused to the aromatic ring. Excellent in vitro and in vivo activity was achieved in 6-halogenated chromane derivatives with the spirohydantoin group attached in the 4-position. In this series, biologic activity is highly stereospecific and associated with the S configuration. Sorbinil, the S isomer of the 6-fluoro derivative in this series, is one such example: it is 30 times more potent than its R isomer in vitro (IC50 0.15 v 4.4 mumol/L) and 100 times more potent in vivo (ED50 0.25 mg/kg po v 25 mg/kg po).

Aldehyde Reductase↗
PubMed1986

Aldose reductase inhibitors in clinical practice. Preliminary studies on diabetic neuropathy and retinopathy.

Extensive animal data now exist to indicate potential benefit of sorbinil in the treatment of the major complications of diabetes mellitus. A clinical programme has been constructed to explore this therapeutic potential and encouraging evidence of drug effect has already been observed in patients with neuropathy and retinopathy. Two small preliminary studies in patients with painful neuropathy have shown that clinically significant reduction of pain was more frequently achieved with sorbinil than with placebo. A 6-month study of patients with retinopathy, using vitreous fluorophotometry as the criterion of retinal damage, showed significant (p = 0.03) benefit for the sorbinil group compared with the placebo group. Drug evaluation in these areas is complex and difficult but it is anticipated that the accumulation of additional data will further substantiate the efficacy suggested by these early findings. The only clinically important adverse effect of sorbinil is the hypersensitivity reaction. This usually occurs during the initial weeks of therapy and is similar to that seen with phenytoin. The long term use of sorbinil is without significant adverse effects.

Aldehyde Reductase↗
PubMed1985

Synthesis, absolute configuration, and conformation of the aldose reductase inhibitor sorbinil.

The aldose reductase inhibitor 2,3-dihydro-6-fluorospiro[4H-1-benzopyran-4,4'-imidazolidine]-2',5 '-dione was resolved into its enantiomers. Sorbinil, the S isomer, was found to be a better inhibitor of the enzyme in vitro and in vivo than the corresponding R isomer. X-ray data on sorbinil, which were used to determine its absolute configuration, are presented. NMR studies of sorbinil in solution indicate the existence of two conformers with a low energy barrier for interconversion.

Aldehyde Reductase↗
PubMed1985

Walking patterns of healthy subjects wearing rocker shoes.

We compared walking in rocker shoes with walking in athletic shoes at free and fast velocities in 15 healthy women who were between the ages of 21 and 30 years. Footswitches, electrogoniometers, surface electromyograms, and a force plate were used for data collection. No significant differences were found in velocity, cadence, gait-cycle duration, single-limb support, or swing-stance ratios in free and fast walking. Double-limb support was decreased by 9% in the rocker shoes in free walking. The ankle range of motion showed accommodation of the foot to the 8.5 degrees of plantar flexion built into the rocker shoes. Electromyographic responses appeared to be similar regardless of shoes or cadence.

Adult↗
PubMed1984

Red blood cell sorbitol as an indicator of polyol pathway activity. Inhibition by sorbinil in insulin-dependent diabetic subjects.

In a double-blind crossover study of 15 diabetic patients, elevated red blood cell (RBC) sorbitol levels were reduced by oral doses of the potent aldose reductase inhibitor, sorbinil (250 mg o.d.), to near-normal ranges. In diabetic rats with severe hyperglycemia, oral sorbinil (5 mg/kg) dramatically reduced (80-90%) sorbitol levels in tissues without affecting blood glucose; the RBC dose-response curve was similar to that in lens and sciatic nerve. In streptozotocin-treated rats with varying degrees of diabetes sorbitol levels in the lens, sciatic nerve, and RBC were elevated in proportion to the degree of hyperglycemia. RBC sorbitol levels in these animals were positively correlated with the levels in lens and sciatic nerve. These results establish that orally administered sorbinil is effective in lowering elevated sorbitol levels, and strongly suggest that the reduction seen in RBC sorbitol levels in human diabetic subjects is likely to reflect comparable effects of the drug in less accessible tissues associated with the long-term complications of diabetes.

Administration, Oral↗
PubMed1982

Spiro oxazolidinedione aldose reductase inhibitors.

Spiro oxazolidinediones (2) derived from five- and six-membered ring aralkyl ketones are potent aldose reductase inhibitors in vitro and in vivo. Their novel and general synthesis has been devised with alpha-hydroxyimidates (5) and 4-alkoxy-2-oxo-3-oxazolines (6) as key intermediates, since traditional synthetic routes through alpha-hydroxy amides (8) usually led to alpha, beta-unsaturated amides (9). Resolution with cinchonidine afforded optically active spiro oxazolidinediones. Optimum biological activity resided in (4S)-6-chlorospiro [4H-2,3-dihydrobenzopyran-4,5'-oxazolidine]-2',4'-dione (21) and its 6,8-dichloro congener (23).

Aldehyde Reductase↗
PubMed1982

Measurement and redistribution of excessive pressures during wheelchair sitting.

The ischial tuberosities, the sacral coccygeal area, and the greater and lesser trochanters and intertrochanteric crests receive excessive pressures when an individual is in the sitting position. Prolonged sitting by patients with insensitive skin and physical disability can cause pressure sores. Pressures below 20 to 30 mmHg are required to prevent capillary occlusion. Pressures are measured with a transducer system as the patient sits in his natural sitting posture in his wheelchair. A seat cushion is then "customized," which will redistribute excessive pressures. The most common cushion used is made of 3-in or 4-in high-density polyurethane foam. This material is easily modified when making ischial tuberosity cutouts and constructing a preischial bar. Because there is no single safe sitting pressure, each patient must be provided with a cushion support system that best reduces his excessive pressures. Although a properly fitted cushion can redistribute pressure, it can never substitute for relief of weight-bearing areas routinely carried out several times each hour.

Humans↗
PubMed1979

CP-45,634: a novel aldose reductase inhibitor that inhibits polyol pathway activity in diabetic and galactosemic rats.

In some tissues containing aldose reductase, increased flux through the polyol pathway has been implicated as being causative in diabetic complications (e.g., cataracts, peripheral neuropathy). We have found CP-45,634 (d-6-fluoro-spiro[chroman-4,4'-imidazolidine]-2',5'-dione) to be a highly potent, structurally novel, uncompetitive inhibitor of calf lens aldose reductase (IC50 approximately 5 X 10(-7)M). In a system in which sorbitol accumulation in isolated rat sciatic nerves was monitored in the presence of high (50 mM) glucose concentrations, CP-45,634 produced inhibition of polyol accumulation at levels as low as 1 X 10(-6)M. To determine if in vitro activity would translate to in vivo models, sorbitol accumulation in rat sciatic nerves was measured 27 hr after induction of diabetes with streptozotocin. Orally administered CP-45,634 was effective at dose levels as low as 0.25 mg/kg, t.i.d., and at 0.75 mg/kg produced an 85% inhibition of sorbitol accumulation. Two weeks after induction of diabetes by streptozotocin, sorbitol levels in rat lens and the sciatic nerve rose to 21,203 nmole/gm and 1,161 nmole/gm, respectively. Subsequent oral administration of CP-45,634 (2.5 mg/kg, b.i.d.) for 1 wk reduced these levels by 92% in nerves and 90% in lenses. In galactosemic rats, CP-45,634 inhibited the rise in lens galactitol and effectively delayed cataract formation at oral doses as low as 5 mg/kg/day. These high levels of in vivo activity suggest that CP-45,634 has potential for assessing the role of the polyol pathway in diabetic complications.

Aldehyde Reductase↗