Prodrugs of L-cysteine as protective agents against acetaminophen-induced hepatotoxicity. 2-(Polyhydroxyalkyl)- and 2-(polyacetoxyalkyl)thiazolidine-4(R)-carboxylic acids.

Eight prodrugs of L-cysteine (1a-h) were synthesized by the condensation of the sulfhydryl amino acid with naturally occurring aldose monosaccharides containing three, five, and six carbon atoms. The resulting 2-(polyhydroxyalkyl)thiazolidine-4(R)-carboxylic acids (TCAs) are capable of releasing L-cysteine and the sugars by nonenzymatic ring opening and hydrolysis. Thus, when added to rat hepatocyte preparations in vitro, these TCAs (1.0 mM) raised cellular glutathione (GSH) levels 1.2-2.1-fold relative to controls. On the basis of this finding, the cysteine prodrugs were tested as protective agents against acetaminophen-induced hepatotoxicity in a mouse model. The TCA derived from D-ribose and L-cysteine (RibCys, 1d) showed the greatest therapeutic promise of the series, with a 100% (12/12) survival profile compared to 17% without treatment. However, the degree of stimulation of GSH production in rat hepatocytes by these prodrugs did not correlate with the extent of protection afforded in mice, suggesting that pharmacokinetic parameters must supervene in vivo. To evaluate the effect of increased lipid solubility, we prepared prodrugs 2a-c by using peracetylated aldehydic sugars in the condensation reaction. These compounds, however, displayed acute toxicity to mice, possibly due to liberation of the acetylated sugars themselves. Nevertheless, the efficacy of the unacetylated TCAs, and RibCys (1d) in particular, suggests that the prodrug approach for the delivery of L-cysteine to the liver represents a viable means of augmenting existing detoxication mechanisms in protecting cells against xenobiotic substances that are bioactivated to toxic, reactive metabolites.

2-Substituted thiazolidine-4(R)-carboxylic acids as prodrugs of L-cysteine. Protection of mice against acetaminophen hepatotoxicity.

A number of 2-alkyl- and 2-aryl-substituted thiazolidine-4(R)-carboxylic acids were evaluated for their protective effect against hepatotoxic deaths produced in mice by LD90 doses of acetaminophen. 2(RS)-Methyl-, 2(RS)-n-propyl-, and 2(RS)-n- pentylthiazolidine -4(R)-carboxylic acids (compounds 1b,d,e, respectively) were nearly equipotent in their protective effect based on the number of surviving animals at 48 h as well as by histological criteria. 2(RS)-Ethyl-, 2(RS)-phenyl-, and 2(RS)-(4-pyridyl)thiazolidine-4(R)-carboxylic acids (compounds 1c,f,g) were less protective. The enantiomer of 1b, viz., 2(RS)- methylthiazolidine -4(S)-carboxylic acid (2b), was totally ineffective in this regard. Thiazolidine-4(R)-carboxylic acid (1a), but not its enantiomer, 2a, was a good substrate for a solubilized preparation of rat liver mitochondrial proline oxidase [Km = 1.1 x 10(-4) M; Vmax = 5.4 mumol min-1 (mg of protein)-1]. Compound 1b was not a substrate for proline oxidase but dissociated to L-cysteine in this system. At physiological pH and temperature, the hydrogens on the methyl group of 1b underwent deuterium exchange with solvent D2O (k1 = 2.5 X 10(-5) s), suggesting that opening of the thiazolidine ring must have taken place. Indeed, 1b labeled with 14C in the 2 and methyl positions was rapidly metabolized by the rat to produce 14CO2, 80% of the dose being excreted in this form in the expired air after 24 h. It is suggested that these 2-substituted thiazolidine-4(R)-carboxylic acids are prodrugs of L-cysteine that liberate this sulfhydryl amino acid in vivo by nonenzymatic ring opening, followed by solvolysis.

The impact of managed care and current governmental policies on an urban academic health care center.

BACKGROUND: Managed care and governmental policies have restructured hospital reimbursement. We examined reimbursement trends in trauma care to assess the impact of this market driven change on an urban academic health center. METHODS: Patients injured between January 1997 and December 1999 were analyzed for Injury Severity Score (ISS), length of hospital stay, hospital cost, payer, and reimbursement. RESULTS: Between 1997 and 1999, the volume of patients with an ISS less than 9 increased and length of stay decreased. In addition, overall cost, payment, and profit margin increased. Commercially insured patients accounted for this margin increase, because the margins of managed care and government insured patients experienced double-digit decreases. Patients with ISS of 9 or greater also experienced a volume increase and a reduction in length of stay; however, costs within this group increased greater than payments, thereby reducing profit margin. Whereas commercially insured patients maintained their margin, managed care and government insured patients did not (double- and triple-digit decreases). CONCLUSIONS: Managed care and current governmental policies have a negative impact on urban academic health center reimbursement. Commercial insurers subsidize not only the uninsured but also the government insured and managed care patients as well. National awareness of this issue and policy action are paramount to urban academic health centers and may also benefit commercial insurers.

Academic practice groups: strategy for survival.

BACKGROUND: The mission of public academic health centers (puAHC) and their affiliated practice groups (APG) focuses on teaching, research, and the clinical care of at-risk populations. Resources to accomplish this mission, however, are becoming scarce. For puAHC to survive and remain competitive, innovative strategies will need to be developed by the APG. We hypothesized that the integration of a surgical academic practice of the APG with a nonacademic integrated health care delivery system (NAIDS) in a managed care environment would benefit all involved. METHODS: A surgical academic practice was integrated with a NAIDS in a 95% managed care market. Faculty alone provided care the first year, and third-year residents were added the following year. To assess outcome, we collected benefit and cost data for the 1-year period before integration and compared them with the two, 1-year periods after integration. RESULTS: In the second year of integration, revenues from the NAIDS referrals to the puAHC and APG increased 89% and 150%, respectively. The NAIDS' general surgical and endoscopy caseload increased by 25%. Additionally, there was a 92% reduction in operating room technician cost with no increase in operating time per case. Finally, the third-year resident experienced a caseload increase of 163%. CONCLUSIONS: In an environment where resources are diminishing and managed care consists of many large NAIDS that drive referrals and revenue, the integration of a surgical academic practice with a NAIDS benefits all shareholders. Academic practice groups that develop strategies that leverage their competitive advantage will have the best chance of surviving in today's turbulent health care market.

Assessment of the relationship between timing of fixation of the fracture and secondary brain injury in patients with multiple trauma.

BACKGROUND: It has been suggested that early fixation of a fracture is deleterious to eventual neurologic outcome. We undertook this study to determine whether the timing of fracture fixation is correlated to neurologic outcome. METHODS: We retrospectively reviewed patients with severe head and orthopedic injuries requiring fracture fixation. Patients were divided into two groups: early fracture fixation (< 24 hours after injury) and late fracture fixation (> 24 hours after injury). RESULTS: One hundred twenty-three patients met entry criteria. During fracture fixation, the early group had a significant 2-, 3-, and 2-fold increase in crystalloid, blood infusion, and blood loss, respectively. There was no difference in oxygen saturation and systolic blood pressure or episodes of cranial hypertension or hypoperfusion. There was no difference in outcomes as measured by in-hospital complications, stay in the intensive care unit or hospital, mortality rates, hospital discharge or follow-up Glasgow Coma Scores, or long-term orthopedic or neurologic results. CONCLUSIONS: Patients undergoing fracture fixation with severe head injury mandate monitoring of intracranial pressure and perfusion and tailored fluid resuscitation to meet specific organ end points. Integrating end organ perfusion and pressure with meticulous fluid status during the definitive repair phase may reduce the exposure to secondary brain injury in patients undergoing early fracture fixation.

Atypical hyperplasia, proliferative fibrocystic change, and exogenous hormone use.

BACKGROUND: The association between breast cancer development and exogenous hormone use (EHU) is suggested by indirect clinical evidence. We undertook this study to better define the relationship that EHU has with proliferative fibrocystic change (PFC) and atypical hyperplasia (AH). METHODS: Women diagnosed with AH without associated carcinoma from January 1990 to December 1999 were compared with control subjects who underwent breast biopsy procedures during the same interval and who were diagnosed with either a proliferative fibrocystic change (PFC) or a nonproliferative fibrocystic change (NPFC). EHU was defined as the use of estrogen or progesterone taken together or separately within 3 months of biopsy. RESULTS: EHU was significantly higher in patients with AH compared with women with NPFC (P =.01). This observation was also significant if all proliferative change (both AH and PFC) was compared with NPFC (P =.03); it was not significant when PFC alone was compared with NPFC. No significant difference in EHU was demonstrated between women with AH and those with PFC. CONCLUSIONS: There is strong association between AH and EHU. These results support the theory that a continuum exists between hyperplasia and carcinoma and that EHU may influence the transition from one to the other in an undefined subset of women. We encourage our patients with AH to discontinue EHU.

Civilian rectal trauma: a changing perspective.

BACKGROUND: Recently the Organ Injury Scaling Committee of the American Association for the Surgery of Trauma developed a Rectal Injury Scaling System (RISS). Little data exist regarding its clinical utility. METHODS: We retrospectively reviewed 45 patients with rectal injuries to assess the impact of the RISS on patient management and outcome. We compared RISS grade I patients (group I, partial-thickness injury) with patients with grades 2, 3, and 4 injuries (group II, full-thickness injury). RESULTS: Group II underwent distal rectal washout and repair of the injury twice as often and had a significantly higher rate of diversion of the fecal stream. This was associated with a 3-fold increase in complications. The only complications in group I were in patients managed with diversion of the fecal stream and distal rectal washout. CONCLUSIONS: Our data suggest that aggressive surgical management for RISS grade I injury may not be necessary. Implementation of therapy based on the RISS may improve outcomes of civilian rectal trauma.

L-cysteine prodrug protects against cyclophosphamide urotoxicity without compromising therapeutic activity.

2(R,S)-D-ribo-(1',2',3',4'-Tetrahydroxybutyl)-thiazolidine-4(R)-ca rboxylic acid (RibCys) is a prodrug of L-cysteine that releases the sulfhydryl amino acid after nonenzymatic ring opening and hydrolysis. The L-cysteine then elevates glutathione (GSH) levels by stimulating its biosynthesis. RibCys was investigated for its ability to protect CDF1 mice from the potent urotoxicity of cyclophosphamide (CTX) without compromising the therapeutic utility of the drug. RibCys induced a significant reduction in weight loss of the animals and in bladder inflammation at 48 h after CTX administration; however, bladder tissue remained inflamed as compared with that in controls. Bladder histology also showed some pathological changes in the presence of RibCys. In contrast, all parameters of toxicity (body weight loss, bladder inflammation, and pathological abnormalities) had been virtually reversed by day 21 after administration. In tests against L1210 leukemia, RibCys did not interfere with CTX anticancer activity. From these preliminary studies, RibCys appears to be a likely candidate for protecting against long-term CTX toxicity, perhaps reversing the original damage caused by a very high dose, without compromising the therapeutic utility of the alkylating agent.

Chemoprotection against cyclophosphamide-induced urotoxicity: comparison of nine thiol protective agents.

Nine thiol chemoprotective compounds were compared for their abilities to reduce the urotoxicity induced by a high dose (1.5 mmol/kg i.p.) of the cancer chemotherapeutic agent, cyclophosphamide (CTX) in male Swiss-Webster mice. Toxicity was assessed by the change in body weight at 48 h, as well as the relative bladder weight (rbw), both a macroscopic and a microscopic rating of bladder damage, and the glutathione (GSH) status of the bladder and the liver. In addition, the rbw, macroscopic assessment, and GSH measurements were also carried out at 4 h, the point of maximal damage and GSH depletion. The powerful effects of compounds with the D-configuration indicated that direct action by the thiols is their most likely mechanism of action. Indirect action through GSH is unlikely because the D-amino acid cannot support GSH's biosynthesis.

N-Acetyl-DL-penicillamine and acetaminophen toxicity in mice.

N-Acetyl-DL-penicillamine (IIIb), a structural analog of N-acetyl-L-cysteine (IIIa), did not protect mice from lethal doses of acetaminophen (I), whereas IIIa offered protection. This lack of efficacy of IIIb probably is due to the decreased nucleophilicity of its sulfhydryl group compared to that of IIIa, the probable involvement of cysteine in and conjugate addition to the reactive intermediates of I, and the absence of metabolic conversion of IIIb to inorganic sulfate.

Anal condyloma: a comparison between HIV positive and negative patients.

HIV positive and negative patients with anal condylomata were compared to determine an association with squamous cell neoplasia, its disease progression, and response to treatment. From 1992 to 2003, 61 patients were diagnosed with anal condylomata by anal biopsy. Thirty-four patients were HIV+ and 27 patients were considered HIV-. Upon retrospective chart review, details on disease progression, development of malignancy, and subsequent treatment were collected. Sixty-one per cent of HIV+ patients had a neoplastic process in contrast to 25 per cent of HIV- patients (P = 0.005). Five patients demonstrated disease progression, of which four were HIV+. Three HIV+ patients were treated for invasive carcinoma with excision and standard chemoradiation therapy. Two patients with T3 lesions developed recurrence and died. Eighteen HIV+ patients had noninvasive carcinoma and were treated with local excision without recurrence at mean follow-up of 28 months. HIV+ patients were shown to have more condylomata harboring squamous cell neoplasia than HIV- patients. Noninvasive carcinoma can be treated effectively with local excision, independent of HIV status; however, long-term follow-up is needed. Chemoradiation therapy in patients who are relatively healthy and have stage I disease may be successful. The role for chemoradiation in AIDS patients with stage III disease remains unclear.

Mastalgia. Tailoring treatment to type of breast pain.

Breast pain is a common, often distressing problem among women. After significant disease is ruled out, most patients respond to simple reassurance. Others, however, require treatment because symptoms interfere with their lifestyle. The authors offer practical suggestions for tailoring treatment for these patients according to type of pain--cyclical mastalgia, non-cyclical mastalgia, or chest wall pain.

Metabolism of paraldehyde to acetaldehyde by rat liver microsomes.

Paraldehyde (PAL) was shown to be metabolized to acetaldehyde (AcH) by rat liver microsomes in vitro only when the cofactors for the cytochrome P-450 system were present. Microsomes from phenobarbital treated rats significantly increased the amount of AcH produced from PAL. Attempts to inhibit this reaction by addition of SKF-525A to the incubation medium resulted in augmentation of the AcH generated, very likely due to the metabolic deethylation of SKF-525A itself to AcH. Rats pretreated with D-penicillamine and then given PAL excreted 2,5,5-trimethylthiazolidine-4-carboxylic acid (TTCA)-a condensation product of AcH and D-penicillamine-in the urine. These results strongly suggest that PAL is metabolized in vivo by the hepatic microsomal system giving rise to AcH as a metabolite.

Percutaneous endoscopic gastrostomy (PEG) in cancer patients.

Ninety-nine cancer patients underwent PEG placement attempt at Rosewell Park Cancer Institute between January 1, 1985, and December 1, 1987. Ninety-eight of these were successful and were retrospectively reviewed to determine if cancer patients constitute a high-risk group for PEG placement. Procedure-related mortality was 2% and morbidity was 19%. Morbidity of 17% was noted at less than 30 days and 2% had late complications. Six complications were considered serious with peritonitis in 3 and tube loss in 3 patients; an additional 4 patients had a failure of adequate GI tract decompression which was the indication for their PEG placement. Ascites was a major factor in morbidity with 4 of 5 patients with ascites having complications including the 2 deaths. Overall major morbidity was not increased in cancer patients without ascites including a group of patients with carcinomatosis (18 patients) and 22 patients requiring preoperative dilatation and/or tumor ablative procedures. We conclude that morbidity in cancer patients is not increased if one excludes those with ascites from the procedure.

Preliminary biological evaluation of polyamidoamine (PAMAM) Starburst dendrimers.

PAMAM Starburst dendrimers are spherical macromolecules composed of repeating polyamidoamino units. They can be produced in successive "generations," each with a defined size, molecular weight, and number of terminal amino groups. Because of these well-defined characteristics, PAMAMs are finding utility in a variety of applications, many of which are biological in nature. Little is known, however, about the biological behavior of the PAMAMs, which is critical to their use in vivo. Generation 3 (G3; MW = 5,147; 24 terminal amines), 5 (G5; MW = 21,563; 96 amines), and 7 (G7; MW = 87,227; 384 amines) PAMAMs were studied in V79 cells or in Swiss-Webster, mice for a number of biological properties, including (1) in vitro toxicity, (2) in vivo toxicity, (3) immunogenicity, and (4) biodistribution. Potential biological complications were observed only with G7 at the highest level tested. No evidence of immunogenicity was seen. The biodistribution properties of the Starburst dendrimers were rather unusual. G3 showed the highest accumulation in kidney tissue (approximately 15% ID/g over 48 h); G5 and G7 appeared to preferentially localize in the pancreas (peak levels approximately 32% ID/g at 24 h, and approximately 20% ID/g at 2 h, respectively). In addition, G7 showed extremely high urinary excretion, with values of 46 and 74% ID/g at 2 and 4 h, respectively. In general, the dendrimers did not exhibit properties that would preclude their use in biological applications. Depending on the situation (desired endpoint, dose, and generation used), however, the biodistribution of biological preparations should be carefully studied.

Comparison of bursting pressure of sutured, stapled and BAR anastomoses.

The study was undertaken to compare anastomotic bursting pressure (ABP) of colorectal canine anastomoses using three different anastomotic techniques. Biofragmentable anastomotic ring (BAR), stapled, and sutured colon anastomoses were sequentially placed in each of 48 dogs following division of the colon at three equally spaced sites. Four groups of 12 dogs were sacrificed either on day 0, 3, 7, or 28 and ABP and bursting wall tension were determined. The data revealed that BAR anastomoses have the greatest strength on the day of surgery, sutured anastomoses are the strongest on the third day and all are comparable by the 7th day. Bursting pressures for all groups by day 28 approach normal colonic bursting pressure, with any differences likely to be a reflection of variation in anastomotic fibrosis and other factors.

Enterocutaneous fistulas. Effects of total parenteral nutrition and surgery.

Fifty patients with 68 enterocutaneous fistulas were retrospectively reviewed at Hennepin County Medical Center from 1967 to June 1981. Eleven of 28 patients, treated with total parenteral nutrition (TPN) as the initial therapy for their fistulas, had spontaneous closure of 22 of 44 fistulas (three gastroduodenal, 17 small-bowel, two colonic fistulas). There were 35 operative procedures resulting in the closure of 26 fistulas, ten of which had failed to close with TPN (two gastroduodenal, ten small-bowel, and fourteen colonic fistulas). Overall mortality was 22 per cent, with five postoperative deaths and four deaths of patients treated with TPN. Aggressive use of TPN has not obviated the need for surgical closure in the authors' experience, particularly low in the gastrointestinal tract. Management should include TPN for up to four weeks and surgery if there has been no improvement with conservative therapy.