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Biomedical subjects

T J Sullivan

Publications and source records attributed to T J Sullivan.

At least 127 records · Page 7Linked to original sources

Acute desensitization of a patient with cystic fibrosis allergic to both beta-lactam and aminoglycoside antibiotics.

A 15-year-old patient with cystic fibrosis developed urticarial reactions to tobramycin, gentamicin, and cephoperazone, and an anaphylactic reaction to ticarcillin during therapy for an extensive pulmonary infection with Pseudomonas aeruginosa and Staphylococcus aureus. Immediate wheal-and-flare skin tests were positive with tobramycin and with penicilloylpoly-L-lysine. Desensitization with tobramycin in gradually increasing intravenous doses was accomplished during 8 hours. The procedure was complicated by a macular rash that remitted within minutes without therapy, but no symptoms or signs of an allergic reaction to tobramycin were detected during full dose therapy. Skin test responses to tobramycin became negative by the end of the desensitization procedure, whereas the responses to penicilloylpoly-L-lysine and histamine remained positive. A worsening course led to an unsuccessful attempt to desensitize the patient to beta-lactam determinants. Wheezing appeared during the administration of oral doses. This case demonstrates the feasibility of acute, antigen-specific desensitization of an aminoglycoside-allergic patient and the failure to achieve a second, simultaneous desensitization. This patient experienced the first serious reaction to oral penicillin desensitization.

Adolescent↗

Acute and chronic desensitization of penicillin-allergic patients using oral penicillin.

The efficacy, safety and mechanisms of penicillin desensitization were studied in 24 adults and two children with serious infections that required therapy with a beta-lactam drug. Indications for desensitization included debilitating as well as life-endangering infections. Increasing oral doses of phenoxymethyl penicillin were administered at 15-minute intervals to a cumulative dose of 1.3 million units. Parenteral therapy with the beta-lactam drug of choice was instituted at that point. Immunologic complications of desensitization or therapy, ranging from pruritus to serum sickness, occurred in 12 patients. The appearance of gradually worsening wheezing led to abandonment of the procedure in one subject with cystic fibrosis and severe pulmonary disease. The remaining 25 patients were successfully desensitized and received full-dose parenteral therapy. Chronic desensitization was maintained in seven individuals with twice daily oral penicillins for 3 weeks to more than 2 years. No allergic complications of chronic desensitization or recurrent full-dose parenteral therapy were detected. Skin test reactions to one or all penicillin determinants became negative in 11 of 15 patients retested after acute desensitization. Two desensitized patients became skin test negative, remained skin test negative after cessation of desensitization, and tolerated subsequent beta-lactam therapy without allergic reactions or resensitization. The results of this study provide new evidence that acute and chronic penicillin desensitization is useful and an acceptably safe approach and suggest that antigen-specific mast cell desensitization contributes to the protection against anaphylaxis.

Administration, Oral↗

Functional heterogeneity of human mast cells from different anatomic sites: in vitro responses to morphine sulfate.

The responses of human cutaneous, pulmonary, intestinal, and cardiac tissue mast cells to the histamine-releasing agent morphine sulfate (MS) were investigated in vitro. Human cutaneous mast cells released significant amounts of histamine in the presence of 1 to 100 mumol/L concentrations of MS. Histamine release was detectable within 5 minutes after challenge and was complete by 15 minutes. A maximal histamine release of 21.6% (+/- 1.4 SEM) was observed after stimulation with 100 mumol/L of MS. This MS effect was inhibited by the opiate receptor antagonist naloxone with a 59% inhibition detected at equimolar concentrations and an 88% inhibition occurring in the presence of a tenfold molar excess of naloxone. Naloxone did not alter the cutaneous mast cell response to the calcium ionophore A23187. Human mast cells derived from pulmonary, intestinal, and cardiac tissues, as well as blood basophils, did not release histamine after stimulation with 1 to 200 mumol/L of MS, whereas each of these cell preparations responded to an IgE-mediated stimulus. The results of this study demonstrate that cutaneous mast cells release inflammatory mediators after stimulation by MS, whereas mast cells residing in lung, heart, and gastrointestinal tissues do not. These observations indicate that human mast cells in different anatomic sites can vary in their functional responses.

Basophils↗

Use of three probes to assess the influence of sex on hepatic drug metabolism.

Clearances of phenytoin (PHT), ethosuximide, and theophylline were estimated by a single-dose, single-sample strategy in healthy, young adult men and women. PHT concentrations were measured in salivary ultrafiltrates, ethosuximide concentrations were measured in saliva, and theophylline concentrations were measured in plasma. Estimates of the clearances of these three probes of hepatic drug-metabolizing enzymes revealed a trend toward slightly lower clearances among women compared to men: mean PHT clearance 15% lower, ethosuximide clearance 27% lower, and theophylline clearance 14% lower. However, only differences in ethosuximide clearances were statistically significant. The use of oral contraceptive steroid (OCS) drugs on PHT and ethosuximide clearance was examined, and no significant effects were detected.

Adult↗

Acute synovial fluid eosinophilia associated with delayed pressure urticaria: a role for mast cells?

We report a case of exercise induced joint effusion with synovial fluid (SF) eosinophilia of 9,540/mm3 in a patient with delayed pressure urticaria. The SF eosinophilia was an acute but transient event associated with some evidence of local complement activation. Histologic assessment revealed a normal synovial membrane but with no detectable intact mast cells. These observations suggest that mast cells and eosinophils acting in concert can cause joint inflammation.

Acute Disease↗

Changes in phospholipid metabolism during B lymphocyte activation.

We have examined phospholipid metabolism in murine B lymphocytes stimulated with anti-Ig bound to Sepharose. T cell-depleted splenic B lymphocytes cultured with Sepharose-coupled, affinity-purified goat anti-mouse Ig (GAMIg) increased the incorporation of 32PO4 into phosphatidic acid and phosphatidylinositol within 3 hr and increased [3H]-thymidine uptake at 48 hr. No increase in labeling was observed in phosphatidylethanolamine, phosphatidylcholine, or phosphatidylserine. Based on both negative and positive selection procedures, it was demonstrated that these responses occurred in B lymphocytes. In contrast to the thymidine uptake response of the GAMIg-stimulated B lymphocytes, the phospholipid response did not require the presence of accessory cells or exogenous cytokines. The same selective changes in phospholipid metabolism were observed in neoplastic B lymphocytes (BCL1) after treatment with Sepharose anti-mu, but not with Sepharose anti-Ia or Sepharose normal Ig. The dose-response relationships of 32PO4 incorporation into phosphatidic acid and phosphatidylinositol and [3H] thymidine uptake were nearly identical in BCL1 cells. The results of these experiments indicate that interaction of B lymphocytes with insolubilized anti-Ig results in prompt and selective changes in phospholipid metabolism that appear to be correlated with B lymphocyte proliferation.

Animals↗

Biphasic and protracted anaphylaxis.

We performed a prospective study of anaphylaxis in 25 consecutive patients. Three distinct clinical patterns were observed: uniphasic, biphasic, and protracted anaphylaxis. Thirteen patients (52%) experienced a single episode. Biphasic anaphylaxis occurred in five patients (20%), two episodes of hypotension or laryngeal edema separated by asymptomatic intervals of 1 to 8 hours. Initial therapy included large doses of glucocorticoids in three of the five patients. Seven patients (28%) suffered hypotension, lower respiratory obstruction, or laryngeal obstruction that persisted 5 to 32 hours despite vigorous therapy that included systemic glucocorticoids. Recurrent or prolonged reactions were 2.8-fold more likely if the onset was 30 or more minutes after exposure to the stimulus or if the offending agent had been administered by mouth (p less than 0.03). Fatal reactions occurred in one patient who was taking propranolol and in one who was adrenal insufficient. The results of this study demonstrate that biphasic and protracted anaphylaxis are common, despite glucocorticoid therapy. Potentially life-endangering recurrences occurred in five (28%) of the 18 patients who responded to initial therapy. These observations indicate that patients should be followed carefully after apparent remission of anaphylaxis.

Adolescent↗

Inability of ibuprofen to alter single dose phenytoin disposition.

The effect of ibuprofen treatment (1600 mg day-1 per os for 7 days) on single dose (300 mg per os) dispositional parameters of phenytoin (DPH) was evaluated in 10 healthy males. Ibuprofen slightly increased the free fraction of DPH from mean (+/- s.d.) value of 6.9 (+/- 0.7)% to 7.8 (+/- 0.3)% (P less than 0.01). DPH total clearance (CL/F) was not significantly changed going from a value of 0.027 (+/- 0.009) 1 h-1 kg-1 to 0.032 (+/- 0.014) 1 h-1 kg-1 (0.05 less than P less than 0.1). Intrinsic unbound DPH clearance (CLuint/F) was unaffected by ibuprofen treatment. Neither DPH's apparent volume of distribution (V/F) nor the apparent volume of distribution of unbound DPH (Vunb/F) were significantly altered by ibuprofen treatment. The slight changes in DPH plasma protein binding that are due to concurrent ibuprofen treatment in doses of 1600 mg day-1 are not likely to produce important changes in DPH dispositional parameters.

Adult↗

Bioavailability of a new oral methoxsalen formulation. A serum concentration and photosensitivity response study.

A new encapsulated liquid preparation of methoxsalen (soft gelatin capsule) was compared with the currently marketed hard gelatin capsule form and with an oral solution of methoxsalen in a random crossover design. Serial serum samples were collected from 25 healthy adult subjects and assayed by a high-performance liquid chromatography technique. Additionally, photosensitivity was determined by serial testing in 12 subjects. The soft-capsule formulation resulted in a 59% increase in extent of absorption and in a greater rate of absorption of methoxsalen than from the hard capsule. This was demonstrated by consistently higher peak serum concentrations (225 vs 199 ng/mL), which occurred at earlier times (1.8 vs 3.0 hours) following administration of the soft capsule. Photosensitivity testing confirmed these results, as photosensitivity was greater (9.53 vs 12.68 J/cm2) and reached a maximum earlier (1.5 vs 4.25 hours) following administration of the soft capsule. The soft capsule can be considered equivalent to the oral solution in both serum concentrations (peak concentration, 231 vs 225 ng/mL, and time of peak, 1.6 vs 1.8 hours) and photosensitivity response (maximum photosensitivity, 9.24 vs 9.53 J/cm2, and time of maximum photosensitivity, 1.32 vs 1.50 hours).

Administration, Oral↗

Penicillin allergy and desensitization in serious infections during pregnancy.

Penicillin allergy presents a major obstacle to the successful management of some antepartum infections. We studied 15 pregnant women with histories of penicillin allergy confirmed by positive immediate wheal-and-flare skin tests. Thirteen had syphilis, one listeria sepsis, and one Streptococcus viridans endocarditis. Each patient was desensitized over four to six hours by oral administration of increasing doses of penicillin V. At the completion of the procedure, full-dose parenteral therapy with penicillin G or ampicillin was instituted. No extracutaneous reactions were detected. Five of the subjects (33 per cent) experienced pruritus (three) or urticaria (two), but no interruption of desensitization or therapy was necessary. All clinically apparent maternal infections were cured. The pregnancy complicated by listeriosis aborted in the first trimester. The 11 neonates delivered to date are normal. These results indicate that oral desensitization is an acceptably safe approach to therapy in pregnant women who are allergic to penicillin and have infections that require beta-lactam drugs.

Desensitization, Immunologic↗

A new approach to establishing individualized maintenance doses of phenytoin.

A new method for arriving at individualized doses of phenytoin (PHT) is described. This method, designated the eta method, operates on two measurements of unbound plasma PHT. One plasma sample is collected 48 h after a single, oral PHT dose (approximately 4.5 mg/kg). From the single dose, single sample measurements of plasma unbound PHT individual estimates of intrinsic unbound PHT clearance (CLuint) can be made. With the use of CLuint and weight-adjusted mean population values of Vmax predicted plasma concentrations of unbound PHT for 11 subjects exhibited a mean prediction error (mpe) of 0.07 mg/L with 95% confidence limits of -0.11 to 0.26 mg/L and an error coefficient of variation [root mean squared error (rmse)/mean unbound concentration at steady state (Cuss)] of 0.4. The second plasma unbound PHT is collected at steady state. From CLuint and one Cuss measurement, Vmax and Km can be directly calculated. Doses calculated by the eta method to produce plasma unbound PHT concentrations of approximately 1.0 mg/L were identical to those calculated by the Bayesian method to yield plasma total PHT concentrations of approximately 10 mg/L. When those doses were administered to six subjects, the plasma unbound PHT concentrations predicted by the eta method exhibited a mpe of -0.13 mg/L, with 95% confidence limits ranging from -0.33 to 0.06 mg/L and an error coefficient of variation of 0.2. The plasma PHT concentrations predicted by the Bayesian method exhibited an mpe of -1.30 mg/L, with 95% confidence limits of -4.02 to 1.42 mg/L and an error coefficient of variation of 0.3. Values of Vmax and doses of PHT calculated to produce a Cuss of 1.0 mg/L calculated by the eta method were nearly identical to Vmax values and doses of PHT calculated by Bayesian double feedback (based on two different Css values) to produce a Css of 10.0 mg/L.

Adult↗

Advances in the diagnosis and management of penicillin allergy.

IgE-mediated acute systemic reactions to penicillin continue to be an important clinical problem. Advances in our understanding of the immunochemistry of penicillin allergy have improved our ability to predict and to avoid these reactions. Immunodiagnostic techniques can identify patients at risk for anaphylaxis to beta-lactam antibiotics with a high degree of precision. Clinical and immunologic studies have demonstrated that penicillin allergic subjects may have allergic reactions to cephalosporins although the absolute frequency of clinical cross-reactions is not clear. If beta-lactam drugs are needed for treatment of penicillin allergic patients, acute desensitization appears to be an acceptably safe procedure for avoiding anaphylaxis.

Anti-Bacterial Agents↗

In vivo strain patterns in the four major canine knee ligaments.

Using mercury gauges, we measured strains in vivo in the four major ligaments of the canine knee joint as the tibia was loaded in valgus or varus at fixed angles of knee flexion. Free axial rotation of the tibia on the femur was allowed. Forces up to 78.4 N were applied to the tibia, producing moments of approximately 9 N-m. We found that with valgus loading, significant strains were observed in the medial collateral ligament at extension. At 45 degrees of flexion, the medial collateral, posterior cruciate, and anterior cruciate were strained. At 90 degrees of flexion, all four ligaments were strained. With varus loading, significant strains were found in the lateral collateral and anterior cruciate at extension. The lateral collateral and anterior cruciate ligaments were strained at 45 degrees of flexion. At 90 degrees of flexion, the lateral collateral, anterior cruciate, and posterior cruciate ligaments were strained. With valgus loading, the tibia rotated internally and the degree of axial rotation increased with flexion. External rotation of the tibia resulted from varus loading, and was relatively constant through the range of flexion. Thus when axial rotation is allowed, stability of the knee in response to valgus and varus loads is maintained by the cruciates as well as the collaterals, and the role of the cruciates increases with flexion and axial rotation.

Animals↗

Allergic reactions to antimicrobial agents: a review of reactions to drugs not in the beta lactam antibiotic class.

Allergic reactions to antimicrobial drugs are common causes of morbidity but rarely of death. Despite the lack of proven immunodiagnostic tests for reactions to the non-beta-lactam drugs, the agents that cause reactions usually can be identified by analysis of their propensity to cause reactions, temporal relationships of exposure to reactions, and remission of reactions when the drugs are discontinued. Measurements of plasma histamine levels, high-molecular-weight neutrophil chemotactic factor, and heparin-like activity and of urinary histamine and prostaglandin D2 metabolites should help clarify the role of mast cell mediator release in the various forms of these reactions. Measurements of C3a, C4a, and C5a, in biologic fluids should facilitate analysis of the contributions of complement activation to the reactions observed. Assessment of these pathophysiologic parameters should provide a more rational basis for the selection of specific pharmacologic interventions to suppress allergic reactions. If no alternative drugs are available, infected patients who are allergic often can be gradually desensitized with the agents to which they are allergic. While much important work remains to be completed, current approaches can minimize the morbidity and mortality rates associated with allergic reactions to antimicrobial agents.

Anti-Bacterial Agents↗