Disposition of cefmetazole in healthy volunteers and patients with impaired renal function.

The disposition of cefmetazole was studied in 25 subjects with various degrees of renal function after a 1,000-mg, constant-rate, 30-min intravenous infusion of cefmetazole sodium. In six subjects with creatinine clearance (CLCR) of greater than 90 ml/min per 1.73 m2 (group 1), the terminal elimination half-life (t1/2 beta) was 1.31 +/- 0.54 h (mean +/- standard deviation), cefmetazole total body clearance (CLP) was 132.8 +/- 25.1 ml/min per 1.73 m2, and volume of distribution at steady state was 0.165 +/- 0.025 liter/kg. The fraction of dose excreted unchanged in the urine was 84.0% +/- 26.1%. Subjects with CLCRS of 40 to 69 (group 2, n = 6) and 10 to 39 (group 3, n = 6) ml/min per 1.73 m2 demonstrated prolongation of the t1/2 beta (3.62 +/- 1.06 and 5.93 +/- 1.81 h, respectively) and significant reductions in cefmetazole CLP (52.8 +/- 14.3 and 30.2 +/- 10.2 ml/min per 1.73 m2, respectively), compared with group 1. In seven subjects on chronic hemodialysis (group 4) studied during an interdialytic period, the cefmetazole t1/2 beta was increased to 24.10 +/- 8.12 h and the CLP was reduced to 6.8 +/- 2.1 ml/min per 1.73 m2. Cefmetazole CLP correlated positively with CLCR (r = 0.951, P less than 0.001): CLP = (1.181 . CLCR) -- 0.287. The disposition of cefmetazole was also assessed in six group 4 subjects during an intradialytic period. The t1/2 beta during hemodialysis (2.09 +/- 0.69 h) was significantly shorter than that observed during the interdialytic period. The hemodialysis clearance of cefmetazole was 86.1 +/- 20.1 ml/min, and the fraction of cefmetazole removed during hemodialysis was 59.8% +/- 5.9%. It is recommended that patients with renal insufficiency received standard doses of cefmetazole at extended intervals and patients on maintenance hemodialysis received standard doses after hemodialysis.

Mechanistic studies of the metabolic chiral inversion of (R)-ibuprofen in humans.

The metabolic chiral inversion of R-(-)-ibuprofen has been studied in human subjects by means of specific deuterium labeling and stereoselective gas chromatography-mass spectrometry methodology. After simultaneous p.o. administration of a mixture of R-(-)-ibuprofen (300 mg) and R-(-)-[3,3,3-2H3]ibuprofen (304 mg) to four adult male volunteers, the enantiomeric composition and deuterium content of the drug in serum, and of the drug and its principal metabolites in urine, were followed over a period of 24 hr. The results of these analyses indicated that: 1) conversion of R-(-)- to S-(+)-ibuprofen takes place with complete retention of deuterium at the beta-methyl (C-3) position; 2) chiral inversion of R-(-)-[2H3]ibuprofen is not subject to a discernible deuterium isotope effect; and 3) replacement of the beta-methyl hydrogen atoms by deuterium has no effect on any of the serum pharmacokinetic parameters for R-(-)- or S-(+)-ibuprofen. These data indicate that the process whereby R-(-)-ibuprofen undergoes metabolic inversion in human subjects does not involve 2,3-dehydroibuprofen as an intermediate, and that the underlying mechanism cannot, therefore, entail a desaturation/reduction sequence.

Human buccal absorption of flurbiprofen.

The buccal absorption of flurbiprofen was studied in normal men to quantify the transport from the oral cavity in humans and to evaluate the closed-perfusion cell apparatus as a means to study drug transport across externally accessible biologic membranes. Flurbiprofen was buccally absorbed by a passive diffusional mechanism and the rate of absorption was pH dependent. Membrane permeability coefficients for flurbiprofen were 4.3 x 10(-4) cm/sec at pH 5.5 and 2.1 x 10(-5) cm/sec at pH 7.0. These findings are in agreement with the pH relationship for buccal transport observed in dog experiments. Delineation of the effective permeability coefficients into components for the aqueous boundary layer and the lipoidal buccal membrane allowed for the prediction of the extent of absorption of the drug over a period of time. It was concluded that the buccal membranes of the human and dog were essentially lipoidal membranes with equivalent permeabilities and no evident aqueous pore pathways.

Effect of intranasal histamine on nasal mucosal blood flow and the antidiuretic activity of desmopressin.

The effects of exogenous histamine on nasal mucosal blood flow and the systemic activity of intranasally administered desmopressin, a vasopressin analogue, were studied in normal volunteers. Ten subjects received either saline or histamine (1, 20, 100, and 500 micrograms) by intranasal spray. Maximal nasal mucosal blood flow response, determined by laser doppler velocimetry, demonstrated a significant (P less than 0.05) linear relationship to histamine dose. Eight additional subjects received each of the following intranasal treatments: 20 micrograms histamine followed by 10 micrograms desmopressin; normal saline followed by 10 micrograms desmopressin; 20 micrograms histamine followed by vehicle; or normal saline and vehicle. Nasal blood flow was determined before and after each treatment. Desmopressin activity was assessed by measuring urine osmolality, flow rate, electrolyte, and creatinine concentration for 24 h after each treatment. The effect of histamine and desmopressin was greater than desmopressin alone, with respect to nasal blood flow response (103 +/- 24 vs. 4 +/- 17%, mean +/- SEM, P less than 0.02), initial urine osmolality (520 +/- 123 vs. 333 +/- 75 mosM, P less than 0.03), urine electrolyte (potassium, 45 +/- 11 vs. 28 +/- 7 meq/liter; sodium, 68 +/- 21 vs. 36 +/- 8 meq/liter, P less than 0.03) and creatinine concentrations (95 +/- 23 vs. 60 +/- 13 mg/dl, P less than 0.03), and the duration of decrease in urine flow rate compared with saline and vehicle. These results suggest that the systemic activity of intranasal desmopressin is enhanced by increasing local nasal blood flow and are consistent with increased transnasal absorption of the peptide.

Beneficial effects of ibuprofen in oleic acid induced lung injury.

Metabolites of arachidonic acid, particularly thromboxanes, have been implicated as mediators of lung injury. The formation of thromboxane A2 can be decreased by glucocorticoid steroids by inhibiting the enzyme phospholipase A2 or by ibuprofen which inhibits fatty acid cyclooxygenase. This study was performed to determine if ibuprofen, methylprednisolone, or a combination of both could improve the pulmonary injury induced by oleic acid. Five groups of dogs were instrumented with pulmonary artery and extravascular lung water (EVLW) catheters and ventilated with 100% O2. Serial determinations of hemodynamic and pulmonary parameters were performed before and after oleic acid infusion. Plasma immunoreactive thromboxane B2 (iTxB2) and ibuprofen levels were also determined. Oleic acid rapidly induced a significant pulmonary injury as evidenced by hypoxemia and increases in extravascular lung water. Plasma iTxB2 rose significantly in the control group receiving only oleic acid. Pulmonary function and hemodynamic parameters were not changed by ibuprofen infusion alone. Ibuprofen attenuated the oleic acid induced hypoxemia and increased EVLW but did not significantly reduce plasma iTxB2. Methylprednisolone did not prevent the increase in plasma iTxB2 and was less effective than ibuprofen in preventing hypoxemia and increases in EVLW. The combination of ibuprofen and methylprednisolone did significantly inhibit the production of iTxB2, however in combination they protected less against the hypoxemia and increased EVLW than either agent alone. These results indicate that ibuprofen may have a protective effect in oleic acid induced lung injury that is not mediated through the inhibition of fatty acid cyclooxygenase. The results are also further evidence that thromboxane is probably not a pathogenetic factor in oleic acid induced lung injury.

Food effects on propranolol systemic and oral clearance: support for a blood flow hypothesis.

The influence of a high-protein meal as compared to fasting on the disposition of simultaneous intravenous and oral doses of propranolol, as well as on indocyanine green clearance, was examined in six normal subjects. The intravenous dose (0.1 mg/kg) was unlabeled propranolol and the oral dose (80 mg) was a stereospecifically deuterium-labeled pseudoracemate of propranolol. Systemic clearance of propranolol increased 38%, from 1005 +/- 57 to 1384 +/- 115 ml/min (mean +/- SE; P less than 0.05) as a result of the meal, with no change in t1/2 or apparent volume of distribution. A 12% decrease in oral clearance occurred with the meal but was not statistically significant (3717 +/- 185 ml/min, fasting; 3245 +/- 498 after meal), whereas bioavailability increased 67% (27.2% +/- 1.7% fasting; 45.5% +/- 4.3% after meal; P less than 0.01). Estimated hepatic blood flow, as measured by indocyanine green clearance, rose 34% 60 minutes after the meal (1719 +/- 155 ml/min fasting; 2304 +/- 218 ml/min after meal; P less than 0.02). A difference was observed in the oral clearance of the propranolol enantiomers in the fasting state, but this difference was unaffected by the meal. These alterations in propranolol disposition, as the result of a high-protein meal, are consistent with a transient increase in hepatic blood flow.

Partial metabolic clearances as determinants of the oral bioavailability of propranolol.

The objective of this study was to determine the relationships between the total oral clearance of propranolol and the partial clearances through its primary metabolic pathways, i.e. glucuronidation, side-chain oxidation and ring oxidation. Seven young, white males were given single 80 mg oral doses of the drug together with tritium-labelled propranolol. Plasma propranolol was measured by GC/MS and fourteen metabolites were measured in urine by h.p.l.c. with radiometric detection. The total oral clearance of propranolol in these subjects varied about three-fold, from 27.5 to 71.4 ml min-1 kg-1. The clearance through glucuronidation was very similar in all subjects, ranging from 6.8 to 9.9 ml min-1 kg-1. The clearance through side-chain oxidation varied 2.4-fold, from 10.9 to 25.8 ml min-1 kg-1. Increased clearance through this pathway correlated with increased total oral clearance (r = 0.84; P less than 0.02). The clearance through ring oxidation varied as much as 5.6-fold, from 7.5 to 41.8 ml min-1 kg-1. Increased clearance through this pathway correlated highly with increased total oral clearance (r = 0.94; P less than 0.002). These observations indicate that the intersubject variability in the oral clearance of propranolol in young, white males is due mainly to differences in the activity of the ring oxidation pathway, to some extent in the side-chain oxidation pathway, but not to differences in the glucuronidation pathway. The partial metabolic clearance approach adopted in this study may be useful in the investigation of factors influencing the oral bioavailability of propranolol.

Human internal mammary artery produces more prostacyclin than saphenous vein.

The patency rate of internal mammary artery grafts is reported to be better than that of saphenous vein grafts in myocardial revascularization operations. To identify a possible biochemical explanation for this phenomenon, we studied the production of prostacyclin by the internal mammary artery and saphenous vein in 11 patients. Segments of internal mammary artery and saphenous vein from each patient were incubated in Krebs-Henseleit buffer at 37 degrees C. After 15 minutes, the basal production of 6-keto-prostaglandin F1 alpha (prostacyclin metabolite) by the internal mammary artery was 152 +/- 39 pg/mg wet weight (mean +/- standard error of the mean), whereas the saphenous vein produced only 68 +/- 17 pg/mg (p less than 0.001). After 30 minutes, the internal mammary artery produced 179 +/- 42 pg/mg, whereas the saphenous vein produced 75 +/- 18 pg/mg (p less than 0.001). After the basal incubation period, the vessels were incubated with arachidonic acid (prostaglandin substrate) for 15 minutes. The internal mammary artery produced 49.4 +/- 9.9 pg/mg, whereas the saphenous vein produced only 22.6 +/- 9.8 pg/mg (p less than 0.01). These observations suggest that the capacity of the internal mammary artery to produce prostacyclin in both a basal and a stimulated state is greater than that of the saphenous vein. Since prostacyclin is a potent vasodilator and inhibitor of platelet function, these results provide a possible biochemical explanation for the clinically observed better patency rate of internal mammary artery grafts.

Sulindac does not preserve renal prostacyclin synthesis during endotoxemia.

Previous reports have suggested that sulindac is a unique non-steroidal anti-inflammatory (NSAID) agent, because it does not inhibit renal prostaglandin synthesis in doses that inhibit platelet thromboxane B2 synthesis when tested ex vivo. NSAIDS are of potential therapeutic benefit in the treatment of septic or endotoxic shock. Therefore, this study was designed to investigate the proposed unique action of sulindac in experimental endotoxemia. In the current study, the effect of sulindac on aortic, portal and renal venous immunoreactive (i) 6-keto-PGF1 alpha levels, the stable metabolite of prostacyclin, was investigated during endotoxemia in the rat. In doses sufficient to reduce the elevation in aortic and portal venous plasma i6-keto-PGF1 alpha levels, sulindac also significantly (p less than 0.05) attenuated the elevated renal venous plasma 6-keto-PGF1 alpha levels, compared to the vehicle group. Using lower doses, sulindac failed to reduce the endotoxin associated increase in either aortic or renal venous plasma i6-keto- PGF1 alpha levels. Thus, sulindac failed to demonstrate any selective sparing effect on renal prostacyclin generation during endotoxemia.

Dazoxiben in human sepsis and adult respiratory distress syndrome.

Levels of thromboxane B2 (TxB2), the stable metabolite of thromboxane A2, are elevated in human and experimental septic shock. The thromboxane synthetase inhibitor dazoxiben has improved survival and decreased pulmonary hypertension in experimental endotoxemia. A randomized prospective study of 10 patients with the clinical diagnosis of sepsis and early adult respiratory distress syndrome (hypoxemia, radiologic evidence of the syndrome, and intrapulmonary shunt greater than 20%) was performed to test the efficacy of dazoxiben in ameliorating the effects of human sepsis. Five subjects received dazoxiben and five received placebo. Dazoxiben, 100 mg, or placebo was injected intravenously every 4 hours for a maximum of 72 hours. Plasma immunoreactive TxB2 (iTxB2) levels were determined by radioimmunoassay. Before dazoxiben, the plasma iTxB2 level was 752 +/- 261 pg/ml (n = 5) and was reduced within 1 hour to 333 +/- 137 pg/ml. The plasma levels of iTxB2 remained significantly decreased with subsequent doses of dazoxiben and it was 201 +/- 67 pg/ml (n = 4) 60 hours after dosing. In contrast, placebo had no significant effect on plasma iTxB2 levels (n = 5) throughout the entire period of observation. Dazoxiben did not induce any significant changes in pulmonary or systemic vascular resistance, intrapulmonary shunting, clotting studies, or extravascular lung water. One of the five subjects in the placebo group died and two of the five subjects in the dazoxiben group died. We conclude that dazoxiben was safe and effectively lowered plasma iTxB2 levels in patients with sepsis and incipient adult respiratory distress symptom, but did not significantly alter the hemodynamic and pulmonary sequelae of established sepsis.

Quantitative account of propranolol metabolism in urine of normal man.

A recent study, identifying several sulfate conjugates, appears to have led to a full qualitative account of propranolol metabolism in man. The objective of the present investigation was to determine the quantitative fate of propranolol, including the relationship between the primary metabolic pathways, i.e. glucuronidation, side-chain oxidation and ring oxidation. Single 80-mg oral doses of propranolol together with [3H]propranolol were administered to seven normal subjects. Urinary metabolites were determined by HPLC with radiometric detection after hydrolysis of glucuronic acid conjugates and fractionation by solvent extraction. About 90% of the dose was recovered in urine. Twelve metabolites accounted for 91% of the recovered dose. When examining the metabolites based on the primary metabolic pathways, 17% of the dose (range, 10-25%) was going through glucuronidation, 41% (range, 32-50%) through side-chain oxidation, and 42% (range, 27-59%) through ring oxidation. These data show that the net elimination of propranolol is largely due to oxidative metabolism. The relative contribution of the primary pathways is well reflected by the four major propranolol metabolites, i.e. propranolol glucuronide, naphthoxylactic acid, and the glucuronic acid and sulfate conjugates of 4'-hydroxypropranolol. These observations should greatly facilitate future studies of the biochemical mechanisms of propranolol disposition.

Protective effects of trans-13-APT, a thromboxane receptor antagonist, in endotoxemia.

The effect of the thromboxane A2/prostaglandin H2 (TxA2/PGH2) receptor antagonist trans-7[2-(p-hydroxyphenethylamino)-cyclopentyl]-heptanoic acid (trans-13-APT) on certain pathogenic sequelae of endotoxic shock and associated changes in arachidonic acid metabolism in the rat was investigated. trans-13-APT, an analog of 13-azaprostanoic acid, was synthesized and found to block human platelet aggregation induced by the thromboxane mimetic U46619. Pretreatment with trans-13-APT did not significantly alter the elevations in plasma immunoreactive (i) TxB2 or iPGE, 0.5 or 4 h after the intravenous administration of Salmonella enteritidis endotoxin. However, in the trans-13-APT-pretreated group, 4 h after administration of the endotoxin, plasma i6-keto-PGF1 alpha was significantly (p less than 0.05) reduced to 1.2 +/- 0.3 ng/ml (n = 17) compared with vehicle-treated rats (2.4 +/- 0.5 ng/ml; n = 18). The elevation in plasma i6-keto-PGF1 alpha seen 0.5 h (n = 17/group) after endotoxin infusion was not altered by trans-13-APT. trans-13-APT also significantly (p less than 0.05) attenuated the endotoxin-induced fall in platelet count (135 +/- 27 X 10(3)/mm3 vs. 350 +/- 65 X 10(3)/mm3 and hypoglycemia (73 +/- 9 vs. 97 +/- 7 mg/dl), but not the leukopenia. Since the reticuloendothelial system may be an important source of iTxB2 and i6-keto-PGF1 alpha during endotoxemia, in vitro studies were conducted with adherent peritoneal cells. High concentrations of trans-13-APT (50 and 100 microM) significantly reduced (p less than 0.05) basal but not endotoxin-induced synthesis of iTxB2 and i6-keto-PGF1 alpha by isolated adherent rat peritoneal cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of oleic acid on pulmonary capillary leak and thromboxanes.

The role of arachidonic acid metabolites in oleic acid-induced lung injury in anesthetized dogs was investigated. Oleic acid was administered as a bolus injection into the pulmonary artery in the following dose sequence: 0.05, 0.10, and 0.20 ml/kg at 30, 60, and 120 min, respectively, after either indomethacin (10 mg/kg iv) or vehicle. A control group (n = 3) received normal saline instead of oleic acid. Measurements of hemodynamic parameters, mean systemic (MAP), pulmonary capillary wedge, and pulmonary artery pressures (PAP), cardiac output, arterial blood gases, extravascular lung waters (EVLW) by thermaldye double indicator dilution techniques and plasma immunoreactive thromboxane B2 ( iTxB2 ), by radioimmunoassay were obtained at zero time (baseline) and 20 min following each oleic acid injection. A new noninvasive technique was employed to measure pulmonary capillary protein leak by the scintigraphic analysis of intravenously administered technetium-99m radiolabeled human serum albumin ( 99mTc -HSA) in the cardiac and lung regions. Oleic acid injection caused a significant dose related fall in MAP (P less than 0.0002), arterial pO2 (P less than 0.0001), and cardiac output (P less than 0.001), and increases in EVLW (P less than 0.003) and plasma iTxB2 (P less than 0.02) in the vehicle pretreated animals, while mean PAP remained unchanged. In contrast, in the indomethacin pretreated dogs, MAP, EVLW, cardiac output, and plasma iTxB2 levels did not change from baseline values and there was an increase in mean PAP. Pulmonary vascular resistance was significantly elevated (P less than 0.05) in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Stereoselective clearance and distribution of intravenous propranolol.

Our objective was to determine the kinetics of (+)- and (-)-propranolol after intravenous doses of racemic drug. Five normal subjects received 0.1 mg/kg of a pseudoracemate of propranolol that consisted of deuterium-labeled (+)-propranolol and unlabeled (-)-propranolol. Plasma concentrations of (+)- and (-)-propranolol as measured by gas chromatography-mass spectrometry demonstrated enantiomeric differences in systemic clearance (Cls) [(+)-propranolol, 1.21 +/- 0.15 l/min; (-)-propranolol, 1.03 +/- 0.12 l/min; P less than 0.01] and apparent volume of distribution (Vd) [(+)-propranolol, 4.82 +/- 0.34 l/kg; (-)-propranolol, 4.08 +/- 0.33 l/kg; P less than 0.001], but no difference in distribution or elimination t1/2s (t1/2 beta 3.5 hr). The higher Cls of (+)-propranolol suggests stereoselective hepatic elimination. The higher apparent Vd of (+)-propranolol is mainly related to its lower plasma binding [(+)-propranolol, 20.3 +/- 0.8% unbound; (-)-propranolol, 17.6 +/- 0.7% unbound; P less than 0.001]. There was no stereoselective uptake by red blood cells. These findings demonstrate that multiple stereoselective mechanisms are involved in the disposition of propranolol and determine the access of the drug to active sites.

Use of nifedipine as an adjunct to current antihypertensive therapy.

Ten hypertensive patients with poor responses to standard antihypertensive therapy were treated with the calcium channel antagonist nifedipine in an attempt to obtain better BP control. The drug was highly effective in significantly lowering BP immediately (average decrease, 58/29 mm Hg) and after three to eight weeks of maintenance therapy (average decrease, 49/27 mm Hg), with no significant change in heart rate observed at either time. No adverse interactions between nifedipine and other concurrent medications, including digoxin and beta-adrenergic blockers, were noted. Drug-related side effects of tachycardia or flushing necessitated the withdrawal of nifedipine therapy in two patients. We conclude that nifedipine may be safely employed in an outpatient setting as a useful adjunct to current antihypertensive drug regimens.

Stereoselective binding of propranolol to human plasma, alpha 1-acid glycoprotein, and albumin.

Our aim was to determine possible stereoselectivity in the plasma binding of propranolol. Equilibrium dialysis with plasma from seven healthy subjects and a deuterium-labeled pseudoracemate of propranolol was used. Plasma binding of the propranolol enantiomers differed with the unbound fraction of (-)-propranolol (22 +/- 2%; mean +/- SE) being smaller than that of (+)-propranolol (25.3 +/- 1.9%). The (-)/(+)-propranolol ratio for the unbound fraction, a measure of the stereoselectivity, was 0.86 +/- 0.02. There was an inverse correlation between the unbound (-)/(+)-propranolol ratio in individual subjects and overall binding of (+/-)-propranolol, indicating greater stereoselectivity at higher total binding. To assess the site of the stereoselective binding to plasma proteins, the binding of (+)- and (-)-propranolol to human alpha 1-acid glycoprotein (AGP) and human serum albumin (HSA) was examined. The binding to AGP was stereoselective for (-)-propranolol with a (-)/(+)-propranolol ratio for the unbound fraction of 0.79 +/- 0.01, whereas (+)-propranolol was bound to a greater extent to HSA with a (-)/(+)-propranolol ratio for the unbound fraction of 1.07 +/- 0.01. Although these results demonstrate opposite stereoselectivity in the binding of (+)- and (-)-propranolol to AGP and HSA, the stereoselective binding of (-)-propranolol to AGP predominates in plasma. This stereoselective plasma binding of the (-)-enantiomer of propranolol could limit the access of this more active enantiomer to beta-receptors or other active sites. The uptake of propranolol by red blood cells was not stereoselective.

Fatality due to paraquat intoxication: confirmation by postmortem tissue analysis.

A brief case report is presented describing a patient who unknowingly ingested a fatal amount of paraquat, presumably mixed in some illicit moonshine alcohol. Despite an initial clinical presentation typical of paraquat intoxication, the herbicide was absent upon analysis of multiple urine and blood specimens, and the diagnosis was confirmed only postmortem after determination of high paraquat tissue concentrations in all the major organs. Autopsy results are presented along with a discussion of the histopathologic changes observed in the lungs, liver, and kidneys. Because the combination of toxicologic sequelae attributable to acute paraquat poisoning is fairly unique to this agent, the diagnosis must be suspected highly early in the clinical course of such cases and appropriate therapy initiated, despite the inability to isolate paraquat on preliminary laboratory screening.

Familial autoimmunity: twenty years later.

This report details a follow-up clinical and serological study of a patient with autoimmune hemolytic anemia and his family with multiple autoimmune related phenomena, originally reported in 1964. Clinical features thought to be related to the demonstration of various organ specific autoantibodies in the patient and in family members include hemolytic anemia, thyrotoxicosis, myocarditis, ulcerative colitis, polyarteritis nodosa and renal disease. The proband in this study demonstrates an abnormality of cellular immune function with a generalized decrease in T cell rosette formation and a large decrease in a subpopulation of T cells which may include suppressor T lymphocytes; this finding is consistent with the theory that autoimmune disease arises as an abnormality in the regulation of autoantibody production by B lymphocytes due to a decrease in suppressor T cell function. The results of our follow-up study of this patient and his family with diseases of immunological aberration strongly support the need for close monitoring of such patients and their family members, since early serological evidence of organ specific autoantibodies may be an initial signal of later target organ damage.

Acute chlordane intoxication.

This report describes a patient who accidentally ingested 215 g of chlordane in a liquid pesticide formulation. The patient experienced multiple acute clinical sequellae attributable to his acute intoxication, including vomiting, diarrhea, seizures, coma and respiratory failure. Upon initial presentation and during the recovery phase, blood and urine specimens were collected to measure the disposition and elimination of chlordane and its metabolites. Whole blood chlordane concentrations measured over the subsequent 49 days suggested a multicompartmental kinetic profile of chlordane distribution, with an approximate terminal elimination half-life of 34 days. Tissue samples obtained from this patient, during elective surgery 58 days post chlordane ingestion, revealed persistent high levels of chlordane related metabolites. This case illustrates the physiological distribution and elimination of chlordane and its related metabolite residues after acute intoxication in an adult patient. Such information is important to improve the clinical management of patients acutely exposed to potentially lethal levels of pesticides.