Clinical Evidence Of Toxicity Research Articles

Clinical Evaluation of Methoximorpholino-Doxorubicin (FCE 23762) in Dogs with Spontaneous Malignancies

We conducted a clinical evaluation of FCE 23762, a methoxymorpholino analog of doxorubicin, in 48 dogs with metastatic, nonresectable, or chemotherapy-resistant spontaneous malignancies at an initial dosage of 50-60 microg/kg IV every 3 weeks. Clinical evidence of toxicity was minimal; 6 dogs developed grades I, II, and III hematologic toxicities after the 1st treatment, and 1 dog developed grade II gastrointestinal toxicity. One dog became pancytopenic 4 months after discontinuation of FCE 23762. No other adverse effects were noted. Partial or complete remissions were observed in 32% of the dogs. Responses were observed both in previously untreated dogs and in those that had received prior chemotherapy, including doxorubicin. FCE 23762 is a promising new antineoplastic agent that can be used safely in dogs with cancer; doses higher than those used in this study may be used eventually in practice.

Clinical Evaluation of Methoximorpholino‐Doxorubicin (FCE 23762) in Dogs with Spontaneous Malignancies

We conducted a clinical evaluation of FCE 23762, a methoxymorpholino analog of doxorubicin, in 48 dogs with metastatic, nonresectable, or chemotherapy‐resistant spontaneous malignancies at an initial dosage of 50–60 μg/kg IV every 3 weeks. Clinical evidence of toxicity was minimal; 6 dogs developed grades I, II, and III hematologic toxicities after the 1st treatment, and 1 dog developed grade II gastrointestinal toxicity. One dog became pancytopenic 4 months after discontinuation of FCE 23762. No other adverse effects were noted. Partial or complete remissions were observed in 32% of the dogs. Responses were observed both in previously untreated dogs and in those that had received prior chemotherapy, including doxorubicin. FCE 23762 is a promising new antineoplastic agent that can be used safely in dogs with cancer; doses higher than those used in this study may be used eventually in practice.

Pharmacokinetics of oral valacyclovir and acyclovir in late pregnancy

Objective: The objective was to obtain preliminary pharmacokinetic data for acyclovir from gravid women receiving herpes simplex virus suppressive therapy with the acyclovir prodrug valacyclovir. Study Design: In a prospective, double-blind trial, 20 women with a history of recurrent genital herpes simplex virus infection and positive herpes simplex virus 2 serologic results were randomly assigned at 36 weeks’ gestation to receive oral valacyclovir (500 mg twice daily) or acyclovir (400 mg 3 times daily). Acyclovir pharmacokinetic profiles were obtained after the initial dose (36 weeks) and at steady state (38 weeks). Amniotic fluid samples were obtained during labor and simultaneous umbilical cord and maternal plasma samples were collected at delivery. Laboratory studies were performed to screen for laboratory evidence of toxicity in mothers and infants. Results: Peak acyclovir plasma concentrations (mean ± standard deviation) were higher in valacyclovir recipients than in acyclovir recipients after the initial dose (3.14 ± 0.7 μg/mL vs 0.74 ± 0.6 μg/mL, P < .0001) and at steady state (3.03 ± 1.0 μg/mL vs 0.94 ± 0.7 μg/mL, P < .001). The daily area under the curve values were higher in valacyclovir recipients than acyclovir recipients after the initial dose (17.8 ± 3.6 h · μg/mLvs 7.71 ± 2.5 h · μg/mL, P < .001) and at steady state (19.65 ± 6.4 h · μg/mL versus 11.0 ± 4.5 h · μg/mL, P = .009). There was no significant difference in drug elimination half-life or in time to peak concentration between valacyclovir and acyclovir recipients at either sampling interval. Acyclovir was concentrated in the amniotic fluid; however, there was no evidence of preferential fetal drug accumulation (mean maternal/umbilical vein plasma ratios at delivery were 1.7 for valacyclovir and 1.3 for acyclovir). Valacyclovir was well tolerated, and no significant laboratory or clinical evidence of toxicity was detected. Conclusion: In this phase I trial maternal valacyclovir therapy resulted in higher plasma acyclovir levels, with significantly higher peak concentrations and daily area under the curve values, than did acyclovir therapy. Additional trials are needed to further evaluate the safety and efficacy of suppressive valacyclovir therapy during late pregnancy. (Am J Obstet Gynecol 1998;179:846-51.)

INHIBITION OF CARBOXYLESTERASES IN SH-SY5Y HUMAN AND NB41A3 MOUSE NEUROBLASTOMA CELLS BY ORGANOPHOSPHORUS ESTERS

Carboxylesterases (CbxE) can be inhibited by organophosphorus esters (OPs) without causing clinical evidence of toxicity. CbxE are thought to protect the critical enzyme acetylcholinesterase (AChE) from OP inhibition in animals. CbxE and AChE are both present in neuroblastoma cells, but, even though these cells have potential to be an in vitro model of OP toxicity, the effect of OPs on CbxE and the relationship of CbxE inhibition and AChE inhibition have not yet been examined in these cells. Therefore, this study examined concentration-related OP-induced inhibition of CbxE in human SHSY5Y and mouse NB41A3 neuroblastoma cells with 11 active esterase inhibitors: paraoxon, malaoxon, chlorpyrifos-oxon, tolyl saligenin phosphate (TSP), phenyl saligenin phosphate (PSP), diisopropyl phosphorofluoridate (DFP), mipafox, dichlorvos, trichlorfon, dibutyryl dichlorovinyl phosphate (DBVP), and dioctyl dichlorovinyl phosphate (DOVP). All could inhibit CbxE, although the enzyme was less likely to be inhibited than AChE following exposure to 9 of the test compounds in the human cell line and to all 11 of the test compounds in the murine cell line. Species differences in concentration-related inhibitions of CbxE were evident. When cells were exposed first to an OP with a low IC50 toward CbxE (PSP), followed by an OP with high affinity for AChE (paraoxon or malaoxon), inhibitions of CbxE and AChE were additive. This indicated that CbxE did not protect AChE from OP-induced inhibition in this cell culture model.

Intravitreal injection of octreotide acetate.

This study was conducted to determine the feasibility of injecting the somatostatin analogue, octreotide acetate (OA), into the vitreous cavity. Previous work suggests that octreotide effectively inhibits angiogenesis in vitro, thus its use in vivo may slow the progression of proliferative eye disease. Fifty micrograms of aqueous OA in 50 microliters aqueous solution was injected into the mid-vitreous of kitten eyes (n = 6), and OA levels were monitored over 4 days. A long-acting release form of octreotide (OA-LAR) was also injected into the mid-vitreous of rabbit eyes at doses of 0.36 (n = 16), 1.1 (n = 1), 2.1 (n = 1), 4.05 (n = 1), 8.2 (n = 1), and 36 mg (n = 3) in solution; and octreotide concentrations were measured at various time points over 42 days. OA concentrations were determined by a highly specific radioimmunoassay. Aqueous octreotide was eliminated rapidly (t1/2 = 16 hours) from the vitreous of the kitten eye, with only negligible amounts recoverable 4 days post-injection. In the long-acting form, OA in the rabbit eye reached peak levels at 28 days. By 42 days, OA levels had declined to the 14-day level. Doses of OA-LAR of 1.1 mg or less produced no gross evidence of clinical toxicity and elicited no grossly visible ocular side effects. Doses greater than 1.1 mg produced significant toxicity, including cataracts and rubeosis. The 28-day peak release for long-acting OA implies that monthly intravitreal injections could provide continual high levels of OA. Intravitreal injection of long-acting OA provides sustained, high concentrations of drug, and deserves further study as a potential treatment of proliferative eye diseases.

Polymeric controlled-release amsacrine chemotherapy in an experimental glioma model.

The purpose of this study was to fabricate and investigate amsacrine containing polymeric rods for use in interstitial chemotherapy of malignant glioma. Ethylene vinyl acetate copolymer (EVAc) rods containing 40% amsacrine (AMSA) were fabricated successfully with an extrusion method. In vitro kinetic studies revealed a high level of reproducibility of the production process. The release of AMSA showed a biphasic pattern consistent with a matrix-type controlled-release system with an initial more rapid release rate followed by a slower and more linear release phase. Release of AMSA was observed for over 6 months and the rods continue to release in a stable fashion. In vitro studies using rat glioma (RG2) in cell culture showed that cells treated with AMSA released from the rods were killed in a dose dependent manner indicating that AMSA incorporated into the polymer remained biologically active. In vivo studies of rats with single AMSA rods implanted five days after RG2 tumour implantation revealed histological evidence of an anti-tumour effect as well as an increased survival (p < 0.0003). The mean survival of the amsacrine treated rats was 78 days with 50% still remaining alive > 5 months after implantation. All control animals developed tumours and died within 15-19 days after tumour implantation (mean = 17 days). Amsacrine implanted animals showed no significant histological or clinical evidence of toxicity. We conclude that amsacrine containing EVAc rods can be safely and efficaciously use against the RG2 experimental glioma in a rat model and warrant further investigation.

Anesthésie de contact à la cocaïne pour chirurgie endonasale. Cinétique et tolérance clinique d'une solution concentrée

• Objective : To assess the pharmacokinetics and clinical tolerance of a 33 % cocaine solution administered topically for intranasal surgery. • Study design : Clinical prospective open trial. • Patients and methods : Twelve ASA I patients scheduled for intranasal surgery were sedated with midazolam 2 mg and fentanyl 50 μg. Topical anaesthesia was obtained with aqueous 33 % cocaine HCl 360 mg, lidocaine HCl 140 mg, adrenaline 0.04 mg and naphazoline 0.4 mg. Venous blood samples were taken before cocaine application and 15, 30, 45, 60, 90, 120, 150, 180, 240 min later. The plasma was immediately separated and the samples were frozen. The concentration of cocaine was measured by HPLC. Potential cardiotoxic and neurotoxic effects were clinically monitored. • Results : The mean dose of cocaine applied was 5.85 ± 1.3 mg · kg −1 and the dose actually delivered was 4 ± 1.5 mg · kg −1. The Cmax was 859 ± 503 ng · mL −1 after a Tmax to 47 ± 17 min. The mean elimination half-life was 87 ± 19 min (mean ± SD). The total clearance and the volume of distribution were respectively 4 521 ± 1 858 mL. min −1 and 568 ± 273 L. No clinical evidence of toxicity was found. • Conclusions : This study shows that it is possible to perform major intranasal surgery under topical anaesthesia with a concentrated solution (33 %) of cocaine at a high dose (6 mg · kg −1). These results differ completely with data obtained in addicts.

Effect of low dosage inhaled nitric oxide on pulmonary hypertension in congenital heart disease.

An evaluation of the pulmonary vascular resistance and the reversibility of pulmonary vascular reaction in children with congenital heart disease is essential for determining the surgical indication and for assessing the long-term prognosis. We report the clinical efficacy of low dosage inhaled nitric oxide and investigate the relationship between its effect and hemodynamic parameters in 18 patients with congenital heart disease. The patients were divided into 3 Groups; Group 1 consisting of 3 patients with Eisenmenger syndrome, Group 2 of 10 patients whose mean pulmonary artery pressure was more than 30 mmHg, and Group 3 consisting of 5 patients whose mean pulmonary artery pressure was less than 30 mmHg. High concentration (90%) oxygen, and also normal oxygen (21%) containing 10 parts per million nitric oxide were administered by cardiac catheterization. In Group 1, both the 90% oxygen and the normal oxygen with nitric oxide showed no affect on the hemodynamical variables. In Group 2, the pulmonary artery pressure and the pulmonary vascular resistance both significantly decreased with the 90% oxygen, and with the nitric oxide inhalation, but these decreases were not found in Group 3. In the 15 patients (of Groups 2 and 3 combined) who were considered to have reversible pulmonary vascular changes, significant correlations were found between the baseline pulmonary artery pressure and the magnitude of pulmonary vasodilation. No clinical evidence of toxicity was seen with the administration of the inhaled nitric oxide. These data suggested that inhaled nitric oxide, even in a low dosage, was a potent and selective pulmonary vasodilator in patients with congenital heart disease complicated with pulmonary hypertension. Since a positive correlation was found between the baseline pulmonary artery pressure and the magnitude of pulmonary vasodilation, this examination demonstrated potential efficacy for objective analysis in patients with pulmonary hypertension.

Preoperative combined chemotherapy and radiation therapy plus radical surgery in advanced head and neck cancer. Five-year results with impressive complete response rates and high survival.

Radiation therapy combined with cisplatin as a chemoradiation sensitizer (CT/RT) has been reported to enhance tumor response in squamous cell carcinoma of the head and neck. In the present study, CT/RT was used preoperatively in advanced Stage III and IV head and neck cancer. Fifty-three patients were entered prospectively into a Phase II study. Treatment consisted of 4500 cGy of radiation therapy in 5 weeks combined with cisplatin 20 mg/m2 for 4 days during weeks 1 and 4 of radiation therapy. This was followed 4 to 8 weeks later by curative surgery. Pretherapy dental care; long-term nutritional support; individualized skin, mouth, and wound care; and continuous interdisciplinary communication were integral parts of this regimen. In four patients, CT/RT toxicity was seen (8%); three episodes of skin reaction or stomatitis and three episodes of leukopenia (less than 2500/microliters), causing a delay in CT/RT treatment in one patient. Three patients died of other causes during the preoperative interval, without clinical evidence of toxicity. Fifty patients (94%) had a complete (CR) or partial response (PR) to CT/RT. Clinical CR was seen in 38 of 51 (75%) primary tumors and 21 of 27 (78%) cervical nodes. Forty-one patients (77%) underwent curative surgery. In 27 of 32 (84%) resected CR primary tumors and 16 of 18 (89%) CR metastatic nodes, the surgical specimen was microscopically free of tumor. Postoperative morbidity was 32%. Five patients (12%) required additional surgery for their complications. Perioperative mortality was 5%. Five patients had tumor recurrence: three postoperatively after clinical PR to CT/RT and two in clinical CR patients who refused further treatment after CT/RT, then had a recurrence and were salvaged surgically. No patient with a CR in both the tumor and nodes who underwent surgery had a tumor recurrence. With a follow-up of 8 years (median, 40 months), the median survival for all patients was 45 months. The 5-year actuarial survival rate was 43% for all patients and 55% for patients who had CT/RT and surgery. This multimodality treatment of advanced head and neck cancer has low toxicity and impressive survival. It renders a significant number of patients tumor-free before surgery. These patients may be candidates for additional study triaging additional CT/RT for complete CR only and surgery for PR and biopsy-proved residual disease.

Monitoring cyanide and thiocyanate concentrations during infusion of sodium nitroprusside in children

Over a 19-month period, all requests for blood cyanide and/or serum thiocyanate concentrations to the Clinical Laboratory of The Children's Hospital, Boston, were reviewed in order to determine how physicians screen for nitroprusside-related toxicity. During that period, 52 patients receiving nitroprusside were monitored for cyanide and/or thiocyanate toxicity. Overall, there were 62 cyanide and 86 thiocyanate determinations. None of the thiocyanate determinations and five of the cyanide concentrations were within the toxic range as established by the reference laboratory, and no patient displayed signs or symptoms of toxicity which could not also be explained by their underlying illness. Our findings suggest that while physicians are concerned with nitroprusside toxicity in children, there exists no apparent consensus as to how to monitor for this toxicity. The results also indicate that the relationship between blood cyanide or serum thiocyanate concentrations and clinical evidence of toxicity is not straightforward and requires further delineation.

Photosensitive complex partial seizures aggravated by phenytoin

A 10-year-old girl is described with pure photosensitive complex partial seizures which consisted of a frightening visual phenomenon of seeing “shadow people“, then staring blankly with lip smacking and sometimes becoming limp. The seizures were triggered by bright sunlight. With the institution of phenytoin therapy, her seizure frequency increased dramatically without any clinical evidence of toxicity and her phenytoin blood levels were within the therapeutic range. Discontinuation of phenytoin led to a return to baseline seizure frequency. The mechanism by which antiepileptic drugs may aggravate seizures is still not understood; therefore, awareness of this phenomenon is crucial for early diagnosis and appropriate treatment.

Subconjunctival High Dose Plasminogen Activator in Rabbit Filtration Surgery

The primary cause of failure in glaucoma filtration surgery is fibroblastic proliferation and subconjunctival fibrosis at the bleb site resulting in decreased aqueous flow. We evaluated New Zealand white rabbits in a masked, placebo controlled pilot study to determine the potential reduction of episcleral fibrosis at the surgical bleb site utilizing 0.3 mls of: balanced salt solution (n = 11); an inert gel delivery vehicle (n = 13); the gel delivery vehicle with incorporated recombinant tissue plasminogen activator (tpa; n = 14), 1 mg/ml. Statistical analysis of computer assisted area measurements from multiple histologic sections demonstrated a significant decrease in episcleral fibrosis in the t-PA group as compared to the two other groups (p less than 0.05). Results from the t-PA group did not demonstrate an effect on intraocular pressure. There was no clinical evidence of toxicity or healing complications in the t-PA group.

Safety and Metabolic Effects of L‐Glutamine Administration in Humans

A series of dose-response studies was conducted to evaluate the clinical safety, pharmacokinetics, and metabolic effects of L-glutamine administered to humans. Initial studies in normal individuals evaluated the short-term response to oral loads of glutamine at doses of 0, 0.1, and 0.3 g/kg. A dose-related increase in blood glutamine occurred after oral loading and elevation of amino acids known to be end products of glutamine metabolism occurred (including alanine, citrulline, and arginine). No evidence of clinical toxicity or generation of toxic metabolites (ammonia and glutamate) was observed. Glutamine was infused intravenously in normal subjects over 4 hr at doses of 0.0125 and 0.025 g/kg/hr. In addition, glutamine was evaluated as a component of parenteral nutrition solutions (0.285 and 0.570 g/kg/day) administered for 5 days to normal subjects. Intravenous administration of glutamine was well tolerated without untoward clinical or biochemical effects. Subsequent studies in patients receiving glutamine-enriched parenteral nutrition for several weeks confirmed the clinical safety of this approach in a catabolic patient population. In addition, nitrogen retention appeared to be enhanced when glutamine was administered at a dose of 0.570 g/kg/day in a balanced nutritional solution providing adequate calories (145% of basal) and protein (1.5 g/kg/day). Nitrogen balance in patients receiving lower doses of glutamine (0.285 g/kg/day) was similar to that in patients receiving standard formulations. Further controlled clinical trials of the metabolic efficacy, tolerance, and dose response of glutamine in other patient groups are necessary to determine the appropriate use of glutamine enrichment of nutrient solutions.

An Approach to Setting Maxima in Infant Formulas

It is clearly necessary to set upper limits for a nutrient in a formula where the nutrient can have a direct toxic effect (e.g., vitamin A) or can lead to a reduced margin of safety (e.g., high dietary renal solute load during gastroenteritis). In addition, there are plausible arguments for setting upper limits for any nutrient added during manufacture. Various expert groups have used different approaches in setting upper limits, particularly for fat and minerals. Evidence of clinical toxicity and various biochemical measurements have been commonly used to determine appropriate upper levels. Less use has been made of the empirical evidence provided by nutrient concentrations in commonly used foods, e.g., breast milk and cow's milk. Four “rules” for setting maxima are suggested: a) Use evidence of clinical toxicity or reduced margin of safety if available; b) Avoid nutrient concentrations that lead to biochemical values in body fluids or tissues very different from those seen in breast-fed babies; c) An upper limit should be set for even apparently harmless nutrients that are added during manufacture; and d) When a nutrient is added, its final concentration should not normally exceed that in breast or cow's milk, whichever is the greater. Using these “rules,” suggested maxima for 33 nutrients are listed.

An Approach to Setting Maxima in Infant Formulas

It is clearly necessary to set upper limits for a nutrient in a formula where the nutrient can have a direct toxic effect (e.g., vitamin A) or can lead to a reduced margin of safety (e.g., high dietary renal solute load during gastroenteritis). In addition, there are plausible arguments for setting upper limits for any nutrient added during manufacture. Various expert groups have used different approaches in setting upper limits, particularly for fat and minerals. Evidence of clinical toxicity and various biochemical measurements have been commonly used to determine appropriate upper levels. Less use has been made of the empirical evidence provided by nutrient concentrations in commonly used foods, e.g., breast milk and cow's milk. Four "rules" for setting maxima are suggested: a) Use evidence of clinical toxicity or reduced margin of safety if available; b) Avoid nutrient concentrations that lead to biochemical values in body fluids or tissues very different from those seen in breast-fed babies; c) An upper limit should be set for even apparently harmless nutrients that are added during manufacture; and d) When a nutrient is added, its final concentration should not normally exceed that in breast or cow's milk, whichever is the greater. Using these "rules," suggested maxima for 33 nutrients are listed.

If a Well‐Stabilized Epileptic Patient Has a Subtherapeutic Antiepileptic Drug Level, Should the Dose Be Increased? A Randomized Prospective Study

In an attempt to determine whether the dose of an antiepileptic drug should be increased in epileptic patients who were seizure-free and had subtherapeutic serum levels, 79 patients with idiopathic generalized tonic-clonic seizures treated with monotherapy [phenytoin (PHT) or phenobarbital (PB)] and with a subtherapeutic serum level were prospectively studied. Their last seizure was at least 3 months prior to entry, and no patient had any clinical evidence of toxicity. They were randomized to study arm A (keeping the level in the subtherapeutic range) or study arm B (increasing the dose until the level reached and stayed at the therapeutic range). Over a mean follow-up period of 24 months, there was no significant difference between the two study arms in the occurrence of seizures, but arm B patients had an increased incidence of neurotoxic side effects from the dose increment. These results confirm the clinical impression that it is unnecessary to increase the dose of the antiepileptic drug despite a subtherapeutic serum concentration in a relatively well-stabilized patient, thus minimizing the frequency of dose adjustment and the need for expensive therapeutic drug monitoring.

Pharmacologic interactions between valproate and other drugs

Valproate is often administered with other antiepileptic drugs, a practice that can lead to clinically significant pharmacologic interactions. Concomitant administration of such enzyme-inducing anti-epileptic drugs as carbamazepine, phenobarbital, primidone, or phenytoin will markedly accelerate the metabolic conversion of valproate, particularly in children. In response to the effects of enzyme induction, valproate dosage may need to be doubled to maintain therapeutic serum levels. Valproate does not appear to induce enzymatic drug metabolism, but rather acts as a metabolic inhibitor. Because of this inhibition, phenobarbital dosage must often be reduced after valproate is added to the therapeutic regimen. Valproate also may markedly increase concentrations of the active epoxide metabolite of carbamazepine. The interaction between phenytoin and valproate results primarily from displacement from plasma proteins. The resulting increase in the free fraction of phenytoin alters the relationship between total phenytoin concentration and the drug's pharmacologic effect. Thus, clinical evidence of toxicity may be present at concentrations usually considered to be in the therapeutic range.

The effect of topically applied n-butylester of 2,4-dichlorophenoxyacetic acid on the immune response in mice.

Six-week-old female CD-1 mice were administered the n-butylester of 2,4-dichlorophenoxyacetic acid (2,4-D). The 2,4-D ester was applied dermally at dosages ranging from 0 to 500 mg/kg (2,4-D content) in the acute studies and 0 to 300 mg/kg in the 3 week subacute studies. Following acute exposure, antibody production against sheep red blood cells was suppressed at higher exposure levels. Evidence of clinical toxicity, myotonia and depression, and histopathological alterations in the central nervous system including perivascular edema and ganglial cell necrosis, was also seen in the mice. No alterations were observed in the T- and B-lymphocyte proliferative responses induced by concanavalin A, a T-lymphocyte mitogen, or Escherichia coli lipopolysaccharide, a B-lymphocyte mitogen. Subacute 2,4-D ester exposure which produced minimal clinical or pathological alterations, had no effect on antibody production, but did enhance the B- and T-lymphocyte proliferative responses. The immunosuppressive effects of acute 2,4-D ester exposure which were observed in this study, were unlikely a direct immunological alteration, but rather a secondary manifestation of the clinical syndrome. Since the subacute exposure levels may be more comparable to occupational or environmental exposure, it is unlikely that 2,4-D esters will have any major immunotoxicological significance in agricultural communities.

Clinical and morphologic cardiac findings after anthracycline chemotherapy: Analysis of 64 patients studied at necropsy

The relation between clinical evidence of and histologic signs of anthracycline cardiotoxicity was evaluated by reviewing the clinical and morphologic findings in 64 patients studied at necropsy, all of whom had received doxorubicin or daunorubicin chemotherapy during life. Of the 64 patients, 20 (31%) had documented clinical toxicity consisting of impaired left ventricular systolic performance; in 7 (35%) of these 20 patients, histologic signs of toxicity were absent. In the remaining 13 patients with clinical toxicity, histologic signs of toxicity ranged from mild to severe. Of the 44 (69%) patients without clinical signs of drug toxicity, 21 (48%) had no histologic sign of cardiotoxicity; in 23 (52%) of the patients without clinical toxicity, however, morphologic signs of cardiotoxicity were nevertheless present—mild in most patients, but extensive in 4. Signs of extensive histologic toxicity (19 [30%] of 64 patients) were associated with large doses (> 450 mg/m 2) of the drug, mediastinal irradiation, and age > 70 years. This study suggests that attempts to monitor cardiotoxicity by serial evaluation of cardiac histology in patients undergoing anthracycline chemotherapy may be seriously limited by the fact that clinical evidence of toxicity may be present without histologic signs of toxicity; likewise, histologic signs of anthracycline toxicity may be present without clinical evidence of toxicity.

Long-term parenteral exposure to mercury in patients with hypogammaglobulinaemia.

Patients with hypogammaglobulinaemia commonly receive regular long-term replacement therapy with a concentrate of pooled normal human immunoglobulin G (IgG) containing an organic mercury compound (thiomersal) as a preservative. In 26 such patients the total estimated mercury dosage received ranged from 4 to 734 mg (mean 157 mg) over treatment periods of six months to 17 years (mean 6.5 years). Nineteen patients (73%) had raised urine mercury concentrations, but no correlation was found between urine mercury and the age of the patient, the IgG dose, or the duration of treatment. Urine mercury concentrations are often used to control exposure and evaluate risks in exposed subjects. Hence most patients with hypogammaglobulinaemia are theoretically at risk from mercury exposure, although no clinical evidence of toxicity is yet apparent.