Chlorpyrifos-induced delayed polyneuropathy

Chlorpyrifos [0,0-diethyl 0-(3,5,6-trichloro-pyridyl) phosphorothioate] caused delayed polyneuropathy in man. Contrary to previous studies, we report here that it also causes delayed polyneuropathy in the hen, the animal model for this toxicity. The minimal neuropathic dose was 60–90 mg/kg p.o., corresponding to 4–6 times the estimated LD₅₀. Consequently, pralidoxime (2-PAM) in conjunction with atropine was necessary to reverse acetylcholinesterase (AChE) inhibition and cholinergic toxicity in hens given high enough doses of chlorpyrifos to cause neuropathy. Chlorpyrifos was slowly absorbed after single oral doses and the threshold of inhibition (>70%) of neuropathy target esterase (NTE), the putative target for delayed neuropathy, was reached within 5–6 days. High AChE inhibition (>90%), however, was measured within hours after dosing because of the higher potency of chlorpyrifos to inhibit this enzyme. In vitro studies showed that chlorpyrifos-oxon, the active metabolite of chlorpyrifos, was 10–20 times more active against AChE than against NTE, confirming the clinical observation. No differences were seen between human and hen enzymes in this respect. Hen and human brain homogenates contain A-esterases which hydrolysed chlorpyrifos to about the same extent in both species. In conclusion, chlorpyrifos causes delayed polyneuropathy in the hen, as was reported in man. The reasons for previous negative data in the hen are probably due to the relatively lower doses which were used. Judging from in vitro studies with hen and human enzymes, there are no differences in the two species as far as their relative sensitivity to delayed polyneuropathy. It is likely that delayed polyneuropathy would develop in both species only after severe cholinergic toxicity requiring aggressive antidotal treatment.Part of this work was presented at the 25th Annual Meeting of the Society of Toxicology held in New Orleans, LA, USA, March 1986, at the International Symposium on Biochemical and Cellular Indices of Toxicity in Occupational and Environmental Medicine held in Milan, Italy, June 1986, and at the 9th Meeting of the Peripheral Nerve Study Group, Praglia (PD), Italy, August – September, 1989     

Reduced cardiotoxicity of doxorubicin given in the form ofN-(2-hydroxypropyl) methacrylamide conjugates: an experimental study in the rat

Summary A rat model was used to evaluate the general acute toxicity and the late cardiotoxicity of 4 mg/kg doxorubicin (DOX) given either as free drug or in the form of threeN-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. In these HPMA copolymers, DOX was covalently bound via peptide linkages that were either non-biodegradable (Gly-Gly) or degradable by lysosomal proteinases (Gly-Phe-Leu-Gly). In addition, one biodegradable conjugate containing galactosamine was used; this residue was targeted to the liver. Over the first 3 weeks after the i.v. administration of free and polymer-bound DOX, all animals showed a transient reduction in body weight. However, the maximal reduction in body weight seen in animals that received polymer-bound DOX (4 mg/kg) was significantly lower than that observed in those that received free DOX (4 mg/kg) or a mixture of the unmodified parent HPMA copolymer and free DOX (4 mg/kg;P<0.01). Throughout the study (20 weeks), deaths related to cardiotoxicity were observed only in animals that received either free DOX or the mixture of HPMA copolymer and free DOX; in these cases, histological investigations revealed marked changes in the heart that were consistent with DOX-induced cardiotoxicity. Sequential measurements of cardiac output in surviving animals that received either free DOX or the mixture of HPMA copolymer and free DOX showed a reduction of 30% in function beginning at the 4th week after drug administration. The heart rate in these animals was 12% lower than that measured in age-matched control rats (P<0.05). Animals that were given the HPMA copolymer conjugates containing DOX exhibited no significant change in cardiac output throughout the study (P<0.05). In addition, no significant histological change was observed in the hearts of animals that received DOX in the form of HPMA copolymer conjugates and were killed at the end of the study. However, these animals had shown a significant increase in heart rate beginning at 8 weeks after drug administration (P<0.01). This study demonstrates that covalent binding of DOX to HPMA copolymer conjugates via both stable and biodegradable peptidyl linkages considerably reduces both the general acute toxicity and the late cardiotoxicity of DOX in the rat and could offer the potential for improving the therapeutic index in the clinical application of DOX.     

Morphological changes in ocular surface in dry eyes and other disorders by impression cytology

A study was conducted on 107 eyes of 70 patients with dry eye disorders and mechanical and chemical extrinsic alterations and 64 eyes of 32 control subjects in order to describe a possible specific response of the conjunctival and corneal surface. We found the presence of snakelike chromatin cells and other nuclear changes, squamous metaplasia, and inflammatory cells in the conjunctiva in all groups. A decrease in goblet cell densities was also found in all groups, except for patients with blepharoconjunctivitis. The corneal cells were slightly larger in patients with keratoconjunctivitis sicca.Correspondence to: L. Rivas     

Cephaloridine-induced nephrotoxicity in the Fischer 344 rat: proton NMR spectroscopic studies of urine and plasma in relation to conventional clinical chemical and histopathological assessments of nephronal damage

The acute toxicological effects of the nephrotoxic antibiotic cephaloridine (CPH, 0–1500 mg/kg) in male Fischer 344 (F344) rats, have been investigated over 48 h using clinical chemistry, histopathology and proton nuclear magnetic resonance (¹H NMR) spectroscopy of urine and plasma. High field (400 and 600 MHz)¹H NMR urinalysis revealed increased excretion of lactic acid, acetoacetate, alanine, valine, lysine, glutamine and glutamate and a severe, time-dependent glycosuria. A major change observed in urine of CPH-treated animals was the dose-dependent increase in HB which may relate to altered energy metabolism. CPH also caused dose-dependent decreases in the urinary excretion of hippurate, allantoin and protein (conventional assay). This abnormal metabolic profile is consistent with a functional defect in the S₁/S₂ regions of the proximal tubule, and was confirmed by histologypost mortem. Functional changes observed included elevations in blood urea nitrogen (BUN) and urine flow rate (UFR) and dose-related decreases in urine osmolality. Spin-echo¹H NMR spectroscopic analysis of lyophilised plasma, reconstituted with²H₂O revealed an abnormal phase modulation of the methyl signal from free alanine and it is postulated that this is due to the release of transaminases from damaged tissue which via a reversible conversion to pyruvate, cause variable deuteration of alanine at the -CH position. This observation suggests that¹H NMR spectral patterns are also dependent on the level of plasma transaminases and this may provide a novel indicator of tissue damage.     

Shortlasting, Unilateral, Neuralgiform Headache Attacks With Conjunctival Injection, Tearing, and Subclinical Forehead Sweating ("Sunct" Syndrome): II. Changes in Heart Rate and Arterial Blood Pressure During Pain Paroxysms.

The recently described "Sunct" syndrome is a rare picture of unilateral, shortlasting headache attacks accompanied by autonomic phenomena (conjunctival injection, tearing, etc.) on the symptomatic side. Heart rate and blood pressure were monitored in two elderly "Sunct" patients during and outside headache attacks. An ultrasound Doppler servo method was used for the non-invasive, continuous, beat-to-beat determination of instantaneous arterial blood pressure. In a third patient, systolic and diastolic blood pressure, both outside and during pain paroxysms, were assessed using the standard Korotkoff method. Heart rate was found to be significantly decreased during pain paroxysms. Systolic blood pressure was observed to be significantly increased during attacks, when compared with the inter-attack period, while a less consistent pattern was observed for diastolic blood pressure. Some of the changes in the cardiovascular system seemed to start prior to pain onset. Therefore, it seems unlikely that these changes were caused by pain activation of the sympathetic nervous system or the oculocardiac reflex.     

Gallium scintigraphy in Hansen's disease

Gallium 67 imaging was used in 12 patients with documented Hansen's disease undergoing treatment or not, in an attempt to determine the pattern of the disease. Diagnosis was confirmed by histopathology in all patients. The Mitsuda reaction was seen in all patients. Specific nuclear studies were performed when needed to evaluate particular organs better. Gallium 67 images show homogeneous, diffuse and moderate accumulation over the entire skin surface (except for the face) of untreated patients with multibacillary disease. The facial skin in these cases presented homogeneous, diffuse but very marked uptake of gallium. Internal organ involvement was variable. There was a very good correlation among clinical, scintigraphic, immunological and histopathological data. The pattern of the body skin (skin outlining) and facial skin (beard distribution) may be distinct for untreated patients with multibacillary leprosy.     

Hypoxaemia in adults in the post-anaesthesia care unit

Continuous pulse oximetry was performed on 173 adults after general anaesthesia for elective inpatient surgery, throughout their post-anaesthesia care unit (PACU) stay. Supplemental oxygen was administered for greater than or equal to 30 min after arrival and subsequently discontinued before discharge to the ward. The mean and minimum oxyhaemoglobin saturation (SpO2) after discontinuing oxygen were lower than those values achieved during oxygen administration and preoperatively (P less than 0.001). At least one hypoxaemic episode (SpO2 less than or equal to 90% for greater than or equal to 15 sec) occurred in 70 subjects (41%) and 45 of these had a moderate-severe episode (SpO2 greater than or equal to 90% for less than or equal to 2 min or SpO2 less than or equal to 85%). The hypoxaemic episodes began 20 +/- 20 min (range 1-100; median 15) after discontinuing supplemental oxygen. Cyanosis was detected in only four of the 70 patients who desaturated. Factors associated with hypoxaemia were: ASA physical status class; surgical duration greater than or equal to 90 min; and preoperative mean SpO2 less than 95%. Factors not associated with hypoxaemia were: age, sex, % ideal body weight, smoking history, preoperative minimum SpO2, premedication and type of surgery. In conclusion, after discontinuing supplemental oxygen in the PACU, hypoxaemia was common, difficult to detect clinically, and associated with ASA class, surgical duration and preoperative mean SpO2.     

Phase transitions in phosphatidylcholine multibilayers

The ²H NMR spectrum of a multilamellar dispersion of 1-myristoyl-2-[14,14,14-²H₃]myristoyl-sn-glycero-3-phosphocholine with 1 mol% cholesterol in excess water has been recorded at temperatures between -15°C and 36°C. Motionally averaged quadrupole coupling constants ν_Q and motionally induced asymmetry parameters η are obtained by spectral analysis. Values of these quantities indicate that, at temperatures below -4°C, any rotational motion of the molecules about their molecular long axis is slow on the NMR time scale. At temperatures immediately above the pretransition these same parameters show that a fast-rotational motion is occurring about the molecular long axis. This rotational motion is hindered in that the molecules flip about a twofold symmetry axis. Between -4°C and the pretransition, spectra appear as the superposition of two powder patterns, one corresponding to the pattern observed below -4°C and the other to the pattern above the pretransition. The relative contribution of the latter increases with temperature until the pretransition is reached. These data have been interpreted in two ways: either the sample between -4°C and the pretransition contains two populations of rapidly and slowly rotating molecules, or there is only a single population of molecules undergoing a 180° flipping motion on the time scale of the NMR measurement. The latter interpretation is more consistent with other experimental findings. At the temperature of the main transition the hydrocarbon chains melt. In the absence of cholesterol, spectra are more complex in that the line shape is reproduced by the superposition of three spectral powder patterns between -4°C and the pretransition and by the superposition of two spectral patterns above the pretransition. It is postulated that these two patterns observed above the pretransition are in direct correspondence to the two ripple structures observed by freeze-fracture electron microscopy in the absence of cholesterol.     

IgA glomerulonephritis

Renal biopsy specimens from 204 patients with glomerulonephritis or nephrotic syndrome have been studied. In ten of the patients not suffering from acute poststreptococcal glomerulonephritis, systemic lupus erythematosus or Schönlein-Henoch syndrome, diffuse, selective mesangial IgA deposition was observed. Clinically, persistent microscopic haematuria, mild proteinuria and, except in one patient, normal renal function were found. Light microscopically the histological picture was dominated by a diffuse or focal increase in volume of the mesangial matrix, and mild mesangial cell proliferation. Exceptionally, there was also crescent formation. Immunofluorescence revealed large IgA, IgG and C3 deposits, as well as small IgM and fibrinogen deposits in the mesangial glomeruli. The authors' assumption that immunocomplexes containing a secretory component might be implicated in the pathomechanism of Berger's disease, could not be proved.On the basis of a lecture given at the XXIIIrd Itinerary Congress of the Transdanubian Section of the Association of Hungarian Internists, held at Gyr on 18th June, 1976. Supported by the Scientific Research Council, Ministry of Health, Hungary (3-18-0304-03-2/H).