The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

Essentiality Toxicity Carcinogenicity Lead(Pb) Exposure Toxicokinetics Toxicity Neurologic, Neurobehavioral, and Developmental Effects in Children Mechanisms of Effects on the Developing Nervous System Peripheral Neuropathy Hematologic Effects Renal Toxicity Lead and Gout Effects on Cardiovascular System Immunotoxicity Bone Effects Reproductive Effects Birth Outcomes Carcinogenicity Other Effects Dose Response Treatment Organic Lead Compounds Mercury (Hg) Exposure Disposition and Toxicokinetics Metabolic Transformation Cellular Metabolism Toxicology Biological Indicators Treatment Nickel (Ni) Exposure Toxicokinetics Essentiality Toxicity Nickel Carbonyl Poisoning Dermatitis Indicators of Nickel Toxicity

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Toxic effects of metals

To measure the neuropsychologic effects of unidentified childhood exposure to lead, the performance of 58 children with high and 100 with low dentine lead levels was compared Children with lead levels scored significantly less well on the Wechsler Intelligence Scale for Children (Revised) than those with low lead levels This difference was also apparent on verbal subtests, on three other measures of auditory or speech processing and on a measure of attention Analysis of variance showed that none of these differences could be explained by any of the 39 other variables studied Also evaluated by a teachers' questionnaire was the classroom behavior of all children (2146 in number) whose teeth were analyzed The frequency of non-adaptive classroom behavior increased in a dose-related fashion to dentine lead level Lead exposure, at doses below those producing symptoms severe enough to be diagnosed clinically, appears to be associated with neuropsychologic deficits that may interfere with classroom performance

Deficits in Psychologic and Classroom Performance of Children with Elevated Dentine Lead Levels

The tissue photosensitizer protoporphyrin IX (PpIX) is an immediate precursor of heme in the biosynthetic pathway for heme. In certain types of cells and tissues, the rate of synthesis of PpIX is determined by the rate of synthesis of 5-aminolevulinic acid (ALA), which in turn is regulated via a feedback control mechanism governed by the concentration of free heme. The presence of exogenous ALA bypasses the feedback control, and thus may induce the intracellular accumulation of photosensitizing concentrations of PpIX. However, this occurs only in certain types of cells and tissues. The resulting tissue-specific photosensitization provides a basis for using ALA-induced PpIX for photodynamic therapy. The topical application of ALA to certain malignant and non-malignant lesions of the skin can induce a clinically useful degree of lesion-specific photosensitization. Superficial basal cell carcinomas showed a complete response rate of approximately 79% following a single exposure to light. Recent preclinical studies in experimental animals and human volunteers indicate that ALA can induce a localized tissue-specific photosensitization if administered by intradermal injection. A generalized but still quite tissue-specific photosensitization may be induced if ALA is administered by either subcutaneous or intraperitoneal injection or by mouth. This opens the possibility of using ALA-induced PpIX to treat tumors that are too thick or that lie too deep to be accessible to either topical or locally injected ALA.

Endogenous protoporphyrin IX, a clinically useful photosensitizer for photodynamic therapy.

https://stacks.cdc.gov/view/cdc/37676/cdc_37676_DS1.pdf

Toxicological Profile for Lead

Acute intermittent porphyria: a study of 50 cases.

The History, Classification, and Incidence of the Porphyrias.- Porphyrins and Enzymes of the Heme Biosynthetic Pathway.- The Acute Porphyrias.- Pathogenesis of the Neuropathy of Acute Porphyria.- Drugs, Chemicals, and Porphyria.- The Photochemistry, Photobiology, and Phototherapeutic Use of Porphyrins.- Cutaneous Hepatic Porphyria.- Erythropoietic Protoporphyria.- Congenital Porphyria.- Porphyrins in Diseases Other than the Porphyrias.- Porphyria in Animals.- Perspective.- References.

Disorders of Porphyrin Metabolism

Diseases of porphyrin metabolism

An investigation has been reported on the clinical and metabolic effects of lead acquired by soft domestic water from lead plumbing systems in 23 Glasgow households. The lead content of water from cold taps was up to 18 times the upper acceptable limit and was proportional to the amount of lead in the plumbing system. The blood lead of 71 inhabitants of these houses showed a significant positive correlation with water lead content. Delta-aminolaevulic acid dehydrase activity, an extremely sensitive indicator of lead exposure, showed a significant negative correlation with water-lead content. Atmospheric lead was within acceptable limits in all but one house and no significant correlation could be found with biochemical measurements. A small number of clinical abnormalities were found but could not be directly attributed to lead toxicity. The results of the study underline the possible danger to health of lead plumbing systems in soft-water regions.

https://www.bmj.com/content/bmj/2/5812/491.full.pdf

Environmental lead pollution in an urban soft-water area.

Hereditary coproporphyria is biochemically distinct from the other porphyrias and is characterized by excessive excretion of coproporphyrin in faeces and usually in urine. The laboratory findings in 28 patients with this disease are presented and the clinical details of eight patients who have been in attack summarised. The remaining 20 patients were latent for the disease. In all patients studied the activity of delta-aminolaevulinic acid synthase was raised and coproporphyrinogen oxidase depressed in the leucocyte. This indicates the partial enzyme block in the haem biosynthetic pathway in this disease. The activities of the other enzymes in the pathway, leucocyte ferrochelatase and erythrocyte delta-aminolaevulinic acid dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase showed no consistent change. On review of 111 cases, 35 per cent presented in acute attack: 80 per cent had abdominal pain, 34 per cent vomiting, 29 per cent solar sensitivity, 23 per cent neurological involvement, 23 per cent psychiatric symptoms and 20 per cent severe constipation. Only two fatalities have been published, both from respiratory failure. There was a female preponderance of cases in attack of 2-5:1 and in the latent cases of 1-5:1 suggesting hormonal provocation in the uncovering of the disease. Drugs were implicated as precipitating 54 per cent of acute attacks and in 34 per cent of cases, these were barbiturates. This study demonstrates the reduction in activity of coproporphyrinogen oxidase in the haem biosynthetic pathway and the elevation of delta-aminolaevulinic acid synthase in the peripheral blood. These features, together with the typical abnormal porphyrin excretion pattern, appear to be diagnostic of hereditary coproporphyria whether in attack, remission, or in the latent form.

Abraham Goldberg

Papers

Acute intermittent porphyria: a study of 50 cases.

Disorders of Porphyrin Metabolism

Diseases of porphyrin metabolism

Environmental lead pollution in an urban soft-water area.

Hereditary coproporphyria. Demonstration of the abnormalities in haem biosynthesis in peripheral blood.