Cesare Patrini

A Study to Compare Oral Sumatriptan with Oral Aspirin plus Oral Metoclopramide in the Acute Treatment of Migraine

In a double-blind, placebo-controlled study, the efficacy, safety and tolerability of 100 mg oral sumatriptan, given as a dispersible tablet, was compared with that of 900 mg oral aspirin plus 10 mg oral metoclopramide in the acute treatment of migraine. A total of 358 patients treated up to three migraine attacks within 3 months, recording clinical information on a diary card. In attack 1, headache relief after 2 h, defined as a reduction in severity from severe or moderate pain to mild or no pain, was recorded in 56% (74/133) of patients who took sumatriptan and 45% (62/138) of patients who took aspirin plus metoclopramide (p = 0.078). This analysis of the primary efficacy end point was not statistically significant. However, for attacks 2 and 3 (secondary end points), headache relief was achieved in 58 versus 36% of patients (p = 0.001) and 65 versus 34% of patients (p less than 0.001), respectively. Relief from nausea, vomiting, photophobia and phonophobia was similar in both treatment groups. Rescue medication was required by fewer patients treated with sumatriptan than by those who received aspirin plus metoclopramide (attack 1, 34 versus 56%, p less than 0.001; attack 2, 32 versus 51%, p = 0.001, and attack 3, 35 versus 54%, p = 0.001). Sumatriptan also produced a faster improvement and resolution of migraine attacks. Comparing the sumatriptan and aspirin plus metoclopramide treatment groups, complete resolution of the attack occurred within 6 h in 32 versus 19% (attack 1), 35 versus 23% (attack 2) and 32 versus 20% of patients (attack 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Thiamine-responsive anemia in DIDMOAD syndrome

Two children with the DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness) developed a megaloblastic and sideroblastic anemia, neutropenia, and borderline thrombocytopenia. Plasma thiamine concentration was low in one patient and normal in the other; in both children, thiamine pyrophosphate in erythrocytes and thiamine pyrophosphokinase activity were lower than the lowest values observed in control subjects. A month after institution of treatment with thiamine, the hematologic findings had returned to normal and the insulin requirements had decreased. Withdrawal of thiamine repeatedly induced relapse of the anemia and an increase in insulin requirements. We propose that an inherited abnormality of thiamine metabolism is responsible for the multisystem degenerative disorder known as DIDMOAD syndrome.

Thiamine content and turnover rates of some rat nervous regions, using labeled thiamine as a tracer

The content of total thiamine radioactivity in some nervous structures and liver of the rat was determined in a steady state condition, using [thiazole-2-14C]thiamine as a tracer. The contents were analyzed by a mamillary type compartmental model which enabled us to calculate the influx and efflux fractional rate constants, turnover times, turnover rates and relative accuracy. Total thiamine turnover rates of the central nervous system regions were found to be ordered in the following sequence: cerebellum (0.55 microgram/g.h) greater than medullar and pons greater than spinal cord and hypothalamus greater than midbrain (plus thalamic area) and corpus striatum greater than cerebral cortex (0.16 microgram/g.h). Sciatic nerve turnover rate was 0.58 microgram/g.h. The turnover times were mainly between 5 and 10 h (range 2.4--16.4 h). The influx rate constants could be ordered as follows: cerebellum greater than hypothalamus, pons and medulla greater than corpus striatum, spinal cord, midbrain (plus thalamic area) and sciatic nerve greater than cerebral cortex. The results show in general a good agreement between turnover rate values and brain regional sensitivity to thiamine deficiency, the most vulnerable areas to thiamine depletion being those with the highest turnover rates.

Further studies on erythrocyte thiamin transport and phosphorylation in seven patients with thiamin-responsive megaloblastic anaemia

SummaryErythrocyte thiamin metabolism and transport were investigated in 7 patients from Brazil, Israel and Italy suffering from thiamin-responsive megaloblastic anaemia (TRMA) associated with diabetes mellitus and sensorineural deafness. All patients discontinued thiamin therapy for 4–7 days before the investigation. TRMA patients showed invariably reduced total thiamin levels in erythrocytes (percentage reduction compared with healthy controls, −46.8±3%; mean±SEM). The proportions of individual thiamin compounds, expressed as a percentage of total thiamin content, were within the normal range, whereas their absolute amounts were significantly decreased in the following order: thiamin monophosphate > thiamin pyrophosphate > thiamin. Thiamin pyrophosphokinase activity was also reduced as compared with controls (mean reduction±SEM, −25.9±1%). The saturable, specific component of thiamin uptake, which normally prevails at physiological concentrations of thiamin (<2µmol/L), was absent in erythrocytes obtained from TRMA patients, while the non-saturable (diffusive) component of uptake was normally present.These results confirm observations made previously in two patients and demonstrate that TRMA is consistently associated with a state of thiamin deficiency, which is presumably secondary to reduced thiamin cellular transport and absorption (caused by lack of a membrane-specific carrier), and to impaired intracellular pyrophosphorylation.

Nervous tissue thiamine metabolism in vivo. II: Thiamine and its phosphoesters dynamics in different brain regions and sciatic nerve of the rat

Different steps of the metabolism of thiamine (T), thiamine mono- (TMP), pyro- (TPP) and triphosphate (TTP) in the cerebellum, brainstem, cerebral cortex and the sciatic nerve were evaluated in the rat in vivo. The radioactivity of T and its phosphoesters was determined at fixed time intervals (0.5-240 h) after an intraperitoneal injection of [14C]T (30 micrograms:1.25 muCi), under steady state conditions. The dynamics of thiamine compounds was evaluated using a compartmental mathematical model that allowed the fractional rate constants (FRC), turnover rates (TR) and turnover times to be calculated. The phosphorylation of T to TPP and the dephosphorylations of TPP to TMP and TMP to T could be estimated in all the structures investigated. Their turnover rates were found to be ordered in the sequence: cerebellum greater than brainstem greater than cerebral cortex greater than sciatic nerve. The transphosphorylation of TPP to TTP was so small that it could not be determined in a reliable way. Regional differences were found both the rate and in the composition of T and TMP mixture released from nervous structures. The shortest turnover time of TPP was found in the cerebellum, while the sciatic nerve exhibited the fastest renewal of T and TMP. In all the structures investigated TPP had a rather short turnover time, suggesting that its function might be associated to a rapid conversion into chemically different forms. The possible relationships between the rates of turnover of T compounds are the sensitivity of the nervous structures to T deficiency are discussed.

Thiamine transport by erythrocytes and ghosts in thiamine-responsive megaloblastic anaemia.

SummaryA 9-year study of thiamine metabolism and cellular transport was performed in two patients with thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and sensorineural deafness, in their relatives, and in age-matched controls from the same area. The ratios between the content of thiamine and that of its phosphoesters in erythrocytes were within the normal range, whereas the absolute values of thiamine and thiamine compounds were reduced by about 40% as compared to controls. Thiamine pyrophosphokinase activity was about 30% lower than in controls. Thiamine treatment restored the levels of thiamine and thiamine compounds to normal values, whereas kinase was unaffected. Both the saturable (specific, predominant at low, < 2 µmol/L, physiological concentrations of thiamine) and the non-saturable component of thiamine transport were investigated. Erythrocytes and ghosts from patients exhibited no saturable component, this abnormality being specific for the patients and not shared by their parents. It is concluded that the cells from thiamine-responsive megaloblastic anaemia patients contain low levels of thiamine compounds, probably due to their inability to take up and retain physiological concentrations of thiamine, as a result of the lack of the saturable, specific component of transport and reduced thiamine pyrophosphokinase.

Monophosphate, the only phosphoric ester of thiamin in the cerebro-spinal fluid

With a specific and sensitive electrophoretic-fluorometric method, thiamin was found in the cerebro-spinal fluid of different mammals both in free and phosphorylated form, monophosphate being the only thiamin phosphoric ester. In humans, its amount was about 60% of total thiamin. Alcoholism greatly lowered total thiamin content, affecting both thiamin forms.

Effects of acute and chronic ethanol administration on regional thiamin pyrophosphokinase activity of the rat brain

Thiamin pyrophosphokinase (TPKase) activity was determined in supernatants of cerebral cortex, cerebellum, pons, medulla, hypothalamus and corpus callosum homogenates obtained from normal rats and from rats given ethanol acutely (a single dose of 4.7 g X kg-1 body wt) or chronically (4.7 g X kg-1 body wt daily for 35 days) by gastric gavage. Regional cell densities (derived from DNA content) and protein contents were also determined. TPKase was detected in all brain regions investigated, the highest activity being found in the cerebellum or in the pons depending on whether it was expressed per mg of protein or per number of cells, respectively. In samples taken following acute ethanol administration protein content was unaffected, while TPKase activity was significantly reduced in the cerebellum, cerebral cortex and hypothalamus at 90 min and in the cerebellum and cerebral cortex at 300 min. Chronic ethanol intake was associated with a significant decrease in regional cell densities, protein contents and TPKase activity. The addition of ethanol to the incubation medium of normal tissue supernatant caused a dose-dependent inhibition of TPKase activity. These results suggest that ethanol markedly impairs thiamin cellular utilization, which may result in depression of brain metabolism.

Nervous tissue thiamine metabolism in vivo. I. Transport of thiamine and thiamine monophosphate from plasma to different brain regions of the rat

The transport of thiamine (T) and thiamine monophosphate (TMP) across the blood-brain barrier was measured in vivo in the rat. Different doses of [14C]T (15-550 nmol) and [14C]TMP (11-110 nmol) were injected into the femoral vein. The content of T and its phosphoesters in blood and brain tissue (cerebellum, pons, medulla and cerebral cortex) 20 s after the injection was determined radiometrically after electrophoretic separation. Blood flow and blood volume in the same regions of the brain was also determined. Both T and TMP entered rapidly the cerebral tissue, where they were found chemically unmodified. The cerebral tissue extracted less than 7% of plasma T. At physiological plasma T concentrations, the rate of transport ranged from 0.43 to 0.65 nmol X g-1 X h-1 with only minor differences among the various regions. T was transported into the nervous tissue by two separate mechanisms: one saturable, that at physiological plasma T levels accounted for 95% (cerebellum) to 91% (cerebral cortex) of the total T taken up, and one non-saturable, that was most efficient in the cerebral cortex. The Km (half-saturation constant) of the former transport mechanism ranged from 1.95 to 2.75 nmol X ml-1 in the 4 areas investigated. Vmax (maximal transport rate) values ranged from 6 to 9 nmol X g-1 X h-1, the highest value being found in the cerebellum. The overall transport rate of TMP was on average 5-10 times as low as that of T and also showed a saturable and a non-saturable component. Both components were slower than those observed for T.

Subacute sensory ataxia and optic neuropathy with thiamine deficiency

Background. A 71 year-old man with a history of partial gastrectomy presented to the emergency department with subacute gait instability associated with painful dysesthesias and clumsiness in both hands. 10 years before presentation he had received a diagnosis of megaloblastic anemia, with no neurological involvement, as a result of vitamin B12 and folate deficiency, for which he was receiving regular supplements.Investigations. Neurological examination; routine laboratory testing; MRI of the spine and brain; lumbar puncture; electromyography; sensory, motor and visual evoked potentials, optic nerve optical coherence tomography; immunoelectrophoresis; cryoglobulins; immunological and infection tests; screening for onconeural antibodies; measurement of serum metabolic values, including vitamins B12 and E, folates, homocysteine, copper, zinc and pyruvic acid; transketolase activity; gastrointestinal endoscopies; and the glucose breath test.Diagnosis. Subacute sensory ataxia with bilateral optic neuropathy related to thiamine deficiency resulting from remote partial gastrectomy.Management. Parenteral thiamine supplementation followed by chronic oral thiamine and short-term, low-dose multivitamins.