Vigabatrin and lamotrigin: experiences with 2 new anticonvulsants in the Swiss epilepsy clinic

Vigabatrin and lamotrigine are two new antiepileptic drugs which have recently become available. Vigabatrin is a specific and irreversible inhibitor of the enzyme gamma-amino-butyric-acid (GABA) transferase. Its administration leads to a long lasting increase in GABA, the most important inhibitory neurotransmitter. Vigabatrin is effective in both adults and children in the treatment of partial and especially complex-partial seizures. After add-on in vigabatrin to their therapeutic drug regime in 116 of our own patients, 39% of previously therapy resistant patients reported a reduced seizure frequency of at least 50% and 6% of them became seizure free. In secondarily generalized epilepsies the best results were observed in axial (infantile) spasms. In addition there was some improvement in tonic and convulsive seizures. Single patients showed increased myoclonic and clonic seizures. Initial efficacy was not always maintained during follow-up. In the experience of other authors, vigabatrin is also effective in the treatment of infantile spasms. It is not suitable for the treatment of generalized epilepsies with absences and myoclonic seizures. Most patients tolerate vigabatrin very well, although psychotic episodes are sometimes reported. So far there have been no relevant hepatic or hematological side effects. Lamotrigine is also effective in the treatment of partial seizures, for which it is approved. However, uncontrolled studies and our own experience have shown that it is even more effective in generalized seizures. As add-on therapy in absences and tonic or tonic-clonic seizures, a significant reduction in seizure frequency--in individual cases seizure freedom--can be achieved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Therapeutic efficacy of ACTH in symptomatic infantile spasms with hypsarrhythmia

The records of twenty-six infants with both symptomatic infantile spasms and classic hypsarrhythmia were reviewed to determine the efficacy of various ACTH dosages and time of initiation of therapy. Mean age of infantile spasm onset was 6.4 months. Most patients (13) had sustained perinatal hypoxic-ischemic insults. Seventeen patients (65%) had complete cessation of spasms. Between these responders and the 9 nonresponders there was no difference in duration of spasms prior to treatment (2.6 and 2.0 months) or mean ACTH dose (87.4 and 84.5 U/m2, respectively). Infants treated with high-dose ACTH (> 100 U/m2) did not have an improved response rate. The most favorable outcomes were associated with spasm onset at > 8 months of age (all of whom were responders, regardless of dose) or when treatment was started within 1 month of onset of infantile spasms with > 80 U/m2 ACTH (88% responders). Infants treated more than 2 months after onset often did not respond (57%) regardless of dose. Nonresponders with spasm onset at < 4 months of age had the worst prognoses; all had poorly controlled seizures and regressed developmentally. Although all infants in the study were neurologically abnormal, development either improved or did not deteriorate in most responder infants following spasm resolution and one-half remained seizure free. Nonresponder infants continued to have infantile spasms or other seizure types. These data suggest that ACTH is valuable in the treatment of significantly impaired infants with symptomatic infantile spasms, but the most important determinants of outcome may be age of onset and rapidity of treatment rather than dosage.     

Temporal relationship modeling: DTP or DT immunizations and infantile spasms

The time relationship between DTP immunization and infantile spasms (IS) onset was examined using three models--association, temporal shift, and no-effect--and the case/control data from the National Childhood Encephalopathy Study (NCES). Infantile spasms cases classified as being previously abnormal (e.g., tuberous sclerosis complex patients) showed a no-effect relationship, whereas those classified as previously normal suggested a fit to the temporal shift model, i.e. no increase in number of cases but a shortening of time to onset of seizure. No data fit the association model. Analyses for vaccine complications should examine for temporal changes (i.e. temporal shift) in addition to increased risks.     

Single-chain Fv with manifold N-glycans as bifunctional scaffolds for immunomolecules

PURPOSE: To investigate the significance of cortical pathology of tonic spasms in patients with tuberous sclerosis. METHODS: The subjects were 38 patients with epilepsy associated with tuberous sclerosis. We analyzed ictal EEGs of tonic spasms and partial seizures by means of video-EEG monitoring for a total of 763 tonic spasms in 20 patients and 107 partial seizures in 15 patients. We also investigated the relation between partial seizures and magnetic resonance imaging (MRI) findings of these patients. RESULTS: Ictal EEG patterns of tonic spasms were divided into generalized and focal patterns. Thirteen patients had only generalized patterns, whereas seven had both patterns. In five patients who had focal ictal patterns of tonic spasms and partial seizures, the location of focal patterns corresponded with the location of onset of partial seizures. Focal discharges were seen immediately before, after, and in the middle of tonic spasms in series in 13 patients. The location of focal discharges also corresponded with the location of the onset of partial seizures in 10 of the 13 patients. Regarding partial seizures, four patients had multiple active epileptogenic foci during the same period, and two others had shifting epileptogenic foci with increasing age. CONCLUSIONS: These findings indicate that cortical pathology plays an important role in the occurrence not only of partial seizures but also of tonic spasms in patients with tuberous sclerosis.     

Excitatory amino acid levels in cerebrospinal fluid of patients with infantile spasms

Infantile spasm is an age-specific epileptic encephalopathy. Long-term intellectual outcome of affected infants remains poor. The pathogenesis of infantile spasms, as well as the development of mental retardation, remains unclear. Increased excitatory amino acid neurotransmission may play a role in neuronal dysfunction and epilepsy. To study the significance of cerebrospinal fluid excitatory amino acids in infantile spasms, we determined glutamate and aspartate concentrations in cerebrospinal fluid of 13 patients with infantile spasms and 13 controls. The aspartate level in cerebrospinal fluid of the patients with infantile spasms (968 +/- 416 nmol/l) was higher than the control group (426 +/- 272 nmol/l). No difference in the mean glutamate levels was found between the patients (966 +/- 395 nmol/l) and the controls (1135 +/- 594 nmol/l). The elevated aspartate levels in cerebrospinal fluid of the patients with infantile spasms might be secondary to change in metabolism of aspartate. Aspartate is an excitatory and neurotoxic neurotransmitter, which might have a role in triggering the spasms and the development of neuronal dysfunctions in the patients with infantile spasms.     

Hydrocortisone induces an increase of amylase content in individual zymogen granules from rat pancreas

This study was performed to evaluate the effects of different doses of hydrocortisone (1, 10 and 25 mg/kg/day) administered for 1, 3 and 8 days on pancreatic enzyme storage in rats. The enzyme content in both pancreas homogenates and in individual isolated zymogen granules (ZGs) was measured using standard biochemical assays and flow cytometry, respectively. Hydrocortisone did not alter the total amount of pancreatic DNA but increased the pancreas enzyme content in a time-dose-dependent way. Amylase activity was significantly increased after hydrocortisone administration at day +8 when 10 mg/kg/day was used, and from the first day of treatment when 25 mg/kg/day was administered. A significant increase in trypsin activity was also observed in response to 25 mg/kg/day of hydrocortisone but only from the third day of treatment onwards. As compared with control rats, chronic administration of either 1 or 10 mg/kg/day of hydrocortisone did not alter significantly either the size or the percentage of the two ZG subpopulations (Z1 and Z2) identified in the pancreas by flow cytometry; in addition, no significant changes were observed in the mean amylase content per individual granule, although its mean concentration increased in rats treated with 10 mg/kg/day for 3 and 8 days. Nevertheless, when 25 mg/kg/day of hydrocortisone were administered for 1 and 3 days, a significant increase in the proportion of Z1 ZGs was observed, which may be related to the formation of new and smaller ZGs. When a very high dose of hydrocortisone (25 mg/kg/day) was used, an overall increase in the pancreatic enzyme content related to an increase in the mean amylase content per individual ZG was observed; this effect was apparent from the first day of treatment in the Z1 subset of ZGs and from day +3 in the Z2 subpopulation. Only a high concentration of hydrocortisone was able to alter the enzyme storage process in individual zymogen granules, but they maintain a normal enzyme load at lower hydrocortisone doses.     

Mycophenolate mofetil, together with cyclosporin A, prevents anti-OKT3 antibody response in kidney transplant recipients

OKT3 monoclonal antibody, a murine IgG2a monoclonal antibody targeting the T cell CD3 antigen, elicits a neutralizing humoral response in 20 to 50% of kidney transplant recipients when the concomitant immunosuppression consists of CsA-Sandimmun (SAND) and azathioprine (AZA). In the present study, we investigated the impact of the newer agents, CsA-Neoral (NEO) and mycophenolate mofetil (MMF) on OKT3 sensitization. Sixty-two consecutive kidney transplant recipients received prophylactic OKT3 (5 mg/d) from days 0 to 13, together with steroids. Concomitant immunosuppression consisted of either AZA + SAND (n=20), AZA + NEO (n=31), or MMF + NEO (n=11). The following doses were used: AZA, 2 mg/kg per d from days 0 to 13, then 1 mg/kg per d; MMF, 2 g/d starting on day 1; and CsA, either SAND or NEO, 6 mg/kg per d from day 6. At least two serum samples per month were available during the initial 3 mo for each patient. IgG anti-OKT3 antibodies were first evaluated by enzyme-linked immunosorbent assay. Patients were considered sensitized if their serum scored positive at a dilution > or = 1/1000. Peak titers of IgG anti-OKT3 antibodies and the incidence of patients harboring neutralizing anti-idiotypic antibodies were also determined. A first reduction in OKT3 sensitization was seen in patients receiving Neoral instead of Sandimmun (AZA + SAND: 10 of 20 [50%] patients sensitized versus 6 of 31 [19%] in the AZA + NEO group; P=0.03). This was probably related to the achievement of higher mean CsA trough blood levels in the NEO group during the first month (253+/-44 versus 186+/-49 ng/ml in SAND patients). Peak antibody titers and the proportion of patients with anti-idiotypic antibodies were similar in the AZA + SAND and AZA + NEO groups. A further reduction in the sensitization rate was observed with the replacement of AZA by MMF (MMF + NEO: 0% sensitized patients; P=0.0013). It is concluded that the combination of CsA-Neoral and MMF efficiently prevents sensitization against OKT3.     

Neck sprain in patients injured in car accidents: a retrospective study covering the period 1970-1994

Vigabatrin (gamma-vinyl GABA) is an antiepileptic drug and blocks GABA transaminase activity resulting in elevations in cellular GABA levels in the brain. Nipecotic acid (NPA) promotes release of GABA from neonatal optic nerve astrocytes, resulting in a bicuculline-sensitive depolarization of the optic nerve axons. The NPA-induced depolarization of vigabatrin-treated rats (100 mg/kg, i.p.) more than doubled, suggesting an elevation in free GABA levels; the GABA transporter inhibitor, NO-711 reduced the depolarization. These results are consistent with the known ability of vigabatrin to block the GABA degradation enzyme GABA-transaminase, suggesting that vigabatrin elevates astrocytic GABA levels, thereby favoring greater release of GABA through the GABA transporter.     

Phase I safety and pharmacokinetics study of micronized atovaquone in human immunodeficiency virus-infected infants and children. Pediatric AIDS Clinical Trials Group

A phase I dose-escalating safety and pharmacokinetic study evaluated an oral suspension of micronized atovaquone (m-atovaquone) in infants and children stratified into age groups from 1 month to 12 years of age. Dosages of 10, 30, and 45 mg/kg of body weight/day were evaluated as single daily doses over a period of 12 days. Steady-state concentrations in plasma were determined on day 12, and single postdose concentrations were measured on days 1, 3, 5, 7, 9, 13, 15, 18, 21, and 24. Prior studies with adults suggest that the average plasma atovaquone concentration of 15 micrograms/ml is associated with therapeutic success in more than 95% of patients with Pneumocystis carinii pneumonitis. The results showed m-atovaquone to be safe and well tolerated. Dosages of 30 mg/kg/day were adequate to achieve an average steady-state concentration of greater than 15 micrograms/ml in children ages 1 to 3 months and 2 to 12 years, but a dosage of 45 mg/kg/day was needed to reach this concentration in infants 3 to 24 months of age. The oral suspension of atovaquone is safe and well tolerated in children. A single daily dose of 30 mg/kg provides bioavailability considered adequate for therapy of P. carinii pneumonia, but infants between 3 and 24 months of age may require a dosage of 45 mg/kg/day.     

A randomized trial in primary biliary cirrhosis comparing ursodeoxycholic acid in daily doses of either 10 mg/kg or 20 mg/kg. Dutch Multicentre PBC Study Group

BACKGROUND: Ursodeoxycholic acid (UDCA) prolongs transplantation-free survival in primary biliary cirrhosis (PBC). However, the optimal therapeutic dose has not been established. AIM: To compare the effects of UDCA administered in daily doses of 10 vs. 20 mg/kg on symptoms, liver biochemistry and biliary UDCA enrichment. METHODS: A 6-month multicentre randomized open controlled trial was conducted to assess the effects of an increase in the dose of UDCA to 20 mg/kg/day vs. continuation of 10 mg/kg/day for patients who had not achieved biochemical normalization during treatment for at least 6 months with the 10 mg/kg dose. Clinical and laboratory evaluations were performed at entry and at 3-month intervals. The percentage UDCA in duodenal bile was assessed at entry and at 6 months. RESULTS: Sixty-one patients were enrolled. No side-effects of UDCA were observed. Within the 20 mg/kg/day group significant decreases were found for alkaline phosphatase (- 8%; P = 0.003), aspartate aminotransferase (- 11%; P = 0.01), alanine aminotransferase (- 17%; P < 0.001), gamma-glutamyl transferase (- 34%; P < 0.001), immunoglobulin M (- 11%; P = 0.002) and cholesterol (- 8.1%; P < 0.001). In the 10 mg/kg group none of these parameters differed significantly from baseline. No significant differences between dose groups for symptom scores or serum bilirubin were found. Biliary enrichment with UDCA increased from 37% to 46% in the 20 mg/kg group (P = 0.02) while remaining stable in the 10 mg/kg group. CONCLUSIONS: Liver biochemistry improved in PBC patients receiving UDCA 20 mg/kg/day compared to a dose of 10 mg/kg/day. Both doses were equally well tolerated. These results indicate that UDCA 10 mg/kg/ day is a suboptimal dose for treating PBC.     

Low transplant mortality in allogeneic bone marrow transplantation for acute myeloid leukemia: a randomized study of low-dose cyclosporin versus low-dose cyclosporin and low-dose methotrexate

Sixty patients undergoing allogeneic bone marrow transplant for acute myeloid leukemia (AML) in first remission (CR1; n = 49) or more advanced phase (n = 11) were entered in a prospective trial of graft-versus-host disease (GvHD) prophylaxis: low-dose cyclosporin A (IdCSA; 1 mg/kg/d from day -1 to +20 day; n = 28) or IdCSA plus low-dose methotrexate (IdMTX; 10 mg/m2 for day +1, 8 mg/m2 for days +3, +6, and +11; n = 32). Primary end points were acute GvHD (aGvHD) and transplant-related mortality (TRM); secondary end points were relapse and survival. The conditioning regimen consisted of cyclophosphamide (120 mg/kg) and fractionated total body irradiation (3.3 Gy/d for 3 consecutive days). The actuarial risk of developing aGvHD grade II-III was 61% for IdCSA alone and 34% for IdCSA + IdMTX (P = .02). The actuarial risk of TRM at 1 year was 11% versus 13%, respectively, and older patients (>/= 29 years) had higher TRM than younger patients (22% v 5%, P = .01). The age effect was significant in the IdCSA group (P = .04) but not in the IdCSA + IdMTX group (P = .1). The median follow-up is 4.4 years, with an overall actuarial survival of 78% for CR1 patients and 36% for patients with advanced disease. For patients in CR1 the outcome of the two regimens was as follows: survival 77% versus 80% (P = .6), relapse 20% versus 9% (P = .1), and TRM 13% versus 17% (P = .6). This study suggests that TRM can be reduced in AML patients undergoing allogeneic marrow transplants with a mild conditioning regimen and low-dose immunosuppression, and this translates in a 78% 5-year survival for CR1 patients. Beyond CR1 the major obstacle remains leukemia relapse, which is not prevented by low-dose in vivo immunosuppression.     

Effects of intracerebroventricular injection of histamine on memory deficits induced by hippocampal lesions in rats

This review was conducted to evaluate the long-term prognosis of children responding to vigabatrin by examining the incidence of increased seizure frequency, loss of efficacy, and appearance of new seizures in a cohort of 196 children (mean age, 68.2 months; range, 2 months to 19 years) with drug-resistant epilepsy, who had received vigabatrin as add-on treatment in clinical trials. The results indicate that an increase in seizure frequency was uncommon, occurring in only 10% of children with highly drug-resistant epilepsy and that it usually appears shortly after the initiation of treatment. It was clearly not dose-dependent and most often occurred in patients with nonprogressive myoclonic epilepsy. No specific seizure type was specially involved and usually the problem reversed on discontinuing vigabatrin. Loss of efficacy was also uncommon (12% of patients), and again no specific seizure type was found to be associated. Epilepsy syndrome does seem to be a better predictor of loss of efficacy because it occurred most often in symptomatic generalized epilepsies and cryptogenic infantile spasms. A total of 21 patients (11%) developed genuinely new types of seizures. Fifteen of these patients developed new partial seizures that had little impact on the patients' overall clinical improvement. The new partial seizures were better tolerated than the initial seizure type which in most cases had disappeared. Approximately 3% of patients experienced new generalized seizures that aggravated their initial condition. These occurred most often in patients with nonprogressive myoclonic epilepsy; therefore vigabatrin should be used with particular caution in such patients.     

A randomized trial of cyclosporine in steroid-resistant idiopathic nephrotic syndrome

To compare the efficacy (induction of remission) and safety of cyclosporine (CsA) with those of supportive therapy in patients with steroid-resistant idiopathic nephrotic syndrome (INS), we organized an open, prospective, randomized, multicentric, controlled study for parallel groups, stratified for adults and children. Forty-five patients with steroid-resistant INS were randomly assigned to supportive therapy or CsA (5 mg/kg/day for adults, 6 mg/kg/day for children) for six months, then tapered off by 25% every two months until complete discontinuation. Four patients were lost to follow-up. During the first year 13/22 CsA-treated patients versus three of 19 controls attained remission of the nephrotic syndrome (P < 0.001). A symptom score was assessed at time 0 and at six months. The mean score significantly decreased in the CsA group (P < 0.001), but remained unchanged in the controls. At month 6 the mean urinary protein excretion, the mean serum proteins and plasma cholesterol had significantly improved in the CsA group but were not changed in the controls. There were no significant differences in serum creatinine and creatinine clearance between treatments (interaction time* treatments, P = 0.089 and P = 0.935, respectively) at month 6 versus basal. The CsA-related side-effects were mild; no significant difference in blood pressure between the two groups was seen at any time. This study shows that CsA can bring about remission in some 60% of patients with steroid-resistant INS. In patients with normal renal function and without severe hypertension, CsA at the therapeutic scheme adopted did not produce severe renal or extrarenal toxicity.     

Calcium metabolism and growth during early treatment of children with X-linked hypophosphataemic rickets

To evaluate the effect of early treatment on calcium metabolism and growth of infants with X-linked hypophosphataemic rickets (XLH), we enrolled eight infants (one boy) with XLH in a prospective study before and during combined treatment with 40 60 mg/kg per day phosphate and 20-40 ng/kg per day 1,25(OH)2D3 (calcitriol). The duration of treatment ranged from 12 to 68 months (median 27 months). We measured the height and several indices of calcium and bone metabolism before and at intervals of 6 weeks to 3 months thereafter during treatment. The diagnosis XLH was established between the age of 3 to 12 weeks by the detection of elevated alkaline phosphatase activities (n = 8) and urinary hydroxyproline (n = 7), whereas only five patients had also hypophosphataemia. Six of seven untreated patients had decreased 1,25(OH)2 vitamin D levels in serum. During treatment alkaline phosphatase and hydroxyproline decreased to normal or slightly elevated levels, whereas serum phosphate remained below the normal range. Several patients treated with more than 40-50 mg/kg per day phosphate developed secondary hyperparathyroidism. One patient receiving a low dose of 20 ng/kg per day calcitriol had prolonged radiological and biochemical signs of rickets and growth delay. The other patients presented with no or only slightly transient signs of rickets. Three patients developed moderate nephrocalcinosis. The statural growth rate decreased slightly below 2 SDs without a further decrease in two patients and remained within the normal range in the other patients. Only four patients developed moderate leg deformities. CONCLUSIONS: Early treatment with calcitriol at a daily dose of at least 30-40 ng/kg and phosphate at a daily dose of maximal 40-50 mg/kg improves mineral metabolism and seems to obviate severe growth delay and leg deformities.     

Evaluation of an intercostal myoneurovascular transposition as a lower esophageal neosphincter

Three hundred and eleven hospitalized weaned infants with acute diarrhea, all under 12 months of age, were studied in order to evaluate the development of lactose intolerance and its association with age, nutritional status, birth weight, dehydration and enteropathogenic agents identified in fecal samples. After been rehydrated the infants received whole cow' milk assuring the intake of 100 kcal/kg per day. Lactose intolerance was defined according t the following criteria: 1) persistence of diarrhea associated with weight loss during 48 hours, 2) development of vomiting and/or abdominal distention associated with excretion of carbohydrate in feces and/or acids tools, 3) metabolic acidosis associated with abdominal distention at anytime of refeeding period. Lactose intolerance was detected in 52.1% (162/311) of the patients and it was significantly associated with age under 6 months (P < 0.01), birth weight under 3000 grams (P < 0.01), development of dehydration (P < 0.01) and with enteropathogenic Escherichia coli (EPEC) serotypes infection (P < 0.01).     

Early treatment of acute graft-versus-host disease with high- or low-dose 6-methylprednisolone: a multicenter randomized trial from the Italian Group for Bone Marrow Transplantation

Ninety-five patients undergoing an allogeneic bone marrow transplant (BMT) and developing acute graft-versus-host disease (aGvHD) were randomized to receive low-dose intravenous 6-methylprednisolone (6MPred; 2 mg/kg /d; n = 47) or high-dose 6MPred (10 mg/kg/d; n = 48) for 5 days, with subsequent tapering doses. On day 5 patients not responding or progressing on low-dose 6MPred could be switched to high-dose 6MPred. All patients, aged 1 to 55 years, were recipients of unmanipulated BMT from HLA identical sibling donors. Patients were stratified at randomization for age (/= 20 years), disease (acute leukemia, chronic myeloid leukemia [CML], nonneoplastic disease), disease status (early/advanced), and GvHD prophylaxis (cyclosporin/cyclosporin + methotrexate). Primary endpoints were response to treatment and evolution of aGvHD to grade III-IV. Secondary endpoints were cytomegalovirus (CMV) infections, transplant-related mortality (TRM), and relapse. The median interval between BMT and treatment was 12 days (6 to 43). Results in the two groups (2 v 10 mg/kg) were as follows: response of aGvHD 68% versus 71% (P = .9), evolution to aGvHD grade III-IV 17% versus 20% (P = . 6), CMV infections 55% versus 60% (P = .7), 3-year actuarial TRM 28% versus 32% (P = .7), relapse 17% versus 7% (P = .1). The actuarial survival at 3 years was 63% versus 62% (P = .9) with a median follow up of 580 and 778 days. On day 5 of therapy, 26 patients assigned to low-dose (2 mg/kg) 6MPred were switched to a higher dose of 6MPred because of no response or progression. Their actuarial TRM was 46%, which is significantly higher than TRM of patients who responded on 2 mg/kg and continued with tapering doses (TRM = 16%, P = .007). In conclusion, early treatment of acute GvHD with 6MPred 10 mg/kg/d does not improve the response rate as compared with 2 mg/kg/d, nor does it prevent evolution to aGvHD grade III-IV. CMV infections, TRM, and survival were also comparable. A group of patients at high risk of TRM can be identified after 5 days of treatment with 6MPred 2 mg/kg and could be eligible for alternative forms of therapy.     

A prospective randomized comparison of quadruple versus triple therapy for first cadaver transplants with immediate function

In January 1988, we initiated a prospective, randomized comparison of prophylactic antilymphoblast globulin (ALG; quadruple therapy) versus no prophylactic ALG (triple therapy) in the setting of immediate graft function (defined by a brisk diuresis and a 20% decline in serum creatinine within 24 hr). Recipients were stratified according to presence of diabetes and age greater or less than 50 years. Recipients on quadruple therapy (n = 61) received 7 days of prophylactic Minnesota ALG (5 mg/kg on day 1, 10 mg/kg on day 2, 20 mg/kg on days 3-7). CsA, 10 mg/kg/day, began on day 6. AZA began at 2.5 mg/kg/day and was adjusted according to white blood cell count. Recipients on triple therapy (n = 60) began immediate CsA, 10 mg/kg/day orally and AZA, 5 mg/kg/day, tapering to 2.5 mg/kg/day by day 8. Both groups received identical prednisone tapers beginning at 1 mg/kg/day, decreasing to 0.5 mg/kg/day by 2 weeks and to 0.15 mg/kg/day by 6 months. Demographic characteristics between groups were not different with respect to diabetes, age, sex, race, per cent panel-reactive antibodies (PRA), or HLA matching. Follow-up ranged from 2 to 4.5 years. Patient survival was 93% for the quadruple therapy group and 90% for triple therapy. Actuarial graft survival was 79% in the quadruple group and 72% in the triple group (P = 0.18). Graft loss due to rejection occurred in 6/61 receiving ALG versus 7/60 in the immediate CsA group. Three of 4 high PRA recipients in the immediate CsA group lost their grafts within 30 days compared with none in the ALG group. The mean time to graft loss was significantly longer for the quadruple therapy group (17 +/- 8 months) compared with the triple therapy group (4 +/- 5 months), P = 0.006. The total number of rejection episodes was similar for both groups (29/61 vs. 31/60), as was the number who were rejection free (51% vs. 47%). The use of OKT3 was also similar between groups (28% vs. 30%). The quadruple therapy group had a higher incidence of CMV infection: 20% vs. 7% (P < 0.05), but no grafts or patients were lost as a result. Serum Cr was not different at 1 and 12 months (1.5 and 1.6 vs. 1.6 and 1.7, respectively), nor were Cr clearances (63 and 68 vs. 60 and 63). Conclusion. Early initiation of oral CsA in the setting of immediate graft function is not associated with significant nephrotoxicity.(ABSTRACT TRUNCATED AT 400 WORDS)     

A comparative evaluation of whey hydrolysate and whey-predominant formulas. How well do infants accept and tolerate them?

Whey hydrolysate formulas are a recent and important innovation in infant feeding. This study compared clinical tolerance and acceptability of a whey hydrolysate formula (WH) with those of a whey-predominant formula (WF) in 45 infants. Four infants (16%) who refused to drink WH formula were eliminated from the study. Mean volume intake was significantly lower for WH (120 mL/kg/day) than for WF (147 mL/kg/day; P < .001). Consequently, mean caloric intake was also significantly different: 80 kcal/kg/day (WF) vs 97 kcal/kg/day (WF; P < .001). Nevertheless, weight gain from birth to 13 weeks of age was nearly identical in both groups (171% for WH vs 178% for WF). No significant differences were noted in duration of feeding, number of pauses during feeding, number of stools per day, or number of regurgitations per day. The lower rate of caloric intake and the dropout rate of 16% for WH raise questions about the use of WH formula in normal infants, as has become the case in some Western European regions.     

Effect of cyclosporine on fertility in male rats

The effect of cyclosporine (CsA) on fertility has assumed greater importance with the increasing numbers of pediatric transplantations being performed all over the world. Conflicting reports on the effects of CsA on sex hormones are available. This experimental animal study was designed to examine the effect of CsA on testicular weight, sperm counts, seminiferous tubular diameter (STD), testicular morphology, DNA flowcytometry, sex hormone levels, and fertility in male rats. Those rats who received CsA (20 mg/kg per day) showed significant reductions in testicular weight (P < 0.05), sperm count (P < 0.01), Johnsen score (P < 0.05), STD (P < 0.01), serum testosterone levels (P < 0.05), haploid cell population (P < 0. 001) in the testis, and fertility (P < 0.001) compared to those receiving CsA 10 mg/kg per day and control rats. These findings will have an important bearing for children receiving cyclosporine for long periods to guide the physician in optimally adjusting long-term treatment.     

Identification of multiple cyclin subunits of human P-TEFb

Unopposed actions of vasoconstrictors, such as angiotensin, play an important role in the effects of chronic nitric oxide synthase (NOS) inhibition. In this study, it is hypothesized that endothelin (ET), another important vasoconstrictor, may also play a role in the development of hypertension and renal lesions during chronic NOS inhibition. The ET(A) receptor was blocked with A-127722 during chronic NOS inhibition with Nomega-nitro-L-arginine (L-NNA), a potent NOS inhibitor without antimuscarinic action. Male Sprague Dawley rats were treated for 3 wk with L-NNA (40 mg/kg per d), L-NNA (40 mg/kg per d) + A-127722 (30 mg/kg per d), or remained untreated (control). In preliminary experiments, L-NNA (40 mg/kg per d) had been found to cause the maximum increase of systolic BP and a 35% decrease in renal NOS activity. Three weeks of L-NNA treatment resulted in a marked rise in systolic BP (240+/-4 versus control 151+/-7 mmHg; P < 0.01), proteinuria (209+/-46 versus control 27+/-3 mg/d; P < 0.01), and a fall in GFR (1.41+/-0.16 versus control 2.23+/-0.19 ml/min; P < 0.05). Renal morphology showed severe vascular injury, characterized by focal adhesion and infiltration of mononuclear cells into the intima and media of preglomerular arteries and arterioles. This was sometimes associated with necrosis of the media and partial or total obstruction of the lumen with thrombotic material. Ischemic glomeruli were also present. Tubulointerstitial damage was moderate and accompanied by an influx of monocytes and macrophages. A-127722 administered simultaneously with L-NNA completely prevented the increase in proteinuria (39+/-8 mg/d) and glomerular ischemia. Vascular injury, tubulointerstitial damage, and the increase in systolic BP (191+/-6 mmHg) were partially prevented. The protective effects of ET(A) receptor blockade suggest that ET has hemodynamic as well as nonhemodynamic effects in the cascade of events following chronic NOS inhibition.