Generic orphan drug substitution: a critical analysis of global practices and Saudi Arabia's perspective.

In an era of cost pressure, substituting generic drugs represents one of the main cost-containment strategies of healthcare systems. Despite the obvious financial benefits, in a minority of cases, substitution may require caution or even be contraindicated. In most jurisdictions, to obtain approval, the bioequivalence of generic products with the brand-name equivalent needs to be shown via bioavailability studies in healthy subjects. Rare diseases, defined as medical conditions with a low prevalence, are a group of heterogenous diseases that are typically severe, disabling, progressive, degenerative, and life-threatening or chronically debilitating, and disproportionally affect the very young and elderly. Despite these unique features of rare diseases, generic bioequivalence studies are typically carried out with single doses and exclude children or the elderly. Furthermore, the excipients and manufacturing processes for generic/biosimilar products can differ from the brand products which may affect the shelf-life of the product, its appearance, smell, taste, bioavailability, safety and potency. This may result in approval of generics/biosimilars which are not bioequivalent/comparable in their target population or that meet bioequivalence but not therapeutic equivalence criteria. Another concern relates to the interchangeability of generics and biosimilars which cannot be guaranteed due to the phenomenon of biocreep. This review summarizes potential concerns with generic substitution of orphan drugs and discusses potentially problematic cases including narrow therapeutic index drugs or critical conditions where therapeutic failure could lead to serious complications or even death. Finally, we put forward the need for refining regulatory frameworks, with emphasis on Saudi Arabia, for generic substitution and recent efforts toward this direction.

[Acute infectious disease of otolaryngology focus]. / Patología infecciosa aguda de foco otorrinolaringológico.

Infections are the most common cause of antibiotic prescription and one of the most frequent reasons for consultation in Primary Care. Among them, stand out acute media otitis and diffuse external otitis, acute pharyngitis and acute rhinosinusitis. Commonly they are viral and self-limited, so their complications are rare. Currently, the indiscriminate use of antibiotics have leaded to bacterial resistances; therefore antibiotic prescription should be more careful. Nowadays, several diagnostic strategies are available. In current updated etiological and pathophysiological factors of each infection, diagnostic and therapeutic strategy to be applied in Primary Care as well as the complications of each pathology and the referral indications to be assessed by specialists in the ENT area, will be reviewed.

[Surgical treatment of secondary hyperparathyroidism in chronic renal failure. Report of 57 cases]. / Traitement chirurgical de l'hyperparathyroidie secondaire des insuffisants renaux: a propos de 57 cas.

AIM: The aim of this study was to report the experience of the department of general surgery (Aile III) Ibn Rochd Hospital in surgical management of hyperparathyroidism in patients with end-stage renal disease (ESRD). METHODS: Fifty seven patients (24 M, 33F) with hyperparathyroidism underwent surgical parathyroidectomy from 1998 to 2004. Surgical indication was established according to clinical or biological assessment. Fifty nine operations were performed (57 first-hand cervicotomies and resumptions in too cases). RESULTS: Histological examination of parathyroid gland specimens disclosed adenoma in 33 patients and hyperplasia in 14 patients. The follow-up was normal in 52 patients, marqued by cervical hematoma in 2 cases and death was deplored in 4 patients. The post-operative calcium level was in the normal range in 43 cases, low comparatively to the baseline in 12 cases and high in 2 cases. The PTH levelwas normal in 55 patients and high in two patients. Long-term outcome was evaluated in 36 patients mean follow-up (18 months). A good evolution was noted in all patient referring to clinical, biological and radiological investigations. CONCLUSION: That, in our context, surgical parathyroidectomy still an appropriate approach for the treatment of hyperparathyroidism in patients with end-stage renal disease.

Diabetic nephropathy in hemodialysis patients in casablanca.

Diabetes is the main cause of end-stage renal disease (ESRD) in the developed countries and its prevalence and incidence have been constantly increasing over the years. To determine the prevalence and profile of diabetic nephropathy in our ESRD population, we retrospectively studied 564 hemodialysis patients in ten dialysis units in Casablanca. The mean age was 49 +/-16.2 years. The diabetic nephropathy came at the third rank with a prevalence of 13.5% behind chronic glomerulonephritis (21.8%) and hypertensive nephropathy (14.7%). Almost 74% of our diabetics were type 2. From the time of diagnosis the type 2 diabetics reached the ESRD earlier than the type 1 diabetics with a mean period of 15.1 +/- 7 years and 18.8 +/- 5 years, respectively; however, the difference was not statistically significant. There was at least another microangiopathic complication in 95.4% of the patients and macroangiopathic complication in 82%. The median hemoglobin A1C in all patients was higher than normal value. We conclude that ESRD is a serious complication of diabetes, which is constantly increasing. The appropriate management of diabetes and a multidisciplinary approach are necessary to avoid it or at least delay its occurrence.

[Phototherapy and hemodialysis pruritus]. / Photothérapies et prurit des hémodialysés.

The renal failure-related pruritus is frequent (10-30%) and this frequency increases in dialysed patients (60-80%). Its physiopathology remains badly known. The prurit is variable in intensity and surface. It predominates on the forehead, the back and the forearms. The skin is normal on it presents non specific lesions. The best treatment would be the renal graft. When it can't be done, phototherapy represents a good therapeutic alternative. We report the experience of our patients from December 1993 to January 2002. The patients could benefit from a steady treatment and be well followed-up. The mean age of our patients was 51 years with a masculine predominance (12 men to 7 women). The mean duration of hemodialysis was 3 years and the one of prurit was 10 months. Between December 1993 and January 2001, UVB phototherapy with a spectrum was used in 14 cases. After this period a phototherapy with a narrow spectrum was used. The mean dose was 2 Joules with a number of sessions. Eventually, the total body irradiation with UVB was the most regularly effective therapy of the hemodialysed prurit. It allows an important reduction, which is a significant result in comparison with UVA irradiation.

[Sexual dysfunction among 78 Moroccan male hemodialysis patients: clinical and endocrine study]. / Troubles sexuels chez 78 hémodialysés chroniques marocains de sexe masculin: étude clinique et endocrinienne.

PURPOSE: To investigate the correlation between biochemical and endocrine variables with sexual disorders in 78 male patients on chronic hemodialysis at the Ibn Rochd University Hospital (Casablanca-Morocco). METHODS: Seventy-eight male hemodialysis patients with chronic renal failure were evaluated with regard to their sexual function. All patients answered a personal questionnaire on their sexual activity. Hormone (FSH, LH, prolactin, testosterone, and parathyroid hormone) and zinc and ferritin assays were also performed. RESULTS: The men reported erection (44.9%), libido (44.9%), ejaculation (26.8%), and orgasm (21.8%) disorders. Gynecomastia was observed in 17.9% of the patients. There was no correlation with weight nor the nature of the causal nephropathy nor with duration of dialysis. Levels of gonadotropins (FSH, LH), prolactin, and parathyroid hormone were elevated. Testosterone levels were low. Ferritinemia was elevated but there was no significant variation in zincemia. There was a negative curvilinear relationship between serum testosterone and sexual disorders, and between gynecomastia and ferritinemia. LH and prolactin levels were positively correlated with gynecomastia. CONCLUSION: Abnormal hormonal and iron overload could be important factors involved in the complex pathogenesis of sexual dysfunction in chronic renal failure patients undergoning hemodialysis.

[Extramembranous glomerulonephritis and myelodysplastic syndrome]. / Glomérulonéphrite extramembraneuse et syndrome myélodysplasique.

Membranous glomerulonephritis (MGN) is the main cause of nephrotic syndrome in adults and is usually idiopathic. We report a case of nephrotic MGN associated with a myelodysplastic syndrome (MDS) in a 43 year old man. The initial treatment consisted of oral corticosteroids (1 mg/kg/day). Within 3 months proteinuria decreased from 22.4 g/day to 3.96 g/day and the blood cell count was normalized. Renal biopsy disclosed type I MGN. Ponticelli's protocol was started with a favorable effect: negative proteinuria, normal blood cell count and normal bone marrow cellularity. The association between MGN and MDS is quite rate. The possible links between the two conditions are reviewed.

[Primary focal segmental glomerulosclerosis in adults: response to treatment and outcome]. / La hyalinose segmentaire et focale primitive de l'adulte: aspects thérapeutiques et evolutifs.

Response to therapy of primary focal segmental glomerulosclerosis (FSGS) in adults is poor, most studies demonstrated no response at all. We report our experience from a retrospective study about 22 adults patients. All patients presented proteinuria at admission with a nephrotic syndrome in 86 percent of cases. A high blood pressure was noted in 25 percent. A response to corticosteroid was obtained in 8 patients (36%) with complete remission in 5 cases (23%). Three patients were corticosteroid-dependant, two out of them went in remission under cyclophosphamide in one case and under chlorambucil in the other case. Fourteen patients did not respond to corticosteroids. Eight received cyclophosphamide with partial remission in 4 cases and progression to chronic renal failure (CRF) in 4 cases. The six non-responders did not receive immunosuppressive drugs because of severe CRF in 4 cases. The mean duration of follow-up was 39 months (20-55). The response to corticosteroid of primary FSGS in adults remain low (30%). The use of cyclophosphamide has improved the global remission to 50 percent.

[Hemodialysis-related pruritus. A study of 134 Moroccans ]. / Prurit des hémodialyses chroniques. Etude de 134 cas marocains.

The prevalence of pruritus varies from 60% to 90% in patients receiving hemodialysis. The aim to this study was to evaluate the frequency of pruritus and its characteristics among moroccan patients receiving hemodialysis. Pruritus related to primary skin disease or other identified cause than chronic renal failure was excluded. Biological parameters were compared between patients with pruritus and those without. Pruritus occurred in 74.4% of hemodialysis patients and concerned 66 men and 68 women, mean age 44.8 + 14 years. Duration of hemodialysis varied between 5 months to 10 years. Main characteristics of pruritus were a general pattern in 70%, moderate intensity in 50%, appearance after dialysis in 81.2% and severe psychologic repercussion in 20.8%. Antihistamines first-line treatment was rarely effective. UVB radiation used in 7 cases leaded to a marked improvement. This study underlined the high frequency of pruritus in moroccan patients with chronic renal failure on maintenance hemodialysis. Hemodialysis can initiate this symptom as well as improve it. Biological parameters were not different between patients with or without pruritus. It also pointed out on therapeutic challenges. However, UVB radiation seems to be an effective therapy in intractable itching as well as increased frequency of weekly courses of hemodialysis. Long term skin hydratation should be also highly recommended.

[Ossifying fibroma of the face and hyperparathyroidism in a chronic hemodialysis patient]. / Fibrome ossifiant de la face et hyperparathyroïdie chez une hémodialysée chronique.

The bony complications in secondary hyperparathyroidism in chronic renal failure are varied. The ossifying fibroma is a rare manifestation. We report a case of a 40 years old woman with indeterminate nephropathy undergoing hemodialysis since 1982. Since may 1995, the patient had a diffuse and intensive bone pain of the two inferior members inducing functional importance with apparition of endobuccal tumefaction in the hard palate with an important increase of the volume of the maxillo-mandibular complex six months later associated to disturbances of the deglutition and phonation. In december 1995, the serum parathyroid hormone level is measured at 1527.6 pg/ml and the serum alkaline phosphatase level at 1620 UI/l. The bony lesions are disseminated to all the skeleton in the form of a demineralization with an ossifying expansive process affecting the maxillo-mandibular complex. Calcemia was at 2.3 mmol/l and phosphoremia at 2.1 mmol/l. The surgical biopsy of this pseudotumor showed an aspect of ossifying fibroma. The cervical echography showed a left inferior parathyroid nodular. In june 1996, a subtotal parathyroidectomy was done. The 9th day after surgery, the serum parathyroid hormone level was at 103 pg/ml with normal calcemia and phosphoremia. Five years later, the volume of the tumor reduced moderately. This observation induces 3 commentaries: the bony manifestations associated to secondary hyperparathyroidism have sometimes a tumoral aspect, the ossifying fibroma may be for known as well as the brown tumor and the treatment of these tumors in complex justifying furthermore a rigorous prevention of the hyperparathyroidism in hemodialyzed patients.

[Renal involvement in Behçet's disease. About six cases]. / L'atteinte rénale au cours de la maladie de Behçet. A propos de six observations.

PURPOSE: To analyze anatomoclinic and evolutive aspects of the renal involvement associated to the Behçet's disease through 6 observations collected in the nephrology department from 1985 to 2000 and to make a review of the literature. METHODS: Retrospective study, diagnosis of Behçet's disease according to the Classification of the International Group Study on the Behçet's disease and renal damage confirmed by histology. RESULTS: Our patients all male are aged between 25 to 55 years with a mean at 34 years old. The renal damage was revelated by a nephrotic syndrome in 3 cases and by a proteinuria at 1 to 2.7 g/day in 3 cases. Microscopic hematuria was present in 2 cases and arterial hypertension in 2 cases. The renal insufficiency has been noted in 2 cases of which severe in one of them. The renal biopsy showed an amyloidosis AA type in 3 cases, a segmental and focal glomerulonephritis in 2 cases and a thrombotic microangiopathy associated to a moderate tubulo-interstitiel lesions by toxicity of ciclosporine in 1 case. The extrarenal signs were dominated by bipolar aphtosis in all cases, necrotic pseudofolliculitis and the no specific cutaneous hyperreactivity in 5 cases and the erythema nodosum in 1 case. The ocular manifestation has been noted in 4 cases and articular manifestation in 3 cases. The vascular manifestation has been noted in one case. The treatment was colchicine in 4 cases and prednisone and cyclophosphamide in 1 case. Three patients were lost of view and a patient died in hemodialysis. The 2 other patients with amylosis had persistent proteinuria with a normal renal function. CONCLUSION: The kidney is one of organs that can alter the prognosis of the Behçet's disease; so, its screening must be realised in each patient with this disease.

[Surgical complications of nephrectomy in living donors]. / Les complications chirurgicales de la néphrectomie chez le donneur vivant.

Renal transplantation from a living donor is now considered the best treatment for chronic renal failure. We reviewed the operative complications in 38 living related donor nephrectomies performed at our institution over the past 14 years. The mean age of our donors was 30 years old with age range between 18 and 58 years old and female predominance (55.2%). These swabs were realized by a posterolateral lumbar lombotomy with resection of the 11 third. The left kidney was removed in 34 donors (90%), surgical complications were noted in 39.4% of the cases: one case of wound of inferior vena cava (2.6%), one case of release of the renal artery clamp (2.6%), four cases of pleural grap (10.5%), one case of pneumothorax (2.6%), one case of pleurisy (2.6%), three cases of urinary infection (7.8%), three cases of parietal infection (7.8%) and one case of patient pain at the level of the wound (2.6%). There were no mortalities. We conclude that the morbidity of living donor nephrectomy is negligible compared with the advantages for the recipient.

[Obstetrical acute renal failure. Experience of the nephrology department, Central University Hospital ibn Rochd, Casablanca]. / Insuffisance rénale aiguë obstétricale. L'expérience du Service de néphrologie, Chu ibn Rochd, Casablanca.

The gravidic acute renal failure (ARF) becomes a rare complications of the pregnancy in the industrialized countries, whereas it is still frequent in the developing countries and responsible of great maternofetal morbidity and mortality. We studied the etiologic and evolutive aspects of the gravidic ARF in 55 patients during 18 years (1981-1998) at the department of nephrology, hospital center Ibn Rochd in Casablanca. The gravidic ARF represents 65% of the gravidic patients. The mean age of the patients is 30.92 +/- 6.44 years old. The mean parity is 3.38 +/- 2.25. The mean term is 31.73 +/- 10.02 weeks of amenorrhea. The main etiology is the preeclampsia and eclampsia, 41 patients (74.5%); the other causes are: the septic conditions: 6 patients (11%); the obstetrical hemorrhages: 4 patients (7.2%); the in uterofetal death: 3 patients (5.5%) and the post-cesarotomy: 1 patient (1.8%). 74.6% of the patients has been hemodialysed. The evolution has been characterized by the normal recuperation of the renal function is 48 patients (87.3%), a chronic renal failure in 2 patients (3.6%) and the death of 5 patients (mortality: 9.1%). The gravidic ARF is still a critical circumstances associated to a severe prognosis as well as in the woman and the fetus. So, the most effective measures are still the prevention and the managing of the obstetrical complications.

[Prevalence of subcutaneous, labial and rectal amyloid lesions in patients wi histologically confirmed renal amyloidosis]. / Prévalence des lésions amyloïdes sous-cutanée, labiale et rectale chez des patients ayant une amylose rénale confirmée histologiquement.

Our work is to evaluate the biopsies rectal (RB), cutaneous and one about the accessory salivary glands (ASGB) in the diagnosis of amyloidosis renal through 20 cases of renal amyloidosis confirmed by renal biopsy in unit of nephrology and hemodialysis in UHC lbn Rochd from February 1996 to January 1998. The mean age of our patients was 39 years old (15-80) with a male predominance of (4/1). The infectious pathology has been the most frequent cause (70%) which consisted essentially in the tuberculosis and the surinfection on dilatation of the bronchi. All the patients had nephrologic symptomatology dominated by the nephrotic syndrome. The 4 biopsies were practised in the 20 patients. Wright's reaction practised in all renal biopsy confirmed the AA nature of the amyloidosis. The amyloïd deposits were noticed in 100% of renal needle biopsy, 80% of accessory gland biopsy, 75% of rectal biopsy and in 35% of cutaneous biopsy. The association of RB and ASGB was positive in 90% of the cases. If the renal biopsy gave more positivity than the other biopsies, it caused complications that were severe sometimes. Also, the biopsy of the ASG, the simple technique is very reliable in the recognition of the amylosis and seems to be the best diagnostic test for this affection.

[Value of the biopsy of accessory salivary glands in amyloidosis]. / Intérêt de la biopsie des glandes salivaires accessoires dans l'amylose.

PURPOSE: To assess the value of accessory salivary gland biopsy for the diagnosis of amyloidosis, a study was conducted in the nephrology and hemodialysis department at Ibn Rochd University Hospital from February 1996 to January 1998. METHODS: Renal amyloidosis was confirmed by renal biopsy accompanying accessory salivary gland biopsy. RESULT: The patient's mean age was 39 years old (range 15-80), with a 4:1-male/female ratio. An infectious cause (either tuberculosis or superinfection and dilatation of the bronchi) was the most frequent (70% of the cases) etiology. All the patients presented renal symptomatology. Nephrotic syndrome predominated. Amyloid deposits were observed in 100% of renal needle biopsies and in 80% of accessory salivary gland biopsies. CONCLUSION: Renal biopsy led to more positive cases than the other biopsies. It may be accompanied by severe complications. Furthermore, biopsy of the accessory salivary glands is a simple and very reliable technique for the diagnosis of amyloidosis. It is currently the best diagnostic test.

[Lupus interstitial cystitis. Apropos of a case]. / Cystite interstitielle lupique. A propos d'un cas.

We report a case of lupus interstitial cystitis in 17 year-old female. The patient presented with suprapubic pain, urinary frequency, dysuria, nocturia and no bacterial growth. Intravenous pyelography showed a low capacity bladder with thickwall, and a bilateral ureterohydronephrosis. Interstitial cystitis was confirmed on bladder biopsy specimen. Clinical symptoms remained eventhough after steroid treatment. Clinical signs of cystitis occurring in a patient with systemic lupus erythematous could be a manifestation of a lupus cystitis.

[Arteriovenous fistula. Apropos of a local experience in Morocco]. / Les fistules artérioveineuses. A propos d'une expérience locale au Maroc.

During eleven years (1983-1994), 684 arteriovenous fistulas (AVF) were realized for 422 patients. The mean follow-up was 39 months. The most frequent AVF was Cimino and Brescia and the most frequent seat was radial. The failure rate in the immediate post-operative period was 10% and 8% after 48 hours. The permeability of the AVF was 59%, 51% and 42% at 1, 2 and 3 years. The late complications were thrombosis (28%), stenosis (15%) and false aneurysm (11%). In spite of recruiting patients with chronic renal failure and deficiency in hospital basic equipment, this experience permit us to start and then, to improve the activity of making AVF and to be able to pick-up patients with chronic renal failure.