874
`
`Tl-IELANCET, APRIL 13, 1985
`
`modificd haemoglobin co-eluting with HbA1. Support for this
`suggestion is provided by a study7 in which raised HbA1,+b levels
`but normal or reduced HbA1C levels were reported in association
`with iron deficiency. Such a modification would not influence
`affinity gel procedures which depend on binding between the gel
`and glucose residues on globin chains only.
`We conclude that when affinity gel separation is used iron-
`~
`deficiency
`anaemia
`does
`not
`produce
`high
`glycosylatecl
`haemoglobin values.
`Department of Pathology,
`Kingston Hospital,
`Galswonhy Road
`‘
`’
`Kingston Upon Thames,
`Surrey KT2 7QB
`
`VAN HEYNINGEN
`DAL-1-ON
`
`R_
`
`,
`1‘ Edlmrlal‘ Glycosylatmn and disease‘ Lam“ 19843 “i 19720;
`2 Nathan DM, Singer DE, Hurxthal K, et al. The clinical information value of the
`glycosylated hemoglobm assay‘ N E"5I]Med 19845 310: 3d‘1C45'
`3 Brooks AP, Metcalfe J, Day JL, Edwards M.
`Iron deficiency and glycosylated
`haemoglobin A, Lancet 1980; ii: 141.
`4. Garlick RL, Mazcr JS, Higgins PJ, Bunn HF Charactcriution of glycosylatecl
`haernoglobins. 5 C/m I1werrl983;71: 1062-72
`5. Fairbanks VF, Zimmerman BR. Measurement ofglycosylated haemoglobin by affinity
`Chromatography Mayo Ch" Pm 1983; 58: 770-73‘
`V
`6. Hall PM, Cook JGI-I, Gould BJ. An inexpensive,
`rapid and precise affinity
`chromatography method for the measurement of glycosylated haemoglobins. Ann
`C11" Bwrhem 1983; 20: 129e35»
`7' H°’1‘;’f:‘5l3fi_H2“9‘65‘_“3"[‘J‘4TH]' Smdl“ °“ ‘h° h°“"'°3°“°“Y°““‘°“‘°g1°b‘“' B’-7H""”“‘
`’
`‘
`'
`
`REGRESSION OF METASTATIC VIPOMA WITH
`SOMATOSTATIN ANALOGUE SMS 201-995
`
`SiR,—Vasoactive intestinal polypeptide(VIP)hasbeenimplicated
`as the cause of the severe watery diarrhoea of Verner-Morrison
`syndrome and raised blood levels are found in patients with
`bronchogenic
`carcinoma, phaeochromocytoma, ganglioneuro
`blastorna, and pancreatic tumours. Early diagnosis and resection of
`a viporna may be curative, but inoperable or metastatic vipomas are
`difficult
`to treat.
`Intravenous
`somatostatin suppresses VIP
`sccretionl but its plasma half-life is only 1- 1-3-0 min? SMS
`201-995 is a synthetic octapeptide with a longer half-life which can
`be given by subcutaneous injection; it also suppresses VIP levels.
`We report a case of a metastatic vipoma treated with SMS 201-995
`50 pg once daily.
`A 75-year-old woman with a 9 year history of watery diarrhoea
`associated with hypokalaemia and mild hyperglycaemia was found
`to have raised plasma VIP levels. The primary tumour was removed
`
`pmol/1 "‘
`
`Dmol/1
`300
`
`<
`._
`
`1¥
`
`200
`
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`
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`
`LDUD
`
`L]
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`g
`.,
`,_,,
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`
`50
`
`1
`3-_
`
`Fig l—Neul'0Ie11sin, VIP and PP levels before and during treatment
`with SMS 201 — 995.
`
`Normal ranges: VIP <30 prnol/1; PP <300 pinol/1; neurotensin <200 prnoll
`
`West-Ward Pharm.
`Exhibit 1062
`Page 001
`
`FLUORESCENT ANTIBODY RESPONSE IN LASSA, MOBALA, AND lPl’Y
`STRAINS USING SPECIFIC ANTIBODIES
`
`Antibody
`
`Lassa
`
`Human anti’-Lama rermr1*
`Immune amnc anrz—I];py-[-
`Marloc/0*ldl»U1tIl’0dI€S=l=
`D —
`2O74_0O07
`2129-0018
`
`+
`+
`
`+
`+
`+
`+
`
`3
`
`“obal
`‘
`+
`+
`
`+
`"'
`+
`+
`
`I
`
`ppy
`+
`+
`
`+
`+
`+
`+
`
`*Convalescent serum from Lassa fever patient (provided by CDC), at working dilution
`1/32.
`*‘]‘i\/louse immune ascitic fluid against Ippy virus prepared in Bangui (no 272), at working
`dilution= l/40.
`:):Lassa/Mozsimbique nucleocapsid specificity, 2093-0004 at working dilution 1120;
`Lassa/Mozambique nucleocapsid specificity, 2054-0006 at working dilution 1/40; Lassa
`glymprmem spemficny) 2074_0007 at wmkmg dilution 1/20$ Lassa/Mozamblque
`.
`.
`c
`,
`.
`nucleocapsid §p€C1f1"l'(y 2129-0018 at working dilution 1/20
`_ MM.
`
`D. Y. MEUNIER
`
`Dr Swanepoel (March 16, p 639) has reported that the prototype
`Strain Oflppy Virus’ ‘isolated in 1970, is a member ofthe Lassa fever
`1
`Th “I
`” strains studied b us and b Swane oel et al
`Comp exavfig C _ plliy
`.
`dy
`_ h
`y 1
`1p
`d
`seem IO 1 CI‘ in I at our Slffalll reacte Wlt UIOIIOC 0112 anti 0 y
`2093-0004 while Swaneopoel’s did not (2093-0004 is the same as
`5293-4). These two strains are identified as Ippy viruses by classical
`tests but the use of monoclonal antibodies may now be revealing
`some differences in epitopes.
`Institut Pasteur de Bangui,
`BP923, Bangui, Central African Republic
`Centers for Disease Control,
`A
`C
`‘lam’ mfg”
`Instirut Pasteur de Bangui
`Orstrom, Bangui
`
`B M
`‘
`CCORMICK
`1‘
`A- 1- GEORGES
`M_
`GEORGES
`
`J. P. GONZALEZ
`
`l. Digoutte JP Annual report of Institut Pasteur, Bangui, Central African Republic,
`1970: 59
`-. Kiley MP, Tomori O, Rcgnery AL, Johnson KM. Characterisation ofthe Arenaviruses
`Lassa and Mozambique. In: Bishop DHL, Compans RVV, eds. The replication of
`negative strand viruses. Amsterdam: Elsevier North Holland, 1981: 1-9.
`3. Gonzalez JP, McCormick JB, Saluzzo JF, Georges AJ. An arenavirus isolatedfrom wild
`caught rodents (Pmnmys sp) in the Central African Republic. Inrer7)zm1agyl983;19:
`10 5- 1 2.
`4. Wiilff H, Lange JV. Indirect immunofiuorescence for the diagnosis of Lassa fever
`infections. BuI1WHO 1975; 52: 429-36.
`5. Johnson KM, Elliott LH,
`I-Ieymann KL. Preparation of polyvalent viral
`immunofluorescent intercellular antigens and use in human serosurveys. _7 Clm
`Microbial 1981; 5: 527-29.
`
`GLYCOSYLATED HAEMOGLOBIN IN
`IRON-DEFICIENCY ANAEMIA
`
`SiR,—A 1984 Lancet editoriall discusses interference with the
`measurement of glycosylated haemoglobin used to evaluate long-
`term control of blood glucose} and cites as an example Brooks and
`colleagues’ report of the increased glycosylation ofhaemoglobin, as
`measured by a cation—exchange microcoluriin method, in association
`with iron-deficiency anaemia? However,
`the ion exchange
`chromatography method yields peaks that are likely to be
`contaminated
`by
`non~glycosylated
`haemoglobin.4 Affinity
`chromatography is thought to be more SpCClf1C,5 and this is the
`method we have usedf’ in our attempt to confirm Brooks’ findings.
`We selected fourteen patients with iron—deficiency anaemia. Four
`patients were male and ten female, ages ranged from 27 to 89 years
`(mean 54 y), and all were non-diabetic. The mean glycosylated Hb
`(6 - 9:0- 9% SD) was not significantly different
`from normal
`(7-0:1- 7%). Only one iron—deficient patient had a value (8 (8%)
`just above the normal range of 5- 3-8 - 6%. All patients responded to
`oral iron with significant increases in haematological indices but
`their mean glycosylated haemoglobin values did not change
`(6 ~ 5:1 -7%).
`reported with cationexchange
`The high levels of HbAl
`chromatography may be due to post-translational modifications of
`haemoglobin other than glycosylation in iron deficiency,
`the
`
`West-Ward Pharm.
`Exhibit 1062
`Page 001
`
`

`

`THE LANCET, APRIL 13, 1985
`
`875
`
`by partial pancreatectorny in October, 1977, but liver secondaries
`could not be resected. In 1981 she was started on tolbutamide for
`diabetes, this treatment being replaced by insulin in March, 1983.
`By June, 1984, she was having watery diarrhoea up to fifteen
`times a day passing 1 - 5-2 litres, had lost weight, and was
`hypokalacmic despite potassium supplementation. Her plasma
`VIP, pancreatic polypeptide (PP), and neurotensin concentration
`were raised; gastrin and glucagon levels were normal.
`SMS 20l«995 50 pg once daily produced a progressive
`improvement in hormone levels (fig 1) accompanied by a weight
`gain of5 kg, reduced stool Frequency and volume, and correction of
`hypokalaemia. There have been no side—effects, apart from a
`reduced insulin requirement. Computerised axial tomography(CT)
`after 5 months oftreatment revealed a reduction in the number, size,
`and contrast enhancement of the liver secondaries (fig 2).
`
`Fig 2——CT scan appearances before (upper) and after (lower) SMS
`201-995 treatment.
`
`Vipomas are often accompanied by increases in neurotensinxlike
`immunoreactivity5 and pancreatic polypeptide levels,4 as in our
`patient. Her main problem was profound secretory diarrhoea, and,
`though the specific peptide responsible for this diarrhoea is not
`known, VIP reiriaiiis the most likely candidate.
`_
`There has been considerable interest in the use ofS1\/IS 201-995
`in the treatment of tumours and» diarrhoea, and some success has
`been reported in the treatment oFvipomas,5‘i0 including one case of
`regression of liver secondaries7 and a response without tumour
`regressiong Our patient has improved considerably on once-daily
`treatment (given at the same time as the insulin by the district nurse)
`with 50 pg of SMS 201-995, with itnprovement of symptoms, CT
`scan appearances, and VIP, PP, and neuroterisin levels. The CT
`evidence supports a direct effect ofSMS 20l~995 on the turnout as
`a mechanism for the clinical and biochemical improvement. This
`patient’s tumour has been successfully controlled with once-daily
`
`treatment for 9 months so far. However, the exact place of SMS
`201-995 remains to be defined in the light oflong-term follow—up of
`its effects and possible Complications.
`We thank Dr R. Shentall of Saiidoz for the supply of SA/IS 2014995. The
`peptide assays were done at the Royal Postgraduate Medical School, London,
`in l’rol“S. R. Bloorrfs department.
`Department ofMedicinc,
`Queen Elizabeth Hospital,
`Birmingham B15 2TH
`
`D. CLEMENTS
`E. ELIAS
`
`1 Ruskone A, Rene E, Chayvialle JA. et al. Effect of somatostatin on diarrhoea and on
`small intestinal water and electrolyte transport in a patient with pancreatic cholera.
`Dig DIS Sci 1982,27: 459-66
`2. Sheppard M, Shapiro B, Pimstone B, Kronheim S, Berelowitz M, Gregory M.
`Metabolic clearance and plasma half-disappearance time ofcxogeriou: somatostatin
`in man. J Clm Endocrine] Alezab 1979; 48: 50-33.
`3 Blackburn AM, Bryant MG, Arian TE, Bloom SR. Pancreatic tumours produce
`rieurotensin. _7 Clm Erzdocrznolildezab 1981; 51: 820-22.
`4 Long RG, Bryant MG, Mitchell 5], et al. Clinicopathological study ofpancreatic and
`gariglioneuroblastoma
`tumours
`secreting vasoactive
`intestinal
`polypeptide
`(vipomas). Br Med] 1982; 282: l767—7l.
`5. Von Wcrder K, Losa M, Muller OA, et al. Treatment ofmetastasing GRF-producing
`tumour with long-acting snmatostatin analogue. Lancet 1984; ii: 282—83
`6. Kraenzlin ME, Ch’ng JC, Wood SM, Bloom SR. Can inhibition ofhormone secretion
`be associated with endocrine tumour shrinkage? Lancet l98'i; ii: 1501
`xi
`Kraenzlin ME, Ch’ng ]I.C, Wood SIM, Bloom SR. Remission of symptoms and
`shrinkage ofmetastasis with long term treatment with sornatostatiri analogue Gut
`1984, 25: A576
`8. Williams NS, Cooper IC, Axon ATR, King RFG], Barker AI. Use ofa long acting
`somatostatin analogue in controlling life threatening ileostomy diarrhoea. Bri’l/led]
`I984, 289: 1027-28.
`9. Maton PN, O’Dorisio TM, l\rScArthur KE, et al. Effect oflong-acting somatostatin
`analogue (SMS 201-995) in a patient with pancreatic cholera. NErigI_7Med 1984,
`312: 17-21
`10. Plewe G, Beyer J, Krause U, Neulield M, Del Pozo E. Long—acting and selective
`suppression of growth hormone by somatostatin analogue SNIS 2014395 in
`actomegaly. Lancet 1984311‘ 782-84.
`
`RENAL FUNCTION IN DIABETICS
`
`StR,—Lancez correspondence about renal function in diabetics
`(]an_5, p 53; Feb 23, p 466) prompted us to review our research. We
`have investigated the prevalence of diabetic nephropathy in a
`general diabetic population (G; n=843) and amongst diabetics
`attending a special eye clinic (R; n= 1 15). Group G was drawn from
`a well~defined epidemiological population and group R consists of
`patients with serious diabetic retinopathy (maculopathy or
`preproliferativc or prolifcrativc
`changes,
`confirmed by an
`ophthalmologist). Both groups contained non-insulin—dependent
`and insulin-dependent diabetics.
`Urine samples were tested for proteinuria (‘Albustix’) and
`patients were asked to submit a timed overnight urine collection to
`measure albumin excretion rate (AER). However, as the response
`rate for these samples was poor, 21 sample from a midstrcam urine
`specimen passed at the clinic was taken and the random urinary
`albumin/creatinine (albumin in mg/1, creatiiiine in mmol/1) ratio
`(RA/ C) measured. A micro-ELISA technique‘ was used to measure
`urinary albumin and the Jalfe method for urinary creatinine. In our
`laboratory the upper limits ofnormal are 7-5 pg/min for AER and
`1-9 for RA/C (mean +2SD after log transformation in 114 non-
`diabetic controls). Infected urine specimens are excluded.
`As expected, the prevalence ofproteinuria was greater in group R
`than in group G (see table). Microalbumiiiutia was also commoner.
`This is consistent with the similar microangiopathic basis of
`retinopathy and nephropathy.
`Our
`findings confirm that macroalbuminuria and micro
`alburninuria
`are more
`common in diabetics with serious
`retinopathy. Since, according to our figures, 40% of patients with
`a treatable blinding condition will be missed, there is little case
`for using microalbuminuria to identify these diabetics with
`retinopathy. Also,
`its use to predict future retinopathy remains
`ALBUMINURIA IN TWO DIABETIC POPULATIONS
`
`Albustix positive
`Raised AER
`Raised RA/C
`
`Group R
`
`18/11S(15-7%)
`33/55 (60%)
`44/63 (65%)
`
`Group G
`
`so/s43( 5- 9%)
`125/447 (28- 0%)
`212/551 (38-5%)
`
`West-Ward Pharm.
`Exhibit 1062
`Page 002
`
`West-Ward Pharm.
`Exhibit 1062
`Page 002
`
`